Marius Trøseid

• Stø, Kristine; Skagen, Karolina Ryeng; Bjerkeli, Vigdis; Ueland, Per Magne; Hov, Johannes Espolin Roksund & Trøseid, Marius [Show all 10 contributors for this article] (2026). Gut microbiota derived indoles are altered and associate with immune activation in moderate and severe carotid stenosis. Frontiers in Immunology. 17. doi: 10.3389/fimmu.2026.1796312. Full text in Research Archive Show summary

  Background: An imbalance of gut microbiota, their metabolites as well as inflammatory mediators have been increasingly linked to both atherosclerosis and stroke. However, data on microbiota derived tryptophan and histidine metabolites in carotid atherosclerosis are scarce. Purpose: We investigated serum microbiota derived indoles, imidazole propionate (ImP) and trimethylamine N-oxide (TMAO), representing three distinct gut bacterial-related metabolites, in patients with carotid atherosclerosis compared with healthy controls with normal findings on carotid ultrasound. We aimed to examine their relation to plaque characteristics, immune activation markers and traditional cardiovascular risk factors. Methods: Thirty patients scheduled for carotid endarterectomy and 18 control subjects were included in this cross-sectional study. Carotid arteries were investigated with ultrasound. Indoles, ImP and TMAO were analyzed by liquid chromatography-tandem mass spectrometry, and Lipopolysaccharide (LPS) by a Limulus Amebocyte Lysate chromogenic assay. Results: Compared to controls, patients exhibited lower levels of indole-3-propionic acid (IPA) (p=0.004) and indole-3-acetic acid (IAA) (p = 0.030). In patients, higher levels of indole metabolites were associated with lower C-reactive protein. ImP and TMAO did not differ between patients and controls. Conclusion: Patients with carotid atherosclerosis exhibited reduced serum concentrations of IPA and IAA, thought to have anti-inflammatory effects, and increased inflammatory markers, possibly suggesting disruptions in the gut–vascular-immune axis.

• Oppegaard, Oddvar; Blomberg, Bjørn; Cox, Rebecca Jane; Iversen, Arild; Myklebust, Nikolai Norevik & Glambek, Marte [Show all 27 contributors for this article] (2026). Nirmatrelvir for acute COVID-19 to prevent long COVID (PANORAMIC Norway): a double-blind, randomised, placebo-controlled trial. The Lancet Infectious Diseases. ISSN 1473-3099. doi: 10.1016/s1473-3099(26)00244-6. Full text in Research Archive Show summary

  Background Long-term symptoms are common after acute COVID-19, particularly fatigue, cognitive problems, and dyspnoea. Cohort studies have suggested that antiviral treatment of acute COVID-19 might prevent development of post-COVID-19 condition (also known as long COVID), but the efficacy of antivirals has yet to be verified in prospective studies. We aimed to investigate whether treatment of acute SARS-CoV-2 infection with nirmatrelvir–ritonavir would reduce the risk of long COVID. Methods In this double-blind, randomised, placebo-controlled trial, participants were recruited from the municipal health-care service at three sites in Norway (Bergen, Oslo, and Ålesund). Non-hospitalised adults aged 18–65 years with SARS-CoV-2 infection confirmed by PCR or lateral flow test and symptoms for 5 days or fewer were eligible for inclusion. Key exclusion criteria included pregnancy or lactation, chronic renal impairment or chronic liver dysfunction, and any person judged by the investigator to need nirmatrelvir–ritonavir treatment due to increased risk of hospitalisation or death. Participants were allocated in a 1:1 ratio to receive oral 300 mg nirmatrelvir and 100 mg ritonavir, or placebo, twice a day for 5 days using a pre-generated randomisation list without stratification or block adjustment. Participants, clinicians, and the study team were masked to treatment allocation. The primary outcome was long COVID, defined as patient-reported fatigue, dyspnoea, and/or cognitive symptoms at 3 months’ follow-up. Safety was analysed as a secondary outcome, and included adverse events, hospital admissions, and deaths. Both the primary outcome and safety were assessed in the intention-to-treat population. The trial is registered with ClinicalTrials.gov (NCT05852873) and is now closed to new participants. Findings Between May 12, 2023, and June 11, 2025, we enrolled 144 participants, of whom 66 were assigned to nirmatrelvir–ritonavir and 78 to placebo. In the protocol we planned to enrol 2000 participants, but the trial was stopped prematurely by the steering committee due to insufficient recruitment. Among the 143 participants who completed follow-up, the risk of long COVID at 3 months was significantly reduced in the nirmatrelvir–ritonavir group (17 [26%] of 66) compared with the placebo group (33 [43%] of 77), corresponding to a relative risk after imputation of data for the single missing value in the placebo group of 0·60 (95% CI 0·37–0·98; p=0·039). In the nirmatrelvir–ritonavir group, five patients discontinued treatment due to adverse events. The most common adverse events in the nirmatrelvir–ritonavir group were change in taste or smell (57 [86%] of 66 in the nirmatrelvir–ritonavir group vs 14 [18%] of 78 in the placebo group) and nausea or vomiting (19 [29%] vs eight [10%]). Inversely, palpitations were more common in the placebo group (ten [13%] of 78) than in the nirmatrelvir-ritonavir group (two [3%] of 66). No severe adverse events were reported. Interpretation Treatment with nirmatrelvir–ritonavir for acute COVID-19 was associated with a significant reduction in the risk of long COVID at 3 months’ follow-up. The limited sample size precludes firm conclusions, and further clinical trials are warranted.

• Myhre, Anders Eivind; Meyer-Myklestad, Malin Holm; Gullaksen, Hanne Hestdal; Søgaard, Ole S.; Tolstrup, Martin & Salgado, Maria [Show all 51 contributors for this article] (2026). Long-term HIV-1 remission achieved through allogeneic haematopoietic stem cell transplant from a CCR5Δ32/Δ32 sibling donor. Nature Microbiology. 11, p. 1374–1386. doi: 10.1038/s41564-026-02304-8. Full text in Research Archive Show summary

  Only few cases of human immunodeficiency virus (HIV) remission have been reported after allogeneic haematopoietic stem cell transplantation (HSCT), mostly involving stem cell donors with the homozygous CCR5Δ32 (CCR5Δ32/Δ32) mutation, which confers resistance to CCR5-tropic HIV-1. Here we report the case of a 63-year-old man in off-treatment HIV remission, 5 years after HSCT with a CCR5Δ32/Δ32 sibling donor for myelodysplastic syndrome. In-depth clinical characterization including virological and immunological analyses of peripheral blood, gut and bone marrow samples revealed that full donor chimerism was achieved. Antiretroviral therapy was discontinued after 24 months, and 48 months after HSCT, no intact HIV DNA was detected in blood or gut biopsies. Replication-competent virus and HIV-specific T cell responses were absent, and HIV antibody responses showed a gradual decline. Full donor chimerism in the gut, which is the primary viral reservoir, underscores the likelihood of a cure.

• Stø, Kristine; Skagen, Karolina Ryeng; Holm, Kristian; Ueland, Thor; Vestad, Beate & Bjerkeli, Vigdis [Show all 10 contributors for this article] (2026). Oral Eikenella as a potential new biomarker of symptomatic carotid atherosclerosis. Journal of Oral Microbiology. 18(1). doi: 10.1080/20002297.2026.2613521. Full text in Research Archive
• Stoltz, Tina Toppevad; Jensen, Anne Marie Reimer; Roed, Anna Katrine Haslund; Frikke-Schmidt, Ruth; Knudsen, Andreas Dehlbæk & Suarez-Zdunek, Moises Alberto [Show all 13 contributors for this article] (2025). Plasma levels of lipoprotein(a) in persons with HIV compared to the general population. AIDS (London). ISSN 0269-9370. 40(1), p. 42–42. doi: 10.1097/qad.0000000000004349. Full text in Research Archive Show summary

  Objective: Elevated lipoprotein(a) increases the risk of cardiovascular disease, and previous research suggests that lipoprotein(a) levels are higher in patients with chronic inflammatory diseases. Knowledge about lipoprotein(a) in persons with HIV (PWH) is sparse. We aimed to assess if living with HIV is associated with high levels of lipoprotein(a). Methods: From the Copenhagen Comorbidity in HIV infection (COCOMO) study, we included 789 PWH matched on sex and age with 3156 controls from the Copenhagen general population study. All participants underwent uniform physical examinations, blood sampling and responded to questionnaires regarding lifestyle and health. Lipoprotein(a) was measured using isoform-insensitive immunoturbidimetric assays. High levels of lipoprotein(a) were defined as plasma levels >50 mg/dl. Results: Living with HIV was not associated with high levels of lipoprotein(a) [adjusted odds ratio (aOR) 0.98 [95% CI: 0.80 to 1.21], P  = 0.88]. Furthermore, none of the examined clinical and demographic factors – including age, sex, diabetes, statin therapy, cholesterol levels, renal function and HIV specific risk factors were significantly associated with elevated lipoprotein(a) levels as well as and none of the examined clinical or demographic risk factors were found to be significantly associated with elevated lipoprotein(a) levels. Conclusion: In this study, living with HIV was not independently associated with high levels of lipoprotein(a) and none of the examined clinical or demographic risk factors were found to be significantly associated with elevated lipoprotein(a) levels.

• Massonnaud, Clément R.; Peiffer-Smadja, Nathan; Poignard, Pascal; Jamard, Simon; Goehringer, François & Danion, François [Show all 85 contributors for this article] (2025). Efficacy, safety, pharmacokinetics, immunogenicity, and serum neutralizing activity of AZD7442 (tixagevimab-cilgavimab) in patients hospitalized with COVID-19: long-term results from the DisCoVeRy trial. Clinical Microbiology and Infection (CMI). ISSN 1198-743X. 32(4), p. 618–628. doi: 10.1016/j.cmi.2025.12.014. Full text in Research Archive
• Mikaeloff, Flora; Gelpi, Marco; Escós, Alejandra; Wang, Tianqi; Gupta, Soham & Olofsson, Anna [Show all 33 contributors for this article] (2025). Host Plasma Microenvironment in Immunometabolically Impaired HIV Infection Leads to Dysregulated Monocyte Function and Synaptic Transmission <i>Ex Vivo</i>. Advanced Science. 12(16). doi: 10.1002/advs.202416453. Full text in Research Archive Show summary

  Abstract Risk stratification using multi‐omics data deepens understanding of immunometabolism in successfully treated people with HIV (PWH) is inadequately explained. A personalized medicine approach integrating blood cell transcriptomics, plasma proteomics, and metabolomics is employed to identify the mechanisms of immunometabolic complications in prolonged treated PWH from the COCOMO cohort. Among the PWHs, 44% of PWH are at risk of experiencing immunometabolic complications identified using the network‐based patient stratification method. Utilizing advanced machine learning techniques and a Bayesian classifier, five plasma protein biomarkers; Tubulin Folding Cofactor B (TBCB), Gamma‐Glutamylcyclotransferase (GGCT), Taxilin Alpha (TXLNA), Pyridoxal Phosphate Binding Protein (PLPBP) and Large Tumor Suppressor Kinase 1 (LATS1) are identified as highly differentially abundant between healthy control (HC)‐like and immunometabolically at‐risk PWHs (all FDR<10 −10 ). The personalized metabolic models predict metabolic perturbations, revealing disruptions in central carbon metabolic fluxes and host tryptophan metabolism in at‐risk phenotype. Functional assays in primary cells and cortical forebrain organoids (FBOs) further validate this. Metabolic perturbations lead to persistent monocyte activation, thereby impairing their functions ex vivo . Furthermore, the chronic inflammatory plasma microenvironment contributes to synaptic dysregulation in FBOs. The endogenous plasma inflammatory microenvironment is responsible for chronic inflammation in treated immunometabolically complicated at‐risk PWH who have a higher risk of cardiovascular and neuropsychiatric disorders.

• Amstutz, Alain; Schandelmaier, Stefan; Ewald, Hannah; Speich, Benjamin; Schwenke, Johannes M & Schönenberger, Christof M [Show all 43 contributors for this article] (2025). Effects of Janus kinase inhibitors in adults admitted to hospital due to COVID-19: a systematic review and individual participant data meta-analysis of randomised clinical trials. The Lancet Respiratory Medicine. ISSN 2213-2600. 13(6), p. 530–544. doi: 10.1016/s2213-2600(25)00055-4. Full text in Research Archive Show summary

  Background: Evidence from randomised clinical trials (RCTs) of Janus kinase (JAK) inhibitors-compared with usual care or placebo-in adults treated in hospital for COVID-19 is conflicting. We aimed to evaluate the benefits and harms of JAK inhibitors compared with placebo or usual care and whether treatment effects differed between prespecified participant subgroups. Methods: For this systematic review and individual participant data meta-analysis (IPDMA), we searched Medline via Ovid, Embase via Elsevier, the Cochrane Central Register of Controlled Trials, the Cochrane COVID-19 Study Register, and the COVID-19 L·OVE Platform, including backward and forward citation searching (last search Nov 28, 2024), for RCTs (unpublished or published in any format and any language) that randomly assigned adults (aged ≥16 years) admitted to a hospital due to COVID-19 to receive either a JAK inhibitor (any type) or no JAK inhibitor (ie, received site-specific standard of care with or without placebo), and requested individual participant data (IPD) from the original trial teams. The primary outcome was all-cause mortality at day 28 after random assignment. We used two-stage meta-analyses adjusting for age and respiratory support, and pooled estimates using random-effects models. The assessment of individual-level effect modifiers was based solely on within-trial information and continuous modifiers were investigated as both linear and non-linear interactions. We used the Instrument for Assessing the Credibility of Effect Modification Analyses to appraise the subgroup analyses and the Grading of Recommendations Assessment, Development, and Evaluation approach to adjudicate the certainty of evidence. Grade 3 or 4 adverse events and serious adverse events by day 28, and adverse events of special interest within 28 days, were assessed among secondary outcomes. This study was registered with PROSPERO (CRD42023431817). Findings: We identified 16 eligible trials. IPD were obtained from 12 trials, corresponding to 12 902 adults admitted to hospital between May, 2020, and March, 2022. These trials represented 12 902 [96·1%] of 13 423 participants from all eligible trials worldwide. Seven trials evaluated baricitinib, three evaluated tofacitinib, and two evaluated ruxolitinib. Overall, 755 (11·7%) of 6465 participants in the JAK inhibitor group died by day 28 compared with 805 (13·2%) of 6108 participants in the no JAK inhibitor group (adjusted odds ratio [aOR] 0·67 [95% CI 0·55-0·82]; high-certainty evidence; 39 fewer per 1000 [95% CI 55 fewer to 21 fewer]). JAK inhibitors decreased the need for new mechanical ventilation or other respiratory support and allowed for faster discharge from hospital by about 1 day. We observed fewer grade 3 and 4 adverse events and serious adverse events in the JAK inhibitor group (14 fewer per 1000 [95% CI 24 fewer to 4 fewer]; moderate-certainty evidence). The rates of adverse events of special interest were similar across both groups. No credible subgroup effect on mortality at day 28 was found for ventilation status, type of JAK inhibitor, presence of comorbidities, timing of treatment initiation after symptom onset, C-reactive protein concentration, or concomitant use of dexamethasone or tocilizumab. We found a moderately credible effect modification by age, with younger participants showing larger relative treatment effects than older participants, but similar absolute treatment effects due to higher baseline risk for older participants. Interpretation: This IPDMA of RCTs in adults admitted to hospital due to COVID-19 found that JAK inhibitors reduced mortality across all levels of respiratory support, independent of dexamethasone or tocilizumab, and probably decreased serious and severe adverse events compared with no JAK inhibitors. Funding: This project has received funding from the EU's Horizon 2020 research and innovation programme under grant agreement number 101015736.

• Nendl, Andraž; Raju, Sajan; Braadland, Peder Rustøen; Nordborg, Anna; Bratseth, Vibeke & Broch, Kaspar [Show all 12 contributors for this article] (2025). Circulating metabolites in patients with chronic heart failure are not related to gut leakage or gut dysbiosis. PLOS ONE. 20(9). doi: 10.1371/journal.pone.0331692. Full text in Research Archive Show summary

  Background The gut microbiota produces numerous metabolites that can enter the circulation and exert effects outside the gut. Several studies have reported altered gut microbiota composition and circulating metabolites in patients with chronic heart failure (HF) compared to healthy controls. Limited data is available on the interplay between dysbiotic features of the gut microbiota and altered circulating metabolites in HF patients. We aimed to examine differences in circulating metabolites between people with and without chronic HF, and their association with gut microbiota dysbiosis and cardiac function. Methods We collected plasma, serum, and stool samples from 123 adult patients with stable chronic HF and left ventricular ejection fraction (LVEF) ≤40%, and healthy controls (plasma: n = 51, stool samples: n = 69). Metabolomic and lipidomic profiling of plasma was performed using liquid chromatography with tandem mass spectrometry. Principal component analysis was used to explore differences in circulating profiles. Over-representation analysis was performed to identify pathways in which relevant metabolites were involved. Stool samples were sequenced using shotgun metagenomics. We calculated a dysbiosis index based on differential abundances of microbial taxa in patients vs. controls. Results After adjusting for age, sex, and sampling location, we identified 67 enriched metabolites and 24 enriched lipids, and 115 depleted metabolites and 6 depleted lipids in HF patients compared to healthy controls. LVEF, N-terminal pro B-type natriuretic peptide, gut leakage markers, dysbiosis index, and fiber intake were not significantly related to any of the differentially abundant metabolites or lipids. Pathways related to energy metabolism differed most between HF patients and controls, however medication adjustment abolished all differences in circulating profiles. Conclusions Patients with chronic HF had distinct metabolomic and lipidomic profiles and energy metabolism differed significantly compared to healthy controls before adjusting for medication use. However, the alterations were not related to gut dysbiosis, gut leakage markers, cardiac function, or fiber intake.

• Bai, Xiangning; Raju, Sajan; Knudsen, Andreas Dehlbæk; Thudium, Rebekka Faber; Arentoft, Nicoline Stender & Gelpi, Marco [Show all 12 contributors for this article] (2025). Microbiome profiling reveals gut bacterial species associated with rapid lung function decline in people with HIV. Frontiers in Immunology. 16. doi: 10.3389/fimmu.2025.1555441. Full text in Research Archive Show summary

  Background: People with HIV (PWH) have an increased risk of pulmonary comorbidities compared to people without HIV. The gut microbiome regulates host immunity and is altered in PWH. This study aims to determine potential associations between gut microbiome, lung function decline, and airflow limitation in PWH. Methods: PWH from the Copenhagen Comorbidity in HIV Infection (COCOMO) Study with available lung function testing and microbiome data were included (n=385). The gut microbiome was characterized using shotgun metagenomic sequencing. Associations between gut microbiome, rapid lung function decline, and airflow limitation were analysed in multivariable logistic regressions adjusted for traditional and HIV-associated risk factors for lung disease. Results: Several bacterial species were significantly enriched in PWH with rapid lung function decline, including opportunistic pathogenic bacterial species Bacteroides coprophilus, Klebsiella michiganensis, and Clostridium perfringens. A gut microbial dysbiosis index based on compositional changes was associated with rapid lung function decline (adjusted odds ratio (aOR) 1.18, 95% confidence interval (CI) [1.11-1.27], p<0.001), and airflow limitation (aOR 1.16, 95% CI [1.04-1.29], p=0.007) in adjusted multivariable logistic regression analyses. Conclusion: Associations between the gut dysbiosis index and rapid lung function decline and airflow limitation suggest a potential role of certain gut bacterial species in the pathogenesis of pulmonary comorbidities in PWH.

• Jørgensen, Silje Fjellgård; Braadland, Peder Rustøen; Ueland, Thor; Fraz, Mai Sasaki Aanensen; Michelsen, Annika Elisabet & Holm, Kristian [Show all 12 contributors for this article] (2025). Tryptophan–kynurenine metabolites associate with inflammation and immunologic phenotypes in common variable immunodeficiency. Journal of Allergy and Clinical Immunology. ISSN 0091-6749. 156(3), p. 814–824. doi: 10.1016/j.jaci.2025.04.031. Full text in Research Archive Show summary

  Background A large proportion of patients with common variable immunodeficiency (CVID) have autoimmune and inflammatory manifestations characterized by chronic T-cell– and monocyte/macrophage activation of unknown etiology. The tryptophan–kynurenine pathway has previously been linked to immune activation involving T cells and monocytes/macrophages, as well as with gut microbial dysbiosis in some inflammatory diseases. Objective We aimed to characterize the tryptophan–kynurenine pathway in CVID and its potential association with clinical/immunologic phenotype and gut microbial dysbiosis. Methods Serum concentrations of a set of tryptophan–kynurenine pathway metabolites and neopterin were measured using liquid chromatography–tandem mass spectrometry in a discovery cohort (n = 40), a validation cohort (n = 53), and healthy controls (n = 60). B-cell phenotype was analyzed in both cohorts, whereas inflammatory markers (enzyme immunoassay), lipopolysaccharide, gut microbial composition, and food frequency questionnaire were measured in the discovery cohort. Results Compared to healthy controls, CVID patients had increased metabolism of the tryptophan–kynurenine pathway as assessed by increased kynurenine/tryptophan ratio, quinolinic acid, and 3-hydroxykynurenine in both the discovery and validation cohorts. The findings were most pronounced in the subgroup with autoimmune/inflammatory complications but was to some degree also observed in CVID patients with infection only. In CVID, the metabolites in the tryptophan–kynurenine pathway associated with soluble (s) markers of monocyte (sCD14, sCD163, neopterin) and T-cell (sCD25) activation as well as B-cell phenotype (eg, naïve B cells). Individual gut microbial taxa may influence tryptophan–kynurenine pathway metabolites, but not lipopolysaccharide or diet. Conclusion We found altered levels of several metabolites in the tryptophan–kynurenine pathway in two different CVID cohorts associated with systemic inflammation and B-cell phenotype.

• Suarez-Zdunek, Moises Alberto; Knudsen, Andreas Dehlbæk; Fuchs, Andreas; Kirkby, Nikolai Søren; Benfield, Thomas & Gerstoft, Jan [Show all 11 contributors for this article] (2025). Cytomegalovirus Antibodies and Coronary Artery Disease in People with HIV: A Cohort Study. Viruses. 17(2). doi: 10.3390/v17020231. Full text in Research Archive
• Patrick-Brown, Dawn Judith; Bourner, Josephine; Kali, Sabrina; Trøseid, Marius; Yazdanpanah, Yazdan & Olliaro, Piero [Show all 7 contributors for this article] (2024). Experiences and challenges with the new European Clinical Trials Regulation. Trials. 25(3). doi: 10.1186/s13063-023-07869-x. Full text in Research Archive
• Trøseid, Marius; Molinaro, Antonio; Gelpi, Marco; Vestad, Beate; Kofoed, Klaus Fuglsang & Fuchs, Andreas [Show all 13 contributors for this article] (2024). Gut Microbiota Alterations and Circulating Imidazole Propionate Levels Are Associated With Obstructive Coronary Artery Disease in People With HIV. Journal of Infectious Diseases. ISSN 0022-1899. 229(3), p. 898–907. doi: 10.1093/infdis/jiad604. Full text in Research Archive Show summary

  Background The impact of gut microbiota and its metabolites on coronary artery disease (CAD) in people with human immunodeficiency virus (PWH) is unknown. Emerging evidence suggests that imidazole propionate (ImP), a microbial metabolite, is linked with cardiometabolic diseases. Methods Fecal samples from participants of the Copenhagen Comorbidity in HIV infection (COCOMO) study were processed for 16S rRNA sequencing and ImP measured with liquid chromatography-tandem mass spectrometry. CAD severity was investigated by coronary computed tomography-angiography, and participants grouped according to obstructive CAD (n = 60), nonobstructive CAD (n = 80), or no CAD (n = 114). Results Participants with obstructive CAD had a gut microbiota with lower diversity and distinct compositional shift, with increased abundance of Rumiococcus gnavus and Veillonella, known producers of ImP. ImP plasma levels were associated with this dysbiosis, and significantly elevated in participants with obstructive CAD. However, gut dysbiosis but not plasma ImP was independently associated with obstructive CAD after adjustment for traditional and HIV-related risk factors (adjusted odds ratio, 2.7; 95% confidence interval, 1.1–7.2; P = .048). Conclusions PWH with obstructive CAD displays a distinct gut microbiota profile and increased circulating ImP plasma levels. Future studies should determine whether gut dysbiosis and related metabolites such as ImP are predictive of incident cardiovascular events.

• Viermyr, Hans-Kittil; Halvorsen, Bente; Sagen, Ellen Lund; Michelsen, Annika Elisabet; Barratt-Due, Andreas & Kåsine, Trine [Show all 73 contributors for this article] (2024). High viral loads combined with inflammatory markers predict disease severity in hospitalized COVID-19 patients: Results from the NOR-Solidarity trial. Journal of Internal Medicine. ISSN 0954-6820. 296(3), p. 249–259. doi: 10.1111/joim.13820. Full text in Research Archive Show summary

  Objectives To investigate temporal changes in the association between SARS-CoV2 viral load (VL) and markers of inflammation during hospitalization, as well as the ability of these markers alone or in combination to predict severe outcomes. Methods Serial oropharyngeal and blood samples were obtained from hospitalized COVID-19 patients (n = 160). Levels of inflammatory markers and oropharyngeal VL were measured during hospitalization (admission, days 3–5, and days 7–10) and related to severe outcomes (respiratory failure/intensive care unit admission). Results Elevated admission levels of IL (interleukin)-6, IL-33, IL-8, monocyte chemoattractant protein-1 (MCP-1), interferon-γ-induced protein 10 (IP-10), IL-1β, and IL-1Ra were associated with severe outcomes during hospitalization. Although no inflammatory markers correlated with VL at baseline, there was a significant correlation between VL and levels of IP-10 and MCP-1 at days 3–5, accompanied by IL-8 and IL-6 at days 7–10. Finally, there was a seemingly additive effect of IP-10, MCP-1, and IL-6 in predicting severe outcomes when combined with high VL at baseline. Conclusions An increasing number of inflammatory markers were associated with VL during the first 10 days of hospitalization, and several of these markers were associated with severe outcomes, in particular when combined with elevated VL. Future studies should assess the potential for combining antiviral and immunomodulatory treatment, preferably guided by viral and inflammatory biomarkers, for the selection of high-risk patients.

• Bortoli, Alessandro De; Nordøy, Ingvild; Connelly, James Pattrick; Viermyr, Hans-Kittil; Bjerkreim, Randi Haukaas & Broch, Kaspar [Show all 15 contributors for this article] (2024). Diagnostics, treatment and outcomes of cardiac sarcoidosis in a Norwegian cohort. International Journal of Cardiology. ISSN 0167-5273. 400. doi: 10.1016/j.ijcard.2024.131809. Full text in Research Archive Show summary

  Background Evidence-based guidelines for cardiac sarcoidosis (CS) regarding use of second- and third-line agents, treatment duration, surveillance and prognostic factors are lacking. Objective To analyze the clinical presentation, diagnostics, treatment, monitoring and clinical outcomes in a Norwegian cohort. Methods Using discharge diagnoses between 2017 through 2020 from a large tertiary center, we identified 52 patients with CS. We performed a systematic chart review following a pre-specified checklist. The primary outcome of major cardiovascular events (MACE) was defined as a composite of cardiovascular hospitalization, defibrillator therapy, cardiac transplantation, or death. Results 18-fluorodeoxyglucose positron emission tomography (FDG-PET) showed pathological tracer uptake in 35/36 (97%) of immunosuppression-naïve patients. Immunosuppressive treatment was administered to 49/52 patients (94%) for a median of 43 (IQR 34) months; 69% were treated with second-line (methotrexate, azathioprine, mycophenolate mofetil) and 25% with third-line (rituximab, infliximab) agents, respectively. Rituximab reduced inflammation as assessed by interval FDG-PET imaging and was overall well tolerated. Median duration to first MACE was 6 (IQR 10) months and 17/23 patients (74%) experienced a MACE within 12 months from CS diagnosis. No mortality was recorded and 20% achieved full remission. Age below the median of 53 years at time of diagnosis was associated with an increased risk of a MACE. Conclusion Long-term immunosuppression including a liberal use of non-steroidal agents, appeared essential in treating CS. Although the burden of cardiovascular events was substantial, the survival was excellent in this contemporary cohort. Prospective randomized studies are urgently needed to define the best therapy for these patients.

• Viermyr, Hans-Kittil; Tonby, Kristian; Ponzi, Erica; Trouillet-Assant, Sophie; Poissy, Julien & Arribas, José R. [Show all 49 contributors for this article] (2024). Safety of baricitinib in vaccinated patients with severe and critical COVID-19 sub study of the randomised Bari-SolidAct trial. EBioMedicine. 111. doi: 10.1016/j.ebiom.2024.105511. Full text in Research Archive Show summary

  Background The Bari-SolidAct randomized controlled trial compared baricitinib with placebo in patients with severe COVID-19. A post hoc analysis revealed a higher incidence of serious adverse events (SAEs) among SARS-CoV-2-vaccinated participants who had received baricitinib. This sub-study aimed to investigate whether vaccination influences the safety profile of baricitinib in patients with severe COVID-19. Methods Biobanked samples from 146 participants (55 vaccinated vs. 91 unvaccinated) were analysed longitudinally for inflammation markers, humoral responses, tissue viral loads, and plasma viral antigens on days 1, 3, and 8. High-dimensional analyses, including RNA sequencing and flow cytometry, were performed on available samples. Mediation analyses were used to assess relationships between SAEs, baseline-adjusted biomarkers, and treatment-vaccination status. Findings Vaccinated participants were older, more frequently hospitalized, had more comorbidities, and exhibited higher nasopharyngeal viral loads. Baricitinib treatment did not affect antibody responses or viral clearance, but reduced markers of T-cell and monocyte activation compared to placebo (sCD25, sCD14, sCD163, sTIM-3). Age, baseline levels of plasma viral antigen, and several inflammatory markers, as well as IL-2, IL-6, Neopterin, CXCL16, sCD14, and suPAR on day 8 were associated with the occurrence of SAEs. However, mediation analyses of markers linked to SAEs, baricitinib treatment, or vaccination status did not reveal statistically significant interactions between vaccination status and SAEs. Interpretation This sub-study did not identify any virus- or host-related biomarkers significantly associated with the interaction between SARS-CoV-2 vaccination status and the safety of baricitinib. However, caution should be exercised due to the moderate sample size.

• Bai, Xiangning; Nielsen, Susanne Dam; Kunisaki, Ken M. & Trøseid, Marius (2024). Pulmonary comorbidities in people with HIV - the microbiome connection. Current Opinion in HIV and AIDS. ISSN 1746-630X. 19(5), p. 246–252. doi: 10.1097/COH.0000000000000871. Full text in Research Archive
• Halvorsen, Bente; Viermyr, Hans-Kittil; Ueland, Thor; Sagen, Ellen Lund; Michelsen, Annika Elisabet & Bjerkeli, Vigdis [Show all 14 contributors for this article] (2024). IL-22 is increased in hospitalized patients with COVID-19 and associates with cardiac involvement. Journal of Infection. ISSN 0163-4453. 89(1). doi: 10.1016/j.jinf.2024.106176. Full text in Research Archive
• Barratt-Due, Andreas; Pettersen, Kristin; Dahl, Tuva Børresdatter; Holter, Jan Cato; Grønli, Renathe Henriksen & Dyrhol-Riise, Anne Ma [Show all 20 contributors for this article] (2024). Escalated complement activation during hospitalization is associated with higher risk of 60-day mortality in SARS-CoV-2-infected patients. Journal of Internal Medicine. ISSN 0954-6820. 296(1), p. 80–92. doi: 10.1111/joim.13783. Full text in Research Archive Show summary

  Background: The complement system, an upstream recognition system of innate immunity, is activated upon SARS-CoV-2 infection. To gain a deeper understanding of the extent and duration of this activation, we investigated complement activation profiles during the acute phase of COVID-19, its persistence post-recovery and dynamic changes in relation to disease severity. Methods: Serial blood samples were obtained from two cohorts of hospitalized COVID-19 patients (n = 457). Systemic complement activation products reflecting classical/lectin (C4d), alternative (C3bBbP), common (C3bc) and terminal pathway (TCC and C5a) were measured during hospitalization (admission, days 3–5 and days 7–10), at 3 months and after 1 year. Levels of activation and temporal profiles during hospitalization were related to disease severity defined as respiratory failure (PO2/FiO2 ratio <26.6 kPa) and/or admission to intensive care unit, 60-day total mortality and pulmonary pathology after 3 months. Findings: During hospitalization, TCC, C4d, C3bc, C3bBbP and C5a were significantly elevated compared to healthy controls. Severely ill patients had significantly higher levels of TCC and C4d (p < 0.001), compared to patients with moderate COVID-19. Escalated levels of TCC and C4d during hospitalization were associated with a higher risk of 60-day mortality (p < 0.001), and C4d levels were additionally associated with chest CT changes at 3 months (p < 0.001). At 3 months and 1 year, we observed consistently elevated levels of most complement activation products compared to controls. Conclusion: Hospitalized COVID-19 patients display prominent and long-lasting systemic complement activation. Optimal targeting of the system may be achieved through enhanced risk stratification and closer monitoring of in-hospital changes of complement activation products.

• Trøseid, Marius; Nielsen, Susanne Dam & Vujkovic-Cvijin, Ivan (2024). Gut microbiome and cardiometabolic comorbidities in people living with HIV. Microbiome. 12(1). doi: 10.1186/s40168-024-01815-y. Full text in Research Archive Show summary

  Background Despite modern antiretroviral therapy (ART), people living with HIV (PLWH) have increased relative risk of inflammatory-driven comorbidities, including cardiovascular disease (CVD). The gut microbiome could be one of several driving factors, along with traditional risk factors and HIV-related risk factors such as coinfections, ART toxicity, and past immunodeficiency. Results PLWH have an altered gut microbiome, even after adjustment for known confounding factors including sexual preference. The HIV-related microbiome has been associated with cardiometabolic comorbidities, and shares features with CVD-related microbiota profiles, in particular reduced capacity for short-chain fatty acid (SCFA) generation. Substantial inter-individual variation has so far been an obstacle for applying microbiota profiles for risk stratification. This review covers updated knowledge and recent advances in our understanding of the gut microbiome and comorbidities in PLWH, with specific focus on cardiometabolic comorbidities and inflammation. It covers a comprehensive overview of HIV-related and comorbidity-related dysbiosis, microbial translocation, and microbiota-derived metabolites. It also contains recent data from studies in PLWH on circulating metabolites related to comorbidities and underlying gut microbiota alterations, including circulating levels of the SCFA propionate, the histidine-analogue imidazole propionate, and the protective metabolite indole-3-propionic acid. Conclusions Despite recent advances, the gut microbiome and related metabolites are not yet established as biomarkers or therapeutic targets. The review gives directions for future research needed to advance the field into clinical practice, including promises and pitfalls for precision medicine. Video Abstract

• Hoel, Hedda; Dahl, Tuva Børresdatter; Yang, Kuan; Skeie, Linda Gail; Michelsen, Annika Elisabet & Ueland, Thor [Show all 13 contributors for this article] (2024). Chronic HIV Infection Increases Monocyte NLRP3 Inflammasome-Dependent IL-1α and IL-1β Release. International Journal of Molecular Sciences. ISSN 1661-6596. 25(13). doi: 10.3390/ijms25137141. Full text in Research Archive Show summary

  Antiretroviral treatment (ART) has converted HIV from a lethal disease to a chronic condition, yet co-morbidities persist. Incomplete immune recovery and chronic immune activation, especially in the gut mucosa, contribute to these complications. Inflammasomes, multi-protein complexes activated by innate immune receptors, appear to play a role in these inflammatory responses. In particular, preliminary data indicate the involvement of IFI16 and NLRP3 inflammasomes in chronic HIV infection. This study explores inflammasome function in monocytes from people with HIV (PWH); 22 ART-treated with suppressed viremia and 17 untreated PWH were compared to 33 HIV-negative donors. Monocytes were primed with LPS and inflammasomes activated with ATP in vitro. IFI16 and NLRP3 mRNA expression were examined in a subset of donors. IFI16 and NLRP3 expression in unstimulated monocytes correlated negatively with CD4 T cell counts in untreated PWH. For IFI16, there was also a positive correlation with viral load. Monocytes from untreated PWH exhibit increased release of IL-1α, IL-1β, and TNF compared to treated PWH and HIV-negative donors. However, circulating monocytes in PWH are not pre-primed for inflammasome activation in vivo. The findings suggest a link between IFI16, NLRP3, and HIV progression, emphasizing their potential role in comorbidities such as cardiovascular disease. The study provides insights into inflammasome regulation in HIV pathogenesis and its implications for therapeutic interventions.

• Murphy, Sarah Louise Mikalsen; Balzer, Nora Reka; Ranheim, Trine; Sagen, Ellen Lund; Huse, Camilla & Bjerkeli, Vigdis [Show all 19 contributors for this article] (2024). Extracellular matrix remodelling pathway in peripheral blood mononuclear cells from severe COVID-19 patients: an explorative study. Frontiers in Immunology. 15. doi: 10.3389/fimmu.2024.1379570. Full text in Research Archive Show summary

  There is a reciprocal relationship between extracellular matrix (ECM) remodelling and inflammation that could be operating in the progression of severe COVID-19. To explore the immune-driven ECM remodelling in COVID-19, we in this explorative study analysed these interactions in hospitalised COVID-19 patients. RNA sequencing and flow analysis were performed on peripheral blood mononuclear cells. Inflammatory mediators in plasma were measured by ELISA and MSD, and clinical information from hospitalised COVID-19 patients (N=15) at admission was included in the analysis. Further, we reanalysed two publicly available datasets: (1) lung tissue RNA-sequencing dataset (N=5) and (2) proteomics dataset from PBCM. ECM remodelling pathways were enriched in PBMC from COVID-19 patients compared to healthy controls. Patients treated at the intensive care unit (ICU) expressed distinct ECM remodelling gene profiles compared to patients in the hospital ward. Several markers were strongly correlated to immune cell subsets, and the dysregulation in the ICU patients was positively associated with plasma levels of inflammatory cytokines and negatively associated with B-cell activating factors. Finally, our analysis of publicly accessible datasets revealed (i) an augmented ECM remodelling signature in inflamed lung tissue compared to non-inflamed tissue and (ii) proteomics analysis of PBMC from severe COVID-19 patients demonstrated an up-regulation in an ECM remodelling pathway. Our results may suggest the presence of an interaction between ECM remodelling, inflammation, and immune cells, potentially initiating or perpetuating pulmonary pathology in severe COVID-19.

• Bratset, Vibeke; Nendl, Andraz; Raju, Sajan; Holm, Kristian; Broch, Kaspar & Hov, Johannes Espolin Roksund [Show all 9 contributors for this article] (2024). Gut dysbiosis and neutrophil extracellular traps in chronic heart failure. International Journal of Cardiology. ISSN 0167-5273. 419. doi: 10.1016/j.ijcard.2024.132689. Full text in Research Archive Show summary

  Background Chronic heart failure (HF) patients have reduced microbiota diversity. Leakage of microbes and their metabolites into the bloodstream may activate neutrophils. Neutrophil extracellular traps (NETs) consist of chromatin and proteases, and may contribute to HF pathogenesis. We assessed associations between circulating NETs and 1) cardiac function, 2) the degree of gut microbiota diversity and 3) gut leakage and microbial metabolites in HF patients. Methods A cross-sectional study including 124 patients with chronic HF and left ventricular ejection fraction ≤40 %. Severe HF was defined as N-terminal pro-B-type natriuretic peptide concentrations above median. We measured citrullinated histone H3 (CitH3), myeloperoxidase- and double-stranded-DNA in the blood. Gut leakage markers included bacterial lipopolysaccharides and soluble cluster of differentiation 14. The microbial metabolites included circulating trimethylamine N-oxide and butyrate producing capacity. We used the Shannon diversity-index and a dysbiosis-index based on bacteria with altered relative abundance to characterize the gut microbiota profile. Results Quartile 4 of CitH3 was associated with more severe HF compared to quartiles 1–3, after adjustments for age, gender and hypertension (adjusted odds ratio [95 %CI] 3.21[1.18–8.69], p = 0.022). CitH3 was moderately associated with hypertension (p = 0.04), higher CRP levels (p = 0.016) and lower Shannon diversity index, (p = 0.039). No other NET marker associated with severe HF. Conclusions In chronic HF patients with reduced LVEF, high levels of CitH3 were associated with disease severity, inflammation and reduced gut microbiota diversity. Our results suggest that enhanced release of NETs could be involved in progressive HF, although the contribution of the gut microbiota seems limited in this context.

• Ueland, Thor; Nkele, Isaac; Hoel, Hedda; Lockman, Shahin; Michelsen, Annika Elisabet & Moshomo, Thato [Show all 10 contributors for this article] (2024). Markers of extracellular matrix degradation and inflammasome activation are associated with carotid plaques in virally suppressed people with HIV in Botswana. AIDS (London). ISSN 0269-9370. 39(1), p. 22–30. doi: 10.1097/QAD.0000000000004014. Full text in Research Archive
• Nendl, Andraz; Andersen, Geir Øystein; Seljeflot, Ingebjørg; Trøseid, Marius & Awoyemi, Ayodeji Olawale (2024). Intestinal fatty acid binding protein is associated with infarct size and cardiac function in acute heart failure following myocardial infarction. Open heart. 11(2). doi: 10.1136/openhrt-2024-002868. Full text in Research Archive Show summary

  Background In acute heart failure (HF), reduced cardiac output, vasoconstriction and congestion may damage the intestinal mucosa and disrupt its barrier function. This could facilitate the leakage of bacterial products into circulation and contribute to inflammation and adverse cardiac remodelling. We aimed to investigate gut leakage markers and their associations with inflammation, infarct size and cardiac function. Methods We examined 61 ST-elevation myocardial infarction (STEMI) patients who developed acute HF within 48 hours of successful percutaneous coronary intervention (PCI). Serial blood samples were taken to measure lipopolysaccharide (LPS), LPS-binding protein (LBP), soluble cluster of differentiation 14 (sCD14) and intestinal fatty acid binding protein (I-FABP). Cumulative areas under the curve (AUCs) from baseline to day 5 were calculated. Serial echocardiography was performed to assess left ventricular ejection fraction (LVEF), global longitudinal strain (GLS) and wall motion score index (WMSI). Single-photon emission CT (SPECT) was performed at 6 weeks to determine infarct size and LVEF. Results I-FABPAUC correlated positively with infarct size (rs=0.45, p=0.002), GLS (rs=0.32, p=0.035) and WMSI (rs=0.45, p=0.002) and negatively with LVEF measured by SPECT (rs=−0.40, p=0.007) and echocardiography (rs=−0.33, p=0.021) at 6 weeks. LPSAUC, LBPAUC and sCD14AUC did not correlate to any cardiac function marker or infarct size. Patients, who at 6 weeks had above median GLS and WMSI, and below-median LVEF measured by SPECT, were more likely to have above median I-FABPAUC during admission (adjusted OR (aOR) 5.22, 95% CI 1.21 to 22.44; aOR 5.05, 95% CI 1.25 to 20.43; aOR 5.67, 95% CI 1.42 to 22.59, respectively). The same was observed for patients in the lowest quartile of LVEF measured by echocardiography (aOR 9.99, 95% CI 1.79 to 55.83) and three upper quartiles of infarct size (aOR 20.34, 95% CI 1.56 to 264.65). Conclusions In primary PCI-treated STEMI patients with acute HF, I-FABP, a marker of intestinal epithelial damage, was associated with larger infarct size and worse cardiac function after 6 weeks.

• Raju, Sajan; Molinaro, Antonio; Awoyemi, Ayodeji Olawale; Jørgensen, Silje Fjellgård; Braadland, Peder Rustøen & Nendl, Andraz [Show all 19 contributors for this article] (2024). Microbial-derived imidazole propionate links the heart failure-associated microbiome alterations to disease severity. Genome Medicine. 16(1), p. 27–27. doi: 10.1186/s13073-024-01296-6. Full text in Research Archive Show summary

  <p><i>Background</i> Interactions between the gut microbiota, diet, and host metabolism contribute to the development of cardiovascular disease, but a firm link between disease-specific gut microbiota alterations and circulating metabolites is lacking. <p><i>Methods</i> We performed shot-gun sequencing on 235 samples from 166 HF patients and 69 healthy control samples. Separate plasma samples from healthy controls (n = 53) were used for the comparison of imidazole propionate (ImP) levels. Taxonomy and functional pathways for shotgun sequencing data was assigned using MetaPhlAn3 and HUMAnN3 pipelines. <p><i>Results</i> Here, we show that heart failure (HF) is associated with a specific compositional and functional shift of the gut microbiota that is linked to circulating levels of the microbial histidine-derived metabolite ImP. Circulating ImP levels are elevated in chronic HF patients compared to controls and associated with HF-related gut microbiota alterations. Contrary to the microbiota composition, ImP levels provide insight into etiology and severity of HF and also associate with markers of intestinal permeability and systemic inflammation. <p><i>Conclusions</i> Our findings establish a connection between changes in the gut microbiota, the presence, etiology, and severity of HF, and the gut-microbially produced metabolite ImP. While ImP appears promising as a circulating biomarker reflecting gut dysbiosis related to HF, further studies are essential to demonstrate its causal or contributing role in HF pathogenesis.

• Patrick-Brown, Thale Dawn; Barratt-Due, Andreas; Trøseid, Marius; Dyrhol-Riise, Anne Ma; Nezvalova-Henriksen, Katerina & Kåsine, Trine [Show all 8 contributors for this article] (2024). The effects of remdesivir on long-term symptoms in patients hospitalised for COVID-19: a pre-specified exploratory analysis. Communications Medicine. 4(231), p. 1–7. doi: 10.1038/s43856-024-00650-4. Full text in Research Archive Show summary

  Background There is an unmet need for treatment of long-term symptoms following COVID-19. Remdesivir is currently the only antiviral approved by the European Medicines Agency for hospitalised patients. Here, we report on the effect of remdesivir in addition to standard of care on long-term symptoms and quality of life in hospitalised patients with COVID-19 as part of the open-label randomised NOR-Solidarity trial (NCT04321616). Methods A total of 185 patients were included in the main trial, of which 118 (60%) were randomised to either remdesivir (n = 42; 36%) or a post-hoc defined control group composed of patients who received standard of care alone or standard of care with hydroxychloroquine (n = 76; 64%). Participants were given quality of life surveys to fill out to gauge their self-reported health over time (the COPD assessment test, the EQ-5D-5L and the RAND SF-36). Results Here we show that after three months, patients treated with remdesivir do not show significant improvements in stated health compared to those who were not. There are self-reported symptoms of fatigue [mean remdesivir group 2.6 (standard deviation 1.5) v control 2.1 (1.6), 95% confidence interval(CI) −1.17 to 0.15, p = 0.129], shortness of breath [3.0 (1.7) v 2.1 (1.8), 95% CI −1.53 to 0.16, p = 0.110] and coughing [1.8 (1.6) v 1.2 (1.5), 95% CI −1.3 to 0.33, p = 0.237] 3 months after randomisation assessed via the COPD Assessment Test. Conclusions Our findings indicate that treatment with remdesivir during hospitalisation does not provide any clinically relevant long-term benefit.

• Braadland, Peder Rustøen; Bergquist, Annika; Kummen, Martin; Bossen, Lars; Engesæter, Lise Katrine & Reims, Henrik Mikael [Show all 21 contributors for this article] (2023). Clinical and biochemical impact of vitamin B6 deficiency in primary sclerosing cholangitis before and after liver transplantation. Journal of Hepatology. ISSN 0168-8278. 79(4), p. 955–966. doi: 10.1016/j.jhep.2023.05.038. Full text in Research Archive Show summary

  Background and aims We previously demonstrated that people with primary sclerosing cholangitis (PSC) had reduced gut microbial capacity to produce active vitamin B6 (pyridoxal 5’-phosphate [PLP]), which corresponded to lower circulating PLP levels and poor outcomes. Here, we define the extent and biochemical and clinical impact of vitamin B6 deficiency in people with PSC from several centers before and after liver transplantation (LT). Methods We used targeted liquid chromatography-tandem mass spectrometry to measure B6 vitamers and B6-related metabolic changes in blood from geographically distinct cross-sectional cohorts totaling 373 people with PSC and 100 healthy controls to expand on our earlier findings. Furthermore, we included a longitudinal PSC cohort (n = 158) sampled prior to and serially after LT, and cohorts of people with inflammatory bowel disease (IBD) without PSC (n = 51) or with primary biliary cholangitis (PBC) (n = 100), as disease controls. We used Cox regression to measure the added value of PLP to predict outcomes before and after LT. Results In different cohorts, 17-38% of people with PSC had PLP levels below the biochemical definition of a vitamin B6 deficiency. The deficiency was more pronounced in PSC than in IBD without PSC and PBC. Reduced PLP was associated with dysregulation of PLP-dependent pathways. The low B6 status largely persisted after LT. Low PLP independently predicted reduced LT-free survival in both non-transplanted people with PSC and in transplant recipients with recurrent disease. Conclusions Low vitamin B6 status with associated metabolic dysregulation is a persistent feature of PSC. PLP was a strong prognostic biomarker for LT-free survival both in PSC and recurrent disease. Our findings suggest that vitamin B6 deficiency modifies the disease and provides a rationale for assessing B6 status and testing supplementation. Impact and implications We previously found that people with PSC had reduced gut microbial potential to produce essential nutrients. Across several cohorts, we find that the majority of people with PSC are either vitamin B6 deficient or have a marginal deficiency, which remains prevalent even after liver transplantation. Low vitamin B6 levels strongly associate with reduced liver transplantation-free survival as well as deficits in biochemical pathways dependent on vitamin B6, suggesting that the deficiency has a clinical impact on the disease. The results provide a rationale for measuring vitamin B6 and to investigate whether vitamin B6 supplementation or modification of the gut microbial community can help improve outcomes for people with PSC.

• Serrano-Villar, Sergio; Tincati, Camilla; Raju, Sajan; Sáenz, Johan S.; Moreno, Elena & Bargiela, Rafael [Show all 19 contributors for this article] (2023). Microbiome-derived cobalamin and succinyl-CoA as biomarkers for improved screening of anal cancer. Nature Medicine. ISSN 1078-8956. 29(7), p. 1738–1749. doi: 10.1038/s41591-023-02407-3. Full text in Research Archive
• Ueland, Thor; Waagsbø, Bjørn; Berge, Rolf Kristian; Trøseid, Marius; Aukrust, Pål & Damås, Jan Kristian (2023). Fatty Acids Composition and HIV Infection: Altered Levels of n-6 Polyunsaturated Fatty Acids Are Associated with Disease Progression. Viruses. 15(7). doi: 10.3390/v15071613. Full text in Research Archive Show summary

  Fatty acids (FAs) are important regulators of immune responses and innate defense mechanisms. We hypothesized that disturbed FA metabolism could contribute to the progression of HIV infection. Plasma levels of 45 FAs were analyzed with gas chromatography in healthy controls and HIV-infected patients with regard to Mycobacterium avium complex (MAC) infection. In vitro, we assessed MAC-PPD-induced release of inflammatory cytokines in peripheral and bone marrow mononuclear cells (PBMC and BMMC) according to levels of n-6 polyunsaturated fatty acids (PUFAs). While plasma saturated FAs were higher in HIV infection, PUFAs, and in particular the n-6 PUFA arachidonic acid (AA), were lower in patients with advanced disease. The ratio between AA and precursor dihomo-γ-linolenic acid, reflecting Δ5-desaturase activity, was markedly lower and inversely correlated with plasma HIV RNA levels in these patients. Depletion of AA was observed prior to MAC infection, and MAC-PPD-induced release of TNF and IL-6 in PBMC and BMMC was lower in patients with low plasma AA. Our findings suggest that dysregulated metabolism of n-6 PUFAs may play a role in the progression of HIV infection. While high AA may contribute to chronic inflammation in asymptomatic HIV-infected patients, low AA seems to increase the susceptibility to MAC infection in patients with advanced disease.

• Knudsen, Andreas D; Fuchs, Andreas; Benfield, Thomas; Gerstoft, Jan; Køber, Lars & Trøseid, Marius [Show all 8 contributors for this article] (2023). Coronary Artery Disease in Persons with Human Immunodeficiency Virus Without Detectable Viral Replication. Open Forum Infectious Diseases. 10(7). doi: 10.1093/ofid/ofad298. Full text in Research Archive Show summary

  Abstract Background We aimed to determine the prevalence of coronary artery disease (CAD) in persons with human immunodeficiency virus (HIV; PWH) and investigate whether inflammatory markers, including interleukin 6, IL-1β, and high-sensitivity C-reactive protein (hsCRP), were associated with CAD. Methods From the Copenhagen Comorbidity in HIV Infection (COCOMO) study, we included virologically suppressed PWH who underwent coronary computed tomographic (CT) angiography. Any atherosclerosis was defined as &amp;gt;0% stenosis, and obstructive CAD as ≥50% stenosis. Results Among 669 participants (mean age [standard deviation], 51 [11] years; 89% male), 300 (45%) had atherosclerosis, and 119 (18%) had obstructive CAD. The following risk factors were associated with any atherosclerosis and with obstructive CAD: age, male sex, hypertension, diabetes, smoking, dyslipidemia, time with HIV, and current protease inhibitor use. Interleukin 6 (IL-6) and hsCRP levels &amp;gt;2 mg/L were associated with any atherosclerosis and with obstructive CAD in univariable analyses but not after adjustment for traditional risk factors. IL-1β was not associated with CAD. Conclusions In a large population of PWH without viral replication, almost half had angiographically verified atherosclerosis. High concentrations of IL-6 and hsCRP were associated with CAD in univariable analyses, but adjustment for cardiovascular risk factors attenuated the association, suggesting that inflammation may mediate the association between traditional risk factors and CAD.

• Mikaeloff, Flora; Gelpi, Marco; Benfeitas, Rui; Knudsen, Andreas D.; Vestad, Beate & Høgh, Julie [Show all 14 contributors for this article] (2023). Network-based multi-omics integration reveals metabolic at-risk profile within treated HIV-infection. eLIFE. 12. doi: 10.7554/eLife.82785. Full text in Research Archive Show summary

  Multiomics technologies improve the biological understanding of health status in people living with HIV on antiretroviral therapy (PWH). Still, a systematic and in-depth characterization of metabolic risk profile during successful long-term treatment is lacking. Here, we used multi-omics (plasma lipidomic, metabolomic, and fecal 16 S microbiome) data-driven stratification and characterization to identify the metabolic at-risk profile within PWH. Through network analysis and similarity network fusion (SNF), we identified three groups of PWH (SNF-1–3): healthy (HC)-like (SNF-1), mild at-risk (SNF-3), and severe at-risk (SNF-2). The PWH in the SNF-2 (45%) had a severe at-risk metabolic profile with increased visceral adipose tissue, BMI, higher incidence of metabolic syndrome (MetS), and increased di- and triglycerides despite having higher CD4 + T-cell counts than the other two clusters. However, the HC-like and the severe at-risk group had a similar metabolic profile differing from HIV-negative controls (HNC), with dysregulation of amino acid metabolism. At the microbiome profile, the HC-like group had a lower α-diversity, a lower proportion of men having sex with men (MSM) and was enriched in Bacteroides. In contrast, in at-risk groups, there was an increase in Prevotella , with a high proportion of MSM, which could potentially lead to higher systemic inflammation and increased cardiometabolic risk profile. The multi-omics integrative analysis also revealed a complex microbial interplay of the microbiome-associated metabolites in PWH. Those severely at-risk clusters may benefit from personalized medicine and lifestyle intervention to improve their dysregulated metabolic traits, aiming to achieve healthier aging.

• Trøseid, Marius; Arribas, José R.; Assoumou, Lambert; Holten, Aleksander Rygh; Poissy, Julien & Terzić, Vida [Show all 56 contributors for this article] (2023). Efficacy and safety of baricitinib in hospitalized adults with severe or critical COVID‑19 (Bari‑SolidAct): a randomised, double‑blind, placebo‑controlled phase 3 trial. Critical Care. ISSN 1364-8535. 27(9), p. 1–15. doi: 10.1186/s13054-022-04205-8. Full text in Research Archive Show summary

  Background Baricitinib has shown efficacy in hospitalized patients with COVID-19, but no placebo-controlled trials have focused specifically on severe/critical COVID, including vaccinated participants. Methods Bari-SolidAct is a phase-3, multicentre, randomised, double-blind, placebo-controlled trial, enrolling participants from June 3, 2021 to March 7, 2022, stopped prematurely for external evidence. Patients with severe/critical COVID-19 were randomised to Baricitinib 4 mg once daily or placebo, added to standard of care. The primary endpoint was all-cause mortality within 60 days. Participants were remotely followed to day 90 for safety and patient related outcome measures. Results Two hundred ninety-nine patients were screened, 284 randomised, and 275 received study drug or placebo and were included in the modified intent-to-treat analyses (139 receiving baricitinib and 136 placebo). Median age was 60 (IQR 49–69) years, 77% were male and 35% had received at least one dose of SARS-CoV2 vaccine. There were 21 deaths at day 60 in each group, 15.1% in the baricitinib group and 15.4% in the placebo group (adjusted absolute difference and 95% CI − 0.1% [− 8·3 to 8·0]). In sensitivity analysis censoring observations after drug discontinuation or rescue therapy (tocilizumab/increased steroid dose), proportions of death were 5.8% versus 8.8% (− 3.2% [− 9.0 to 2.7]), respectively. There were 148 serious adverse events in 46 participants (33.1%) receiving baricitinib and 155 in 51 participants (37.5%) receiving placebo. In subgroup analyses, there was a potential interaction between vaccination status and treatment allocation on 60-day mortality. In a subsequent post hoc analysis there was a significant interaction between vaccination status and treatment allocation on the occurrence of serious adverse events, with more respiratory complications and severe infections in vaccinated participants treated with baricitinib. Vaccinated participants were on average 11 years older, with more comorbidities. Conclusion This clinical trial was prematurely stopped for external evidence and therefore underpowered to conclude on a potential survival benefit of baricitinib in severe/critical COVID-19. We observed a possible safety signal in vaccinated participants, who were older with more comorbidities. Although based on a post-hoc analysis, these findings warrant further investigation in other trials and real-world studies.

• Knudsen, Andreas D; Eskelund, Christian Winther; Benfield, Thomas; Yanan, Zhao; Gelpi, Marco & Køber, Lars [Show all 13 contributors for this article] (2023). Clonal hematopoiesis of indeterminate potential in persons with HIV. AIDS (London). ISSN 0269-9370. 38(4), p. 487–495. doi: 10.1097/QAD.0000000000003788. Full text in Research Archive
• Trøseid, Marius; Holter, Jan Cato; Holm, Kristian; Vestad, Beate; Sazonova, Taisiia & Granerud, Beathe Kiland [Show all 17 contributors for this article] (2023). Gut microbiota composition during hospitalization is associated with 60-day mortality after severe COVID-19. Critical Care. ISSN 1364-8535. 27(1). doi: 10.1186/s13054-023-04356-2. Full text in Research Archive Show summary

  Background Gut microbiota alterations have been reported in hospitalized COVID-19 patients, with reduced alpha diversity and altered microbiota composition related to respiratory failure. However, data regarding gut microbiota and mortality are scarce. Methods Rectal swabs for gut microbiota analyses were collected within 48 h after hospital admission (baseline; n = 123) and three-month post-admission (n = 50) in a subset of patients included in the Norwegian SARS-CoV2 cohort study. Samples were analysed by sequencing the 16S rRNA gene. Gut microbiota diversity and composition at baseline were assessed in relation to need for intensive care unit (ICU) admission during hospitalization. The primary objective was to investigate whether the ICU-related gut microbiota was associated with 60-day mortality. Results Gut microbiota diversity (Shannon index) at baseline was lower in COVID-19 patients requiring ICU admission during hospitalization than in those managed in general wards. A dysbiosis index representing a balance of enriched and reduced taxa in ICU compared with ward patients, including decreased abundance of butyrate-producing microbes and enrichment of a partly oral bacterial flora, was associated with need of ICU admission independent of antibiotic use, dexamethasone use, chronic pulmonary disease, PO2/FiO2 ratio, C-reactive protein, neutrophil counts or creatinine levels (adjusted p < 0.001). The ICU-related dysbiosis index at baseline correlated with systemic inflammation and was associated with 60-day mortality in univariate analyses (Hazard ratio 3.70 [2.00–8.6], p < 0.001), as well as after separate adjustment for covariates. At the three-month follow-up, the dysbiosis index remained elevated in ICU patients compared with ward patients (adjusted p = 0.007). Conclusions Although our data should be regarded as exploratory due to low number of clinical end points, they suggest that gut microbiota alterations during hospitalization could be related to poor prognosis after severe COVID-19. Larger studies of gut involvement during COVID-19 in relation to long-term clinical outcome are warranted.

• Murphy, Sarah Louise Mikalsen; Halvorsen, Bente; Holter, Jan Cato; Huse, Camilla; Tveita, Anders & Trøseid, Marius [Show all 24 contributors for this article] (2023). Circulating markers of extracellular matrix remodelling in severe COVID-19 patients. Journal of Internal Medicine. ISSN 0954-6820. 294(6), p. 784–797. doi: 10.1111/joim.13725. Full text in Research Archive Show summary

  Background Abnormal remodelling of the extracellular matrix (ECM) has generally been linked to pulmonary inflammation and fibrosis and may also play a role in the pathogenesis of severe COVID-19. To further elucidate the role of ECM remodelling and excessive fibrogenesis in severe COVID-19, we examined circulating levels of mediators involved in various aspects of these processes in COVID-19 patients.<p> <p>Methods Serial blood samples were obtained from two cohorts of hospitalised COVID-19 patients (n = 414). Circulating levels of ECM remodelling mediators were quantified by enzyme immunoassays in samples collected during hospitalisation and at 3-month follow-up. Samples were related to disease severity (respiratory failure and/or treatment at the intensive care unit), 60-day total mortality and pulmonary pathology after 3-months. We also evaluated the direct effect of inactivated SARS-CoV-2 on the release of the different ECM mediators in relevant cell lines. <p>Results Several of the measured markers were associated with adverse outcomes, notably osteopontin (OPN), S100 calcium-binding protein A12 and YKL-40 were associated with disease severity and mortality. High levels of ECM mediators during hospitalisation were associated with computed tomography thorax pathology after 3-months. Some markers (i.e. growth differential factor 15, galectin 3 and matrix metalloproteinase 9) were released from various relevant cell lines (i.e. macrophages and lung cell lines) in vitro after exposure to inactivated SARS-CoV-2 suggesting a direct link between these mediators and the causal agent of COVID-19. <p>Conclusion Our findings highlight changes to ECM remodelling and particularly a possible role of OPN, S100A12 and YKL-40 in the pathogenesis of severe COVID-19.

• Thudium, Rebekka F; Arentoft, Nicoline S; Hoel, Hedda; Afzal, Shoaib; Stemann, Jakob H Von & Forman, Julie L [Show all 15 contributors for this article] (2023). Elevated Levels of Interleukin-1β and Interleukin-10 Are Associated with Faster Lung Function Decline in People with Well-Treated Human Immunodeficiency Virus. Journal of Infectious Diseases. ISSN 0022-1899. 228(8), p. 1080–1088. doi: 10.1093/infdis/jiad233. Full text in Research Archive
• Ueland, Thor; Michelsen, Annika Elisabet; Tveita, Anders; Kåsine, Trine; Dahl, Tuva Børresdatter & Finbråten, Ane-Kristine [Show all 16 contributors for this article] (2023). Coagulopathy and adverse outcomes in hospitalized patients with COVID-19: results from the NOR-Solidarity trial. Research and Practice in Thrombosis and Haemostasis (RPTH). 8(1). doi: 10.1016/j.rpth.2023.102289. Full text in Research Archive Show summary

  Background - Several studies have examined parameters of increased thrombogenicity in COVID-19, but studies examining their association with long-term outcome and potential effects of antiviral agents in hospitalized patients with COVID-19 are scarce.<p> <p>Objectives - To evaluate plasma levels of hemostatic proteins during hospitalization in relation to disease severity, treatment modalities, and persistent pulmonary pathology after 3 months.<p> <p>Methods - In 165 patients with COVID-19 recruited into the NOR-Solidarity trial (NCT04321616) and randomized to treatment with hydroxychloroquine, remdesivir, or standard of care, we analyzed plasma levels of hemostatic proteins during the first 10 days of hospitalization (n = 160) and at 3 months of follow-up (n = 100) by enzyme immunoassay.<p> <p>Results - Our main findings were as follows: (i) tissue plasminogen activator (tPA) and tissue factor pathway inhibitor (TFPI) were increased in patients with severe disease (ie, the combined endpoint of respiratory failure [Po2-to-FiO2 ratio, <26.6 kPa] or need for treatment at an intensive care unit) during hospitalization. Compared to patients without severe disease, tPA levels were a median of 42% (P < .001), 29% (P = .002), and 36% (P = .015) higher at baseline, 3 to 5 days, and 7 to 10 days, respectively. For TFPI, median levels were 37% (P = .003), 25% (P < .001), and 10% (P = .13) higher in patients with severe disease at these time points, respectively. No changes in thrombin-antithrombin complex; alpha 2-antiplasmin; a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13; or antithrombin were observed in relation to severe disease. (ii) Patients treated with remdesivir had lower levels of TFPI than those in patients treated with standard of care alone. (iii) TFPI levels during hospitalization, but not at 3 months of follow-up, were higher in those with persistent pathology on chest computed tomography imaging 3 months after hospital admission than in those without such pathology. No consistent changes in thrombin-antithrombin complex, alpha 2-antiplasmin, ADAMTS-13, tPA, or antithrombin were observed in relation to pulmonary pathology at 3 months of follow-up.<p> <p>Conclusion - TFPI and tPA are associated with severe disease in hospitalized patients with COVID-19. For TFPI, high levels measured during the first 10 days of hospitalization were also associated with persistent pulmonary pathology even 3 months after hospital admittance.

• Terzić, Vida; Levoyer, Léa; Figarella, Mélanie; Bigagli, Elisabetta; Mercier, Noémie & Gastines, Lucie De [Show all 27 contributors for this article] (2023). Implementation of a centralized pharmacovigilance system in academic pan-European clinical trials: Experience from EU-Response and conect4children consortia. British Journal of Clinical Pharmacology. ISSN 0306-5251. 89(4), p. 1318–1328. doi: 10.1111/bcp.15669. Full text in Research Archive Show summary

  Setting-up a high quality, compliant and efficient pharmacovigilance (PV) system in multi-country clinical trials can be more challenging for academic sponsors than for companies. To ensure the safety of all participants in academic studies and that the PV system fulfils all regulations, we set up a centralized PV system that allows sponsors to delegate work on PV. This initiative was put in practice by our Inserm-ANRS MIE PV department in two distinct multinational European consortia with 19 participating countries: conect4children (c4c) for paediatrics research and EU-Response for Covid-19 platform trials. The centralized PV system consists of some key procedures to harmonize the complex safety processes, creation of a local safety officer (LSO) network and centralization of all safety activities. The key procedures described the safety management plan for each trial and how tasks were shared and delegated between all stakeholders. Processing of serious adverse events (SAEs) in a unique database guaranteed the full control of the safety data and continuous evaluation of the risk–benefit ratio. The LSO network participated in efficient regulatory compliance across multiple countries. In total, there were 1312 SAEs in EU-Response and 83 SAEs in c4c in the four trials. We present here the lessons learnt from our experience in four clinical trials. We managed heterogeneous European local requirements and implemented efficient communication with all trial teams. Our approach builds capacity for PV that can be used by multiple academic sponsors.

• Nendl, Andraz; Raju, Sajan; Broch, Kaspar; Mayerhofer, Christiane Caroline; Holm, Kristian & Halvorsen, Bente [Show all 12 contributors for this article] (2023). Intestinal fatty acid binding protein is associated with cardiac function and gut dysbiosis in chronic heart failure. Frontiers in Cardiovascular Medicine. 10. doi: 10.3389/fcvm.2023.1160030. Full text in Research Archive Show summary

  Background: The gut microbiota in patients with chronic heart failure (HF) is characterized by low bacterial diversity and reduced ability to synthesize beneficial metabolites. These changes may facilitate leakage of whole bacteria or bacterial products from the gut into the bloodstream, which may activate the innate immune system and contribute to the low-grade inflammation seen in HF. In this exploratory cross-sectional study, we aimed to investigate relationships between gut microbiota diversity, markers of gut barrier dysfunction, inflammatory markers, and cardiac function in chronic HF patients.<p> <p>Methods: In total, 151 adult patients with stable HF and left ventricular ejection fraction (LVEF) < 40% were enrolled. We measured lipopolysaccharide (LPS), LPS-binding protein (LBP), intestinal fatty acid binding protein (I-FABP), and soluble cluster of differentiation 14 (sCD14) as markers of gut barrier dysfunction. N-terminal pro-B-type natriuretic peptide (NT-proBNP) level above median was used as a marker of severe HF. LVEF was measured by 2D-echocardiography. Stool samples were sequenced using 16S ribosomal RNA gene amplification. Shannon diversity index was used as a measure of microbiota diversity. <p>Results: Patients with severe HF (NT-proBNP > 895 pg/ml) had increased I-FABP (p < 0.001) and LBP (p = 0.03) levels. ROC analysis for I-FABP yielded an AUC of 0.70 (95% CI 0.61–0.79, p < 0.001) for predicting severe HF. A multivariate logistic regression model showed increasing I-FABP levels across quartiles of NT-proBNP (OR 2.09, 95% CI 1.28−3.41, p = 0.003). I-FABP was negatively correlated with Shannon diversity index (rho = −0.30, p = <0.001), and the bacterial genera Ruminococcus gauvreauii group, Bifidobacterium, Clostridium sensu stricto, and Parasutterella, which were depleted in patients with severe HF. <p>Conclusions: In patients with HF, I-FABP, a marker of enterocyte damage, is associated with HF severity and low microbial diversity as part of an altered gut microbiota composition. I-FABP may reflect dysbiosis and may be a marker of gut involvement in patients with HF.

• Pan, Hongchao; Peto, Richard; Karim, Quarraisha Abdool; Alejandria, Marissa M.; Henao-Restrepo, Ana-Maria & Hernández-García, César [Show all 51 contributors for this article] (2022). Remdesivir and three other drugs for hospitalised patients with COVID-19: final results of the WHO Solidarity randomised trial and updated meta-analyses. The Lancet. ISSN 0140-6736. 399(10339), p. 1941–1953. doi: 10.1016/S0140-6736(22)00519-0. Full text in Research Archive Show summary

  Background The Solidarity trial among COVID-19 inpatients has previously reported interim mortality analyses for four repurposed antiviral drugs. Lopinavir, hydroxychloroquine, and interferon (IFN)-β1a were discontinued for futility but randomisation to remdesivir continued. Here, we report the final results of Solidarity and meta-analyses of mortality in all relevant trials to date. Methods Solidarity enrolled consenting adults (aged ≥18 years) recently hospitalised with, in the view of their doctor, definite COVID-19 and no contraindication to any of the study drugs, regardless of any other patient characteristics. Participants were randomly allocated, in equal proportions between the locally available options, to receive whichever of the four study drugs (lopinavir, hydroxychloroquine, IFN-β1a, or remdesivir) were locally available at that time or no study drug (controls). All patients also received the local standard of care. No placebos were given. The protocol-specified primary endpoint was in-hospital mortality, subdivided by disease severity. Secondary endpoints were progression to ventilation if not already ventilated, and time-to-discharge from hospital. Final log-rank and Kaplan-Meier analyses are presented for remdesivir, and are appended for all four study drugs. Meta-analyses give weighted averages of the mortality findings in this and all other randomised trials of these drugs among hospital inpatients. Solidarity is registered with ISRCTN, ISRCTN83971151, and ClinicalTrials.gov, NCT04315948. Findings Between March 22, 2020, and Jan 29, 2021, 14 304 potentially eligible patients were recruited from 454 hospitals in 35 countries in all six WHO regions. After the exclusion of 83 (0·6%) patients with a refuted COVID-19 diagnosis or encrypted consent not entered into the database, Solidarity enrolled 14 221 patients, including 8275 randomly allocated (1:1) either to remdesivir (ten daily infusions, unless discharged earlier) or to its control (allocated no study drug although remdesivir was locally available). Compliance was high in both groups. Overall, 602 (14·5%) of 4146 patients assigned to remdesivir died versus 643 (15·6%) of 4129 assigned to control (mortality rate ratio [RR] 0·91 [95% CI 0·82–1·02], p=0·12). Of those already ventilated, 151 (42·1%) of 359 assigned to remdesivir died versus 134 (38·6%) of 347 assigned to control (RR 1·13 [0·89–1·42], p=0·32). Of those not ventilated but on oxygen, 14·6% assigned to remdesivir died versus 16·3% assigned to control (RR 0·87 [0·76–0·99], p=0·03). Of 1730 not on oxygen initially, 2·9% assigned to remdesivir died versus 3·8% assigned to control (RR 0·76 [0·46–1·28], p=0·30). Combining all those not ventilated initially, 11·9% assigned to remdesivir died versus 13·5% assigned to control (RR 0·86 [0·76–0·98], p=0·02) and 14·1% versus 15·7% progressed to ventilation (RR 0·88 [0·77–1·00], p=0·04). The non-prespecified composite outcome of death or progression to ventilation occurred in 19·6% assigned to remdesivir versus 22·5% assigned to control (RR 0·84 [0·75–0·93], p=0·001). Allocation to daily remdesivir infusions (vs open-label control) delayed discharge by about 1 day during the 10-day treatment period. A meta-analysis of mortality in all randomised trials of remdesivir versus no remdesivir yielded similar findings. Interpretation Remdesivir has no significant effect on patients with COVID-19 who are already being ventilated. Among other hospitalised patients, it has a small effect against death or progression to ventilation (or both).

• Stø, Kristine; Valeur, Jørgen; Ueland, Thor; Malmstrøm, Gunn Helen; Bjerkeli, Vigdis & Trøseid, Marius [Show all 12 contributors for this article] (2022). Fecal level of butyric acid, a microbiome-derived metabolite, is increased in patients with severe carotid atherosclerosis. Scientific Reports. 12(1), p. 1–9. doi: 10.1038/s41598-022-26759-x. Full text in Research Archive Show summary

  Abstract The short-chain fatty acid (SCFA) butyric acid maintains a healthy gut barrier and vascular endothelium. We aimed to investigate the association between fecal butyric acid, carotid atherosclerosis and risk factors for ischemic stroke. Patients with severe carotid atherosclerosis (i.e. ≥ 50% stenosis) (n = 43) were compared with healthy controls (n = 38). We analyzed fecal SCFAs by gas chromatography, microbiota composition by 16S rRNA sequencing, markers of gut barrier damage and inflammasome activation by immunoassay, and plasma SCFAs by ultra-high performance liquid chromatography-tandem mass spectroscopy. Patients had higher fecal butyric acid level ( p  = 0.024), along with increased functional potential of microbial butyric acid production ( p  = 0.031), compared with controls. Dietary fiber intake was comparable. Patients had higher levels of gut barrier damage markers CCL25 and IFABP, and the inflammasome activation marker IL-18, whereas plasma level of butyric was similar. Increased fecal butyric acid was associated with higher BMI, waist-hip ratio, HbA1c, CRP and leukocyte count. Contrary to our hypothesis, patients with severe carotid atherosclerosis had higher fecal butyric acid level, and increased microbial production, compared with controls. Gut barrier damage in patients might indicate decreased absorption of butyric acid and hence contribute to the higher fecal level.

• Larsen, Christopher Storm; Hande, Liv Nesse; Kummen, Martin; Thunhaug, Hilde; Vestad, Beate & Hansen, Simen Hyll [Show all 10 contributors for this article] (2022). Reduced gut microbial diversity in familial hypercholesterolemia with no effect of omega-3 polyunsaturated fatty acids intervention–a pilot trial. Scandinavian Journal of Clinical and Laboratory Investigation. ISSN 0036-5513. 82(5), p. 363–370. doi: 10.1080/00365513.2022.2102540. Full text in Research Archive Show summary

  Individuals with familial hypercholesterolemia (FH) undergo an aggressive treatment with cholesterollowering drugs to prevent coronary heart disease. Recent evidence suggests an interplay between the gut microbiota, blood lipid levels and lipid-lowering drugs, but this has yet to be studied in individuals with FH. The objective of the study was to characterize the gut microbiota of individuals with familial hypercholesterolemia and examine if effects of omega-3 polyunsaturated fatty acids (PUFAs) on blood lipids act through modification of the gut microbiome. The gut microbiota composition of individuals with FH (N ¼ 21) and healthy controls (N ¼ 144) was analyzed by extracting DNA from stool samples and sequencing of the V3–V4 region of the 16S rRNA gene. A subgroup (n ¼ 15) of the participants received omega-3 polyunsaturated fatty acids (PUFAs) supplementation or placebo in a crossover manner, and the effect of PUFAs on the gut microbiota was also investigated. Individuals with FH had a different gut microbiota composition compared to healthy controls, characterized by reduced richness (p ¼ .001) and reduction of several genera belonging to Clostridia and Coriobacteriia. Patients using ezetimibe in addition to statins appeared to have lower richness compared to those only using statins (p ¼ .01). Intervention with omega-3 PUFAs had negligible impact on the microbiota composition. Positive effects on blood lipids after intervention with omega-3 PUFA were not associated with baseline gut microbiota composition or gut microbial changes during treatment. Further, patients with FH have an altered gut microbiota compared to healthy controls, possibly driven by the use of ezetimibe.

• Suarez-Zdunek, Moises Alberto; Høgh, Julie; Kirkegaard-Klitbo, Ditte Marie; Jensen, Anne Marie R.; Rupert, Adam & Trøseid, Marius [Show all 9 contributors for this article] (2022). High incidence of subclinical peripheral artery disease in people with HIV. AIDS (London). ISSN 0269-9370. 36(10), p. 1355–1362. doi: 10.1097/QAD.0000000000003252. Full text in Research Archive
• Tveita, Anders Aune; Murphy, Sarah Louise Mikalsen; Holter, Jan Cato; Kildal, Anders Benjamin; Michelsen, Annika Elisabet & Lerum, Tøri Vigeland [Show all 28 contributors for this article] (2022). High Circulating Levels of the Homeostatic Chemokines CCL19 and CCL21 Predict Mortality and Disease Severity in COVID-19. Journal of Infectious Diseases. ISSN 0022-1899. 226(12), p. 2150–2160. doi: 10.1093/infdis/jiac313. Full text in Research Archive Show summary

  Background Immune dysregulation is a major factor in the development of severe coronavirus disease 2019 (COVID-19). The homeostatic chemokines CCL19 and CCL21 have been implicated as mediators of tissue inflammation, but data on their regulation in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is limited. We thus investigated the levels of these chemokines in COVID-19 patients. Methods Serial blood samples were obtained from patients hospitalized with COVID-19 (n = 414). Circulating CCL19 and CCL21 levels during hospitalization and 3-month follow-up were analyzed. In vitro assays and analysis of RNAseq data from public repositories were performed to further explore possible regulatory mechanisms. Results A consistent increase in circulating levels of CCL19 and CCL21 was observed, with high levels correlating with disease severity measures, including respiratory failure, need for intensive care, and 60-day all-cause mortality. High levels of CCL21 at admission were associated with persisting impairment of pulmonary function at the 3-month follow-up. Conclusions Our findings highlight CCL19 and CCL21 as markers of immune dysregulation in COVID-19. This may reflect aberrant regulation triggered by tissue inflammation, as observed in other chronic inflammatory and autoimmune conditions. Determination of the source and regulation of these chemokines and their effects on lung tissue is warranted to further clarify their role in COVID-19.

• Trøseid, Marius; Dahl, Tuva Børresdatter; Holter, Jan Cato; Kildal, Anders Benjamin; Murphy, Sarah Louise Mikalsen & Yang, Kuan [Show all 28 contributors for this article] (2022). Persistent T-cell exhaustion in relation to prolonged pulmonary pathology and death after severe COVID-19: Results from two Norwegian cohort studies. Journal of Internal Medicine. ISSN 0954-6820. 292(5), p. 816–828. doi: 10.1111/joim.13549. Full text in Research Archive Show summary

  Background: T-cell activation is associated with an adverse outcome in COVID-19, but whether T-cell activation and exhaustion relate to persistent respiratory dysfunction and death is unknown. Objectives: To investigate whether T-cell activation and exhaustion persist and are associated with prolonged respiratory dysfunction and death after hospitalization for COVID-19. Methods: Plasma and serum from two Norwegian cohorts of hospitalized patients with COVID-19 (n = 414) were analyzed for soluble (s) markers of T-cell activation (sCD25) and exhaustion (sTim-3) during hospitalization and follow-up. Results: Both markers were strongly associated with acute respiratory failure, but only sTim-3 was independently associated with 60-day mortality. Levels of sTim-3 remained elevated 3 and 12 months after hospitalization and were associated with pulmonary radiological pathology after 3 months. Conclusion: Our findings suggest prolonged T-cell exhaustion is an important immunological sequela, potentially related to long-term outcomes after severe COVID-19.

• Knudsen, Andreas D.; Bouazzi, Randa; Afzal, Shoaib; Gelpi, Marco; Benfield, Thomas & Høgh, Julie [Show all 10 contributors for this article] (2022). Monocyte count and soluble markers of monocyte activation in people living with HIV and uninfected controls. BMC Infectious Diseases. 22(1). doi: 10.1186/s12879-022-07450-y. Full text in Research Archive
• Aune, Susanne Kristine; Bonnevie-Svendsen, Martin; Nyborg, Christoffer; Trøseid, Marius; Seljeflot, Ingebjørg & Hisdal, Jonny [Show all 7 contributors for this article] (2022). Gut Leakage and Cardiac Biomarkers after Prolonged Strenuous Exercise. Medicine & Science in Sports & Exercise. ISSN 0195-9131. 54(9), p. 1476–1482. doi: 10.1249/MSS.0000000000002948. Full text in Research Archive
• Vestad, Beate; Ueland, Thor; Lerum, Tøri Vigeland; Dahl, Tuva Børresdatter; Holm, Kristian & Barratt-Due, Andreas [Show all 37 contributors for this article] (2022). Respiratory dysfunction three months after severe COVID-19 is associated with gut microbiota alterations. Journal of Internal Medicine. ISSN 0954-6820. 291(6), p. 801–812. doi: 10.1111/joim.13458. Full text in Research Archive Show summary

  Background: Although coronavirus disease 2019 (COVID-19) is primarily a respiratory infection, mounting evidence suggests that the gastrointestinal (GI) tract is involved in the disease, with gut barrier dysfunction and gut microbiota alterations being related to disease severity. Whether these alterations persist and are related to long-term respiratory dysfunction remains unknown. Methods: Plasma was collected during hospital admission and after three months from the NOR-Solidarity trial (n = 181) and analysed for markers of gut barrier dysfunction and inflammation. At the three-month follow-up, pulmonary function was assessed by measuring the diffusing capacity of the lungs for carbon monoxide (DLCO ). Rectal swabs for gut microbiota analyses were collected (n = 97) and analysed by sequencing the 16S rRNA gene. Results: Gut microbiota diversity was reduced in COVID-19 patients with respiratory dysfunction, defined as DLCO below the lower limit of normal three months after hospitalisation. These patients also had an altered global gut microbiota composition, with reduced relative abundance of 20 bacterial taxa and increased abundance of five taxa, including Veillonella, potentially linked to fibrosis. During hospitalisation, increased plasma levels of lipopolysaccharide-binding protein (LBP) were strongly associated with respiratory failure, defined as pO2 /fiO2 -(P/F ratio)

• Gelpi, M; Vestad, Beate; Raju, Sajan; Hansen, Simen Hyll; Høgh, J & Midttun, Øivind [Show all 13 contributors for this article] (2022). Association of the Kynurenine Pathway of Tryptophan Metabolism with Human Immunodeficiency Virus-Related Gut Microbiota Alterations and Visceral Adipose Tissue Accumulation. Journal of Infectious Diseases. ISSN 0022-1899. 225(11), p. 1948–1954. doi: 10.1093/infdis/jiac018. Full text in Research Archive
• Meyer-Myklestad, Malin Holm; Medhus, Asle Wilhelm; Stiksrud, Birgitte; Lorvik, Kristina Berg; Seljeflot, Ingebjørg & Hansen, Simen Hyll [Show all 13 contributors for this article] (2022). Probiotics to HIV-infected immunological nonresponders: Altered mucosal immunity and microbial diversity restricted to ileum. Journal of Acquired Immune Deficiency Syndromes. ISSN 1525-4135. 89(1), p. 77–86. doi: 10.1097/QAI.0000000000002817. Full text in Research Archive
• Dhillon, Amandeep Kaur; Rupp, Christian; Bergquist, Annika; Voitl, Robert; Folseraas, Trine & Trøseid, Marius [Show all 12 contributors for this article] (2021). Associations of neopterin and kynurenine–tryptophan ratio with survival in primary sclerosing cholangitis. Scandinavian Journal of Gastroenterology. ISSN 0036-5521. 56(4), p. 443–452. doi: 10.1080/00365521.2021.1880627. Full text in Research Archive Show summary

  Background and aims Biomarkers of inflammation may be of clinical utility in primary sclerosing cholangitis (PSC). We aimed to investigate the interferon gamma-related biomarkers neopterin and kynurenine–tryptophanratio (KT-ratio) in PSC. Methods Circulating neopterin, tryptophan and kynurenine were measured with LC-MS/MS in multiple cross-sectional cohorts comprising in total of 524 PSC patients and 100 healthy controls from Norway, Germany and Sweden. Results Neopterin and KT-ratio were significantly increased in PSC patients compared with controls in both a discovery and a validation cohort from Norway. Furthermore, high neopterin and KT-ratio levels were associated with a shorter transplantation-free survival in the PSC patients in the Norwegian discovery cohort and the German validation cohort. However, in the validation PSC cohort from Sweden, no relationship between neopterin and KT-ratio and liver transplantation-free survival was observed. The correlations between neopterin and KT-ratio were moderate to strong and similar in all cohorts (rho 0.50–0.67). Neopterin and KT-ratio also correlated with C-reactive protein (rho 0.17-0.63) and revised Mayo risk score (rho 0.23–0.42) in all cohorts. Conclusions Neopterin and KT-ratio were elevated in PSC and associated with liver transplantation-free survival in two independent PSC cohorts, highlighting a possible role of interferon gamma-driven inflammation in the pathogenesis. However, the lack of association with survival in one of the cohorts reduces the potential clinical value of neopterin and KT-ratioas biomarkers and highlights the need to validate new biomarkers in PSC in multiple cohorts.

• Lerum, Tøri Vigeland; Maltzahn, Niklas; Aukrust, Pål; Trøseid, Marius; Nezvalova-Henriksen, Katerina & Kåsine, Trine [Show all 27 contributors for this article] (2021). Persistent pulmonary pathology after COVID-19 is associated with high viral load, weak antibody response, and high levels of matrix metalloproteinase-9. Scientific Reports. 11, p. 1–12. doi: 10.1038/s41598-021-02547-x. Full text in Research Archive Show summary

  The association between pulmonary sequelae and markers of disease severity, as well as pro-fibrotic mediators, were studied in 108 patients 3 months after hospital admission for COVID-19. The COPD assessment test (CAT-score), spirometry, diffusion capacity of the lungs (DLCO), and chest-CT were performed at 23 Norwegian hospitals included in the NOR-SOLIDARITY trial, an open-labelled, randomised clinical trial, investigating the efficacy of remdesivir and hydroxychloroquine (HCQ). Thirty-eight percent had a CAT-score ≥ 10. DLCO was below the lower limit of normal in 29.6%. Ground-glass opacities were present in 39.8% on chest-CT, parenchymal bands were found in 41.7%. At admission, low pO2/FiO2 ratio, ICU treatment, high viral load, and low antibody levels, were predictors of a poorer pulmonary outcome after 3 months. High levels of matrix metalloproteinase (MMP)-9 during hospitalisation and at 3 months were associated with persistent CT-findings. Except for a negative effect of remdesivir on CAT-score, we found no effect of remdesivir or HCQ on long-term pulmonary outcomes. Three months after hospital admission for COVID-19, a high prevalence of respiratory symptoms, reduced DLCO, and persistent CT-findings was observed. Low pO2/FiO2 ratio, ICU-admission, high viral load, low antibody levels, and high levels of MMP-9 were associated with a worse pulmonary outcome.

• Kåsine, Trine; Riise, Anne Margarita Dyrhol; Barratt-Due, Andreas; Kildal, Anders Benjamin; Olsen, Inge Christoffer & Nezvalova-Henriksen, Katerina [Show all 39 contributors for this article] (2021). Neutrophil count predicts outcome in hospitalized COVID-19 patients. Results from the NOR-Solidarity trial. Journal of Internal Medicine. ISSN 0954-6820. 291(2), p. 241–243. doi: 10.1111/joim.13377. Full text in Research Archive Show summary

  Despite numerous studies on SARS-CoV-2-induced inflammation, we still lack markers for rapid disease progression with admission to intensive care unit (ICU) or respiratory failure(RF). Few studies have evaluated the prognostic value of routine diagnostic repertoire available at most hospitals. The NOR-Solidarity trial is an independent add-on study to the WHO Solidarity trial, evaluating hydroxychloroquine (HCQ)and remdesivir compared to standard of care in hospitalized COVID-19 patients [1]. We explored whether standard biomarkers in peripheral blood could give information on ICU admission and RFin hospitalized COVID-19 patients.

• Ianevski, Aleksandr; Yao, Rouan; Zusinaite, Eva; Lello, Laura Sandra; Wang, Sainan & Jo, Eunji [Show all 28 contributors for this article] (2021). Synergistic interferon-alpha-based combinations for treatment of sars-cov-2 and other viral infections. Viruses. 13:2489(12), p. 1–18. doi: 10.3390/v13122489. Full text in Research Archive Show summary

  Background: There is an urgent need for new antivirals with powerful therapeutic potential and tolerable side effects. Methods: Here, we tested the antiviral properties of interferons (IFNs), alone and with other drugs in vitro. Results: While IFNs alone were insufficient to completely abolish replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), IFNα, in combination with remdesivir, EIDD-2801, camostat, cycloheximide, or convalescent serum, proved to be more effective. Transcriptome and metabolomic analyses revealed that the IFNα–remdesivir combination suppressed SARS-CoV-2-mediated changes in Calu-3 cells and lung organoids, although it altered the homeostasis of uninfected cells and organoids. We also demonstrated that IFNα combinations with sofosbuvir, telaprevir, NITD008, ribavirin, pimodivir, or lamivudine were effective against HCV, HEV, FLuAV, or HIV at lower concentrations, compared to monotherapies. Conclusions: Altogether, our results indicated that IFNα can be combined with drugs that affect viral RNA transcription, protein synthesis, and processing to make synergistic combinations that can be attractive targets for further pre-clinical and clinical development against emerging and re-emerging viral infections.

• Thudium, Rebekka F.; Knudsen, Andreas; Stemann, Jakob Hjorth Von; Hove-Skovsgaard, Malene; Hoel, Hedda Benedicte & Mocroft, Amanda [Show all 14 contributors for this article] (2021). Independent Association of Interleukin 6 With Low Dynamic Lung Function and Airflow Limitation in Well-Treated People With Human Immunodeficiency Virus. Journal of Infectious Diseases. ISSN 0022-1899. 223(10), p. 1690–1698. doi: 10.1093/infdis/jiaa600. Full text in Research Archive
• Aune, Susanne Kristine; Byrkjeland, Rune; Solheim, Svein; Arnesen, Harald; Trøseid, Marius & Awoyemi, Ayodeji Olawale [Show all 8 contributors for this article] (2021). Gut related inflammation and cardiorespiratory fitness in patients with CAD and type 2 diabetes: a sub-study of a randomized controlled trial on exercise training. Diabetology & Metabolic Syndrome. 13(1), p. 1–9. doi: 10.1186/s13098-021-00655-2. Full text in Research Archive Show summary

  Aim Gut leakage has been shown to associate with low-grade inflammation and lower cardiorespiratory fitness in diabetic subjects. We aimed to investigate whether gut leakage markers related to cardiorespiratory fitness in patients with both coronary artery disease and type 2 diabetes, and whether these were affected by long-term exercise training. Methods Patients with angiographically verified coronary artery disease and type 2 diabetes mellitus (n = 137) were randomized to either 12 months exercise intervention or conventional follow-up. A cardiopulmonary exercise test and fasting blood samples were obtained before and after intervention to assess VO2peak and the biomarkers soluble CD14, lipopolysaccharide-binding protein and intestinal fatty-acid binding protein as markers of gut leakage. Results 114 patients completed the intervention satisfactory. VO2peak correlated inversely to sCD14 (r = − 0.248, p = 0.004) at baseline. Dividing sCD14 into quartiles (Q), VO2peak was significantly higher in Q1 vs. Q2–4 (p = 0.001), and patients in Q2-4 (sCD14 > 1300 ng/mL) had an OR of 2.9 (95% CI 1.2–7.0) of having VO2peak below median (< 23.8 ml/kg/min) at baseline. There were no statistically significant differences in changes in gut leakage markers between the two randomized groups (all p > 0.05) after 12 months. Conclusions Cardiorespiratory fitness related inversely to sCD14, suggesting physical capacity to be associated with gut leakage in patients with CAD and T2DM. Long-term exercise training did not affect circulating gut leakage markers in our population. Trial registration NCT01232608, Registered 02 November 2010—Retrospectively registered at https://clinicaltrials.gov/ct2/show/NCT01232608?term=NCT01232608&draw=2&rank=1

• Aune, Susanne Kristine; Cwikiel, Joanna; Flaa, Arnljot; Arnesen, Harald; Solheim, Svein & Awoyemi, Ayodeji Olawale [Show all 9 contributors for this article] (2021). Gut leakage markers in response to strenuous exercise in patients with suspected coronary artery disease. Cells. 10(9). doi: 10.3390/cells10092193. Full text in Research Archive Show summary

  Elevated levels of gut leakage markers have been shown after strenuous exercise in healthy individuals. Any association between a temporary increase in these markers and the presence of coronary artery disease (CAD) is unknown. We therefore aimed to explore circulating gut leakage markers in response to a bout of strenuous exercise in patients with symptoms of CAD. Patients referred to exercise stress testing due to symptoms of CAD were included (n = 287). A maximal exercise ECG stress test was performed and venous blood samples were drawn at rest and within five minutes after, for analysis of soluble cluster of differentiation 14 (sCD14), lipopolysaccharide-binding protein (LBP), intestinal fatty-acid binding protein (I-FABP), lipopolysaccharide (LPS) and gene expression of toll-like receptor 4 (TLR4) in circulating leukocytes. Patients then underwent coronary angiography. LPS, LBP and sCD14 increased significantly after strenuous exercise in patients with symptoms of CAD, suggesting that even short bouts of vigorous exercise are associated with gut leakage. The gene expression of TLR4 decreased significantly after exercise, possibly as a negative feedback to the increase in LPS. There were no differences in exercise-induced changes between the groups of CAD, suggesting gut leakage to be independent of the presence of CAD.

• Awoyemi, Ayodeji Olawale; Mayerhofer, Christiane Caroline; Felix, Alex S.; Hov, Johannes Espolin Roksund; Moscavitch, Samuel D. & Lappegård, Knut Tore [Show all 23 contributors for this article] (2021). Rifaximin or Saccharomyces boulardii in heart failure with reduced ejection fraction: Results from the randomized GutHeart trial. EBioMedicine. 70. doi: 10.1016/j.ebiom.2021.103511. Full text in Research Archive Show summary

  Background The gut microbiota represents a potential treatment target in heart failure (HF) through microbial metabolites such as trimethylamine N-oxide (TMAO) and systemic inflammation. Treatment with the probiotic yeast Saccharomyces boulardii have been suggested to improve left ventricular ejection fraction (LVEF). Methods In a multicentre, prospective randomized open label, blinded end-point trial, we randomized patients with LVEF <40% and New York Heart Association functional class II or III, despite optimal medical therapy, to treatment (1:1:1) with the probiotic yeast Saccharomyces boulardii, the antibiotic rifaximin, or standard of care (SoC) only. The primary endpoint, the baseline-adjusted LVEF at three months, was assessed in an intention-to-treat analysis. Findings We enrolled a total of 151 patients. After three months’ treatment, the LVEF did not differ significantly between the SoC arm and the rifaximin arm (mean difference was -1•2 percentage points; 95% CI -3•2 - 0•7; p=0•22) or between the SoC arm and the Saccharomyces boulardii arm (mean difference -0•2 percentage points; 95% CI -2•2 - 1•9; p=0•87). We observed no significant between-group differences in changes in microbiota diversity, TMAO, or C-reactive protein. Interpretation Three months’ treatment with Saccharomyces boulardii or rifaximin on top of SoC had no significant effect on LVEF, microbiota diversity, or the measured biomarkers in our population with HF.

• Drivsholm, Ninna; Knudsen, Andreas; Faurholt-Jepsen, Maria; Midttun, Øivind; Trøseid, Marius & Kirkegaard-Klitbo, Ditte M. [Show all 9 contributors for this article] (2021). Alterations in the Kynurenine Pathway of Tryptophan Metabolism Are Associated With Depression in People Living With HIV. Journal of Acquired Immune Deficiency Syndromes. ISSN 1525-4135. 87(2), p. e177–e181. doi: 10.1097/QAI.0000000000002664. Full text in Research Archive
• Thudium, Rebekka F.; Ringheim, Hedda; Ronit, Andreas; Hoel, Hedda; Benfield, Thomas & Mocroft, Amanda [Show all 12 contributors for this article] (2021). Independent Associations of Tumor Necrosis Factor-Alpha and Interleukin-1 Beta With Radiographic Emphysema in People Living With HIV. Frontiers in Immunology. 12. doi: 10.3389/fimmu.2021.668113. Full text in Research Archive
• Vestad, Beate; Nyman, Tuula A.; Hove-Skovsgaard, Malene; Stensland, Maria; Hoel, Hedda Benedicte & Siebke, Anne-Marie [Show all 13 contributors for this article] (2021). Plasma extracellular vesicles in people living with HIV and type 2 diabetes are related to microbial translocation and cardiovascular risk. Scientific Reports. 11(1). doi: 10.1038/s41598-021-01334-y. Full text in Research Archive Show summary

  Abstract HIV and type 2 diabetes (T2D) are both associated with gut microbiota alterations, low-grade endotoxemia and increased cardiovascular risk. We investigated the potential role of plasma extracellular vesicles (EVs) in relation to these processes. Plasma EVs were isolated by size exclusion chromatography in fasting individuals with HIV and T2D (n = 16), T2D only (n = 14), HIV only (n = 20) or healthy controls (n = 19), and characterized by transmission electron microscopy, western blot, nanoparticle tracking analysis and quantitative proteomics. The findings were compared to gut microbiota alterations, lipopolysaccharide levels and cardiovascular risk profile. Individuals with concomitant HIV and T2D had higher plasma EV concentration, which correlated closely with plasma lipopolysaccharides, triglycerides and Framingham score, but not with gut microbiota alterations. Proteomic analyses identified 558 human proteins, largely related to cardiometabolic disease genes and upstream regulation of inflammatory pathways, including IL-6 and IL-1β, as well as 30 bacterial proteins, mostly from lipopolysaccharide-producing Proteobacteria. Our study supports that EVs are related to microbial translocation processes in individuals with HIV and T2D. Their proteomic content suggests a contributing role in low-grade inflammation and cardiovascular risk development. The present approach for exploring gut-host crosstalk can potentially identify novel diagnostic biomarkers and therapeutic targets.

• Diallo, Alpha; Trøseid, Marius; Simensen, Victoria C; Boston, Anaïs; Demotes, Jacques & Olsen, Inge Christoffer [Show all 28 contributors for this article] (2021). Accelerating clinical trial implementation in the context of the COVID-19 pandemic: challenges, lessons learned and recommendations from DisCoVeRy and the EU-SolidAct EU response group. Clinical Microbiology and Infection (CMI). ISSN 1198-743X. 28(1), p. 1–6. doi: 10.1016/j.cmi.2021.10.011. Full text in Research Archive
• Barratt-Due, Andreas; Olsen, Inge Christoffer; Nezvalova-Henriksen, Katerina; Kåsine, Trine; Lund-Johansen, Fridtjof & Hoel, Hedda Benedicte [Show all 43 contributors for this article] (2021). Evaluation of the Effects of Remdesivir and Hydroxychloroquine on Viral Clearance in COVID-19 : A Randomized Trial. Annals of Internal Medicine. ISSN 0003-4819. 174(9), p. 1261–1269. doi: 10.7326/M21-0653. Full text in Research Archive Show summary

  Background: New treatment modalities are urgently needed for patients with COVID-19. The World Health Organization (WHO) Solidarity trial showed no effect of remdesivir or hydroxychloroquine (HCQ) on mortality, but the antiviral effects of these drugs are not known. Objective: To evaluate the effects of remdesivir and HCQ on all-cause, in-hospital mortality; the degree of respiratory failure and inflammation; and viral clearance in the oropharynx. Design: NOR-Solidarity is an independent, add-on, randomized controlled trial to the WHO Solidarity trial that included biobanking and 3 months of clinical follow-up (ClinicalTrials.gov: NCT04321616). Setting: 23 hospitals in Norway. Patients: Eligible patients were adults hospitalized with confirmed SARS-CoV-2 infection. Intervention: Between 28 March and 4 October 2020, a total of 185 patients were randomly assigned and 181 were included in the full analysis set. Patients received remdesivir (n = 42), HCQ (n = 52), or standard of care (SoC) (n = 87). Measurements: In addition to the primary end point of WHO Solidarity, study-specific outcomes were viral clearance in oropharyngeal specimens, the degree of respiratory failure, and inflammatory variables. Results: No significant differences were seen between treatment groups in mortality during hospitalization. There was a marked decrease in SARS-CoV-2 load in the oropharynx during the first week overall, with similar decreases and 10-day viral loads among the remdesivir, HCQ, and SoC groups. Remdesivir and HCQ did not affect the degree of respiratory failure or inflammatory variables in plasma or serum. The lack of antiviral effect was not associated with symptom duration, level of viral load, degree of inflammation, or presence of antibodies against SARS-CoV-2 at hospital admittance. Limitation: The trial had no placebo group. Conclusion: Neither remdesivir nor HCQ affected viral clearance in hospitalized patients with COVID-19.

• Hustad, Nina Berger; Degerud, Hanna M; Hjelmerud, Ingrid; Fraz, Mai Sasaki Aanensen; Nordøy, Ingvild & Trøseid, Marius [Show all 9 contributors for this article] (2021). Real-World Experiences With Facilitated Subcutaneous Immunoglobulin Substitution in Patients With Hypogammaglobulinemia, Using a Three-Step Ramp-Up Schedule. Frontiers in Immunology. 12, p. 1–7. doi: 10.3389/fimmu.2021.670547. Full text in Research Archive Show summary

  Immunoglobulin replacement therapy with facilitated subcutaneous immunoglobulin (fSCIg) can be self-administrated at home and given at longer intervals compared to subcutaneous immunoglobulin (SCIg) therapy, but real-word experience of home-based fSCIg therapy is limited. Herein we present our real-word clinical experiences with home-based fSCIg therapy using a three-step ramp-up schedule. We registered data from all patients with immunodeficiency starting fSCIg from 01.01.2017 to 31.12.2019. For comparison we also included patients starting conventional SCIg training. Fifty-four patients followed for a median of 18 months (IQR 12, range 0–40), received fSCIg training, and 84 patients received conventional SCIg training. Out of 54 patients starting with fSCIg, 41 patients had previous experience with conventional SCIg therapy, and the main reason for starting fSCIg was ‘longer intervals between therapies’ (n=48). We found an increase in training requirement for fSCIg (3 ± 1 [2-9] days) compared to conventional SCIg (2 ± 0 [1-7] days), P &amp;lt; 0.001 (median ± IQR, [range]). For fSCIg training, IgG levels were stable from baseline (8.9 ± 2.3 g/L), 3-6 months (10.2 ± 2.2 g/L) and 9-12 months (9.9 ± 2.3 g/L), P = 0.11 (mean ± SD). The most common side-effect was: ‘rubor around injection site’ (n=48, 89%). No patients experienced severe adverse events (grade 3-4). Thirteen patients (24%) discontinued fSCIg therapy due to local adverse events (n=9), cognitive/psychological difficulties (n=6) and/or systemic adverse events (n=3). In conclusion, fSCIg training using a three-step ramp-up schedule is safe and well tolerated by the majority of patients, but requires longer training time compared to conventional SCIg.

• Skaarud, Kristin Aneta Joan; Hov, Johannes Espolin Roksund; Hansen, Simen Hyll; Kummen, Martin; Valeur, Jørgen & Seljeflot, Ingebjørg [Show all 12 contributors for this article] (2021). Mortality and microbial diversity after allogenic hematopoietic stem cell transplantation: secondary analysis of a randomized nutritional intervention trial. Scientific Reports. 11. doi: 10.1038/s41598-021-90976-z. Full text in Research Archive Show summary

  Gut mucosal barrier injury is common following allogeneic hematopoietic stem cell transplantation (allo-HSCT) and associated with poor clinical outcomes. Diet is critical for microbial diversity, but whether nutritional support affects microbiota and outcome after allo-HSCT is unknown. We present a secondary analysis of a randomized controlled nutritional intervention trial during allo-HSCT. We investigated if the intervention influenced gut microbiota, short-chain fatty acids (SCFAs), and markers of gut barrier functions, and if these parameters were associated with clinical outcomes. Fecal specimens were available from 47 recipients, and subjected to 16S rRNA gene sequencing. We found no significant differences between the intervention group and controls in investigated parameters. We observed a major depletion of microbiota, SCFAs, and altered markers of gut barrier function from baseline to 3 weeks post-transplant. One-year mortality was significantly higher in patients with lower diversity at 3 weeks post-HSCT, but not related to diversity at baseline. The relative abundance of Blautia genus at 3 weeks was higher in survivors. Fecal propionic acid was associated with survival. Markers of gut barrier functions were less strongly associated with clinical outcomes. Possibly, other strategies than dietary intervention are needed to prevent negative effects of gut microbiota and clinical outcomes after allo-HSCT.

• Hoel, Hedda Benedicte; Ueland, Thor; Knudsen, Andreas; Kjær, Andreas; Michelsen, Annika & Sagen, Ellen Lund [Show all 12 contributors for this article] (2020). Soluble Markers of Interleukin 1 Activation as Predictors of First-Time Myocardial Infarction in HIV-Infected Individuals. Journal of Infectious Diseases. ISSN 0022-1899. 221(4), p. 506–509. doi: 10.1093/infdis/jiz253. Full text in Research Archive
• Gelpi, Marco; Ueland, Per Magne; Trøseid, Marius; Mocroft, Amanda; Lebech, Anne-Mette & Ullum, Henrik [Show all 9 contributors for this article] (2020). Abdominal Adipose Tissue Is Associated With Alterations in Tryptophan-Kynurenine Metabolism and Markers of Systemic Inflammation in People With Human Immunodeficiency Virus. Journal of Infectious Diseases. ISSN 0022-1899. 221(3), p. 419–427. doi: 10.1093/infdis/jiz465. Full text in Research Archive
• Hoel, Hedda Benedicte; Ueland, Thor; Hove-Skovsgaard, Malene; Hartling, Hans Jakob; Gelpi, Marco & Benfield, Thomas [Show all 11 contributors for this article] (2020). Soluble T-Cell Immunoglobulin Mucin Domain-3 Is Associated With Hepatitis C Virus Coinfection and Low-Grade Inflammation During Chronic Human Immunodeficiency Virus Infection. Open Forum Infectious Diseases. 29(7). doi: 10.1093/ofid/ofaa033. Full text in Research Archive Show summary

  Abstract Background In well treated human immunodeficiency virus infection (HIV), there is a residual immune activation and immune exhaustion that may contribute to increased risk of comorbidities. T-cell immunoglobulin mucin domain-3 (Tim-3) is an inhibitory molecule involved in HIV-associated T-cell dysfunction. The Tim-3 can be cleaved to soluble Tim-3 (sTim-3) that may serve as a soluble marker of immune exhaustion. Methods We measured sTim-3 with enzyme-linked immunosorbent assay DuoSets in a cross-sectional cohort of 1010 people with HIV (PWH) on antiretroviral therapy (ART), and 76 controls from the Copenhagen Co-Morbidity in HIV Infection (COCOMO) study, and in a longitudinal cohort of 60 PWH before and during ART. Results In the cross-sectional cohort, levels of sTim-3 were elevated in PWH on ART compared with controls, especially in hepatitis C virus (HCV)-coinfected individuals, and were associated with HCV viremia and inflammation. In the longitudinal cohort, pretreatment sTim-3 correlated with HIV viral load and decreased after ART initiation. Pretreatment sTim-3 correlated inversely with CD4 counts, but it did not predict immunological response in multivariable analyses. Conclusions Levels of sTim-3 decreased after ART initiation. In a cross-sectional cohort, levels of sTIM-3 were higher in PWH than in controls and were independently associated with HCV coinfection and high-sensitivity C-reactive protein, representing a potential link between immune exhaustion, inflammation, and risk of comorbidities.

• Gelpi, Marco; Vestad, Beate; Hansen, Simen Hyll; Holm, Kristian; Drivsholm, Ninna & Götz, Alexandra [Show all 17 contributors for this article] (2020). Impact of human immunodeficiency virus-related gut microbiota alterations on metabolic comorbid conditions. Clinical Infectious Diseases. ISSN 1058-4838. 71(8), p. e359–e367. doi: 10.1093/cid/ciz1235. Full text in Research Archive Show summary

  Abstract Background We aimed to identify a human immunodeficiency virus (HIV)–related microbiota signature, independent of sexual preferences and demographic confounders, in order to assess a possible impact of the microbiome on metabolic comorbid conditions. Methods Bacterial 16S ribosomal RNA analyses were performed on stool samples from 405 HIV-infected and 111 uninfected participants of the Copenhagen Comorbidity in HIV Infection (COCOMO) study. Individuals were stratified according to sexual behavior (men who have sex with men [MSM] vs non-MSM). Results After excluding MSM-associated microbiota traits and adjusting for confounders, we identified an HIV-related microbiota signature, consisting of lower biodiversity, increased relative abundance of the bacterial clades Gammaproteobacteria and Desulfovibrionaceae and decrease in several Clostridia. This microbiota profile was associated with a 2-fold excess risk of metabolic syndrome, driven by increase in Desulfovibrionaceae and decrease in Clostridia (Butyrivibrio, Coprococcus 2, Lachnospiraceae UCG-001 and CAG-56). This association was accentuated (5-fold excess risk) in individuals with previous severe immunodeficiency, which also modified the association between HIV-related microbiota signature and visceral adipose tissue (VAT) area (P for interaction = .01). Accordingly, HIV-related microbiota was associated with 30-cm2 larger VAT in individuals with history of severe immunodeficiency, but not in those without. Conclusion The HIV-related microbiota was associated with increased risk of metabolic syndrome and VAT accumulation, particularly in individuals with previous severe immunodeficiency, driven by increased Desulfovibrionaceae and lower abundance of several Clostridia. Our findings suggest a potential interplay between HIV-related microbiota, immune dysfunction and metabolic comorbid conditions. Interventions targeting the gut microbiome may be warranted to reduce cardiovascular risk, particularly in individuals with previous immunodeficiency.

• Nordøy, Ingvild; Fraz, Mai Sasaki Aanensen; Trøseid, Marius; Fevang, Børre & Aukrust, Pål (2020). Høyt serum-ferritin ikke kun uttrykk for leversvikt. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 140(8). doi: 10.4045/tidsskr.20.0376. Full text in Research Archive
• Hoel, Hedda Benedicte; Heggelund, Lars; Reikvam, Dag Henrik; Stiksrud, Birgitte; Ueland, Thor & Michelsen, Annika [Show all 15 contributors for this article] (2020). Elevated markers of gut leakage and inflammasome activation in COVID-19 patients with cardiac involvement. Journal of Internal Medicine. ISSN 0954-6820. 289(4). doi: 10.1111/joim.13178. Full text in Research Archive Show summary

  Background A high proportion of COVID‐19 patients have cardiac involvement, even those without known cardiac disease. Downregulation of angiotensin converting enzyme 2 (ACE2), a receptor for SARS‐CoV‐2 and the renin‐angiotensin system, as well as inflammatory mechanisms have been suggested to play a role. ACE2 is abundant in the gut and associated with gut microbiota composition. We hypothesized that gut leakage of microbial products, and subsequent inflammasome activation could contribute to cardiac involvement in COVID‐19 patients. Methods Plasma levels of a gut leakage marker (LPS‐binding protein, LBP), a marker of enterocyte damage (intestinal fatty acid binding protein, IFABP), a gut homing marker (CCL25, ligand for chemokine receptor CCR9) and markers of inflammasome activation (IL‐1β, IL‐18 and their regulatory proteins) were measured at three time points (day 1, 3–5 and 7–10) in 39 hospitalized COVID‐19 patients and related to cardiac involvement. Results Compared to controls, COVID‐19 patients had elevated plasma levels of LBP and CCL25 but not IFABP, suggesting impaired gut barrier function and accentuated gut homing of T cells without excessive enterocyte damage. Levels of LBP were twice as high at baseline in patients with elevated cardiac markers compared with those without and remained elevated during hospitalization. Also, markers of inflammasome activation were moderately elevated in patients with cardiac involvement. LBP was associated with higher NT‐pro‐BNP levels, whereas IL‐18, IL‐18BP and IL‐1Ra were associated with higher troponin levels. Conclusion Patients with cardiac involvement had elevated markers of gut leakage and inflammasome activation, suggestive of a potential gut‐heart axis in COVID‐19.

• Meyer-Myklestad, Malin Holm; Medhus, Asle Wilhelm; Lorvik, Kristina Berg; Seljeflot, Ingebjørg; Hansen, Simen Hyll & Holm, Kristian [Show all 13 contributors for this article] (2020). HIV-infected immunological non-responders have colon-restricted gut mucosal immune dysfunction. Journal of Infectious Diseases. ISSN 0022-1899. doi: 10.1093/infdis/jiaa714. Full text in Research Archive Show summary

  Abstract Background Human immunodeficiency virus (HIV)–infected immunological nonresponders (INRs) fail to reconstitute their CD4+ T-cell pool after initiation of antiretroviral therapy, and their prognosis is inferior to that of immunological responders (IRs). A prevailing hypothesis is that the INR phenotype is caused by a persistently disrupted mucosal barrier, but assessments of gut mucosal immunology in different anatomical compartments are scarce. Methods We investigated circulating markers of mucosal dysfunction, immune activation, mucosal Th17 and Th22 cells, and mucosa-adherent microbiota signatures in gut mucosal specimens from sigmoid colon and terminal ileum of 19 INRs and 20 IRs in addition to 20 HIV-negative individuals. Results INRs had higher blood levels of the enterocyte damage marker intestinal fatty acid–binding protein than IRs. In gut mucosal biopsies, INRs had lower fractions of CD4+ T cells, higher fractions of interleukin 22, and a tendency to higher fractions of interleukin 17–producing CD4+ T cells. These findings were all restricted to the colon and correlated to circulating markers of enterocyte damage. There were no observed differences in gut microbial composition between INRs and IRs. Conclusions Restricted to the colon, enterocyte damage and mucosal immune dysfunction play a role for insufficient immune reconstitution in HIV infection independent of the gut microbiota.

• Kummen, Martin; Thingholm, Louise B.; Rühlemann, Malte C.; Holm, Kristian; Hansen, Simen Hyll & Moitinho-Silva, Lucas [Show all 22 contributors for this article] (2020). Altered Gut Microbial Metabolism of Essential Nutrients in Primary Sclerosing Cholangitis. Gastroenterology. ISSN 0016-5085. 160(5). doi: 10.1053/j.gastro.2020.12.058. Full text in Research Archive Show summary

  Background & Aims To influence host and disease phenotype, compositional microbiome changes, which have been demonstrated in patients with primary sclerosing cholangitis (PSC), must be accompanied by functional changes. We therefore aimed to characterize the genetic potential of the gut microbiome in patients with PSC compared with healthy controls (HCs) and patients with inflammatory bowel disease (IBD). Methods Fecal DNA from 2 cohorts (1 Norwegian and 1 German), in total comprising 136 patients with PSC (58% with IBD), 158 HCs, and 93 patients with IBD without PSC, were subjected to metagenomic shotgun sequencing, generating 17 billion paired-end sequences, which were processed using HUMAnN2 and MetaPhlAn2, and analyzed using generalized linear models and random effects meta-analyses. Results Patients with PSC had fewer microbial genes compared with HCs (P < .0001). Compared with HCs, patients with PSC showed enrichment and increased prevalence of Clostridium species and a depletion of, for example, Eubacterium spp and Ruminococcus obeum. Patients with PSC showed marked differences in the abundance of genes related to vitamin B6 synthesis and branched-chain amino acid synthesis (Qfdr < .05). Targeted metabolomics of plasma from an independent set of patients with PSC and controls found reduced concentrations of vitamin B6 and branched-chain amino acids in PSC (P < .0001), which strongly associated with reduced liver transplantation–free survival (log-rank P < .001). No taxonomic or functional differences were detected between patients with PSC with and without IBD. Conclusions The gut microbiome in patients with PSC exhibits large functional differences compared with that in HCs, including microbial metabolism of essential nutrients. Alterations in related circulating metabolites associated with disease course, suggesting that microbial functions may be relevant for the disease process in PSC.

• Hove-Skovsgaard, Malene; Abildgaard, Julie; Gelpi, Marco; Gaardbo, Julie C.; Kolte, Lilian & Ullum, Henrik [Show all 9 contributors for this article] (2020). No evidence of a synergistic effect of HIV infection and diabetes mellitus type 2 on fat distribution, plasma adiponectin or inflammatory markers. BMC Infectious Diseases. 20(1). doi: 10.1186/s12879-020-05594-3. Full text in Research Archive Show summary

  Background Altered fat distribution and chronic inflammation are found in both persons living with HIV (PLWH) and persons with diabetes mellitus type 2 (DM2) and are known risk factors for cardiovascular diseases (CVD). We aimed to investigate if a synergistic effect of HIV infection and DM2 was found on fat distribution and inflammation. Methods A cross-sectional study was performed including PLWH with HIV RNA < 200 copies/mL (18 with DM2 (HIV + DM2+), 18 without DM2 (HIV + DM2-)) and controls (19 with DM2 (controls with DM2) and 25 without DM2 (healthy controls). We measured fat distribution using dual-energy X-ray absorptiometry scan. Plasma concentrations of adiponectin, interleukin-6 (IL-6), tumor necrosis factor-alfa (TNF- α) and soluble CD14 (sCD14) was measured using snap-frozen plasma. Results HIV + DM2+ and HIV + DM2- had comparable trunk/limb fat ratio. In contrast, HIV + DM2+ had a higher trunk/ limb fat ratio than controls with DM2 and healthy controls (p = 0.013 and p < 0.001, respectively). However, HIV + DM2+ and controls with DM2 had comparable amount of trunk fat mass (kg) (p = 0.254). A lower concentration of plasma adiponectin and higher concentration of IL-6 was found in HIV + DM2+ than in HIV + DM2-(p = 0.037 and p = 0.039) and in healthy controls (p = 0.001 and p = 0.012). In contrast, plasma adiponectin and IL-6 concentrations were comparable in HIV + DM2+ and controls with DM2 (p = 0.345 and p = 0.825). Concentration of sCD14 was comparable in HIV + DM2+ and HIV + DM2–(p = 0.850), but elevated in HIV + DM2+ compared to controls with DM2 (p < 0.001) and healthy controls (p = 0.007). No statistical interactions were found between HIV infection and DM2 for any of the depending variables. Conclusion A synergistic effect of HIV and DM2 was not found for any of the outcomes. However, HIV + DM2+ had features related to both HIV infection and DM2 with a high trunk/limb ratio, high trunk fat mass, low concentration of plasma adiponectin and elevated concentrations of IL-6 and sCD14. This could contribute to elevated risk of CVD.

• Reikvam, Dag Henrik; Meyer-Myklestad, Malin Holm; Trøseid, Marius & Stiksrud, Birgitte (2020). Probiotics to manage inflammation in HIV infection. Current Opinion in Infectious Diseases. ISSN 0951-7375. 33(1), p. 34–43. doi: 10.1097/QCO.0000000000000612. Full text in Research Archive
• Fretheim, Håvard Halland; Chung, Brian K.; Didriksen, Henriette; Bækkevold, Espen Sønderaal; Midtvedt, Øyvind & Brunborg, Cathrine [Show all 18 contributors for this article] (2020). Fecal Microbiota Transplantation in Systemic Sclerosis: A Double-Blind, Placebo-Controlled Randomized Pilot Trial. PLOS ONE. 15:e0232739(5), p. 1–14. doi: 10.1371/journal.pone.0232739. Full text in Research Archive Show summary

  Objectives Systemic sclerosis (SSc) is an auto-immune, multi organ disease marked by severe gastrointestinal (GI) involvement and gut dysbiosis. Here, we aimed to determine the safety and efficacy of fecal microbiota transplantation (FMT) using commercially-available anaerobic cultivated human intestinal microbiota (ACHIM) in SSc. Methods Ten patients with SSc were randomized to ACHIM (n = 5) or placebo (n = 5) in a double-blind, placebo-controlled 16-week pilot. All patients had mild to severe upper and lower GI symptoms including diarrhea, distention/bloating and/or fecal incontinence at baseline. Gastroduodenoscopy transfer of ACHIM or placebo was performed at weeks 0 and 2. Primary endpoints were safety and clinical efficacy on GI symptoms assessed at weeks 4 and 16. Secondary endpoints included changes in relative abundance of total, immunoglobulin (Ig) A- and IgM-coated fecal bacteria measured by 16s rRNA sequencing. Results ACHIM side effects were mild and transient. Two placebo controls experienced procedure-related serious adverse events; one developed laryngospasms at week 0 gastroduodenoscopy necessitating study exclusion whilst one encountered duodenal perforation during gastroduodenoscopy at the last study visit (week 16). Decreased bloating, diarrhea and/or fecal incontinence was observed in four of five patients in the FMT group (week 4 or/and 16) and in two of four in the placebo group (week 4 or 16). Relative abundance, richness and diversity of total and IgA-coated and IgM-coated bacteria fluctuated more after FMT, than after placebo. Conclusions FMT of commercially-available ACHIM is associated with gastroduodenoscopy complications but reduces lower GI symptoms by possibly altering the gut microbiota in patients with SSc.

• Kummen, Martin; Solberg, Ole Geir; Larsen, Christopher Storm; Holm, Kristian; Ragnarsson, Asgrimur & Trøseid, Marius [Show all 18 contributors for this article] (2020). Rosuvastatin alters the genetic composition of the human gut microbiome. Scientific Reports. 10:5397, p. 1–9. doi: 10.1038/s41598-020-62261-y. Full text in Research Archive Show summary

  The gut microbiome contributes to the variation of blood lipid levels, and secondary bile acids are associated with the effect of statins. Yet, our knowledge of how statins, one of our most common drug groups, affect the human microbiome is scarce. We aimed to characterize the effect of rosuvastatin on gut microbiome composition and inferred genetic content in stool samples from a randomized controlled trial (n = 66). No taxa were significantly altered by rosuvastatin during the study. However, rosuvastatin-treated participants showed a reduction in the collective genetic potential to transport and metabolize precursors of the pro-atherogenic metabolite trimethylamine-N-oxide (TMAO, p < 0.01), and an increase of related metabolites betaine and γ-butyrobetaine in plasma (p < 0.01). Exploratory analyses in the rosuvastatin group showed that participants with the least favorable treatment response (defined as < median change in high-density/low-density lipoprotein (HDL/LDL) ratio) showed a marked increase in TMAO-levels compared to those with a more favorable response (p < 0.05). Our data suggest that while rosuvastatin has a limited effect on gut microbiome composition, it could exert broader collective effects on the microbiome relevant to their function, providing a rationale for further studies of the influence of statins on the gut microbiome.

• Macpherson, Magnhild Eide; Hov, Johannes Espolin Roksund; Ueland, Thor; Dahl, Tuva Børresdatter; Kummen, Martin & Otterdal, Kari [Show all 14 contributors for this article] (2020). Gut microbiota-dependent trimethylamine N-oxide associates with inflammation in common variable immunodeficiency. Frontiers in Immunology. 11. doi: 10.3389/fimmu.2020.574500. Full text in Research Archive Show summary

  A substantial proportion of patients with common variable immunodeficiency (CVID) have inflammatory and autoimmune complications of unknown etiology. We have previously shown that systemic inflammation in CVID correlates with their gut microbial dysbiosis. The gut microbiota dependent metabolite trimethylamine N-oxide (TMAO) has been linked to several metabolic and inflammatory disorders, but has hitherto not been investigated in relation to CVID. We hypothesized that TMAO is involved in systemic inflammation in CVID. To explore this, we measured plasma concentrations of TMAO, inflammatory markers, and lipopolysaccharide (LPS) in 104 CVID patients and 30 controls. Gut microbiota profiles and the bacterial genes CutC and CntA, which encode enzymes that can convert dietary metabolites to trimethylamine in the colon, were examined in fecal samples from 40 CVID patients and 86 controls. Furthermore, a food frequency questionnaire and the effect of oral antibiotic rifaximin on plasma TMAO concentrations were explored in these 40 patients. We found CVID patients to have higher plasma concentrations of TMAO than controls (TMAO 5.0 [2.9–8.6] vs. 3.2 [2.2–6.3], p = 0.022, median with IQR). The TMAO concentration correlated positively with tumor necrosis factor (p = 0.008, rho = 0.26), interleukin-12 (p = 0.012, rho = 0.25) and LPS (p = 0.034, rho = 0.21). Dietary intake of meat (p = 0.678), fish (p = 0.715), egg (p = 0.138), dairy products (p = 0.284), and fiber (p = 0.767) did not significantly impact on the TMAO concentrations in plasma, nor did a 2-week course of the oral antibiotic rifaximin (p = 0.975). However, plasma TMAO concentrations correlated positively with gut microbial abundance of Gammaproteobacteria (p = 0.021, rho = 0.36). Bacterial Macpherson et al. Microbiota, TMAO, Inflammation in CVID gene CntA was present in significantly more CVID samples (75%) than controls (53%), p = 0.020, potentially related to the increased abundance of Gammaproteobacteria in these samples. The current study demonstrates that elevated TMAO concentrations are associated with systemic inflammation and increased gut microbial abundance of Gammaproteobacteria in CVID patients, suggesting that TMAO could be a link between gut microbial dysbiosis and systemic inflammation. Gut microbiota composition could thus be a potential therapeutic target to reduce systemic inflammation in CVID.

• Mayerhofer, Christiane Caroline; Kummen, Martin; Holm, Kristian; Broch, Kaspar; Awoyemi, Ayodeji Olawale & Vestad, Beate [Show all 17 contributors for this article] (2020). Low fibre intake is associated with gut microbiota alterations in chronic heart failure. ESC Heart Failure. 7(2), p. 456–466. doi: 10.1002/ehf2.12596. Full text in Research Archive Show summary

  Aims Recent reports have suggested that patients with heart failure (HF) have an altered gut microbiota composition; however, associations with diet remain largely uninvestigated. We aimed to explore differences in the gut microbiota between patients with HF with reduced ejection fraction and healthy controls, focusing on associations with diet and disease severity. Methods and results The microbiota composition of two cross-sectional cohorts (discovery, n = 40 and validation, n = 44) of patients with systolic HF and healthy controls (n = 266) was characterized by sequencing of the bacterial 16S rRNA gene. The overall microbial community (beta diversity) differed between patients with HF and healthy controls in both cohorts (P < 0.05). Patients with HF had shifts in the major bacterial phyla, resulting in a lower Firmicutes/Bacteroidetes (F/B) ratio than controls (P = 0.005). Patients reaching a clinical endpoint (listing for heart transplant or death) had lower bacterial richness and lower F/B ratio than controls (P < 0.01). Circulating levels of trimethylamine-N-oxide were associated with meat intake (P = 0.016), but not with gut microbiota alterations in HF. Low bacterial richness and low abundance of several genera in the Firmicutes phylum were associated with low fibre intake. Conclusions The gut microbiota in HF was characterized by decreased F/B ratio and reduced bacterial diversity associated with clinical outcome. The gut microbiota alterations in HF were partly related to low fibre intake, emphasizing the importance of diet as a covariate in future studies. Our data could provide a rationale for targeting the gut microbiota in HF with high-fibre diet.

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• König, Marton; Holmøy, Trygve; Nygaard, Gro Owren; Riise, Jon; Midtvedt, Karsten & Goll, Guro Løvik [Show all 11 contributors for this article] (2026). Vaccination of immunosuppressed patients. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. doi: 10.4045/tidsskr.25.0555. Full text in Research Archive
• Dahl, Tuva Børresdatter; Aftab, Friha; Prebensen, Christian Haugland; Berdal, Jan-Erik; Ueland, Thor & Barratt-Due, Andreas [Show all 15 contributors for this article] (2025). Imidazole propionate is increased in severe COVID-19 and correlates with cardiac involvement. Journal of Infection. ISSN 0163-4453. 90(6). doi: 10.1016/j.jinf.2025.106494. Full text in Research Archive
• Jørgensen, Silje Fjellgård; Macpherson, Magnhild Eide; Bjørnetrø, Tonje; Holm, Kristian; Kummen, Martin & Rashidi, Azita [Show all 18 contributors for this article] (2024). Retraction to: Rifaximin alters gut microbiota profile, but does not affect systemic inflammation - a randomized controlled trial in common variable immunodeficiency (Scientific Reports, (2019), 9, 1, (167), 10.1038/s41598-018-35367-7). Scientific Reports. 14(1). doi: 10.1038/s41598-024-54117-6. Full text in Research Archive
• Trøseid, Marius (2024). Viral, Host Factors or Both as COVID-19 Biomarkers. Clinical Infectious Diseases. ISSN 1058-4838. 78(6), p. 1504–1505. doi: 10.1093/cid/ciad779. Full text in Research Archive
• Hites, Maya; Lapique, Eva Larranaga; Massonnaud, Clément R.; Belhadi, Drifa; Jamard, Simon & Goehringer, François [Show all 86 contributors for this article] (2024). Tixagevimab-cilgavimab (AZD7442) for the treatment of patients hospitalized with COVID-19 (DisCoVeRy): A phase 3, randomized, double-blind, placebo-controlled trial. Journal of Infection. ISSN 0163-4453. 88(3). doi: 10.1016/j.jinf.2024.106120. Full text in Research Archive
• Serrano-Villar, Sergio; Tincati, Camilla; Raju, Sajan; Sáenz, Johan S.; Moreno, Elena & Bargiela, Rafael [Show all 19 contributors for this article] (2023). Author Correction: Microbiome-derived cobalamin and succinyl-CoA as biomarkers for improved screening of anal cancer (Nature Medicine, (2023), 29, 7, (1738-1749), 10.1038/s41591-023-02407-3). Nature Medicine. ISSN 1078-8956. doi: 10.1038/s41591-023-02529-8. Full text in Research Archive
• Juul, Frederik Emil; Hov, Johannes Espolin Roksund; Trøseid, Marius; Johnsen, Peter Holger & Valeur, Jørgen (2023). Tarmflora og tarmsykdom - en edruelig formaning. 143(10), p. 849–850. doi: 10.4045/tidsskr.23.0121. Full text in Research Archive
• Ueland, Thor; Äikäs, Lauri A.O.; Dahl, Tuva Børresdatter; Gregersen, Ida; Olsen, Maria Belland & Michelsen, Annika Elisabet [Show all 20 contributors for this article] (2023). Low-density lipoprotein particles carrying proinflammatory proteins with altered aggregation pattern detected in COVID-19 patients 3 months after hospitalization. Journal of Infection. ISSN 0163-4453. 86(5), p. 489–492. doi: 10.1016/j.jinf.2023.02.024. Full text in Research Archive
• Moreno, Elena; Trøseid, Marius; Vujkovic-Cvijin, Ivan; Marchetti, Giulia; Martín-Pedraza, Laura & Serrano-Villar, Sergio (2023). Editorial: Targeting the microbiota to attenuate chronic inflammation. Frontiers in Immunology. 14. doi: 10.3389/fimmu.2023.1202222. Full text in Research Archive
• Gregersen, Ida; Ueland, Thor; Holter, Jan Cato; Olsen, Maria Belland; Michelsen, Annika Elisabet & Murphy, Sarah L [Show all 22 contributors for this article] (2022). CXCL16 associates with adverse outcome and cardiac involvement in hospitalized patients with Covid-19. Journal of Infection. ISSN 0163-4453. 85(6), p. 735–738. doi: 10.1016/j.jinf.2022.09.029. Full text in Research Archive
• Awoyemi, Ayodeji Olawale; Hov, Johannes Espolin Roksund & Trøseid, Marius (2022). Phenylacetylglutamine From the Gut Microbiota: A Future Therapeutic Target in Heart Failure? Circulation: Heart Failure. ISSN 1941-3289. doi: 10.1161/CIRCHEARTFAILURE.122.010222. Full text in Research Archive
• Murphy, Sarah Louise Mikalsen; Halvorsen, Bente; Barratt-Due, Andreas; Dyrhol-Riise, Anne Ma; Aukrust, Pål & Trøseid, Marius [Show all 7 contributors for this article] (2022). Remdesivir modifies interferon response in hospitalized COVID-19 patients. Journal of Infection. ISSN 0163-4453. 85(5), p. 573–607. doi: 10.1016/j.jinf.2022.07.021. Full text in Research Archive
• Hentzien, Maxime; Owen, Andrew; Strub-Wourgaft, Nathalie; Pérez-Casas, Carmen; Trøseid, Marius & Calmy, Alexandra (2022). Rethinking treatment paradigms for the deployment of SARS-CoV-2 antiviral drugs on the shifting landscape of new variants. Frontiers in Microbiology. 13. doi: 10.3389/fmicb.2022.998287. Full text in Research Archive
• Trøseid, Marius; Diallo, Alpha; Hites, Maya; Røttingen, John-Arne & Yazdanpanah, Yazdan (2022). Accelerating clinical trial implementation in the context of the COVID-19 pandemic: author's response. Clinical Microbiology and Infection (CMI). ISSN 1198-743X. 28(5), p. 743–744. doi: 10.1016/j.cmi.2021.12.014. Full text in Research Archive
• Stø, Kristine; Valeur, Jørgen; Ueland, Thor; Malmstrøm, Gunn Helen; Bjerkeli, Vigdis & Kazmi, Syed Sajid Hussain [Show all 10 contributors for this article] (2021). Increased fecal levels of the SCFA butyrate may indicate poor absorption due to disrupted gut barrier in patients with carotid stenosis. Full text in Research Archive
• Tangen, Jorun; Aukrust, Pål; Barrat-Due, A; Trøseid, Marius; Olsen, Inge Christoffer & Nezvalova-Henriksen, Katerina [Show all 15 contributors for this article] (2021). Cardiac function is normal in most patients recovered from COVID-19. Full text in Research Archive
• Trøseid, Marius; Hites, Maya; Barratt-Due, Andreas; Ader, Florence & Yazdanpanah, Yazdan (2021). Assessing the evidence on remdesivir. The Lancet Infectious Diseases. ISSN 1473-3099. 21(12), p. 1630–1631. doi: 10.1016/S1473-3099(21)00695-2. Full text in Research Archive
• Trøseid, Marius (2020). Når covid-19 møter afrikansk helsevesen. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 104(7), p. 1–2. doi: 10.4045/tidsskr.20.0283. Full text in Research Archive
• Trøseid, Marius; Lutro, Olav & Ormaasen, Vidar (2020). Utprovende behandling for covid-19 bor forega i randomiserte studier. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 140(7), p. 1–3. doi: 10.4045/TIDSSKR.20.0282. Full text in Research Archive

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