Purpose of review: This review summarizes recent progress in our understanding of the role of the gut microbiota in sepsis pathogenesis and outlines the potential role of microbiota-targeted therapies. Recent findings: The composition of the gut microbiome is profoundly distorted during sepsis, with a loss of commensal bacteria and an overgrowth of potential pathogenic micro-organisms. These alterations also extend to nonbacterial intestinal inhabitants. Disruptions of these intestinal communities are associated with both an increased susceptibility to develop sepsis, as well as a higher risk of adverse outcomes. Preclinical studies have characterized the effects of several microbiota-derived metabolites (such as D-lactate, butyrate, and deoxycholic acid) on enhancing the host immune response during critical illness. Microbiota-targeted therapies (e.g. probiotics or fecal microbiota transplantation) might be of benefit, but can also be associated with increased risks of bloodstream infections. Summary: Emerging evidence display an important role of gut micro-organisms (including bacteria, fungi, eukaryotic viruses, and bacteriophages) and their derived metabolites in both the susceptibility to, as well as outcomes of sepsis. Despite recent progress in the mechanistic understanding of microbiota-mediated protection, clinical breakthroughs in the development of microbiota-based prognostic tools or therapies are thus far lacking in the field of sepsis.

Rationale: Bacterial lung microbiota are correlated with lung inflammation and acute respiratory distress syndrome (ARDS) and altered in severe coronavirus disease (COVID-19). However, the association between lung microbiota (including fungi) and resolution of ARDS in COVID-19 remains unclear. We hypothesized that increased lung bacterial and fungal burdens are related to nonresolving ARDS and mortality in COVID-19. Objectives: To determine the relation between lung microbiota and clinical outcomes of COVID-19–related ARDS. Methods: This observational cohort study enrolled mechanically ventilated patients with COVID-19. All patients had ARDS and underwent bronchoscopy with BAL. Lung microbiota were profiled using 16S rRNA gene sequencing and quantitative PCR targeting the 16S and 18S rRNA genes. Key features of lung microbiota (bacterial and fungal burden, α-diversity, and community composition) served as predictors. Our primary outcome was successful extubation adjudicated 60 days after intubation, analyzed using a competing risk regression model with mortality as competing risk. Measurements and Main Results: BAL samples of 114 unique patients with COVID-19 were analyzed. Patients with increased lung bacterial and fungal burden were less likely to be extubated (subdistribution hazard ratio, 0.64 [95% confidence interval, 0.42–0.97]; P = 0.034 and 0.59 [95% confidence interval, 0.42–0.83]; P = 0.0027 per log₁₀ increase in bacterial and fungal burden, respectively) and had higher mortality (bacterial burden, P = 0.012; fungal burden, P = 0.0498). Lung microbiota composition was associated with successful extubation (P = 0.0045). Proinflammatory cytokines (e.g., tumor necrosis factor-α) were associated with the microbial burdens. Conclusions: Bacterial and fungal lung microbiota are related to nonresolving ARDS in COVID-19 and represent an important contributor to heterogeneity in COVID-19–related ARDS.

Microbiota alterations are common in patients hospitalised for severe infections, and preclinical models have shown that anaerobic butyrate-producing gut bacteria protect against systemic infections. However, the relationship between microbiota disruptions and increased susceptibility to severe infections in humans remains unclear. We investigated the relationship between gut microbiota and the risk of future infection-related hospitalisation in two large population-based cohorts. In this observational microbiome study, gut microbiota were characterised using 16S rRNA gene sequencing in independent population-based cohorts from the Netherlands (HELIUS study; derivation cohort) and Finland (FINRISK 2002 study; validation cohort). HELIUS was conducted in Amsterdam, Netherlands, and included adults (aged 18-70 years at inclusion) who were randomly sampled from the municipality register of Amsterdam. FINRISK 2002 was conducted in six regions in Finland and is a population survey that included a random sample of adults (aged 25-74 years). In both cohorts, participants completed questionnaires, underwent a physical examination, and provided a faecal sample at inclusion (Jan 3, 2013, to Nov 27, 2015, for HELIUS participants and Jan 21 to April 19, 2002, for FINRISK participants. For inclusion in our study, a faecal sample needed to be provided and successfully sequenced, and national registry data needed to be available. Primary predictor variables were microbiota composition, diversity, and relative abundance of butyrate-producing bacteria. Our primary outcome was hospitalisation or mortality due to any infectious disease during 5-7-year follow-up after faecal sample collection, based on national registry data. We examined associations between microbiota and infection risk using microbial ecology and Cox proportional hazards. We profiled gut microbiota from 10 699 participants (4248 [39·7%] from the derivation cohort and 6451 [60·3%] from the validation cohort). 602 (5·6%) participants (152 [3·6%] from the derivation cohort; 450 [7·0%] from the validation cohort) were hospitalised or died due to infections during follow-up. Gut microbiota composition of these participants differed from those without hospitalisation for infections (derivation p=0·041; validation p=0·0002). Specifically, higher relative abundance of butyrate-producing bacteria was associated with a reduced risk of hospitalisation for infections (derivation cohort cause-specific hazard ratio 0·75 [95% CI 0·60-0·94] per 10% increase in butyrate producers, p=0·013; validation cohort 0·86 [0·77-0·96] per 10% increase, p=0·0077). These associations remained unchanged following adjustment for demographics, lifestyle, antibiotic exposure, and comorbidities. Gut microbiota composition, specifically colonisation with butyrate-producing bacteria, was associated with protection against hospitalisation for infectious diseases in the general population across two independent European cohorts. Further studies should investigate whether modulation of the microbiome can reduce the risk of severe infections. Amsterdam UMC, Porticus, National Institutes of Health, Netherlands Organisation for Health Research and Development (ZonMw), and Leducq Foundation.

Gut microbiota influence the severity of pneumonia by producing metabolites that enhance systemic and pulmonary immune responses. Preclinical studies suggested that gut microbiota-derived indoles have protective effects against numerous diseases, including influenza and abdominal infections. However, the precise role of tryptophan metabolites during pneumonia is unknown. Here, we perform translational analyses in a large general-population cohort (n = 13,464), critically ill patients with severe community-acquired pneumonia (CAP; n = 158; NCT01905033), a randomized human intervention trial on antibiotic-mediated microbiota modulation (NCT03051698), and mice to investigate the effects of tryptophan metabolites, specifically indole-3-acetic acid (IAA), on pneumonia. In the population-based cohort, baseline IAA is associated with a higher risk of future hospital admission for pneumonia (cause-specific hazard ratio 1.15, 95% confidence interval 1.09-1.22 p < 0.0001). In patients with severe CAP higher levels of IAA are associated with increased mortality, independent from potential confounders (hazard ratio 1.30 per log2 increase, 95% confidence interval 1.02-1.68, p = 0.037). In a mouse model of bacterial pneumonia, IAA supplementation aggravates pulmonary damage while reducing systemic dissemination, which is mediated by the aryl hydrocarbon receptor (AhR) and increased release of reactive oxygen species from neutrophils. In summary, these findings from general population and severe pneumonia cohorts, and murine pneumonia experiments, show that the gut microbiota-derived tryptophan metabolite IAA affects pneumonia, suggesting that various indoles may have diverging, context-dependent effects.

Introduction Patients with COVID-19-related acute respiratory distress syndrome (ARDS) show limited systemic hyperinflammation, but immunomodulatory treatments are effective. Little is known about the inflammatory response in the lungs and if this could be targeted using high-dose steroids (HDS). We aimed to characterise the alveolar immune response in patients with COVID-19-related ARDS, to determine its association with mortality, and to explore the association between HDS treatment and the alveolar immune response. Methods In this observational cohort study, a comprehensive panel of 63 biomarkers was measured in repeated bronchoalveolar lavage (BAL) fluid and plasma samples of patients with COVID-19 ARDS. Differences in alveolar–plasma concentrations were determined to characterise the alveolar inflammatory response. Joint modelling was performed to assess the longitudinal changes in alveolar biomarker concentrations, and the association between changes in alveolar biomarker concentrations and mortality. Changes in alveolar biomarker concentrations were compared between HDS-treated and matched untreated patients. Results 284 BAL fluid and paired plasma samples of 154 patients with COVID-19 were analysed. 13 biomarkers indicative of innate immune activation showed alveolar rather than systemic inflammation. A longitudinal increase in the alveolar concentration of several innate immune markers, including CC motif ligand (CCL)20 and CXC motif ligand (CXCL)1, was associated with increased mortality. Treatment with HDS was associated with a subsequent decrease in alveolar CCL20 and CXCL1 levels. Conclusions Patients with COVID-19-related ARDS showed an alveolar inflammatory state related to the innate host response, which was associated with a higher mortality. HDS treatment was associated with decreasing alveolar concentrations of CCL20 and CXCL1.