Higher abundance of <i>Faecalibacterium prausnitzii</i> in the gut microbiome is associated with a lower risk of sepsis development among 6,372 individuals followed for 20 years

ABSTRACT The human gut microbiome has been suggested to be linked with the risk of developing sepsis, a life-threatening medical emergency. However, it remains unclear whether the gut microbiome is an independent predictor of long-term sepsis risk in the general adult population. Here, we investigated for the first time the prospective association between the gut microbiome and incident sepsis in the general population. The study sample (FINRISK) consisted of 6,372 individuals who underwent fecal sampling in 2002 and were followed for incident sepsis. We used multivariable-adjusted models to study the associations of microbial alpha-diversity, beta-diversity, taxa, butyrate producers, and predicted pathways with incident sepsis. Two hundred and forty participants developed sepsis over a follow-up of 19.8 years. A 1-SD increase in Faecalibacterium prausnitzii_C_71351 abundance was associated with 21% (95% CI, 10%–30%; FDR = 0.03) lower risk of sepsis. Higher abundances of six other species were associated with higher sepsis risk (FDR &lt; 0.05 for all). Five of these species were positively associated with C-reactive protein. The species-sepsis associations were consistent across various subgroups. Moreover, in an independent validation cohort of 4,248 individuals, we found a similar association between Faecalibacterium and a lower risk of future sepsis. Additionally, overall pathways related to carbohydrate degradation, energy production, and sulfur metabolism were positively linked to incident sepsis. We did not detect any associations of alpha-diversity, beta-diversity, or butyrate producers with incident sepsis. Future studies should investigate the causality of these associations and the mechanisms by which the identified species may influence sepsis development. IMPORTANCE Previous cross-sectional and case-control studies have linked changes in the gut microbiome with the occurrence of sepsis. However, the relationship between the gut microbiome and the risk of incident sepsis in the general adult population remains unexplored. Here, we found clear evidence on the association of gut microbiome species with incident sepsis in a large population cohort. In particular, we provided an in-depth analysis of the negative link between F. prausnitzii and sepsis risk, which was robust across independent cohorts. This finding supports a potential protective role of F. prausnitzii , but further experimental investigation is required. We also show that six species, including Clostridium symbiosum —a causative agent of bacteremia/sepsis in few cases—are positively linked to incident sepsis. Most of these species were also positively linked to an inflammatory marker. Our research provides the groundwork for future experimental analysis of the detected associations to understand their role in infection.