Associations of alcohol with the human gut microbiome and prospective health outcomes in the FINRISK 2002 cohort

Background and aims: Alcohol remains a global risk factor for non-communicable diseases with the gut microbiome emerging as a novel elucidator. We investigated how gut microbiome associates with alcohol on population level, if there is mediation reflected in health outcomes, and how functional potential is related. Methods: Our sample consisted of 4575 shallow-shotgun sequenced fecal samples from the FINRISK 2002 cohort (25-74yrs., 52.5% women). Alcohol (g 100% alcohol/week) use was self-reported. Diversity and differential species abundances were analyzed using multiple linear regression. Compositional differences were analyzed using PERMANOVA, and prospective associations with Cox-regression. Connections between alcohol, microbiome, inflammatory markers, and outcomes were assessed using serial mediation. Functional associations were assessed using KEGG-orthologies and multiple linear regression. Results: High-risk alcohol consumers had significantly lower bacterial diversity when compared to low-risk consumers (mean±SD:4.04±0.41 vs. 4.11±0.43, p = 9.56 × 10 ^{− 4}). Alcohol also associated with significant shifts in overall composition (PERMANOVA; p ≤ 1.00 × 10 ^{− 4}) and differential abundances of 344 species (ANCOM-BC2; q ≤ 0.05). These shifts were characterized by an increase in relative abundances of Gram-negative bacteria, the top genera of which were Bacteroides and Prevotella, and a decrease in putatively beneficial species in genera such as Lactobacillus, Bifidobacterium, and Akkermansia. Prospective associations with all-cause mortality (HR:1.12 [1.02—1.23]), and liver disease (HR:1.53 [1.22—1.92]) were observed. The association between alcohol and liver disease had a mediating link via a proinflammatory beta-diversity principal coordinate (OR:1.04 [1.001—1.10]). Functional associations were observed with 1643 KO-groups (q < 0.05, n _positive=431, n _negative=1212). Antioxidative and gut integrity maintaining functions were diminished and lipopolysaccharide synthesis enriched. Conclusions: Alcohol use is associated with community-level shifts in composition towards enriched Gram-negative bacteria, and diminished levels of putatively beneficial bacteria. Alcohol use associates with a proinflammatory gut microbiome profile that mediates alcohol’s effect on incident liver disease risk, possibly via increased proliferation of endotoxins through the gut epithelial lining.