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, npositive=431, nnegative=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.