A global-scale framework for quantifying the gut microbiome's mediating role in environmental and personal...

The human gut microbiome mediates health risks from the exposome, but research focuses on diet and lifestyle, leaving the impact of environmental characteristics unclear. Furthermore, the microbiota's quantitative, mediating role in linking the full exposome to disease is poorly understood. We conducted a global-scale association and mediation analysis of 13,463 American Gut Project participants, linking 128 environmental/personal factors to 10 gut microbial indices. We identified 390 significant but moderate associations (R² < 0.03, FDR < 0.05) between exposome factors and the microbiota, revealing it is influenced by numerous small, cumulative effects. Our analysis confirmed expected patterns, such as reduced gut diversity with antibiotic use and exposure to pollutants like PM_2.5 and SO₂. However, it also revealed counterintuitive findings, notably that several hazardous exposures, including alcohol, airborne persistent organic pollutants (POPs), and mycotoxin deoxynivalenol, were associated with increased alpha diversity (FDR < 0.05). Our mediation analysis linking these factors to 24 self-reported health outcomes identified 1129 significant pathways (p < 0.05), confirming established links such as antibiotic-associated risk for irritable bowel syndrome (IBS) and the protective effects of vegetable consumption on allergies. Our analysis also revealed striking paradoxes: exposure to POPs increased inflammatory bowel disease (IBD) risk, partly via an increase in gut alpha diversity (1.5%-15.7% mediated effect), directly challenging the "higher diversity is better" paradigm. Our global-scale analysis provides the first comprehensive map of the gut microbiome's mediating role in the human exposome, establishing a methodological blueprint for assessing the microbial contribution to the global burden of environmental disease.