Gut Microbiome Mediates Age- and Sex-Divergent Effects of Environmental Exposures on Human Health

The gut microbiome acts as a critical interface between environmental exposures and human health, yet the influence of intrinsic host factors on this interaction remains poorly understood. We hypothesized that the microbiome’s role as a mediator of environmental risks is fundamentally stratified by host age and sex. Integrating 16S rRNA gene sequencing from 13,991 American Gut Project participants with extensive geospatial environmental datasets, we performed stratified regression and formal mediation analyses on 86 environmental/personal factors and 24 self-reported health outcomes. We identified distinct, age- and sex- dependent microbial trajectories; alpha diversity increased with age, while the abundance of potential risk bacteria exhibited a U-shaped distribution, peaking in children and the elderly (p < 0.001). Females had a higher abundance of Bacteroides and potential risk bacteria, whereas males were enriched in butyrate-producing bacteria (p < 0.001). The influence of environmental factors was highly stratified; for example, the impact of diet and exercise on alpha diversity was strongest in children, while travel’s impact was greatest in the elderly (q < 0.05). Mediation analysis identified potential stratified risk pathways. The microbiome-mediated risk of thyroid dysfunction from POPs was significant only in older adults (p < 0.05). Furthermore, the risk pathway for ASD linked to Endosulfan exposure was sex-dependent: a direct toxicological effect was significant in males, whereas the primary pathway in females was microbiota-mediated. These stratified pathways provide potential mechanistic insights into well-known demographic disparities in human diseases. Our findings provide a data-driven rationale for moving beyond “one-size-fits-all” models toward age- and sex-informed strategies for disease prevention and public health.