Abstract

Abstract Background The gut microbiome modulates the effects of diet on host health, but it remains unclear which specific foods and microbial features interact to influence risk of depression. To understand this interplay, we leveraged decades of dietary and depression data from a longitudinal cohort of women ( n = 32,427), along with fecal metagenomics and plasma metabolomics from a substudy ( n = 207) nested in this cohort, as well as an independent validation cohort of men ( n = 307). Results We report that citrus intake and its components are prospectively associated with a lower risk of depression and altered abundance of 15 gut microbial species, including enriched Faecalibacterium prausnitzii . In turn, we found a lower abundance of F. prausnitzii and its metabolic pathway, S-adenosyl-L-methionine (SAM) cycle I in participants with depression. To explore causality, we found that lower SAM production by F. prausnitzii may decrease intestinal monoamine oxidase A gene expression implicated in serotonin and dopamine synthesis. Conclusions These data underscore the role of diet in the prevention of depression and offer a plausible explanation for how the intestinal microbiome modulates the influence of citrus on mental health.