Distinct Roles of Gut Microbial Genera and Circulating Propionate in Multi-Modal Stress Responses

The gut microbiota and their metabolites, particularly short-chain fatty acids (SCFAs), have been implicated in mood disorders; however, their joint contributions to psychobiological stress responses remain poorly understood. In this preregistered cross-sectional analysis of pooled data from 216 healthy men, we investigated associations between butyrate- and propionate-producing genera, circulating and fecal SCFA concentrations, and physiological and self-reported stress responses. Analyses were based on data from quantitative microbiome profiling, serum and fecal SCFA quantification, salivary cortisol awakening response (CAR), and acute stress responses to the Maastricht Acute Stress Test (MAST). Linear mixed models were used to assess associations between microbial genera, SCFAs, and stress outcomes, followed by mediation analyses of genera-metabolite-outcome relationships. Day-averaged serum propionate and total serum SCFAs were negatively associated with the CAR and cortisol responses to the MAST ( p _FDR < 0.05), whereas fecal SCFAs showed no associations. A composite score of propionate-, but not butyrate-, producing genera (including Akkermansia, Alistipes, Bacteroides and Prevotella ), was positively associated with cortisol responses to acute stress ( p  = 0.028). Associations between individual genera and cortisol outcomes were mediated through serum propionate. Additionally, a positive association between Faecalibacterium and negative affect was found ( p _FDR = 0.022) as well as a Dialister -by-time interaction for self-reported stress responses to the MAST ( p _FDR = 0.007). Together, these findings highlight distinct associations of gut microbial genera and SCFAs with stress, with circulating propionate linked to hypothalamic-pituitary-adrenal axis regulation and specific microbial genera primarily related to aspects of perceived stress.