Variability in threat processing is related to endogenous butyrate levels in healthy men

The gut microbiota and its metabolites have been implicated in anxiety-like behavior in preclinical models. Recent correlational evidence in humans has linked fear learning with the abundance of specific bacterial taxa, suggesting that bacterial metabolites such as short-chain fatty acids (SCFAs) may act as gut-brain signaling mediators. Using a human fear conditioning paradigm, we initially analyzed data from 146 healthy male participants and found that interindividual differences in the circulating SCFA butyrate-but not acetate or propionate-were associated with physiological threat-safety discrimination during fear acquisition, as measured by skin conductance responses. However, a replication analysis in an independent sample of 71 participants found no such association. A post-hoc pooled analysis across all participants (N = 217) suggested that butyrate was linked with the magnitude of threat-safety discrimination, but only in individuals with at least minimal physiological discrimination (n = 165). These preliminary correlational findings require further confirmation, including causal investigations into butyrate's potential epigenetic role in modulating memory- and plasticity-related genes.