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.