Butyrate deficiency due to microbial dysbiosis promotes anxiety
Individuals with diabetes frequently suffer from anxiety; however, the mechanistic basis for this association remains incompletely understood. Diabetes-associated genes have been implicated in the control of central nervous system (CNS) disorders. In the current study, we observed a significant downregulation of secretagogin (SCGN) across multiple organs in diabetic mouse models. Consequently, SCGN knockout (Scgn-/-) mice developed diabetes, confirming SCGN as a diabetes-associated gene. Behavioral analyses revealed that Scgn-/- mice exhibited anxiety-like phenotypes compared to wild-type (WT) mice. Notably, germ-free (GF) Scgn-/- mice did not manifest these behavioral abnormalities, demonstrating that SCGN influences anxiety through gut microbiota-dependent mechanisms. Subsequent 16S rRNA sequencing confirmed gut microbiota dysbiosis in Scgn-/- mice. Fecal microbiota transplantation (FMT) from Scgn-/- donors into GF mice recapitulated the anxiety-like phenotypes. Given the established roles of microbial metabolites in gut-brain axis signaling, we quantified short-chain fatty acids (SCFAs), identifying marked depletion of a key neuroactive metabolite, butyrate, in the Scgn-/- fecal and plasma samples. Immunohistochemical analysis revealed neural overactivation via c-Fos expression in the medial prefrontal cortex (mPFC) of Scgn-/- mice, which was corroborated by metabolomic profiling indicating dysregulated tryptophan metabolism in this region. Mechanistically, the upregulation of indoleamine 2,3-dioxygenase 1 (IDO1) and kynureninase (KYNU) promoted excessive quinolinic acid production. This NMDA receptor agonist enhanced pyramidal neuron excitability in the mPFC, driving anxiety-like behaviors in Scgn-/- mice. Critically, butyrate administration reversed this pathological cascade in vivo and in vitro, as validated by electrophysiological recordings. Taken together, our findings demonstrate that SCGN deficiency induces gut dysbiosis, reduces butyrate bioavailability, and promotes mPFC excitotoxicity through disrupted tryptophan metabolism, ultimately culminating in anxiety. This SCGN-modulated gut-brain axis identifies novel therapeutic targets for diabetes-associated anxiety.