Ligilactobacillus murinus alleviates binge-eating behavior by restoring serotonin metabolism.

Abstract

Overeating disorder (OD) is characterized by recurrent binge eating episodes without compensatory behaviors. It is linked to gut dysbiosis and impaired serotonin (5-HT) metabolism; however, the specific microbial mechanisms driving these neurochemical changes remain poorly understood. To address this research gap, a stress and food restriction-based mouse model that recapitulates key OD phenotypes, including elevated palatable food intake, increased caloric consumption, and heightened food impulsivity, accompanied by systemic suppression of 5-HT and its metabolite 5-HIAA in both brain and serum, was established. Antibiotic-mediated gut microbiota depletion significantly exacerbated binge-eating behaviors and further suppressed the 5-HT metabolic pathway, suggesting a causal role for the microbiota. Through 16S rRNA gene sequencing, OD-associated dysbiosis marked by reduced α-diversity and depletion of Ligilactobacillus, whose relative abundance positively correlated with serum 5-HT, was identified. Targeted probiotic intervention with Ligilactobacillus murinus (L. murinus) restored 5-HT metabolism in the prefrontal cortex, hippocampus, and serum, and significantly ameliorated behavioral measures (palatable food preference, total energy intake, and food impulsivity). The co-administration of a 5-HT synthesis inhibitor abolished these benefits, confirming the 5-HT-dependent action of L. murinus. Mechanistically, L. murinus-derived indole-3-acetic acid (IAA) activated aryl hydrocarbon receptor (AHR) signaling, which upregulated the rate-limiting enzymes TPH1 and TPH2, thereby enhancing 5-HT synthesis and release. These findings establish L. murinus as a key microbiota-based modulator of host 5-HT signaling and binge-eating behavior, highlighting its therapeutic potential as a next-generation probiotic strategy for OD.