Lysine-restricted diet alleviates obesity-related anxiety-like behaviors by increasing Oscillibacter ruminantium regulating tryptophol

Background The role of dietary interventions, particularly lysine-restricted diets(LRD), in mitigating obesity-associated anxiety-like behaviors remains poorly understood, with limited insight into gut microbiota-metabolite-brain axis mechanisms.
Results LRD significantly improved anxiety behavior related by a high-fat diet (HFD) by reducing body weight and glucose metabolism levels.In addition, LRD significantly reshaped the structure of the gut microbiota, as manifested by a significant increase in the relative abundance of Oscillibacter. We then screened and found that supplementation with either active or encapsulated Oscillibacter ruminantium could improve obesity/chronic restraint stress-related anxiety-like behavior, with microcapsule intervention having a better effect. Notably, the HFD-related reduction in tryptophol and intestinal barrier damage was restored by an LRD. Mechanistic studies further demonstrated that tryptophol supplementation can alleviate HFD-related anxiety-like behavior by inhibiting Fto-mediated reader protein IGF2BP1 and reducing m6A modification of Lgr6 mRNA.
Conclusion LRD alleviates obesity-related anxiety-like behavior by increasing O. ruminantium and further regulating tryptophol to activate the FTO-IGF2BP1-LGR6-axis.These findings position LRD as a microbiota-targeted strategy for metabolic-stress-associated neurobehavioral disorders.