Lysine restriction attenuates obesity-related anxiety-like behaviors via increasing Oscillibacter ruminantium-mediated tryptophol regulation.

BACKGROUND: The contribution of dietary interventions, particularly lysine-restricted diets (LRD), to ameliorating obesity-associated anxiety-like behaviors remains elusive, with limited evidence clarifying microbiota-metabolite-brain axis pathways involved. RESULTS: Herein, our results demonstrated that LRD attenuated high-fat diet (HFD)-induced anxiety-like behaviors while concomitantly reducing body weight and improving glucose metabolism. Furthermore, LRD significantly remodeled gut microbiota composition, most notably enriching the abundance of Oscillibacter. We then screened and identified that both viable and encapsulated Oscillibacter ruminantium alleviated obesity- and chronic restraint stress-induced anxiety-like behaviors, with microencapsulated formulations conferring superior anxiolytic efficacy. Notably, the obtained data revealed that LRD reversed HFD-induced the depletion of tryptophol, which was established as the metabolite of Oscillibacter ruminantium, and LRD could also alleviate the intestinal barrier impairment caused by HFD. Mechanistic results further demonstrated that tryptophol supplementation ameliorated HFD-driven anxiety-like phenotypes by inhibiting FTO-mediated reader protein IGF2BP1, and thereby reducing m⁶A modification of Lgr6 mRNA. CONCLUSION: LRD attenuates obesity-associated anxiety-like behaviors by enriching Oscillibacter ruminantium and modulating tryptophol production, thereby activating the FTO-IGF2BP1-LGR6 signaling axis. These findings would indicate LRD as a microbiota-directed therapeutic strategy for neurobehavioral comorbidities of metabolic stress.