Methionine Restriction Regulates Cognitive Function in High-fat Diet-fed Mice: Roles of Diurnal Rhythms of SCFAs Producing- and Inflammation- related Microbes.

SCOPE: Methionine restriction (MR) is known to potently alleviate inflammation and improve gut microbiome in obese mice. The gut microbiome exhibits diurnal rhythmicity in composition and function, and this, in turn, drives oscillations in host metabolism. High-fat diet (HFD) strongly altered microbiome diurnal rhythmicity, however, the role of microbiome diurnal rhythmicity in mediating the improvement effects of MR on obesity-related metabolic disorders remains unclear. METHODS AND RESULTS: Ten-week-old male C57BL/6J mice were fed a low-fat diet (LFD) or HFD for 4 weeks, followed with a full diet (0.86% methionine, w/w) or a methionine-restricted diet (0.17% methionine, w/w) for 8 weeks. Analyzing microbiome diurnal rhythmicity at six time points, our results showed that HFD disrupted the cyclical fluctuations of the gut microbiome in mice. MR partially restored these cyclical fluctuations, which led to time-specifically enhance the abundance of short-chain fatty acids (SCFAs) producing bacteria, increased the acetate and butyric, and dampened the oscillation of inflammation-related Desulfovibrionales and Staphylococcaceae over the course of one day. Notably, MR, which protected against systemic inflammation, influenced brain function and synaptic plasticity. CONCLUSION: MR could serve as a potential nutritional intervention for attenuating obesity-induced cognitive impairments by balancing the circadian rhythm in microbiome-gut-brain homeostasis. This article is protected by copyright. All rights reserved.