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 10-week-old male C57BL/6J mice are fed a low-fat diet 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, the results show that HFD disrupts the cyclical fluctuations of the gut microbiome in mice. MR partially restores these cyclical fluctuations, which lead to time-specifically enhance the abundance of short-chain fatty acids producing bacteria, increases the acetate and butyric, and dampens the oscillation of inflammation-relatedDesulfovibrionalesandStaphylococcaceaeover the course of 1 day. Notably, MR, which protects against systemic inflammation, influences 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.