Gut microbiota-regulated glutathione metabolic rhythms restore obesity-induced colonic inflammatory oscillations

Obesity disrupts circadian inflammatory rhythms, a defining feature of metabolic syndrome. However, the mechanisms connecting microbial and host circadian communication remain unclear. By using the fermentable fiber fructo-oligosaccharide (FOS) to restore microbial rhythmicity, we found that a high-fat diet (HFD) disrupts microbiota-regulated oscillations in glutathione metabolism, thereby dampening colonic inflammatory rhythms independently of the core clock machinery. Fecal microbiota transplantation (FMT) further supported a causal role for rhythmic fecal microbial signals in restoring inflammatory oscillations. Integrated multi-omics analysis highlighted circadian glutathione metabolism as a prominent candidate pathway linking microbial rhythmicity to host inflammatory oscillations. Importantly, colon-specific knockdown of Gclc, the rate-limiting enzyme in glutathione synthesis, abolished the restorative effects of microbial rhythms, functionally positioning host glutathione metabolism as a critical downstream mediator. Collectively, our study supports the existence of a microbiota-glutathione axis that contributes to the regulation of colonic inflammatory rhythms, uncovering a new chronobiological layer of microbial control over host inflammation.