Microbial Activation of the GLP-2R Mitigates Gastrointestinal Inflammation

There is an urgent need for sustainable protein sources to meet rising global nutritional demands. Here, we show that a commercially scalable microbial lysate from Methylococcus capsulatus Bath (McB), used as a dietary protein, orchestrates host-diet-microbe interactions that protect against gastrointestinal inflammation. McB administration rapidly reshapes the gut microbiota and upregulates microbial fermentation pathways, while robustly increasing peripherally induced regulatory T cells (pTregs) across intestinal regions, independent of the microbiota. In contrast, McB-driven induction of tolerogenic Th17 cells requires a functional microbiota. In models of mucositis and colitis, McB preserves villus architecture, restores mucosal integrity, and reduces disease severity. Mechanistically, these effects depend on microbial fermentation and functional GLP-2 receptor signalling, yet are independent of endogenous GLP-2 secretion, indicating a fermentation-driven molecular mimicry of GLP-2R activation. Collectively, our findings position microbial lysates as a sustainable nutritional strategy that improves gastrointestinal health through defined immune and microbial pathways.