Gut Microbiota-Derived Propionate Regulates the Expression of Reg3 Mucosal Lectins and Ameliorates Experimental Colitis in Mice Original paper

What was studied?

This paper reported an original experimental study that investigated how gut microbiota–derived propionate regulates intestinal antimicrobial defense and epithelial repair through the induction of Reg3 mucosal lectins, and how this axis influences disease severity in colitis. The authors directly tested the hypothesis that specific microbial metabolites, rather than microbial presence alone, control epithelial antimicrobial programs and tissue regeneration. Using antibiotic perturbation, gnotobiotic colonization, receptor-deficient mouse models, intestinal organoids, and chemically induced colitis, the study dissected a causal pathway linking commensal Clostridia, short-chain fatty acids, epithelial signaling, and mucosal homeostasis.

Who was studied?

The study was conducted primarily in murine systems, including conventionally housed mice, germ-free mice, and multiple genetically modified strains lacking Reg3B, GPR43, GPR109, or MyD88. These in vivo models were complemented by ex vivo intestinal organoids derived from mouse epithelium to isolate epithelial-specific responses. The disease context was modeled using dextran sodium sulfate–induced colitis, which mimics epithelial injury and inflammatory features relevant to human inflammatory bowel disease. Although no human subjects were directly studied, the experimental systems were chosen to reflect clinically relevant mechanisms of microbiome disruption, antimicrobial defense loss, and impaired mucosal healing.

What were the most important findings?

The study demonstrated that depletion of gut commensals, particularly Clostridia clusters IV and XIVa, led to a marked reduction in intestinal Reg3B and Reg3G expression. This effect was mechanistically linked to reduced luminal short-chain fatty acids, with propionate emerging as the dominant regulator of Reg3 expression. Propionate directly induced Reg3 lectins in intestinal organoids and in gnotobiotic mice, and this induction required signaling through the SCFA receptor GPR43. In contrast, butyrate did not induce Reg3 under physiological conditions and at higher concentrations impaired epithelial viability. Reg3B-deficient mice developed more severe colitis with reduced crypt proliferation, establishing Reg3B as a functional mediator of epithelial protection and regeneration. Propionate supplementation attenuated colitis severity, enhanced crypt proliferation, and restored stem cell–associated markers such as Lgr5 and Olfm4 after injury. Major microbial associations implicated in this protective axis included propionate-producing Clostridia, with downstream effects on epithelial antimicrobial lectins that restrict pathogen proximity, limit microbial translocation, and promote tissue repair.

What are the greatest implications of this study?

This study provides direct mechanistic evidence that microbiome-derived metabolites actively instruct epithelial defense and regeneration programs. For clinicians, it reframes antimicrobial peptide expression as a metabolite-driven process rather than a purely immune-triggered response. The findings suggest that restoring propionate-producing microbes or propionate signaling may represent a therapeutic strategy to enhance mucosal healing in inflammatory bowel disease and other conditions marked by epithelial injury.