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

Abstract

Background and Aims Regenerating islet-derived protein type 3 [Reg3] lectins are antimicrobial peptides at mucosal surfaces of the gut, whose expression is regulated by pathogenic gut microbes via interleukin-22- or Toll-like receptor signalling. In addition to antimicrobial effects, tissue protection is hypothesized, but has been poorly investigated in the gut. Methods We applied antibiotic-induced microbiota perturbations, gnotobiotic approaches and a dextran-sodium sulfate [DSS] colitis model to assess microbial Reg3 regulation in the intestines and its role in colitis. We also used an intestinal organoid model to investigate this axis in vitro. Results First, we studied whether gut commensals are involved in Reg3 expression in mice, and found that antibiotic-mediated reduction of Clostridia downregulated intestinal Reg3B. A loss in Clostridia was accompanied by a significant reduction of short-chain fatty acids [SCFAs], and knock-out [KO] mice for SCFA receptors GPR43 and GPR109 expressed less intestinal Reg3B/-G. Propionate was found to induce Reg3 in intestinal organoids and in gnotobiotic mice colonized with a defined, SCFA-producing microbiota. Investigating the role of Reg3B as a protective factor in colitis, we found that Reg3B-KO mice display increased inflammation and less crypt proliferation in the DSS colitis model. Propionate decreased colitis and increased proliferation. Treatment of organoids exposed to DSS with Reg3B or propionate reversed the chemical injury with a loss of expression of the stem-cell marker Lgr5 and Olfm4. Conclusions Our results suggest that Clostridia can regulate Reg3-associated epithelial homeostasis through propionate signalling. We also provide evidence that the Reg3–propionate axis may be an important mediator of gut epithelial regeneration in colitis.

Impact of diet and the bacterial microbiome on the mucous barrier and immune disorders

“…Propionate, produced by many Clostridia spp., promotes production of the antimicrobial peptides regenerating islet‐derived protein type‐3β (Reg3B) and γ (Reg3G), which drive epithelial proliferation and intestinal barrier repair in mice 102 . This was mediated through activation of the G protein–coupled receptor (Gpr)43, although downregulation of Reg3B and Reg3G in mice lacking the butyrate receptor Gpr109A indicated that other SCFAs likely have similar impacts 102 . Tolerance towards the commensal microbiome and food antigens is essential to limit GI inflammation and promote effective functioning of the mucosal barrier 89 .…”

“…HFDs increase Proteobacteria and reduce A muciniphila and mucus thickness, impair tight junctions and cause low‐grade inflammation in mice, which predisposes to colitis and this can be alleviated by supplementation with soluble fibre such as inulin or pectin 124,127,165,166 . Although these effects were independent of SCFA production, other studies show that fibre deficiency predisposes mice to infection‐induced colitis, 82 while acetate and propionate promote mucin and REG3 production, as well as GPR43‐induced proliferation of intestinal ILC3s to maintain the mucous barrier and reduce disease severity 102,124,167 …”

“…124,127,165,166 Although these effects were independent of SCFA production, other studies show that fibre deficiency predisposes mice to infection-induced colitis, 82 while acetate and propionate promote mucin and REG3 production, as well as GPR43-induced proliferation of intestinal ILC3s to maintain the mucous barrier and reduce disease severity. 102,124,167 Diets Moreover, the microbiome in biopsies from inflamed tissue of IBD patients is markedly different from noninflamed tissue, suggesting F I G U R E 5 Summary of dysbiosis and diet-related immune disorders. Numerous immune disorders, including inflammatory bowel diseases, obesity/diabetes, rheumatoid arthritis, atopic dermatitis, psoriasis, chronic obstructive pulmonary disease (COPD) and asthma, are associated with changes in the microbiome and diet.…”

Propionate catabolism by CD-associated adherent-invasive E. coli counteracts its anti-inflammatory effect

“…Recently, a fascinating study highlighted the role of Reg3-mucosal lectins, gut microbiota-derived propionate and its GPR43 receptor as a crucial mediator axis for gut epithelial regeneration in colitis. 14 Acetate and propionate serve as the most potent activators of the GPR43 receptor, followed by butyrate and other SCFAs. 6 In contrast to acetate, propionate levels have been reported to be markedly decreased in patients with CD compared with healthy individuals.…”

Microbial Metabolites in Colorectal Cancer: Basic and Clinical Implications

“…Although the majority of propionate is absorbed to enter the circulation and is metabolized in liver, it has also shown to have protective effects on colonic cells [ 68 ]. Propionate inhibits colonic inflammation [ 69 , 70 ]. Much less is known with regards to the molecular mechanism of propionate in colon cancer; however, it may share a similar mechanism with butyrate through inhibition of HDACs [ 71 ].…”