The goblet cell-derived mediator RELM-β drives spontaneous colitis in Muc2-deficient mice by promoting commensal microbial dysbiosis

Abstract

Intestinal goblet cells are potentially key players in controlling susceptibility to ulcerative colitis (UC). Although impaired mucin (Muc2) production by goblet cells increases microbial stimulation of the colonic mucosa, goblet cells secrete other mediators that may influence or promote UC development. Correspondingly, Muc2-deficient ((-/-)) mice develop spontaneous colitis, concurrent with the dramatic upregulation of the goblet cell mediator, resistin-like molecule-beta (RELM-β). Testing RELM-β's role, we generated Muc2(-/-)/Retnlb(-/-) mice, finding that RELM-β deficiency significantly attenuated colitis development and symptoms compared with Muc2(-/-) mice. RELM-β expression in Muc2(-/-) mice strongly induced the production/secretion of the antimicrobial lectin RegIIIβ, that exerted its microbicidal effect predominantly on Gram-positive Lactobacillus species. Compared with Muc2(-/-)/Retnlb(-/-) mice, this worsened intestinal microbial dysbiosis with a selective loss of colonic Lactobacilli spp. in Muc2(-/-) mice. Orally replenishing Muc2(-/-) mice with murine Lactobacillus spp., but not with a probiotic formulation containing several human Lactobacillus spp. (VSL#3), ameliorated their spontaneous colitis in concert with increased production of short-chain fatty acids. These studies demonstrate that the goblet cell mediator RELM-β drives colitis in Muc2(-/-) mice by depleting protective commensal microbes. The ability of selective commensal microbial replacement to ameliorate colitis suggests that personalized bacterial therapy may prove beneficial for treatment of UC.

Effect of a probiotic beverage consumption (Enterococcus faecium CRL 183 and Bifidobacterium longum ATCC 15707) in rats with chemically induced colitis

“…A recent study conducted by Morampudi et al [118] discussed a similar result founded by the present research group. According to their findings, Mucin2 deficient mice showed significant increased acetate and propionate levels, but not butyrate, when treated with Lactobacillus spp.…”

Perfluorooctane sulfonate affects intestinal immunity against bacterial infection

“…Mucins produced by goblet cells in the intestinal epithelium are crucial for maintaining a healthy community of microbiota in the gut 50, 51 . Pro-inflammatory cytokines including IL-17 and IFN-γ have been indicated to cause tissue damage or result in loss of goblet cells during intestinal inflammation 52, 53 .…”

Novel insights into microbiome in colitis and colorectal cancer

“…MUC2 deficiency in mice leads to overexpression of the goblet cells-derived mucosal defense factor RELM-β, which induces colonic production of the antimicrobial lectins REGIIIβ and REGIIIγ(4**). REGIIIβ predominantly targets Lactobacillus species, potent producers of beneficial short-chain fatty acids, and oral gavage of murine Lactobacilli isolates reduced RELM-β and REGIIIβ levels and ameliorated spontaneous colitis in Muc2 -/- mice (4**).…”

“…MUC2 deficiency in mice leads to overexpression of the goblet cells-derived mucosal defense factor RELM-β, which induces colonic production of the antimicrobial lectins REGIIIβ and REGIIIγ(4**). REGIIIβ predominantly targets Lactobacillus species, potent producers of beneficial short-chain fatty acids, and oral gavage of murine Lactobacilli isolates reduced RELM-β and REGIIIβ levels and ameliorated spontaneous colitis in Muc2 -/- mice (4**). In contrast, MUC4 appears to promote colitis and tumorigenesis as Muc4 -/- mice are more resistant to DSS colitis and AOM/DSS-induced tumorigenesis, which might be due to compensatory upregulation of MUC2 and MUC3 in mutant mice (5).…”