title: 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.
authors.affiliation: Division of Gastroenterology, Department of Pediatrics, Child and Family Research Institute, Vancouver, British Columbia, Canada.
authors.forename: V
authors.initials: V
authors.lastname: Morampudi
authors.affiliation: Division of Gastroenterology, Department of Pediatrics, Child and Family Research Institute, Vancouver, British Columbia, Canada.
authors.forename: U
authors.initials: U
authors.lastname: Dalwadi
authors.affiliation: Division of Gastroenterology, Department of Pediatrics, Child and Family Research Institute, Vancouver, British Columbia, Canada.
authors.forename: G
authors.initials: G
authors.lastname: Bhinder
authors.affiliation: Division of Gastroenterology, Department of Pediatrics, Child and Family Research Institute, Vancouver, British Columbia, Canada.
authors.forename: H P
authors.initials: HP
authors.lastname: Sham
authors.affiliation: Department of Biology, Okanagan, University of British Columbia, Kelowna, British Columbia, Canada.
authors.forename: S K
authors.initials: SK
authors.lastname: Gill
authors.affiliation: Division of Gastroenterology, Department of Pediatrics, Child and Family Research Institute, Vancouver, British Columbia, Canada.
authors.forename: J
authors.initials: J
authors.lastname: Chan
authors.affiliation: Division of Gastroenterology, Department of Pediatrics, Child and Family Research Institute, Vancouver, British Columbia, Canada.
authors.forename: K S B
authors.initials: KS
authors.lastname: Bergstrom
authors.affiliation: Division of Gastroenterology, Department of Pediatrics, Child and Family Research Institute, Vancouver, British Columbia, Canada.
authors.forename: T
authors.initials: T
authors.lastname: Huang
authors.affiliation: Division of Gastroenterology, Department of Pediatrics, Child and Family Research Institute, Vancouver, British Columbia, Canada.
authors.forename: C
authors.initials: C
authors.lastname: Ma
authors.affiliation: Division of Gastroenterology, Department of Pediatrics, Child and Family Research Institute, Vancouver, British Columbia, Canada.
authors.forename: K
authors.initials: K
authors.lastname: Jacobson
authors.affiliation: Department of Biology, Okanagan, University of British Columbia, Kelowna, British Columbia, Canada.
authors.forename: D L
authors.initials: DL
authors.lastname: Gibson
authors.affiliation: Division of Gastroenterology, Department of Pediatrics, Child and Family Research Institute, Vancouver, British Columbia, Canada.
authors.forename: B A
authors.initials: BA
authors.lastname: Vallance
mesh_terms: D000818:Animals; D003093:Colitis, Ulcerative / Q000235:genetics / Q000276:immunology* / Q000382:microbiology / Q000517:prevention & control; D003106:Colon / Q000276:immunology / Q000382:microbiology; D064806:Dysbiosis; D005232:Fatty Acids, Volatile / Q000096:biosynthesis; D005786:Gene Expression Regulation; D020397:Goblet Cells / Q000276:immunology* / Q000382:microbiology; D006729:Hormones, Ectopic / Q000235:genetics / Q000276:immunology*; D036341:Intercellular Signaling Peptides and Proteins; D007413:Intestinal Mucosa / Q000276:immunology* / Q000382:microbiology; D007778:Lactobacillus / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D055262:Mucin-2 / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D000073718:Pancreatitis-Associated Proteins; D019936:Probiotics / Q000008:administration & dosage; D011506:Proteins / Q000235:genetics / Q000276:immunology; D012720:Severity of Illness Index; D015398:Signal Transduction; D013559:Symbiosis / Q000276:immunology
chemical_list: D005232:Fatty Acids, Volatile; D006729:Hormones, Ectopic; D036341:Intercellular Signaling Peptides and Proteins; C524626:Muc2 protein, mouse; D055262:Mucin-2; D000073718:Pancreatitis-Associated Proteins; D011506:Proteins; C490253:Reg3b protein, mouse; C486522:Retnlb protein, mouse
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