title: NOD2-mediated dysbiosis predisposes mice to transmissible colitis and colorectal cancer.
abstract: Instability in the composition of gut bacterial communities (dysbiosis) has been linked to common human intestinal disorders, such as Crohn's disease and colorectal cancer. Here, we show that dysbiosis caused by Nod2 deficiency gives rise to a reversible, communicable risk of colitis and colitis-associated carcinogenesis in mice. Loss of either Nod2 or RIP2 resulted in a proinflammatory microenvironment that enhanced epithelial dysplasia following chemically induced injury. The condition could be improved by treatment with antibiotics or an anti-interleukin-6 receptor-neutralizing antibody. Genotype-dependent disease risk was communicable via maternally transmitted microbiota in both Nod2-deficient and WT hosts. Furthermore, reciprocal microbiota transplantation reduced disease risk in Nod2-deficient mice and led to long-term changes in intestinal microbial communities. Conversely, disease risk was enhanced in WT hosts that were recolonized with dysbiotic fecal microbiota from Nod2-deficient mice. Thus, we demonstrated that licensing of dysbiotic microbiota is a critical component of disease risk. Our results demonstrate that NOD2 has an unexpected role in shaping a protective assembly of gut bacterial communities and suggest that manipulation of dysbiosis is a potential therapeutic approach in the treatment of human intestinal disorders.
authors.affiliation: University Lille Nord de France, Lille, France.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Couturier-Maillard
authors.forename: Thomas
authors.initials: T
authors.lastname: Secher
authors.forename: Ateequr
authors.initials: A
authors.lastname: Rehman
authors.forename: Sylvain
authors.initials: S
authors.lastname: Normand
authors.forename: Adèle
authors.initials: A
authors.lastname: De Arcangelis
authors.forename: Robert
authors.initials: R
authors.lastname: Haesler
authors.forename: Ludovic
authors.initials: L
authors.lastname: Huot
authors.forename: Teddy
authors.initials: T
authors.lastname: Grandjean
authors.forename: Aude
authors.initials: A
authors.lastname: Bressenot
authors.forename: Anne
authors.initials: A
authors.lastname: Delanoye-Crespin
authors.forename: Olivier
authors.initials: O
authors.lastname: Gaillot
authors.forename: Stefan
authors.initials: S
authors.lastname: Schreiber
authors.forename: Yves
authors.initials: Y
authors.lastname: Lemoine
authors.forename: Bernhard
authors.initials: B
authors.lastname: Ryffel
authors.forename: David
authors.initials: D
authors.lastname: Hot
authors.forename: Gabriel
authors.initials: G
authors.lastname: Nùñez
authors.forename: Grace
authors.initials: G
authors.lastname: Chen
authors.forename: Philip
authors.initials: P
authors.lastname: Rosenstiel
authors.forename: Mathias
authors.initials: M
authors.lastname: Chamaillard
mesh_terms: D000818:Animals; D003092:Colitis / Q000209:etiology* / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D015179:Colorectal Neoplasms / Q000209:etiology* / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D004064:Digestive System / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008297:Male; D054892:Metagenome; D051379:Mice; D018345:Mice, Knockout; D053473:Nod2 Signaling Adaptor Protein / Q000172:deficiency* / Q000235:genetics; D011247:Pregnancy; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics; D012307:Risk Factors
chemical_list: D053473:Nod2 Signaling Adaptor Protein; C495945:Nod2 protein, mouse; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C506255:Ripk2 protein, mouse