NOD2-mediated dysbiosis predisposes mice to transmissible colitis and colorectal cancer
Aurélie Couturier-Maillard, … , Philip Rosenstiel, Mathias Chamaillard
Aurélie Couturier-Maillard, … , Philip Rosenstiel, Mathias Chamaillard
Published January 2, 2013
Citation Information: J Clin Invest. 2013;123(2):700-711. https://doi.org/10.1172/JCI62236.
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Research Article Oncology

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

Aurélie Couturier-Maillard, Thomas Secher, Ateequr Rehman, Sylvain Normand, Adèle De Arcangelis, Robert Haesler, Ludovic Huot, Teddy Grandjean, Aude Bressenot, Anne Delanoye-Crespin, Olivier Gaillot, Stefan Schreiber, Yves Lemoine, Bernhard Ryffel, David Hot, Gabriel Nùñez, Grace Chen, Philip Rosenstiel, Mathias Chamaillard

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Figure 1

The absence of NOD2/RIP2 confers a transmissible risk for colitis, even to immunocompetent hosts.

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The absence of NOD2/RIP2 confers a transmissible risk for colitis, even ...
(A) Five days after AOM administration (at 8 mg/kg), age- and gender-matched SH-WT (n = 5), SCH-WTNod2–/– (n = 5), CH-WTNod2–/– (n = 5), SCH-WTRIP2–/– (n = 5), and CH-WTRIP2–/– (n = 4) mice received ad libitum 2% (w/v) DSS (molecular mass, 35–40 kDA; TdB Consultancy) for 7 days followed by 2 days of regular drinking water. Mutant and WT animals were cohoused at a 3:2 or 1:1 ratio on the same diet for a 4-week period. WT cohoused mice were either left with or separated from mutant mice before being challenged by 1 cycle of DSS-AOM. The cross indicates necropsy. Changes in body weight of (B) CH-WTNod2–/–, (C) CH-WTRIP2–/–, and (D) SCH-WTNod2–/– and SCH-WTRIP2–/– mice were evaluated daily and compared to that in SH-WT animals. (E) Histological scoring was determined at day 9. (F) Representative H&E and PAS staining of paraffin-embedded longitudinal sections from colons of SH-WT, SCH-WTRIP2–/–, and CH-WTRIP2–/– mice at day 9. Scale bar: 100 μm. *P < 0.05; **P < 0.01; ***P < 0.001.