Abstract
Nod2 or Rip2 deficiency confers a communicable risk of colitis and colorectal cancer in mice.
Major finding: Nod2 or Rip2 deficiency confers a communicable risk of colitis and colorectal cancer in mice.
Mechanism: Nod2 loss disrupts the gut microbial balance and induces an IL-6–driven inflammatory response.
Impact: Antibiotic treatment or IL-6 neutralization reduces disease severity and tumor progression.
Bacterial communities within the colonic mucosa are essential for proper epithelial differentiation and maintenance of a protective immune environment. Disruption of the balance between commensal microbes, or dysbiosis, is associated with Crohn disease, an inflammatory intestinal disorder that enhances the risk of colitis-associated colorectal carcinoma. Couturier-Maillard and colleagues hypothesized that dysbiosis contributes to intestinal disease and investigated the role of nucleotide-binding oligomerization domain-containing protein 2 (NOD2), which regulates the abundance of intestinal bacterial populations, in this process. Cohousing with animals lacking Nod2 or its adaptor receptor-interacting serine-threonine kinase 2 (Ripk2 or Rip2) resulted in body weight loss and increased intestinal pathology in wild-type mice following colitis induction with dextran sodium sulfate (DSS) and augmented colorectal tumor growth, similar to the phenotype in Nod2−/− mice, suggesting that loss of these genes confers a communicable risk of disease. This increased disease risk was mediated by inheritance of dysbiotic microbes that sensitized the colonic mucosa to injury and was associated with elevated expression of the proinflammatory cytokine interleukin (IL)-6 by dendritic-like cells and intestinal epithelial cells. Treatment with broad-spectrum antibiotics or a neutralizing IL-6 receptor antibody decreased epithelial dysplasia and tumor burden, reversed IL-6–mediated inflammation, and induced changes in the abundance of mucosal bacterial communities in both wild-type and mutant mice. Furthermore, reciprocal fecal transplants confirmed that recolonization of wild-type hosts with dysbiotic microbes from Nod2−/− mice enhanced disease risk, whereas transfer of microbes from wild-type mice to mice lacking Nod2 diminished disease severity and restored a balanced intestinal microbiome. These results identify a protective role for NOD2 in the maintenance of intestinal microbial populations and suggest modulation of dysbiosis as a therapeutic strategy for patients with Crohn disease or colitis-associated colorectal carcinoma.
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