Critical role for the DNA receptor AIM2 in stem-cell proliferation and cancer
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE69436 | GEO | 2015/07/15
SECONDARY ACCESSION(S): PRJNA285491
REPOSITORIES: GEO
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Project description:Colorectal cancer is a leading cause of cancer-related deaths. Mutations in the innate immune receptor AIM2 are frequently identified in patients with colorectal cancer, but how AIM2 modulates colonic tumorigenesis is unknown. Here, we found that Aim2-deficient mice were hypersusceptible to colonic tumor development. Production of inflammasome-associated cytokines and other inflammatory mediators were largely intact in Aim2-deficient mice, however, intestinal stem cells were prone to uncontrolled proliferation. Aberrant Wnt signaling expanded a population of tumor-initiating stem cells in the absence of AIM2. Susceptibility of Aim2-deficient mice to colorectal tumorigenesis was enhanced by a dysbiotic gut microbiota, which was reduced by reciprocal exchange of gut microbiota with wild-type healthy mice. These findings uncover a synergy between a specific host genetic factor and gut microbiota in determining the susceptibility to colorectal cancer. Therapeutic modulation of AIM2 expression and microbiota has the potential to prevent colorectal cancer. We used microarrays to compare the transcriptome Aim2 deficent mice to wild type mice in colon tumor and colitis samples. Here were 12 mice in total, 3 for each genotype and tissue combination.
2015-07-15 | E-GEOD-69436 | biostudies-arrayexpress
Project description:Instability in the composition of gut bacterial communities, referred as dysbiosis, has been associated with important human intestinal disorders such as CrohnM-bM-^@M-^Ys disease and colorectal cancer. Here, we show that dysbiosis coupled to Nod2 or Rip2 deficiency suffices to cause an increased risk for intestinal inflammation and colitis-associated carcinogenesis in mice. Aggravated epithelial lesions and dysplasia upon chemical-induced injury associated with loss of Nod2 or Rip2 can be prevented by antibiotics or anti-IL6R treatment. Nod2-mediated risk for intestinal inflammation and colitis-associated tumorigenesis is communicable through maternally-transmitted microbiota even to wild-type hosts. Disease progression was identified to drive complex NOD2-dependent changes of the colonic-associated microbiota. Reciprocal microbiota transplantation rescues the vulnerability of Nod2-deficient mice to colonic injury. Altogether, our results unveil an unexpected function for NOD2 in shaping a protective assembly of gut microbial communities, providing a rationale for intentional manipulation of genotype-dependent dysbiosis as a causative therapeutic principle in chronic intestinal inflammation. Analysis used RNA extracted from colonic mucosa of untreated, antibiotics-treated or metronidazole-treated C57Bl/6J and Nod2-deficient mice in CAC model. Direct comparisons were performed as follow: C57Bl/6J untreated mice vs Nod2-deficient untreated mice, C57Bl/6J antibiotics-treated mice vs Nod2-deficient antibiotics-treated mice, C57Bl/6J metronidazole-treated mice vs Nod2-deficient metronidazole-treated mice, C57Bl/6J untreated mice vs C57Bl/6J antibiotics-treated mice, C57Bl/6J untreated mice vs C57Bl/6J metronidazole-treated mice, Nod2-deficient untreated mice vs Nod2-deficient antibiotics-treated mice, Nod2-deficient untreated mice vs Nod2-deficient metronidazole-treated mice. Indirect comparisons with control data were made across multiple arrays with raw data pulled from different channels for data analysis.
2013-01-02 | E-GEOD-32421 | biostudies-arrayexpress
Project description:Instability in the composition of gut bacterial communities, referred as dysbiosis, has been associated with important human intestinal disorders such as Crohn’s disease and colorectal cancer. Our data showed that Nod2-mediated risk of intestinal inflammation in colitis model is communicable to WT mice by cohousing. Here, we investigated if Nod2-deficient mice microbiota is able to change transcript profiles in Nod2-immunocompetent mice (C57Bl6/J mice) independently of colitis. Analysis used RNA extracted from colonic mucosa of C57Bl/6J mice co-housed with Nod2-deficient mice and C57Bl/6J mice alone. Direct comparisons of 4 biologicals replicates of C57Bl/6J mice cohoused with Nod2-deficient mice vs C57Bl/6J mice were performed.
2013-01-02 | E-GEOD-36481 | biostudies-arrayexpress
Project description:Instability in the composition of gut bacterial communities, referred as dysbiosis, has been associated with important human intestinal disorders such as Crohn’s disease and colorectal cancer. Here, we show that dysbiosis coupled to Nod2 or Rip2 deficiency suffices to cause an increased risk for intestinal inflammation and colitis-associated carcinogenesis in mice. Aggravated epithelial lesions and dysplasia upon chemical-induced injury associated with loss of Nod2 or Rip2 can be prevented by antibiotics or anti-IL6R treatment. Nod2-mediated risk for intestinal inflammation and colitis-associated tumorigenesis is communicable through maternally-transmitted microbiota even to wild-type hosts. Disease progression was identified to drive complex NOD2-dependent changes of the colonic-associated microbiota. Reciprocal microbiota transplantation rescues the vulnerability of Nod2-deficient mice to colonic injury. Altogether, our results unveil an unexpected function for NOD2 in shaping a protective assembly of gut microbial communities, providing a rationale for intentional manipulation of genotype-dependent dysbiosis as a causative therapeutic principle in chronic intestinal inflammation.
2013-01-02 | GSE32421 | GEO
Project description:Instability in the composition of gut bacterial communities, referred as dysbiosis, has been associated with important human intestinal disorders such as Crohn’s disease and colorectal cancer. Our data showed that Nod2-mediated risk of intestinal inflammation in colitis model is communicable to WT mice by cohousing. Here, we investigated if Nod2-deficient mice microbiota is able to change transcript profiles in Nod2-immunocompetent mice (C57Bl6/J mice) independently of colitis.
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Project description:Colorectal cancer risk is associated with diets high in red meat. Heme, the pigment of red meat, induces cytotoxicity of colonic contents and elicits epithelial damage and compensatory hyperproliferation, leading to hyperplasia. Here we explore the possible causal role of the gut microbiota in heme-induced hyperproliferation. To this end, mice were fed a purified control or heme diet (0.5 μmol/g heme) with or without broad-spectrum antibiotics for 14 d. Heme-induced hyperproliferation was shown to depend on the presence of the gut microbiota, because hyperproliferation was completely eliminated by antibiotics, although heme-induced luminal cytotoxicity was sustained in these mice. Colon mucosa transcriptomics revealed that antibiotics block heme-induced differential expression of oncogenes, tumor suppressors, and cell turnover genes, implying that antibiotic treatment prevented the heme-dependent cytotoxic micelles to reach the epithelium. Our results indicate that this occurs because antibiotics reinforce the mucus barrier by eliminating sulfide-producing bacteria and mucin-degrading bacteria (e.g., Akkermansia). Sulfide potently reduces disulfide bonds and can drive mucin denaturation and microbial access to the mucus layer. This reduction results in formation of trisulfides that can be detected in vitro and in vivo. Therefore, trisulfides can serve as a novel marker of colonic mucolysis and thus as a proxy for mucus barrier reduction. In feces, antibiotics drastically decreased trisulfides but increased mucin polymers that can be lysed by sulfide. We conclude that the gut microbiota is required for heme-induced epithelial hyperproliferation and hyperplasia because of the capacity to reduce mucus barrier function. Mice were fed a Westernized high fat control diet, or the same diet supplemented with 0.5 µmol heme/g diet. One group of control and one group of heme mice received a mixture of broad spectrum Antibiotics (Abx) (ampicilin, neomycin and metronidazole) in their drinking water. After 14 days of intervention, mice were killed and gene expression was profiled in colon.
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