ZIA BC 011153 (ZIA) | |||
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Title | Role of mouse microbiome in cancer and inflammation | ||
Institution | NCI, Bethesda, MD | ||
Principal Investigator | Trinchieri, Giorgio | NCI Program Director | N/A |
Cancer Activity | N/A | Division | CCR |
Funded Amount | $896,140 | Project Dates | null - null |
Fiscal Year | 2018 | Project Type | Intramural |
Research Topics w/ Percent Relevance | Cancer Types w/ Percent Relevance | ||
Cancer (100.0%) Digestive Diseases (40.0%) Inflammatory Bowel Disease (20.0%) |
Colon/Rectum (40.0%) | ||
Research Type | |||
Exogenous Factors in the Origin and Cause of Cancer Resources and Infrastructure Related to Cancer Control, Survivorship, and Outcomes Research |
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Abstract | |||
We extensively use mice deficient for immune or inflammation-related genes and it is always difficult to distinguish a direct effect of those genes on the colitis or cancer, or an indirect one through the regulation of the intestinal microbiota. Overall these studies will greatly benefit by the access to a germ free facility that we are contributed to establish in Frederick and particularly by the availability of committed expertise in gut microbiology based on state of the art sequencing and bioinformatics, expertise that is provided by the microbiome core that we have established in Bethesda. We have established methods for the determination of mouse microbioma using 454 sequencing or MiSeq sequencingof 16 RNA, metagenomic analysis using NextSeq sequencing, and cytofluorimetric analysis of FISH labeling of specific bacterial types. We also initiated studies with germ free mice, gnotobiotic mice with defined intestinal flora, and mice reconstitute after antibiotic treatment. Initially we studied the role of the intestinal microbiota in experimental models of colitis and colitis-associated cancer using mice genetically deficient for inflammation-controlling genes such as MyD88, IL-18, TNF, TLRs, and others. In these mice the genetic defects induce a dysbiosis that can be transferred to normal mice by co-housing or fecal transplant and enhance susceptibility to chemical carcinogenesis. The bacterial species responsible of this increased susceptibility to carcinogenesis and their mechanism of action are being investigated. The role of commensal microbiota in energetic alteration associated with cancer (i.e. obesity, cachexia, anorexia, cancer treatment, irradiation) has been initiated in murine experimental models and in observational clinical experimentation. Compartmentalized control of skin immunity by resident commensals (Science. 2012;337:1115-9). Intestinal commensal bacteria induce protective and regulatory responses that maintain host-microbial mutualism. However, the contribution of tissue-resident commensals to immunity and inflammation at other barrier sites has not been addressed. We found that in mice, the skin microbiota has an autonomous role in controlling the local inflammatory milieu and tuning resident T lymphocyte function. Protective immunity to a cutaneous pathogen was found to be critically dependent on the skin microbiota but not the gut microbiota. Furthermore, skin commensals tuned the function of local T cells in a manner dependent on signaling downstream of the interleukin-1 receptor. These findings underscore the importance of the microbiota as a distinctive feature of tissue compartmentalization, and provide insight into mechanisms of immune system regulation by resident commensal niches in health and disease. Commensal bacteria control cancer response to therapy by modulating the tumor microenvironment (Science 342:967-970). The gut microbiome influences both local and systemic inflammation. Although the role of inflammation in cancer is well documented, whether commensal bacteria can exert distant effects on the inflammation in the sterile tumor microenvironment remains unclear. Here we show that microbiota perturbation impairs the response of subcutaneous cancers to CpG-oligonucleotide-immunotherapy or platinum chemotherapy. In antibiotic-treated or germ-free mice, decreased cytokine production from tumor-infiltrating monocyte-derived cells following CpG-ODN treatment reduced tumor necrosis, whereas deficient chemotherapy-induced production of reactive oxygen species by myeloid cells impaired genotoxicity and tumor destruction. Thus, optimal response to cancer immunotherapy and chemotherapy requires an intact commensal microbiota that acts distantly by modulating myeloid-derived cell function in the tumor microenvironment. These findings underscore the importance of the microbiota in the outcome of disease treatment. The toxicity mediated by cisplatin (intestinal mucosa damage, nephrotoxicity, de |