期刊
CANCER RESEARCH
卷 73, 期 14, 页码 4222-4232出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-13-0022
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资金
- NIH [ES09519, CA133928, AI078885, DK46763, P30 CA016042]
- Crohn's and Colitis Foundation of America [3153]
- Broad Center of Regenerative Medicine
- Stem Cell Research
- Austrian Federal Ministry of Science and Research
- NASA [NNX11AB44G]
- Ruzic Research Foundation
- UC TSR&TP and UCLA Graduate Division
- Direct For Education and Human Resources [1139928] Funding Source: National Science Foundation
- Division Of Human Resource Development [1139928] Funding Source: National Science Foundation
- NASA [NNX11AB44G, 149565] Funding Source: Federal RePORTER
Ataxia-telangiectasia is a genetic disorder associated with high incidence of B-cell lymphoma. Using an ataxiatelangiectasia mouse model, we compared lymphoma incidence in several isogenic mouse colonies harboring different bacterial communities, finding that intestinal microbiota are a major contributor to disease penetrance and latency, lifespan, molecular oxidative stress, and systemic leukocyte genotoxicity. High-throughput sequence analysis of rRNA genes identified mucosa-associated bacterial phylotypes that were colony-specific. Lactobacillus johnsonii, which was deficient in the more cancer-prone mouse colony, was causally tested for its capacity to confer reduced genotoxicity when restored by short-term oral transfer. This intervention decreased systemic genotoxicity, a response associated with reduced basal leukocytes and the cytokine-mediated inflammatory state, and mechanistically linked to the host cell biology of systemic genotoxicity. Our results suggest that intestinal microbiota are a potentially modifiable trait for translational intervention in individuals at risk for B-cell lymphoma, or for other diseases that are driven by genotoxicity or the molecular response to oxidative stress. (C) 2013 AACR.
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