Huge unexplained inter- and intra-laboratory differences in the lifespan of isogenic Atm deficient mice from 2 months to 11.5 months exist in the literature. The intestinal microbiota plays a critical role in our health; in part because these bacteria outnumber the human cells in our body by 10-fold and because they have a huge metabolic capacity. The intricate interplay between the body, especially the immune system, and intestinal microbiota strongly suggests that the intestinal microbiota affects systemic homeostasis. Differences in intestinal microbiota composition are linked to diseases such as obesity, diabetes and behavior. The role of normal, non-pathogenic gut bacteria in carcinogenesis however, is currently unclear.
Current Research Projects
Dr. Robert Schiestl‘s Lab has made the striking observation that the nature of gut bacteria significantlyinfluences genetic instability, longevity and lymphoma latency in Atm deficient mice. ATM is important in DNA double-strand break repair, checkpoint control, and redox balance. Atm-/- mice model the human disease ataxia telangiectasia (AT), which is characterized by loss of motor skills, a compromised immune system, and an increased and premature risk of cancer. There is no cure for AT. They kept mice in sterile versus non-sterile environments and in addition specifically tested the contribution of the intestinal microbiota by experimentally changing such microbiota. They showed that isogenic Atm-/- mice have significant variations of DNA deletions at the pun locus between 10 and 43%, they have a significant variation of lifespan between 32 and 51 weeks and the lymphoma latency varied significantly between 25 and 60 weeks under different intestinal flora conditions.
Furthermore, the Schiestl Lab isolated one bacterium Lactobacillus johnsonii from the health beneficial microbiota which by itself significantly reduced genotoxicity, reduced inflammatory cytokines, induced anti-inflammatory cytokines, and reduced the prevalence of natural killer cells, cytotoxic T cells, and CD3 cells in the liver and peripheral blood, which are all linked to inflammation. In addition they found similar differences in P53 deficient mice and even to a lesser extend in wild type mice. Thus, this effect is of general importance. Their findings present an until-now uncharacterized experimental variable, which may have tremendous implications. First in the prevention or delay of lymphoma in AT patients, and secondly for basic research, in which the numerous inter- and intra-laboratory differences in Atm and possibly other cancer predisposed mouse models are in part or entirely explainedby differences in intestinal microbiota. In addition our AT mouse model is hypersensitive to intestinal inflammation. Since inflammation is linked to a host of diseases, such as heart disease, all cancers, neurodegenerative diseases, arthritis, asthma, diabetes, inflammable bowel disease, Crohns disease, and others, bacteria identified in this animal model may benefit as probiotics all those diseases.
- Yamamoto, L. I. Maier , A. T. Dang , D. Berry , J. Liu, P. M. Ruegger , J. Yang, P. A. Soto, L. L. Presley, R. Reliene , A. M. Westbrook , B. Wei , A. Loy , C.r Chang , J. Braun , J. Borneman, R. H. Schiestl (2013) Intestinal bacteria modify lymphoma penetrance in genetically susceptible mice via inflammation-mediated systemic host oxidative stress and leucocyte genotoxicity- Cancer Research 73(14):4222-4232 July 15, 2013 PMCID: PMC3718495
- Westbrook, A. and R.H. Schiestl (2010) Atm deficient mice exhibit increased sensitivity to dextran sulfate sodium-induced colitis characterized by elevated DNA damage and persistent immune activation. Cancer Research 70, 1875, March 1, 2010. PMCID: PMC2831166