Microbial regulation of intestinal radiosensitivity.

We describe a method for treating germ-free (GF) mice with gamma-irradiation and transplanting them with normal or genetically manipulated bone marrow while maintaining their GF status. This approach revealed that GF mice are markedly resistant to lethal radiation enteritis. Furthermore, administering lethal doses of total body irradiation to GF mice produces markedly fewer apoptotic endothelial cells and lymphocytes in the mesenchymal cores of their small intestinal villi, compared with conventionally raised animals that have acquired a microbiota from birth. Analysis of GF and conventionally raised Rag1-/- mice disclosed that mature lymphocytes are not required for the development of lethal radiation enteritis or the microbiota-associated enhancement of endothelial radiosensitivity. Studies of gnotobiotic knockout mice that lack fasting-induced adipose factor (Fiaf), a fibrinogen/angiopoietin-like protein normally secreted from the small intestinal villus epithelium and suppressed by the microbiota, showed that Fiaf deficiency results in loss of resistance of villus endothelial and lymphocyte populations to radiation-induced apoptosis. Together, these findings provide insights about the cellular and molecular targets involved in microbial regulation of intestinal radiosensitivity.

[1]  E. Purdom,et al.  Diversity of the Human Intestinal Microbial Flora , 2005, Science.

[2]  A. Haimovitz-Friedman,et al.  ATM regulates target switching to escalating doses of radiation in the intestines , 2005, Nature Medicine.

[3]  T. Macdonald,et al.  Immunity, Inflammation, and Allergy in the Gut , 2005, Science.

[4]  F. Bäckhed,et al.  Host-Bacterial Mutualism in the Human Intestine , 2005, Science.

[5]  Ting Wang,et al.  The gut microbiota as an environmental factor that regulates fat storage. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[6]  Guoqing Yang,et al.  Oligomerization state-dependent hyperlipidemic effect of angiopoietin-like protein 4 Published, JLR Papers in Press, August 1, 2004. DOI 10.1194/jlr.M400138-JLR200 , 2004, Journal of Lipid Research.

[7]  L. Yao,et al.  Mast cell-derived angiopoietin-1 plays a critical role in the growth of plasma cell tumors. , 2004, The Journal of clinical investigation.

[8]  W. Wahli,et al.  The Direct Peroxisome Proliferator-activated Receptor Target Fasting-induced Adipose Factor (FIAF/PGAR/ANGPTL4) Is Present in Blood Plasma as a Truncated Protein That Is Increased by Fenofibrate Treatment* , 2004, Journal of Biological Chemistry.

[9]  B. Lévy,et al.  Aldosterone Enhances Ischemia-Induced Neovascularization Through Angiotensin II–Dependent Pathway , 2004, Circulation.

[10]  R. Kammerer,et al.  Designed angiopoietin-1 variant, COMP-Ang1, protects against radiation-induced endothelial cell apoptosis. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[11]  J. Gordon,et al.  Gnotobiotic zebrafish reveal evolutionarily conserved responses to the gut microbiota. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[12]  S. Rabot,et al.  Protective effects of Brussels sprouts, oligosaccharides and fermented milk towards 2-amino-3-methylimidazo[4,5-f]quinoline (IQ)-induced genotoxicity in the human flora associated F344 rat: role of xenobiotic metabolising enzymes and intestinal microflora. , 2004, Journal of chromatography. B, Analytical technologies in the biomedical and life sciences.

[13]  A. Macpherson,et al.  Induction of Protective IgA by Intestinal Dendritic Cells Carrying Commensal Bacteria , 2004, Science.

[14]  J. Loscalzo,et al.  Hypoxia Potentiates Nitric Oxide-mediated Apoptosis in Endothelial Cells via Peroxynitrite-induced Activation of Mitochondria-dependent and -independent Pathways* , 2004, Journal of Biological Chemistry.

[15]  Guoqing Yang,et al.  Oligomerization and Regulated Proteolytic Processing of Angiopoietin-like Protein 4* , 2004, Journal of Biological Chemistry.

[16]  Pierre Corvol,et al.  Angiopoietin-like 4 is a proangiogenic factor produced during ischemia and in conventional renal cell carcinoma. , 2003, The American journal of pathology.

[17]  T. Graubert,et al.  Enhanced green fluorescent protein targeted to the Sca-1 (Ly-6A) locus in transgenic mice results in efficient marking of hematopoietic stem cells in vivo. , 2003, Experimental hematology.

[18]  Jeffrey I. Gordon,et al.  Developmental regulation of intestinal angiogenesis by indigenous microbes via Paneth cells , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[19]  S. Rabot,et al.  Metabolism of sinigrin (2-propenyl glucosinolate) by the human colonic microflora in a dynamic in vitro large-intestinal model. , 2002, Carcinogenesis.

[20]  J. Gordon,et al.  29 Combining gnotobiotic mouse models with functional genomics to define the impact of the microflora on host physiology , 2002 .

[21]  Z. Somosy,et al.  Morphological aspects of ionizing radiation response of small intestine. , 2002, Micron.

[22]  P. Sansonetti,et al.  Molecular cellular microbiology , 2002 .

[23]  J. Gordon,et al.  How host-microbial interactions shape the nutrient environment of the mammalian intestine. , 2002, Annual review of nutrition.

[24]  Zvi Fuks,et al.  Endothelial Apoptosis as the Primary Lesion Initiating Intestinal Radiation Damage in Mice , 2001, Science.

[25]  Wei Zheng,et al.  Vascular Endothelial Growth Factor and Basic Fibroblast Growth Factor Differentially Modulate Early Postnatal Coronary Angiogenesis , 2001, Circulation research.

[26]  T. Billiar,et al.  Nitric oxide as a bioregulator of apoptosis. , 2001, Biochemical and biophysical research communications.

[27]  Thomas N. Sato,et al.  Universal GFP reporter for the study of vascular development , 2000, Genesis.

[28]  Hong-Hee Kim,et al.  Hepatic expression, synthesis and secretion of a novel fibrinogen/angiopoietin-related protein that prevents endothelial-cell apoptosis , 2000 .

[29]  R. Weichselbaum,et al.  Blockade of the Vascular Endothelial Growth Factor Stress Response Increases the Antitumor Effects of Ionizing Radiation , 1999 .

[30]  P. Okunieff,et al.  In vivo radioprotective effects of angiogenic growth factors on the small bowel of C3H mice. , 1998, Radiation research.

[31]  I. Brook,et al.  Short and long courses of ofloxacin therapy of Klebsiella pneumoniae sepsis following irradiation. , 1992, Radiation research.

[32]  I. Brook,et al.  Effect of antimicrobial therapy on bowel flora and bacterial infection in irradiated mice. , 1988, International journal of radiation biology and related studies in physics, chemistry, and medicine.

[33]  D. Savage.  Gastrointestinal microflora in mammalian nutrition. , 1986, Annual review of nutrition.

[34]  D. Savage,et al.  Transit time of epithelial cells in the small intestines of germfree mice and ex-germfree mice associated with indigenous microorganisms , 1981, Applied and environmental microbiology.

[35]  K. Uchida,et al.  Effect of intestinal microflora on the survival time of mice exposed to lethal whole-body gamma irradiation. , 1981, Radiation research.

[36]  E. Livstone,et al.  The gastrointestinal microflora of irradiated mice. II. Effect of oral antibiotic administration on the colonic flora and survival of adult mice. , 1970, The Yale journal of biology and medicine.

[37]  T. Fliedner,et al.  A comparison of radiation-induced bone marrow degeneration in germfree and conventional mice. , 1970, Radiation research.

[38]  Kenneth A. Khoury,et al.  SMALL INTESTINAL MUCOSAL CELL PROLIFERATION AND BACTERIAL FLORA IN THE CONVENTIONALIZATION OF THE GERMFREE MOUSE , 1969, The Journal of experimental medicine.

[39]  R. Wilson.  The effects of micro-organisms on radiation pathology, and bone marrow therapy in wholebody irradiation. , 1968, The Journal of the American Osteopathic Association.

[40]  T. Matsuzawa.  SURVIVAL TIME IN GERMFREE MICE AFTER LETHAL WHOLE BODY X-IRRADIATION. , 1965, The Tohoku journal of experimental medicine.

[41]  D. Jacobus,et al.  EFFECTS OF THE GERMFREE STATE ON RESPONSES OF MICE TO WHOLE-BODY IRRADIATION. , 1964, Radiation research.

[42]  G. Sacher,et al.  Generation Cycle in the Duodenal Crypt Cells of Germ-Free and Conventional Mice , 1964, Nature.

[43]  G. Abrams,et al.  Influence of the normal flora on mucosal morphology and cellular renewal in the ileum. A comparison of germ-free and conventional mice. , 1963, Laboratory investigation; a journal of technical methods and pathology.