Microbial regulation of intestinal radiosensitivity
- Center for Genome Sciences and Departments of Molecular Biology and Pharmacology and Medicine, Washington University School of Medicine, St. Louis, MO 63108
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Edited by Kurt J. Isselbacher, Massachusetts General Hospital, Charlestown, MA (received for review June 9, 2005)
Abstract
We describe a method for treating germ-free (GF) mice with γ-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.
Footnotes
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↵ * To whom correspondence should be addressed. E-mail: jgordon{at}molecool.wustl.edu.
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Author contributions: P.A.C. and J.I.G. designed research; P.A.C. performed research; and P.A.C. and J.I.G. analyzed data and wrote the paper.
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This paper was submitted directly (Track II) to the PNAS office.
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Abbreviations: GF, germ-free; Fiaf, fasting-induced adipose factor; CONV-R, conventionally raised; CONV-D, conventionalized with a microbiota from a CONV-R donor; TBI, total body irradiation; BMT, bone marrow transplantation; TEM, transmission electron microscopy; iNOS, inducible nitric oxide synthase.
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Freely available online through the PNAS open access option.
- Copyright © 2005, The National Academy of Sciences
