Effects of Radiation on the Microbiota and Intestinal Inflammatory Disease
Abstract
This project addresses the Fiscal Year 2014 Peer Reviewed Medical Research Program (FY14 PRMRP) Topic Area "Illnesses Related to Radiation." Exposure to radiation leads to immediate damage to tissue and the health risks associated with that damage as well to more long-term, or delayed, health risks. When thinking about long-term radiation risks, most people think about cancer, but there are other important risks. In fact, radiation therapy is commonly used to treat cancer, and these risks often define the limits of therapy that can be applied. This project focuses on the gastrointestinal effects of radiation exposure. Acute, high-dose radiation exposure to the intestines can lead rapidly to symptoms including fever, nausea, vomiting, and diarrhea. Radiation therapy for tumors in the abdominal and pelvic regions can cause the same effects, present considerable risks to patients, lead to increases in the time patients must spend in the hospital, and increase costs associated with treatment. Many patients, even those with minimal acute symptoms, will develop long-term gastrointestinal consequences of irradiation including permanent changes to bowel function and intestinal fibrosis, which can cause strictures or even bowel obstructions. Patients with inflammatory bowel disease (including over 40,000 U.S. Veterans, and another FY14 PRMRP Topic Area) are at increased risk of intestinal damage when exposed to radiation, and this is a significant impediment to providing effective radiation therapy for abdominal or pelvic tumors in this population. Despite its prevalence and significant morbidity, there are currently no approved therapies to prevent or treat this intestinal pathology other than to manage the symptoms until they go away. The mechanisms by which radiation exposure makes patients more susceptible to intestinal inflammatory disease are not clear. Historically, radiation-induced injury to the cells lining the gut has been viewed as the cause. However, more recent studies have begun to implicate our own intestinal immune cells and the microbes that live in our guts as key factors. In fact, ground-breaking experiments in the 1960s with "germ-free" mice (mice raised in a perfectly sterile "bubble" environment) revealed that the animals are substantially protected from radiation-induced intestinal damage. When discussing the microbial makeup of the intestines, most people (including scientists) think about bacteria. In every person there are over 100 trillion bacteria in the gut representing hundreds of different species. Numerous studies have demonstrated that bacterial composition of the gut is an important factor in health and susceptibility to intestinal inflammatory disease (including radiation-induced susceptibility to intestinal inflammatory disease). We have recently documented that the healthy gut also contains a diverse population of fungi and that immune responses to fungi can be a significant factor in intestinal inflammation in mouse models and in humans. The experiments proposed in this application will examine the relationships between bacteria and fungi and immune cells in the intestines in the context of radiation exposure and radiation-induced susceptibility to inflammatory disease in the intestines using a novel mouse model. Most studies on radiation exposure in mice relate to whole body exposure. While this is useful when trying to understand whole body irradiation, doses are limited by the lethality of the exposure. Much more common in people is exposure of a small area of the body to radiation, and in this context the doses can be much higher and can be exploited for anti-cancer therapy. We have developed an approach for focally irradiating the mouse abdomen to model this type of exposure. We have developed novel approaches for defining the fungi found in the gut to complement existing approaches for characterizing bacterial communities. We will (1) evaluate the coordinated
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 29, 2016
- Source ID
- W81XWH1510300
Entities
People
- David M Underhill
Organizations
- Cedars-Sinai Medical Center
- United States Army