"This study provides insights into the mutually beneficial partnerships forged between mammals and their native microbes," says principal investigator Jeffrey I. Gordon, M.D., the Dr. Robert J. Glaser Distinguished University Professor and head of the Department of Molecular Biology and Pharmacology. "These symbiotic relationships probably are most important in the gut, which contains the largest and most complex collection of bacteria."
Gordon's team found that a key developmental program – orchestrating formation of blood vessels in the gut following birth – is a responsibility shared by intestinal bacteria and their host. The study appears in the November 5 issue of the Proceedings of the National Academy of Sciences; Thaddeus S. Stappenbeck, M.D., Ph.D., instructor of molecular biology and pharmacology, is first author and Lora Hooper, Ph.D., instructor of molecular biology and pharmacology, is co-author.
The team examined three groups of six-week-old male mice. One group of animals was reared with normal bacteria; another group was reared without any intestinal bacteria; a third group began bacteria-free but then were colonized with microbes taken from intestines of normal mice.
An imaging technique called confocal microscopy provided three-dimensional images of sections of intestinal tissue taken from each group of animals. The images offer a clear view of cells and blood vessels in tissue samples, and allow investigators to measure the density of capillaries, small blood vessels in the wall of the intestine.
In mice lacking intestinal bacteria, blood vessel formation stopped early during postnatal development. Remarkably, this developmental program restarted and was completed just 10 days after implanting microbes into bacteria-free mice.
Moreover, colonization by one particular type of bacteria commonly found in normal mouse and human intestine, called Bacteroides thetaiotaomicron, or B. thetaiotaomicron, stimulated blood vessel development as efficiently as implantation of a whole microbial society.
The researchers also examined the pathway by which bacteria influence blood vessel formation. They engineered mice lacking Paneth cells, normal components of the intestinal lining that help defend the body against attacks by harmful bacteria. Without Paneth cells, blood vessels could not completely develop, even when microbes such as B. thetaiotaomicron were introduced. The team concluded that B. thetaiotaomicron and Paneth cells work together to stimulate postnatal blood vessel formation.
"Our findings illustrate the importance of co-evolution of animals and their microbial partners," says Gordon. "Bacteria that live in the intestine appear to provide mammals with several necessary services for healthy development. Unraveling the molecular foundations of these relationships may provide new ways of preventing or treating a variety of diseases."
Stappenbeck TS, Hooper LV, Gordon JI. Developmental regulation of intestinal angiogenesis by indigenous microbes via Paneth cells. Proceedings of the National Academy of Sciences, November 5, 2002.
Funding from the National Institutes of Health, AstraZeneca and the Burroughs-Wellcome Foundation supported this research.
The full-time and volunteer faculty of Washington University School of Medicine are the physicians and surgeons of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient-care institutions in the nation. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC HealthCare.
Journal
Proceedings of the National Academy of Sciences