Using a two-pronged strategy, gut microbes first break down otherwise indigestible dietary components, effectively increasing the amount of calories we can harvest; then they promote fat storage from the harvested calories.
The research team found that the gut microbes promote fat storage by suppressing the gut's production of a protein called fasting-induced adipocyte factor (Fiaf). Fiaf functions to help keep the gates to fat cells closed.
The findings will be reported in the Nov. 2, 2004 issue of the Proceedings of the National Academy of Sciences and are currently available online.
"Finding that Fiaf is directly manipulated by the gut microbiota is intriguing," says senior author Jeffrey Gordon, M.D. "It raises the possibility that an individual's predisposition to obesity or leanness may be partly determined by the composition of the microbes living in the gut."
Gordon is the Dr. Robert J. Glaser Distinguished University Professor and director of the new Center for Genome Sciences--the Center was launched as part of BioMed 21, the University's initiative for using the latest knowledge of the human genome to develop new ways to diagnose, treat and ultimately prevent a variety of human diseases.
Treatments for obesity that require long-term dietary changes almost always fail. According to Gordon, this research suggests that derivatives of Fiaf could potentially become therapeutic agents.
"We uncovered the importance of Fiaf by studying mice raised without ever being exposed to microorganisms. These so-called germ-free mice eat 30 percent more than normal mice yet have 50 percent less body fat," says Fredrik Bäckhed, Ph.D., postdoctoral research scholar in the Center for Genome Sciences. In the germ-free mice, no microorganisms were present to suppress production of Fiaf in gut lining cells, allowing this circulating protein to work to limit fat storage in distant fat cells.
After exposure to the normal community of gut microbes, the previously germ-free mice increased their fat stores by a remarkable 60 percent in just two weeks, even as they began to consume less food. As do people who gain fat, the mice also became insulin resistant.
The response of Fiaf to microbes is an ancient one. The research team's studies of germ-free zebrafish have documented a similar suppression of Fiaf when these fish are exposed to gut microbes.
"Fiaf is one of many host factors that we are finding to be influenced by gut microbes," Gordon says. "There are 10-100 trillion microbes coexisting in the adult human gut, and this vast community of microbes has evolved ways of manipulating our biology to benefit themselves and us."
In fact, Gordon prefers to think of the gut microbiota as one of the body's organs, one exquisitely attuned to our physiological needs. "Over their millions of years of coevolution with us, microbes have learned to manipulate networks of human genes," Gordon says. "By defining these networks, we can learn 'new ways' to promote health."
As a result of such research, physicians may one day opt to make specific changes in the mixture of a person's gut microorganisms to improve heath or use the natural products that gut microbes manufacture as therapeutic agents.
"With our research, we take a broad view of our genetic landscape," Gordon says, "one that recognizes that based on cell number, each of us is 90 percent microbial and 10 percent human. The genomes of our gut microbes probably contain 100 times more genes than our own genome, providing us with traits we haven't needed to develop on our own."
Bäckhed F, Ding H, Wang T, Hooper LV, Koh GY, Nagy A, Semenkovich CF, Gordon JI. The gut microbiota as an environmental factor that regulates fat storage. Proc. Natl. Acad. Sci., Nov. 2, 2004.
Funding from the National Institutes of Health and the Canadian Institute of Health Research supported this research.
Washington University School of Medicine's full-time and volunteer faculty physicians also are the medical staff 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, currently ranked second in the nation by U.S. News & World Report. 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