Frederic Bushman, Ph.D., James Lewis, M.D., M.S.C.E., and Gary Wu, M.D., are examining how diet influences the gut microbiome in people with Crohn’s disease.
for the development of IBD. And we know that the composition of the microbiota is abnormal in patients with IBD.” One way that the gut microbiome may influence the development of intestinal bowel disease is through the immune system. “A significant portion of our total immune system is associated with the gastrointestinal tract, so it’s an interaction between commensal microbes and the mammalian immune system that plays a critical role in balancing whether there is a state of health or a state of disease in the GI tract,” says Gregory Sonnenberg, Ph.D., research associate in the Division of Gastroenterology and the Institute for Immunology. And it’s not only the gut that is affected, he continues. “What’s going on in the gut also plays a key role in the health of the cardiovascular system, the liver, spleen, central nervous system, and other body systems.” Sonnenberg’s lab, in collaboration with the Artis lab, is studying how balance is maintained between commensal bacteria and the immune system. When this balance is disrupted, notes Sonnenberg, the immune system attacks commensal bacteria with an inflammatory response that may underlie many chronic diseases such as IBD, diabetes, cancer, and cardiovascular disease. His lab recently identified a previously unrecognized innate immune cell that appears to play a central role in regulating the balance be-
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tween commensal bacteria and the host. He believes that a better understanding of how this cell functions could lead to new therapies for chronic diseases.
Beyond bacteria in the gut Bacteria are not, of course, the only commensal organisms in the human gut. Viruses, fungi, and archaea (a distinct type of microorganism similar in some ways to bacteria) also inhabit the intestinal ecosystem. Bushman is especially interested in studying the predators that eat gut bacteria – a group of viruses called bacteriophage. Bacteriophage (or “phage”) are perhaps the most abundant organisms on the planet, far exceeding the number of bacteria. While humans carry around huge and diverse populations of bacteria in their guts, the number and diversity of gut bacteriophage particles is potentially even greater. Researchers like Bushman are just beginning to clarify the importance of phage in human disease. They are known to carry genes for toxins and antibiotics – and probably many other important genes involved in physiological processes, including metabolism. And because they move easily between different strains of bacteria, they are likely to have an enormous influence on the composition of the microbiota as well as the pathogenicity of various organisms.
In addition, it’s not just the gut microbiome that is important in human disease. Microbes colonize every barrier surface in the body. Even the lung, which was thought to be a sterile environment in healthy people, harbors low levels of bacteria, according to Ronald Collman, M.D. Collman, professor of medicine and co-director of the Penn Center for AIDS Research, became interested in the microbiome as a means of better understanding how HIV triggers lung complications in infected people. New technologies developed for studying the gut microbiome enabled Collman and colleagues to ask whether the immunodeficiency in AIDS patients may lead to changes in bacterial or fungal populations that could contribute to lung disease. But to answer these questions, the researchers first had to develop another new set of sampling and bioanalytic techniques to ensure that the gene sequences being analyzed came from the lung and not from cross-contamination from the upper respiratory tract or reagents. “These techniques enabled us to open up this set of questions and apply it not only to HIV infection but also the impact of bacteria in lung transplantation,” says Collman. “And we’re also using it to look for potential novel pathogens in diseases of unknown origin,” such as sarcoidosis, an inflammatory disease that can affect almost any organ but most commonly the lungs. Although research on the lung microbiome lags far behind that of the gut microbiome, the field is evolving quickly. As he says, “There’s a growing sense that even in diseases such as asthma, there may be changes in the microbiome with consequences for patients, but we aren’t there yet in terms of an overarching new vision.” Studies of the skin microbiome also lag behind the gut but are beginning to catch up, according to Elizabeth Grice, Ph.D., assistant professor of dermatology.