Good Bugs Gone Bad: Gut Immune Cells Keep Beneficial Microbes in Their Place, Says Penn Study

Good microbes that promote normal health can ‘turn bad’ if found outside the intestine

PHILADELPHIA – The healthy human intestine is colonized with over 100 trillion beneficial, or commensal, bacteria of many different species. In healthy people, these bacteria are limited to the intestinal tissues and have a number of helpful properties, including aiding in the digestion of food and promoting a healthy immune system.

However, when it comes to commensal bacteria, location is key. While commensal bacteria in the intestine provide positive effects, several chronic human diseases, including HIV/AIDS, inflammatory bowel disease, viral hepatitis, and obesity are associated with the spread of these intestinal commensal bacteria to the blood stream and other peripheral tissues, which can cause chronic inflammation. ‘Good bugs’ that promote normal health can ‘turn bad’ if found in the wrong location.

In earlier work, researchers from the Perelman School of Medicine at the University of Pennsylvania found that barrier surfaces -- the skin, gut, lung – are guarded by immune cells and limit the inner body’s exposure to viruses, bacteria, and parasites, as well as allergens and pollutants. But, how immune cells play a role in limiting the location of commensal bacteria to intestinal and other barrier sites remains unclear.

Now, David Artis, PhD, associate professor of Microbiology, and Gregory F. Sonnenberg, PhD, a postdoctoral researcher in the Artis lab, have identified that immune cells, called innate lymphoid cells, are resident in the intestinal tissues of healthy humans, mice, and non-human primates, and are critical in limiting the location of commensal bacteria. If the innate lymphoid cells are depleted in mice, commensal bacteria move to peripheral tissues and promote inflammation. The research appears this week in Science.

Remarkably, the commensal bacteria that were found in peripheral tissues were all members of a group called Alcaligenes, indicating that the immune system may have developed highly selective pathways to regulate containment of different groups of commensal bacteria. “A fundamental question that has puzzled researchers for many years is how did the human body evolve to accommodate all these commensal bacteria and keep them in their correct locations?,” asks Artis. “The indication from these studies is that the body may have many different pathways to limit the spread of commensal bacteria and these pathways may be tailored to specific types of bacteria.”

Supporting experiments in animal models, Alcaligenes-specific immune responses were associated with patients with Crohn's disease or progressive hepatitis C virus infection, two debilitating human diseases linked to the spread of commensal bacteria to systemic tissues. “The identification of systemic Alcaligenes-specific immune responses in these patient populations suggests that, coupled with other groups of bacteria, the spread of Alcaligenes to tissues outside the intestine may be contributing to chronic inflammation and disease progression,” suggests Sonnenberg.

Innate immune cells may become impaired in chronic human diseases, resulting in the spread of Alcaligenes bacteria and pathologic inflammation, which may represent a novel pathway to target in human disease, say the investigators.

“Although it’s still early days for this line of research, these findings suggest that targeting innate lymphoid cell responses or directly targeting specific groups of commensal bacteria may be useful in the treatment of some chronic inflammatory diseases,” adds Artis.

The research was funded by the National Institute of Allergy and Infectious Disease (AI061570, AI087990, AI074878, AI083480, AI095466, AI095608, T32-AI007532, T32-RR007063, K08-DK093784, AI47619); the NIH-funded Penn Center for AIDS Research (P30 AI 045008); the Burroughs Wellcome Fund Investigator in Pathogenesis of Infectious Disease Award; the Philadelphia VA Medical Research and Merit Review; and the American Gastroenterological Association.

Co-authors in addition to Artis and Sonnenberg are Laurel A. Monticelli, Theresa Alenghat, Thomas C. Fung, Natalie A. Hutnick, Stephanie Grunberg, Rohini Sinha, Adam M. Zahm, Ronald G. Collman, Abraham Shaked, David B. Weiner, Joshua R. Friedman, Frederic D. Bushman, and Kyong-Mi Chang, all from Penn, as well as Jun Kunisawa, Naoko Shibata, and Hiroshi Kiyono from the University of Tokyo; Mélanie R. Tardif, and Philippe A. Tessier from Laval University; Lynette A Fouser from Pfizer Worldwide R&D; and Taheri Sathaliyawala, Masaru Kubota, and Donna L. Farber from Columbia University.

Penn Medicine is one of the world's leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System, which together form a $4.3 billion enterprise.

The Perelman School of Medicine is currently ranked #2 in U.S. News & World Report's survey of research-oriented medical schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $479.3 million awarded in the 2011 fiscal year.

The University of Pennsylvania Health System's patient care facilities include: The Hospital of the University of Pennsylvania -- recognized as one of the nation's top 10 hospitals by U.S. News & World Report; Penn Presbyterian Medical Center; and Pennsylvania Hospital — the nation's first hospital, founded in 1751. Penn Medicine also includes additional patient care facilities and services throughout the Philadelphia region.

Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2011, Penn Medicine provided $854 million to benefit our community.

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