MedicalResearch.com Interview with:
Dr. Sridhar Mani MD
Departments of Genetics and Medicine
Albert Einstein College of Medicine
Bronx, NY 10461
Medical Research: What are the main findings of the study?
Dr. Mani: In a series of studies using cells grown in the lab and mouse studies, the researchers found that a metabolite called indole 3-propionic acid (IPA)—produced exclusively by so-called commensal bacteria —both strengthens the intestinal epithelium’s barrier function and prevents its inflammation by activating an orphan nuclear receptor, Pregnane X Receptor (PXR). Specifically, PXR activation suppresses production of an inflammatory protein called tumor necrosis factor alpha (TNF-á) while increasing levels of a protein that strengthens the junctions between intestinal epithelial cells (makes the intestines less permeable to noxious substances). Loss of PXR protein and/or IPA results in a disrupted intestinal barrier and increased propensity towards intestinal inflammation and/or toxin induced injury to the intestines.
Medical Research: Were any of the findings unexpected?
Dr. Mani: While it was suspected that IPA could potentially activate PXR, it turns out that multiple forms of the metabolite is needed to activate the human form of PXR. Furthermore, since PXR knockout mice develop normally, we did not expect to find much in the way of intestinal damage or other issues in their intestines. Our study revealed very specific but subclinical damage to the intestinal epithelium that explained why these mice were very susceptible to inflammation and toxin induced injury. The fact that a single toll-like receptor (TLR4) might be critical in mediating these effects, even though several TLRs were up-regulated was a surprise.
Medical Research: What should clinicians and patients take away from your report?
Dr. Mani: Commensal bacteria might be very important in maintaining a good intestinal barrier. Indiscriminate use of drugs (antibiotics) or even food agents (that could potentially down-regulate or antagonize PXR) could be harmful to patients who are at risk for developing intestinal inflammation.
Medical Research: What recommendations do you have for future research as a result of this study?
Dr. Mani: In the future, after much work is done to confirm this observation in humans, adding probiotics in the form of IPA-producing bacteria to the intestine or by administering IPA analogs directly, we may be able to prevent or treat IBD and other inflammatory disorders that occur when the intestinal epithelium has been compromised. Indeed if research confirms that the barrier function is important in other diseases ( certain forms of liver disease, diabetes, asthma, allergies), such strategies may have very broad applicability for medicine.