Happy Bacteria, Happy Epithelia: How Gut Microbiota Help Suppress Inflammation

by Pauline Hughes, Contributing Writer

Your intestines are teeming with microorganisms. But, not to worry; these microorganisms, known as the intestinal microbiota, are incredibly important to your health as they help digest food, produce vitamins, and create other molecules needed for your organs to work properly1. New research has even found that the microbiota play an important role in protecting us from disease by regulating the immune system.

The inside of your intestinal tract is lined with epithelial cells that separate the microbiota residing in the gut cavity from the underlying tissue. The intestinal epithelium acts as a barrier to maintain a healthy give-and-take relationship between gut microbiota and host immunity. However, perturbations to the barrier’s function can lead to immune responses resulting in intestinal inflammation1.

Chronic inflammation of this sort is seen in inflammatory bowel diseases such as ulcerative colitis and Crohn’s disease. These diseases are characterized by inflammation of the gastrointestinal tract leading to tissue damage. They are attributed to the interaction of genetic and environmental factors along with abnormal immune responses caused by disturbances to microbiota. While Crohn’s disease can affect anywhere along the gastrointestinal tract (from the mouth to the anus), it occurs most commonly in either the small intestine, large intestine, or both. Patients with Crohn’s disease often have symptoms of abdominal pain, diarrhea, fever, and weight loss.  Ulcerative colitis affects the large intestine and causes uncontrolled inflammation of the epithelial lining. Patients affected by the disease experience similar symptoms to those with Crohn’s disease, with the additional symptoms of rectal bleeding and bloody diarrhea2. Incidences of inflammatory bowel diseases worldwide have been on the rise over the past several decades, especially in places where they were once uncommon3. Hence, understanding exactly how these diseases arise is crucial.

In a 2021 study, researchers at the University of Massachusetts Chan Medical School were able to determine how certain bacteria of the gut microbiome help maintain balance in this relationship by driving the expression of a protein that suppresses over-inflammation4. The protein in question, P-glycoprotein (P-gp), is found in the membrane of epithelial cells. It pumps foreign substances, such as toxins and drugs, out of the cells. P-gp also suppresses the movement of a type of immune cell called the neutrophil across the epithelium. As the body’s first line of defence against invading pathogens, neutrophils are essential to the immune system. However, they can play a dual role in the body, capable of killing harmful microbes, but also of damaging healthy tissue in the gut5. In a healthy gut, where there is normal P-gp expression in epithelial cells, P-gp regulates the movement of neutrophils across the epithelium to modulate immune responses to microbiota and maintain the balance. A lack of P-gp in the gut leads to an accumulation of neutrophils that damage the cells and cause inflammation. Reduced P-gp expression is observed in patients with ulcerative colitis6. The inflammatory bowel disease is also associated with disturbances in the microbiome, as well as reduced concentration of certain metabolic end-products. This new study puts together the pieces to explain how these conditions are linked to one another in the manifestation of ulcerative colitis.

To determine if elements of the bacterial community play a role in inducing P-gp expression, the researchers treated mice with various antibiotics to clear a subset of the bacteria in their intestines. They discovered that mice treated with the antibiotic vancomycin had significantly reduced P-gp expression. From these experiments, they concluded that these vancomycin-sensitive bacteria help drive P-gp expression. But how?

To answer this, the researchers then went on to sequence the DNA of microbiota communities treated with vancomycin, which had low P-gp expression, and untreated communities with normal P-gp expression. Comparing the two groups, they determined two metabolic end-products made by gut bacteria that correlated with P-gp expression. By activating receptors and signaling pathways, these metabolic end-products induced P-gp expression and were essential to the proper functioning of the intestinal epithelium.

From the findings of their study, the researchers proposed a model in which elements of the gut microbiota in other organisms, including humans, produce metabolic end-products that promote the expression of functional P-gp. This P-gp suppresses neutrophil migration and pumps out foreign substances to prevent the over-inflammation of the intestines. This deeper understanding of the mechanisms underlying over-inflammation in the gut can provide valuable insight into the promotion of good gut health, as well as into the management and treatment of chronic inflammatory conditions like ulcerative colitis.

Edited by Muhammad Shahzad

References

1. Okumura, R., & Takeda, K. (2017). Roles of intestinal epithelial cells in the maintenance of gut homeostasis. Experimental & Molecular Medicine, 49(e338).      https://doi.org/10.1038/emm.2017.20

2. Thoreson, R., & Cullen, J.J. (2007). Pathophysiology of Inflammatory Bowel Disease: An Overview. Surgical Clinics of North America, 87(3), 575-585. https://doi.org/10.1016/j.suc.2007.03.001

3. Molodecky, N. A., Soon, I. S., Rabi, D. M., Ghali, W. A., Ferris, M., Chernoff, G., Benchimol, E.I., Panaccione, R., Ghosh, S., Barkema, H.W., & Kaplan, G. G. (2012). Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review. Gastroenterology, 142(1), 46-54.e42. https://doi.org/10.1053/j.gastro.2011.10.001

4. Foley, S.E., Tuohy, C., Dunford, M. Grey, M.J., De Luca, H., Cawley, C., Szabady, R.L., Maldonado-Contretas, A., Houghton, J.M., Ward, D.V., Mrsny, R.J., & McCormick, B.A. (2021). Gut microbiota regulation of P-glycoprotein in the  intestinal epithelium in maintenance of homeostasis. Microbiome, 9(183). https://doi.org/10.1186/s40168-021-01137-3

5. Fournier, B., & Parkos, C. (2012). The role of neutrophils during intestinal inflammation. Mucosal Immunol, 5, 354–366. https://doi.org/10.1038/mi.2012.24

6. Blokzijl, H., Vander Borght, S., Bok. L.I.H., Libbrecht, L., Geuken, M., van den Heuvel, F.A.J., Dijkstra, G., Roskams, T.A.D., Moshage, H., Jansen, P.L.M., & Nico Faber, K. (2007). Decreased P-glycoprotein (P-gp/MDR1) expression in inflamed human intestinal epithelium is independent of PXR protein levels. Inflammatory  Bowel Diseases, 13(6), 710–20. https://doi.org.proxy3.library.mcgill.ca/10.1002/ibd.20088.

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