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Research from McCormick lab identifies new link between microbiome and intestinal function

Discovery brings scientists closer to developing new treatments for inflammatory diseases of the gut

By Jim Fessenden

UMass Chan Medical School Communications

November 12, 2021

Scientists from UMass Chan Medical School and the University of Bath have identified a new connection between molecules produced by the microbiome and the function of a human protein that impacts gut inflammation. These findings offer a new direct connection between the microbiome and intestinal function, bringing investigators one step closer to understanding how a good balance of microbes in our guts is linked to the body’s immune system and intestinal health. It also raises the possibility of new treatments to manage debilitating inflammatory diseases of the gut, such as ulcerative colitis and Crohn’s disease.

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Beth McCormick, PhD

“Achieving new breakthroughs in the biomedical microbiome sciences field needs to go beyond correlative studies. In order to gain a better understanding of the microbiome’s impact on health and disease, we need to identify the specific molecules that contribute to health and disease, as well as how all these signals are integrated in the complex intestinal environment,” said Beth McCormick, PhD, the Worcester Foundation for Biomedical Research Chair II, vice chair and professor of microbiology & physiological systems and director of the UMass Center for Microbiome Research. “Our work is taking important steps in this direction. For the first time we established a mechanistic link between the microbiome community and host mucosal surface to promote gastrointestinal homeostasis and suppress inflammation.”

“Ultimately, understanding the mechanism by which certain microbiota members promote health in the intestine brings us one step further in the development of therapies with the goal of modulating the microbiota to prevent or alleviate certain diseases, such as ulcerative colitis,” said Dr. McCormick.

Distinct microbial communities live in and on nearly every part of the human body, including on the skin, in the nose and in the gut. These microbes live symbiotically with the host and are essential for our bodies to function. No two humans have the same microbiome. The gut microbiome is the collection of microorganisms (including bacteria) that live in a person’s intestine. There are more than 100 trillion different microbial organisms in our gut—that’s 10 times more than all the human cells in a body. The composition of the gut microbiome is largely dependent on the microbes passed on to us from birth and the diet that we eat.

Correlative studies have established the existence of a connection between the microbiome and health. However, how exactly the microbiome affects health is still poorly understood. In this study, published in Microbiome, McCormick and colleagues identify specific classes of microbes that produce core molecules that are important for regulating levels of P-glycoprotein (P-gp) in the gut and its ability to function.

Found on the cell surface, P-gp is responsible for waste removal—pumping foreign matter, debris and toxins out of the cell. This helps promote the health of the intestinal lining. In the presence of good bacteria, P-gp helps suppress unnecessary inflammation and maintains a state of equilibrium. Conversely, when the intestine encounters potential pathogens, it alerts the immune system to activate pro-inflammatory pathways in the intestine, and P-gp is downregulated while the infection is cleared. Dysregulation of this important protein has been shown to contribute directly to inflammatory disorders of the intestine.

Yet, despite an understanding of the role of P-gp, the mechanisms controlling its expression and regulation have remained unknown. In this study, authors identified short-chain fatty acids and secondary bile acids produced by the Clostridia and Bacilli classes of bacteria that exist in the gut in healthy quantities only when these microbes are given the right conditions to thrive. These short-chain fatty acids and secondary bile acids, when present, prompt an increase of P-gp to release potent anti-inflammatory compounds into the gut.

This work shows a definitive cause and effect link between the health of gut bacteria and the functioning of human protein, P-gp, that impacts human health and the immune system.

“We are excited to find that not only is there a link between the gut microbiome and P-gp regulation in the intestine, but that two classes of microbial molecules actually work together to trigger expression of P-gp,” said study first author Sage Foley, a doctoral student in the Morningside Graduate School of Biomedical Sciences and a member of the McCormick lab.

Co-author Randy Mrsny, PhD, professor of pharmacy & pharmacology at the University of Bath said, “The upshot of this research is that we now know the specific molecules produced by the microbiome bacteria that are linked to P-gp, and hence, a healthy intestine. These molecules work in concert to stimulate P-gp to increase the release of molecules that suppress intestinal inflammation.”

The team’s findings provide new opportunities for the management of inflammatory intestinal diseases. Future treatments could include the delivery of specific bacteria or bacterial products to a person’s gut, or dietary changes that would support a microbiome to promote or sustain P-gp expression in the intestine, thereby protecting against unwanted inflammation.

In the intestine, Clostridia and Bacilli bacteria contribute to the digestion of food elements, such as fiber and green leafy vegetables. It is possible that dietary changes that nurture these bacteria can have a positive impact on health. Conversely, this balance may also be disturbed by changes in diet. A diet high in simple sugars and fats, and low in plant-based protein, has been associated with a decrease in the quantities of bacteria in the gut that produce short-chain fatty acids and secondary bile acids. This in turn may result in unregulated inflammation in the gut.

“This highlights the importance of a functioning core microbial community to have maximal impact on the human body,” added Foley. “While even within an individual the relative abundance of microbes can fluctuate, we’re beginning to understand the importance of nourishing the microbial community as a whole. Though there is still much to explore, we suspect this may be possible through changes to the diet or through the delivery of groupings of microbes.”

McCormick and colleagues have not established exactly how these molecules influence the production of P-gp, but the McCormick lab plans to examine the role these molecules play in gene and protein regulation in future work.

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