Researchers at Institut Hospital del Mar d’Investigacions Mèdiques (IMIM) in Barcelona, in collaboration with the Icahn School of Medicine at Mount Sinai in New York and other U.S. Institutions, have found that intestinal mucus not only acts as a physical barrier against commensal bacteria and dietary antigens, but also prevents the onset of inflammatory reactions against these agents. This fundamental property of mucus was unknown until now and its discovery could potentially improve the life of people suffering from inflammatory bowel disease.
Mucus is a colloidal gel produced by glands present in our mucosal surfaces, including the intestine. “Our body produces on average a liter of mucus every day. Despite its abundance, mucus has been poorly studied and thus very little is known about its composition, synthesis and functional properties. Part of the problem may be that mucus is traditionally viewed as a symbol of disease and thus represents an antivalue” explains Dr. Andrea Cerutti, ICREA Research Professor, coordinator of the research group in B Cell Biology at IMIM, Professor of Medicine at Mount Sinai and responsible for the study. “In addition, mucus is fundamentally ambiguous. Its fluidity exists in slow motion and there is sticky thickness in its liquidity. This ambiguity may have conditioned a depreciatory estimate of the value of mucus by physicians, who have often put forth every effort to brush, wash or dissolve away mucus as if it were an evil thing” adds Dr. Meimei Shan, the first author of the study and a collaborator of Dr. Cerutti at Mount Sinai in New York.
“Immunologists have always been interested in finding out why we do not develop an inflammatory reaction to the trillions of bacteria and large amounts of food antigens that come in contact with our intestinal mucosa. Yet, these same agents cause dangerous inflammatory reactions and even death when other parts of our body are exposed to them. The discovery published in this study helps to explain this long-standing question.” explains Maurizio Gentile, a PhD student in Dr. Cerutti’s lab and major contributor of this work.
The building block of gut mucus is the mucin MUC2. This molecule not only acts as a physical barrier, but also provides anti-inflammatory signals to dendritic cells, which is an immune cell type that regulates the health of our intestine and helps us to fight against bacteria and food antigens. Dr. Cerutti’s team used complex techniques involving cellular immunology and molecular biology to describe this process. “By showing the beneficial anti-inflammatory activity of mucus, our work opens up a broad field of research. The natural pharmacological properties of mucus might provide a promising complementary way to treat inflammatory bowel disease, including ulcerative colitis and Crohn’s disease” comments Dr. Linda Cassis, another member of the team involved in this research. A collaborator of Dr. Cerutti at IMIM, Dr. Anna Bigas, was instrumental to define a transcription factor of the anti-inflammatory signaling pathway activated by MUC2 in dendritic cells.
Ulcerative colitis and Crohn’s disease have an incidence in Spain of 125 cases out of 100,000 and more than 200 out of 100,000 inhabitants, respectively. Both are chronic pathologies that often affect young people whose quality of life is negatively impacted by major physical problems. Drugs for inflammatory bowel disease do exist, but are complicated by numerous collateral effects. Natural or synthetic mucus might offer a valuable adjuvant therapy that could permit to reduce the dose of currently available drugs, thus attenuating their side effects. However, further experimentation is needed to ascertain the therapeutic value of mucus. Laura Comerma, a physician in the Department of Pathology of Hospital del Mar and another member of the Cerutti lab, adds that “our discovery could also help people affected with food allergies, who indeed can develop gut inflammation besides asthma and dermatitis“.
In the future, efforts should concentrate on further exploring the mechanisms underlying the immunological function of mucus. Dr. Cerutti and his collaborator Dr. Montserrat Cols at Mount Sinai explain that “mucus is altered in patients with inflammatory bowel disease and thus attempts should also be made to artificially synthesize MUC2-derived compounds for oral administration that might be capable to mitigate the symptoms of these diseases”. Last but not least, the findings of this study may have ramifications in cancer. Indeed, some colon, ovarian and breast cancers produce mucus. Due to its anti-inflammatory properties, mucus produced by malignant cells may impair protective immune responses against the cancerous cells. Thus, a better understanding of the tolerogenic properties of mucus could also have a positive impact in the therapy of these tumors.
“Mucus Enhances Gut Homeostasis and Oral Tolerance by Delivering Immunoregulatory Signals” Meimei Shan, Maurizio Gentile, John R. Yeiser, A. Cooper Walland, Victor U. Bornstein, Kang Chen, Bing He, Linda Cassis, Anna Bigas, Montserrat Cols , Laura Comerma, Bihui Huang, J. Magarian Blander, Huabao Xiong, Lloyd Mayer, Cecilia Berin, Leonard H. Augenlicht, Anna Velcich, Andrea Cerutti. Science.
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