Gut Enzyme Causes Inflammation in Ulcerative Colitis

Gut bacteria , gut flora, microbiome. Bacteria inside the small intestine, concept, representation. 3D illustration.
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In a new study, researchers at Rutgers University-Newark have discovered that the gut enzyme lysozyme known to stop bacterial growth in the large intestine of people with ulcerative colitis, instead stimulates inflammation.

Their findings were recently published in the journal Immunity in a paper entitled “Paneth Cell-Derived Lysozyme Defines the Composition of Mucolytic Microbiota and the Inflammatory Tone of the Intestine,” and led by Nan Gao, Ph.D., associate professor of cell biology in the department of biological sciences, School of Arts and Sciences-Newark.

“This study demonstrated the existence of a delicate balance between inflammatory and anti-inflammatory factors in our intestines,” said Gao, who conducted it with postdoctoral researcher Richard Yu and doctoral student Iyshwarya Balasubramanian. “Insights about how to gain such beneficial immune balance may be useful for future intervention of inflammatory bowel disease.”

Ulcerative colitis is an inflammatory bowel disease that causes long-lasting inflammation and ulcers in the digestive tract. In North America, ulcerative colitis affects approximately 40 to 240 in 100,000 people. It is estimated that more than 750,000 North Americans are affected by this disorder.

“This study demonstrated the existence of a delicate balance between inflammatory and anti-inflammatory factors in our intestines,” said Gao, who conducted it with postdoctoral researcher Richard Yu and doctoral student Iyshwarya Balasubramanian. “Insights about how to gain such beneficial immune balance may be useful for future intervention of inflammatory bowel disease.”

In biochemical and genetic mouse laboratory studies, Gao and the researchers focused on Paneth cells, the main producers of lysozyme, which are typically found in the small intestine and rarely observed in the large intestine or healthy colon.

“Paneth cell metaplasia in this region and aberrant lysozyme production are hallmarks of inflammatory bowel disease (IBD) pathology. Here, we examined the impact of aberrant lysozyme production in colonic inflammation. Targeted disruption of Paneth cell lysozyme (Lyz1) protected mice from experimental colitis,”write the investigators.

The intestinal Paneth cells limit bacterial invasion by secreting antimicrobial proteins including lysozyme.The researchers discovered that lysozyme secreted by Paneth cells located in the colon results in suppressing the growth of certain bacterial species and results in an imbalance in the gut microbiome which leads to intestinal inflammation.

Lyz1-deficiency diminished intestinal immune responses to bacterial molecular patterns and resulted in the expansion of lysozyme-sensitive mucolytic bacteria, including Ruminococcus gnavus, a Crohn’s disease-associated pathobiont. Ectopic lysozyme production in colonic epithelium suppressed lysozyme-sensitive bacteria and exacerbated colitis. Transfer of R. gnavus into Lyz1 −/− hosts elicited a type 2 immune response, causing epithelial reprograming and enhanced anti-colitogenic capacity. In contrast, in lysozyme-intact hosts, processed R. gnavus drove pro-inflammatory responses. Thus, Paneth cell lysozyme balances intestinal anti- and pro-inflammatory responses, with implications for IBD,” noted the researchers.

In individuals that have normal production of gut lysozyme, these bacteria flourish enabling an individual immune response that prevents colitis.

“This delicate balance is achieved and maintained by a constant interaction between our body and the commensal microorganisms that play a significant role in digestion, metabolism, and the immune system,” explained Gao.

Their findings may help develop future treatments for inflammatory bowel disease.

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