New Research Identifies Cause of Inflammatory Bowel Disease

New Research Identifies Cause of Inflammatory Bowel Disease

Maintaining a healthy gut microbiota is important for the health of the whole body. Many studies have been conducted on the importance of maintaining a good balance of microbes in the gut – a good summary of research was published in Therapeutic Advances in Gastroenterology in 2013¹ – which pulled together various research studies that suggested a link between gut microbiota and gut conditions and diseases such as irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), colorectal cancer, and diabetes.

IBD is thought to be triggered by environmental factors that affect gut microbiota, but what those factors are and how they trigger IBD is poorly understood. However, new research by scientists in the United Kingdom and United States has cast new light on how IBD can be triggered.

The microbial toxin microcin B17 has been extensively studied and has been shown to trigger gastrointestinal inflammation. The research teams at Brigham and Women’s Hospital, Harvard Medical School, and the UK’s John Innes Centre also discovered compounds structurally related to microcin B17 can also trigger gut inflammation by modifying the activity of the histocompatibility complex (MHC) molecule, CD1d. CD1d is found in intestinal epithelial cells (IECs) and hematopoietic cells and presents lipid antigens to natural killer T (NKT) cells.

Previous research has also shown a compound called oxazolone can cause colitis in animal models, and further research has shown that oxazolone-induced colitis is dependent on CD1d and NKT cells. Commensal bacteria can have an impact on NKT responses and CD1d.

The US team of researchers thought oxazolone could be just one of a large group of compounds that could trigger CD1d-restricted NKT cell responses, and uncovered several other compounds from dietary, industrial, and microbial sources that could similarly drive CD1d-dependent inflammation by activating the aryl hydrocarbon receptor pathway in colonic IECs.

The compounds – which also contain a five-membered oxazole ring – were found in meat, coffee, and peanuts and could trigger weight loss and an inflammatory gut response in mice. Non-dietary sources of these compounds included thiazole-/oxazole-modified microcins (TOMMs) – a class of bacterial-derived antimicrobial toxins. Microcin B17 is one compound in this group that can trigger an inflammatory gut response, which the researchers obtained from intestinal Escherichia coli.

The identification of the E. Coli microcin B17 as an IBD trigger was a chance finding, according to Tony Maxwell, Ph.D. from the John Inness Centre. “We have been studying this toxin for its antibacterial properties and we were contacted by Richard Blumberg, who leads the Boston group for quite different reasons—they thought there might be a connection between the toxin and IBD.”

The research supports the theory that exposure to oxazole-containing compounds results in transcriptional changes in the intestinal epithelium. That influences CD1d-restricted antigen presentation pathways and increases NKT cell inflammatory responses, ultimately leading to the development of colitis.

“These findings will advance our understanding of how gut inflammation associated with IBD may be triggered and offer new hope of potential future therapy,” said Fred Collin, Ph.D., a researcher in Maxwell’s Lab.

The study – Dietary and Microbial Oxazoles Induce Intestinal Inflammation by Modulating Aryl Hydrocarbon Receptor Responses – was recently published in the journal Cell.

¹ Role of the gut microbiota in health and chronic gastrointestinal disease: understanding a hidden metabolic organ, Caitriona M. Guinane & Paul D. Cotter. Therap Adv Gastroenterol. 2013 Jul; 6(4): 295–308. DOI:  10.1177/1756283X13482996

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