Adherent-invasive E. coli metabolism drives inflammation in Crohn's disease

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By Marilynn Larkin

NEW YORK (Reuters Health) - Researchers have identified the process by which adherent-invasive Escherichia coli (AIEC) bacteria drive inflammation in Crohn's disease.

They found that AIEC, which colonize the intestinal mucosa by adhering to and invading intestinal epithelial cells, can produced a metabolite that interacts with the intestine's immune cells to induce inflammation.

"Our study links the metabolic activity of bacteria associated with Crohn's disease (AIEC) to the underlying intestinal inflammation," Dr. Randy Longman of Weill Cornell Medicine and NewYork-Presbyterian/Weill Cornell Medical Center told Reuters Health by email.

"This finding... has both diagnostic and therapeutic potential," Dr. Longman said. "Fecal markers of this metabolic pathway may identify patients with microbial-driven inflammation as well as highlight those that would benefit from therapeutic strategies--dietary prebiotics or small molecule inhibitors--that target this pathway."

As reported in Cell Host and Microbe, Dr. Longman and colleagues targeted a process AIEC use to grow. Specifically, the bacteria use 1,2-propanediol, a byproduct of the breakdown of fucose, to produce propionate.

"Fucose is abundant in the mucosal surface of the intestine in the form of fucosylated oligosaccharides, which can serve as a nutrient source for bacteria tightly associated with the epithelial surface," Dr. Longman explained.

The interaction of propionate with mononuclear phagocytes (MNPs) in the lining of the gut triggers an inflammatory cascade.

When the researchers genetically engineered AIEC bacteria to lack a key enzyme in this process, propanediol dehydratase, the bacteria did not set off a cascade of inflammation in a mouse model of Crohn's disease. Limiting the availability of fucose in the gut also reduced AIEC propionate production and inflammation.

Summing up, the authors state, "These findings identify MNPs as metabolic sensors linking AIEC metabolism with intestinal inflammation and identify microbial metabolism as a potential therapeutic target in Crohn's disease treatment."

Dr. Longman said, "Our study showed that inhibiting mucosal fucosylation reduced the inflammatory effect of the bacteria. Many patients with IBD have mutations in the main fucosyltransferase of the gut (called FUT2). Future studies will need to assess if this genetic predisposition or a dietary prebiotic could regulate the inflammation potential of these bacteria."

Dr. Jean Frederic Colombel, codirector of the Susan and Leonard Feinstein Inflammatory Bowel Disease Clinical Center at Mount Sinai Hospital in New York City, commented in an email to Reuters Health, "This paper is another piece of information concerning the potential role of the AIEC pathotype in IBD. Since its discovery more than two decades ago... progress has been made in unravelling this bacteria's characteristics and its interaction with the gut immune system."

Dr. Colombel was among the first to identify AEIC in the ileal mucosa of Crohn's disease patients in 1998. (https://bit.ly/3s9a0IV)

"This novel study reveals that AIEC could induce inflammation in the gut through the production of a specific metabolite that interacts with the immune cells of the gut," he said. "The authors propose that interfering with this process could block the triggering of inflammation by AIEC and thus have therapeutic implications. More work is still needed in humans in order to confirm the validity of this approach."

"In the meantime," he said, "several clinical trials targeting AIEC are already ongoing in patients with Crohn's disease, such as blocking the mechanism allowing AIEC to adhere to the intestinal mucosa or getting rid of the bug in the gut by using a bactericidal specific phage."

SOURCE: https://bit.ly/3asIb8c Cell Host and Microbe, online February 5, 2021.

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