Researchers from Weill Cornell Medicine and New York-Presbyterian have demonstrated that patients with Crohn’s disease have an overabundance of a type of gut bacteria called adherent-invasive Escherichia coli (AIEC), which promotes inflammation in the intestine. Their experiments revealed that a metabolite produced by the bacteria interacts with immune system cells in the lining of the intestine, triggering inflammation. Interfering with this process, by either reducing the bacteria’s food supply or eliminating a key enzyme in the process relieved gut inflammation in a mouse model of Crohn’s disease. This finding of a weak spot in the gut bacteria may lead to more targeted therapies for Crohn’s disease, according to the researchers.
Their findings were published in the journal Cell Host and Microbe, in a paper entitled “Adherent-invasive E. coli metabolism of propanediol in Crohn’s disease regulates phagocytes to drive intestinal inflammation.”
“Adherent-invasive E. coli are enriched in the intestinal microbiota of patients with Crohn’s disease (CD) and promote intestinal inflammation,” the researchers wrote. “Yet, how AIEC metabolism of nutrients impacts intestinal homeostasis is poorly defined. Here, we show that AIEC encoding the large subunit of propanediol dehydratase (PduC), which facilitates the utilization of fucose fermentation product 1,2-propanediol, are increased in the microbiome of CD patients and drive AIEC-induced intestinal T cell inflammation.”
Their findings reveal a therapeutically targetable weak point in the bacteria. To find this vulnerability, the researchers targeted a process the AIEC bacteria uses to convert a byproduct of sugar fermentation in the gut to grow. When the AIEC converts 1,2-propanediol—a byproduct of the breakdown of a type of sugar called fucose—it produces propionate. Propionate was observed to interact with a type of immune system cell called mononuclear phagocytes that are also found in the lining of the gut and lead to inflammation.
The researchers then genetically engineered AIEC bacteria to lack a key enzyme called propanediol dehydratase. Without propanediol dehydratase, the bacteria do not set off a cascade of inflammation in a mouse model of Crohn’s disease.
“Changing one metabolic pathway in one type of bacteria can have a big impact on intestinal inflammation,” explained Monica Viladomiu, PhD, a postdoctoral associate in medicine in the division of gastroenterology and hepatology and the Jill Roberts Institute for Research in Inflammatory Bowel Disease at Weill Cornell Medicine.
More than four million people worldwide suffer from Crohn’s disease. This finding can lead to better treatments. Antibiotics are often used to treat Crohn’s, which can kill both beneficial and harmful bacteria, but this new strategy can potentially reduce inflammation while preserving beneficial bacteria.
“If we can develop small molecule drugs that inhibit propanediol dehydratase or use dietary modifications to reduce the availability of fucose, we may be able to reduce intestinal inflammation in patients with Crohn’s disease with fewer side effects,” said Randy Longman, MD, PhD, associate professor of medicine in the division of gastroenterology and hepatology and the director of the Jill Roberts Center for Inflammatory Bowel Disease at Weill Cornell Medicine and NewYork-Presbyterian/Weill Cornell Medical Center.