Bacterial "Achilles heel" offers new target in Crohn's disease therapy
Crohn's disease is an inflammatory bowel disease that leads to great discomfort, is difficult to treat and has no cure. Understanding what causes the condition could lead to new treatment targets and improve outcomes for sufferers, and scientists have just placed the crosshairs over a key enzyme they say acts as an "Achilles heel" for inflammation linked to the disease.
The breakthrough is the handiwork of scientists at Weill Cornell Medicine and New York-Presbyterian Hospital, who focused on a type bacteria called adherent-invasive Escherichia coli (AIEC), which is present in greater concentrations in the guts of Crohn's disease sufferers and drives inflammation in the intestine.
Looking to delve further into the mechanisms behind this process, the scientists focused their efforts on the way the bacteria leverages the natural breakdown of sugars in the body to grow. As this takes place, the AIEC bacteria capture a byproduct of sugar breakdown called 1,2-propanediol and turns it into propionate, a short-chain fatty acid that helps the bacteria grow.
By examining this process, the team showed that propionate interacts with immune cells in the lining of the gut called mononuclear phagocytes, triggering inflammation. Scientist have suspected that an over-zealous reaction to bacteria by the immune system is what may drive inflammation in Crohn's disease as our body's natural defenders inadvertently attack healthy cells in the digestive tract, and this research feeds into that line of thinking.
The team then worked with forms of AIEC bacteria that had been genetically engineered to lack an enzyme central to this process, called propanediol dehydratase. This was tested out in mouse models where it did indeed break the chain of events leading to inflammation. In separate experiments, the team lowered the supply of sugar to the animal's gut and found that this also lowered inflammation.
“The study reveals a therapeutically targetable weak point in the bacteria,” says senior author Dr. Randy Longman.
From here, the team plans to start investigating potential ways to target the propanediol dehydratase enzyme, which they describe as an "Achilles heel." The hope is to improve on current treatments that include antibiotics, anti-inflammatory drugs and medications that suppress the immune system.
“If we can develop small molecule drugs that inhibit propanediol dehydratase or use dietary modifications to reduce the availability of fucose (sugar), we may be able to reduce intestinal inflammation in patients with Crohn’s disease with fewer side effects,” says Dr. Longman.
The research was published in the journal Cell Host and Microbe.
Source: Weill Cornell Medicine