Bioactive Lipids and Gastrointestinal Inflammation

Inflammation is the protective biological response to infection, irritation, and injury. The inflammatory response is vital to survival, but can cause inadvertent damage if not carefully controlled. This is particularly true in the gastrointestinal (GI) tract, which is home to trillions of microbes and constantly exposed to inflammatory stimuli. As a result, the inner lining of the GI tract, known as the mucosa, has evolved many mechanisms to prevent unchecked inflammation and to ensure its timely and complete resolution.

Many GI diseases are characterized by excessive or uncontrolled inflammation, suggesting a failure of these regulatory mechanisms. This appears to be the case with inflammatory bowel disease (IBD), a disorder affecting 1.4 million people in the U.S. IBD is thought to result from an inappropriate inflammatory response to normally harmless gut bacteria.

GI inflammation is regulated by a complex network of interactions between cells within the intestinal wall and cells belonging to the immune system. These cells communicate with each other by producing and releasing molecules that induce specific behaviors. For example, a set of molecules known as “chemokines” are produced by cells in the colon following injury and act as a homing beacon to recruit the immune system into action.

Once inflammation has served its protective purpose, it must be replaced with a healing and repair process known as “resolution”. When resolution does not occur, the inflamed tissue does not return to its normal state and inflammation becomes chronic. Scientists believe this may be a key factor in many inflammation-related GI diseases.

It is now understood that lipid molecules play key roles in the onset and resolution of inflammation. Omega-3 fatty acids protect the body from uncontrolled inflammation by acting as a counterbalance to pro-inflammatory omega-6 fatty acids. Moreover, the inflammatory resolution process itself is directed by key omega-3 and omega-6 metabolites known as “Specialized Proresolving Mediators” or “SPMs”. SPMs promote inflammation resolution by inhibiting the production of pro-inflammatory signals, deactivating immune cells, boosting the production of anti-microbial substances, and initiating tissue repair processes. Because of these properties, new drugs based on these bioactive lipids may be useful for treating GI diseases with an inflammatory component.

Thetis Pharmaceuticals is developing novel drugs based on bioactive lipids for the treatment of orphan GI diseases. Using our HEALER™ chemistry platform, Thetis transforms endogenous bioactive lipids into small molecule pharmaceuticals, thereby unlocking their powerful healing properties to address significant unmet medical needs.