Androgen-dependent regulation of colonic inflammation by gut-innervating nociceptors.

Males and females with Inflammatory Bowel Disease (IBD) differ in terms of incidence of disease, symptoms and response to treatments. The underlying reasons are largely unknown. Understanding why these sex differences exist could reveal why many patients develop IBD as they enter young adulthood. Sex hormones such as testosterone surge during adolescence and then circulate at very different levels in males and females. These hormones are powerful signaling molecules that regulate diverse aspects of physiology and may play a role in IBD. Clinical studies hint that testosterone signaling is protective in IBD, but it is largely unclear which cells this hormone signals to in the gut and how this signaling might influence intestinal inflammation. We have discovered that testosterone signals to an important population of nerve cells along the gut-brain axis, called nociceptors, that communicate information about the gut to the brain and regulate local immune responses. Using mice in which we can specifically disable testosterone signaling in nociceptors without altering it in the rest of the body, we will determine how testosterone influences inflammation and tissue repair in colitis. The results will advance the understanding of how sex hormones impact disease activity in IBD, potentially explain sex-dependent outcomes and inform therapeutic strategies.