Grant: Project Grant

Irritable bowel syndrome (IBS) is characterized by abdominal pain and altered bowel habits. It is extremely common, affecting over 10% of the adult population in North America and exerts a tremendous societal impact. For example, it is among the most common reasons for workplace absenteeism and in Canada, costs over $1B annually for diagnosis alone. Despite this, the mechanisms that underlie IBS remain poorly understood and as a result, the available treatments are not very effective. The most debilitating symptom is abdominal pain, and we have evidence that inflammatory mediators in the gut, known as proteases, can activate pain-sensing nerves in the gut and intensify the IBS patient's pain. Our previous studies and preliminary data have revealed that: 1) in IBS patients, multiple proteases are released and trigger sustained activation of pain-sensing visceral nerves; 2) changing the diet of IBS patients can alter the activation of inflammatory cells called mast cells (an important source of gut proteases); and 3) in germ-free mice inoculated with the microbiome of IBS patients, we can recapitulate the increased pain signaling and protease activity when we feed these mice diets comparable to those in humans. Based on these findings, we believe that multiple proteases lead to sustained pain signaling in IBS and that dietary factors sustain this abnormal neuronal activation. Using human biopsies in animal IBS models, we will define the protease profile released in response to changes in diet, and examine if the microbiome of a given patient influences the degree of protease-induced pain. We will also investigate how these proteases, once triggered, can sustain excitation of gut pain-sensing nerves and determine whether protease signaling is amplified by other mast cell mediators, such as histamine. Together, our work will clarify how proteases trigger and prolong pain signaling and in doing so, identify novel targets for treating IBS pain.