Project 453255

This proposal seeks to find novel treatments for abdominal pain in patients suffering from chronic abdominal pain, such as those with the irritable bowel syndrome (IBS). Unfortunately, many pain medications have side effects that limit treatment options. This lack of effective treatments exists because we don't adequately understand what causes this pain and, given that multiple causes likely exist, which patient suffers from which cause. The human gut contains trillions of resident bacteria that are vital for maintaining health within and outside the gut. Changes to the composition and stability of this bacterial population have been seen in some patients with IBS in which abdominal pain is a common feature. We have made the novel discovery that in a significant subset of patients, gut bacteria produce high levels of histamine, a mediator that activates pain sensing nerves in the gut. These bacteria increase pain that may be due to recruitment of gut immune cells that also produce histamine or by directly signaling to the nerves. Therefore, in this proposal, we will study the mechanisms of how this gut bacteria increases abdominal pain through the release of histamine. We will transfer microbiota from IBS patients into germ free mice and identify the major pathways from the microbiota to the nerves leading to abdominal pain and the specific roles of bacterial and host histamine in these pathways. Additionally, we will follow a small group of IBS patients with high histamine producing bacteria and study how this relates to changes in abdominal pain. We will also study the prevalence of high histamine producing bacteria in a large cohort of IBS patients. Collectively, we expect to discover mechanisms underlying how gut bacteria drive abdominal pain and possible ways of identifying patients affected by this pathway. Ultimately, this will lead to novel treatment strategies for patients in whom these strategies are most likely to work.