TLR Transduction of Dysbiotic Pelvic Pain

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Chronic pelvic pain is debilitating and afflicts millions of patients in the U.S., yet pelvic pain etiologies and effective therapies remain elusive. Microglia are CNS immune cells that play significant roles in pain and are poised to respond to changes in microbiota, yet the roles of microglia in pelvic pain are not fully described. Similarly, the microbiome influences many biological processes and is recently appreciated to modulate pain, and we have identified gut dysbiosis in pelvic pain patients and clinically relevant mouse models of pelvic pain. Microglia can transduce microbiome signals by virtue of Toll-like receptors, but their roles in mediating pelvic pain modulation by microbiota have not been explored. Here, we will evaluate the role of microglia responses to microbiota in clinically-relevant models of pelvic pain. We hypothesize that TLR4 mediates microglial responses to gut microbiota. We will test this hypothesis using two clinically relevant mouse models of distinct underlying mechanisms that mimic postulated etiologies of urologic pelvic pain, an infection model and a genetic susceptibility model. In Aim 1, we will quantify the role of microglia in rodent correlates of pain responses and cognitive function and define microglial phenotypes. In Aim 2, we will define the role of TLR4 in microglia- mediated pain. And in Aim 3, we will examine microglial responses to microbiota. Together, these rigorous and innovative studies will provide the first characterization of TLR4 in microglia- dependent pelvic pain responses to microbiota and thus pave the way for future probiotic strategies for the treatment of urologic chronic pelvic pain.