PROJECT SUMMARY Chronic visceral pain is one of the most common clinical manifestations in such conditions as irritable bowel syndrome, chronic pelvic pain, pancreatitis, and interstitial cystitis. This condition is debilitating and dramatically decreases quality of life. Women are more likely to exhibit visceral pain during the low estrogen phase of the menstrual cycle and the estrogen-deficient menopause state. This clinical observation is recapitulated in animal models as visceral hypersensitivity is exacerbated during the low estrogen phase of the estrous cycle5. Furthermore, ovariectomized, estrogen-deficient mice present more visceral, mechanical, and thermal hyperalgesia than do gonadally intact, estrogen-sufficient, mice. This exacerbation of hyperalgesia exhibited by ovariectomized mice is nullified upon estrogen supplementation. However, the exact molecular mechanism(s) responsible for the protective effect of estrogen therapy on pain modulation remains unresolved. Additionally, estrogen replacement therapy is not a viable option for a number of women due to the potential negative health risks associated with its use if it is initiated after menopause. Therefore, understanding the mechanism(s) by which estrogen protects against visceral pain and developing new therapies to combat this debilitating condition is of significant clinical importance. Studies have revealed that administration of estrogen and phytoestrogen compounds in animals and humans augments microbial diversity which is a key component of a healthy and resilient gut microbiome. Pre-clinical studies have shown that sex differences exist across the lifespan in the gut-microbiome axis and it was recently revealed that estrogen-deficient-induced visceral hypersensitivity is microbiota-dependent. However, a greater understanding of the microbial composition and/or microbial metabolites that regulate this effect is lacking. To investigate the mechanisms by which estrogen and phytoestrogens mediate their anti-nociceptive effects, we propose to use isoxanthohumol (IXO), a natural phytoestrogen prenylflavonoid found in hops (Humulus lupulus L.), in conjunction with visceral hypersensitivity assessment, gut microbial sequencing, and fecal transplants to test the hypothesis that IXO and estrogen mitigate hypersensitivity via changes in the gut microbiome composition. This research will lay the foundation for understanding the mechanism by which estrogen and a new, natural therapy, IXO, reduces visceral hypersensitivity resulting from estrogen deficiency. Furthermore, the proposed research is within the scope of the parent grant as it investigates the use of a dietary compound to treat a debilitating condition. Additionally, this proposal falls in line with the mission of NCCIH to treat the pain management crisis through complementary and integrative management of pain.

PROJECT NARRATIVE Visceral pain is a debilitating condition that greatly affects women during estrogen deficiency. Limited research has been performed to examine novel, natural therapies for pain treatment in this population. The project will examine if isoxanthohumol can serve as a novel therapy for estrogen-deficient-induced hyperalgesia.