Gut Microbiome-Driven Microglial Activation Links Dysbiosis to Pain in Interstitial Cystitis/Bladder Pain Syndrome.

Background: Interstitial cystitis/bladder pain syndrome (IC/BPS) is a debilitating condition of chronic pelvic pain associated with urinary frequency and comorbid anxiety and depression. Recent studies in IC/BPS patients and rodent models implicate fecal dysbiosis and increased systemic exposure to endotoxin. These changes potentially elicit innate immune responses via the activation of microglial cells in the central nervous system, key mediators of pain. Microglial ablation and inactivation have previously been associated with analgesia in preclinical studies, underscoring the role of microglia in IC/BPS pain. Here, we investigated whether IC/BPS-associated fecal microbiota differentially activate microglia and whether activation correlates with patient symptoms. Methods: Microbiome-microglia interactions were assessed using three complementary Results: In all culture models, microglia exhibited significantly increased proinflammatory responses to fecal microbiota of IC/BPS patients relative to controls. Mixed glial cultures, incorporating astrocyte-microglia interactions, exhibited the most robust cytokine responses. Cytokine levels positively correlated with GUPI pain scores. Conclusions: Together, these findings further support a role for gut dysbiosis in IC/BPS symptoms and suggest microglial activation and glial-glial interactions as a contributing mechanism. Understanding gut-brain axis interactions in IC/BPS will thus enable development of novel microbiome-based therapies for treating IC/BPS patients.