Biology subjects

Klumpp, D.

Publications and source records attributed to Klumpp, D..

3 recordsLinked to original sources

bioRxiv2026

MULTI-COHORT TRANSCRIPTOMIC ANALYSIS REVEALS SHARED INFLAMMATORY SIGNALING AND UROTHELIAL DYSFUNCTION ACROSS IC/BPS PHENOTYPES

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a heterogeneous disorder characterized by bladder pain, inflammation, and urothelial dysfunction, yet the molecular features shared across clinically defined disease phenotypes remain incompletely understood. Toll-like receptor 4 (TLR4) and acyloxyacyl hydrolase (AOAH), a regulator of TLR4 ligand activity, have been implicated in IC/BPS in clinical and preclinical mechanistic studies. Here, we performed a multi-cohort reanalysis of four independent human IC/BPS transcriptomic datasets spanning bladder tissue and urine sediment from non-ulcer/non-Hunner, ulcerative/Hunner, normal-capacity, low-capacity, non-lesion, and lesion phenotypes. We evaluated immune cell-associated expression, urothelial differentiation and barrier integrity, TLR4 and pro-inflammatory signaling, and AOAH expression. IC/BPS exhibited phenotype-specific immune remodeling, yet shared features were also identified. Bladder-tissue IC/BPS was consistently associated with reduced expression of urothelial differentiation and barrier markers, together with increased TLR4 recognition and pro-inflammatory signaling. AOAH expression was elevated across all three bladder-tissue cohorts and was associated with monocyte/macrophage and pro-inflammatory transcriptional states. TLR4 signaling similarly paralleled myeloid and inflammatory features, whereas inflammatory programs generally showed inverse relationships with urothelial barrier markers. Notably, independently defined severe phenotypes of ulcerative IC and low-capacity IC showed concordant molecular remodeling characterized by increased leukocyte and monocyte/macrophage signatures, enhanced TLR4 signaling, elevated AOAH expression, and reduced urothelial barrier-associated expression. Together, these findings identify reproducible molecular signatures that extend across IC/BPS phenotypes and support a model in which urothelial dysfunction and TLR4-AOAH-associated myeloid inflammatory states coexist across disease phenotypes. These results provide a molecular framework for stratifying IC/BPS beyond clinical labels and identify shared and subtype-specific molecular signatures that may inform therapeutic response evaluation and clinical management.

immunology↗

bioRxiv2026

Microglial TLR4 Mediates Post-UTI Chronic Pelvic Pain

Urinary tract infections (UTIs) are a major risk factor for interstitial cystitis/bladder pain syndrome (IC/BPS), yet the mechanisms driving chronic pelvic pain and associated symptoms remain poorly understood. Here, we investigated the role of microglia and Toll-like receptor 4 (TLR4) in a mouse model of post-UTI chronic pelvic pain (PUPP). Infection with E. coli induced persistent pelvic allodynia that was significantly attenuated by microglial depletion (PLX5622) or inhibition (minocycline), indicating a key role for microglia in pain maintenance. In contrast, microglial depletion did not improve urinary dysfunction or anxiety- and depression-like behaviors. Prefrontal cortex microglia of PUPP mice exhibited reduced microglial branching complexity and a less ramified phenotype, indicative of an activated microglial state. Transcriptomic profiling of brain CD11b+ cells revealed a reactive microglial signature enriched for chemokines, NFKB-related genes, and immediate early response genes, alongside pathways involved in immune regulation and leukocyte recruitment. Both general and microglia-specific TLR4 deletion reduced pelvic allodynia and reduced microglial morphological features of activation. Consistent with this, pharmacological TLR4 inhibition in vitro suppressed LPS-induced NFKB activation, cytokine secretion, and CD68 expression. Together, these findings identify microglial TLR4 as a critical mediator of post-UTI chronic pelvic pain.

neuroscience↗

bioRxiv2021

Acyloxyacyl Hydrolase is a Host Determinant of Gut Microbiome-Mediated Pelvic Pain

Dysbiosis of gut microbiota is associated with many pathologies, yet host factors modulating microbiota remain unclear. Interstitial cystitis/bladder pain syndrome (IC/BPS or "IC") is a debilitating condition of chronic pelvic pain often with co-morbid urinary dysfunction and anxiety/depression, and recent studies find fecal dysbiosis in IC/BPS patients. We previously identified the locus encoding acyloxyacyl hydrolase, Aoah, as a modulator of pelvic pain severity in a murine IC/BPS model. AOAH-deficient mice spontaneously develop rodent correlates of pelvic pain, increased responses to induced pelvic pain models, voiding dysfunction, and anxious/depressive behaviors. Here, we report that AOAH-deficient mice exhibit dysbiosis of GI microbiota. AOAH-deficient mice exhibit an enlarged cecum, a phenotype long associated with germ-free rodents, and reduced trans-epithelial electrical resistance consistent with a "leaky gut" phenotype. AOAH-deficient ceca showed altered gene expression consistent with inflammation, Wnt signaling, and urologic disease. 16S rRNA sequencing of stool revealed altered microbiota in AOAH-deficient mice, and GC-MS identified altered metabolomes. Co-housing AOAH-deficient mice with wild type mice resulted in converged microbiota and altered predicted metagenomes. Co-housing also abrogated the pelvic pain phenotype of AOAH-deficient mice, which was corroborated by oral gavage of AOAH-deficient mice with stool slurry of wild type mice. Converged microbiota also alleviated comorbid anxiety-like behavior in AOAH-deficient mice. Oral gavage of AOAH-deficient mice with anaerobes cultured from IC/BPS stool resulted in exacerbation of pelvic allodynia. Together, these data indicate that AOAH is a host determinant of normal gut microbiota, and the dysbiosis associated with AOAH deficiency contributes to pelvic pain. These findings suggest that the gut microbiome is a potential therapeutic target for IC/BPS.

systems biology↗