Background: Gastrointestinal pathologies, including simple impairments like constipation, may cause recurrent urinary tract infections (UTIs). Serotonin (5-HT), a pivotal molecule in inflammation, is primarily synthesized and released in the gastrointestinal tract by enterochromaffin cells. 5-HT activity is regulated by the serotonin reuptake transporter (SERT), which transports serotonin from the extracellular fluid to mucosal epithelial cell’s intracellular compartments, where it is either stored or degraded via monoamine oxidase. Peripheral 5-HT activity significantly influences leukocyte recruitment and function during inflammatory processes. Neutrophil gelatinase-associated lipocalin (NGAL), renowned for its ability to bind bacterial formylpeptides, serves as an inflammation marker, with its expression escalating notably during inflammation. Consequently, this study aims to understand how 5-HT, SERT, and NGAL affect urinary tract health and susceptibility to uropathogenic Escherichia coli UPEC infections. Methods: We utilized 6-8-week-old female Sert null mice, characterized by reduced serotonin transporter levels and elevated extracellular serotonin concentrations. Sert null mice exhibit spontaneous desensitization of 5-HT receptors, leading to alternating episodes of diarrhea and constipation that mimic gastrointestinal pathologies. Our study aimed to investigate urethral inflammation and susceptibility to UPEC infection in Sert null mice compared to wild-type (WT) controls.Immunohistochemistry on urethral tissue sections from both WT and Sert null mice was used to assess urethral epithelial cell NGAL expression. Additionally, female WT and Sert null mice (n=6 per group) were anesthetized, and UPEC was introduced into the distal urethra to initiate an ascending infection. Bladders were collected four hours post-UPEC instillation to measure bacterial burden.Results: Sert null mice exhibit heightened basal NGAL expression in urethral epithelial cells, suggesting ongoing inflammatory processes. Following UPEC instillation, Sert null mice demonstrated a more severe bladder infection than WT mice. Figure 1. Uninfected Sert null mice have higher NGAL expression in urethral epithelium than WT mice, possibly contributing to their increased sensitivity to bladder infection. A, B) Female urethral tissue was stained for NGAL (red) and DAPI (blue). C) Sert null mice had significantly more E. coli CFUs compared to controls (p = 0.0108; Mann-Whitney test).Conclusion: This study underscores the critical role of 5-HT and SERT in modulating urethral inflammation and susceptibility to UPEC infections. The heightened inflammatory response in Sert null mice, characterized by increased NGAL expression and possibly immune cell recruitment, highlights the potential influence of serotonergic signaling in the urinary tract. These findings suggest that targeting 5-HT pathways may offer novel therapeutic strategies to reduce the risk of recurrent UTIs in patients with bowel and bladder dysfunction. Further research is warranted to delineate the precise mechanisms by which 5-HT and SERT regulate immune responses in the urinary tract, potentially informing the development of targeted interventions for pediatric patients at risk of recurrent UTIs due to underlying inflammatory conditions.
