Gut Serotonergic Signaling in Traumatic Brain Injury

Johns Hopkins University, Baltimore MD

Investigators

Abstract

Project Summary/Abstract: Traumatic brain injury (TBI) represents a significant public health concern in the United States, with an estimated annual economic burden of $56.3 billion and a subsequent risk of neuropsychiatric and neurodegenerative diseases. Emerging research has highlighted the significant communication along the brain-gut axis as a driver of increased neuroinflammation. Furthermore, both preclinical and clinical studies have identified serotonin (5-HT) as a key player in the pathogenesis of TBI, with existing literature primarily focusing on brain serotonergic signaling. In our proposal, we aim to address this gap by investigating the role of serotonergic signaling in the gut. Enteroendocrine cells (EECs) are specialized cells that line the intestinal epithelium forming the body’s largest endocrine system and are responsible for producing 90% of the body’s serotonin. Our lab recently discovered a significant reduction in EEC expression and differentiation, as well as a decrease in serotonin synthesis following TBI. Additionally, we have demonstrated that TBI triggers the gut’s inflammatory immunoendocrine axis, as observed by an increase in inflammatory macrophages and decreased serotonin production, indicating a potential interaction between infiltrating macrophages and serotonin production by EECs. Alterations in the gut microbiome further modulate serotonin metabolism, suggesting a complex interplay between microbiota and intestinal serotonin. This proposal will investigate the mechanisms by which serotonin interacts with the various macrophage/microglial populations and how these interactions modulate the brain’s inflammatory response. Serotonin signaling will be restored through two novel approaches: (1) pharmacologically, by supplementing the prokinetic/laxative prucalopride, known to activate serotonin receptors (5HT4 receptor agonist), and (2) genetically, by generating mice that selectively overexpress EECs and serotonin in the gut epithelium. Behavioral outcomes, including spatial learning and memory, risk-taking/anxiety, and depressive-like behaviors, will be assessed at acute and chronic time points. We hypothesize that TBI induces EEC dysfunction and decreases serotonin production, which ultimately worsens brain neuroinflammation by inducing macrophage polarization into a pro- inflammatory state and modulating vagus nerve function. The overarching goal is to enhance serotonin production and suppress the proinflammatory response, with the aim of improving neurocognitive outcomes (Aims 1&2). Furthermore, we aim to utilize novel treatment strategies, such as non-invasive transcutaneous auricular vagus nerve stimulation (taVNS), to improve gut function and reverse brain neuroinflammation post- TBI (Aim 3). Collectively, the proposed studies will identify a key role for serotonin as a paracrine/endocrine hormone mediating the inflammatory response along the brain-gut-brain axis through its effects on macrophages, microbiota and vagus nerve function, with the potential for novel therapeutic interventions for TBI patients.