Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) are widely used in psychiatry for mood and anxiety disorders but remain underexplored in chronic gastrointestinal conditions such as inflammatory bowel disease (IBD) and disorders of gut-brain interaction (DGBI). This review synthesizes emerging evidence on their potential therapeutic role, focusing on shared neurobiological and immunometabolic mechanisms within the bidirectional microbiota-gut-brain axis. We reviewed preclinical and clinical studies investigating SSRIs and SNRIs in IBD and DGBI, emphasizing neuroimmune, enteric, and microbial pathways relevant to disease modulation. SSRIs and SNRIs inhibit serotonin (SERT) and norepinephrine (NET) transporters, increasing central 5-HT and NE signaling across corticolimbic and autonomic networks. These effects enhance neuroplasticity and BDNF activity, reduce microglial activation and proinflammatory cytokines, and partially normalize hypothalamic-pituitary-adrenal (HPA) axis reactivity. Peripherally, epithelial, and enteric SERT blockade elevates luminal 5-HT, activating 5-HT<inf>3</inf> and 5-HT<inf>4</inf> receptors that promote motility, secretion, and sensory modulation. Both classes also enhance vagal antiinflammatory tone and tighten epithelial barrier integrity by suppressing nuclear factor kappa (NF-κB) signaling and increasing interleukin 10 (IL-10). Through integrated central, enteric, and immune actions, SSRIs and SNRIs can influence mood, pain perception, gut motility, and mucosal inflammation, key determinants of symptom burden in IBD and DGBI. SSRIs and SNRIs hold promise as multimodal modulators of the microbiota-gut-brain axis, bridging psychiatric and gastroenterological care. However, mechanistic preclinical studies and rigorously designed, adequately powered randomized trials are needed to define causal pathways, optimal dosing, and patient stratification strategies.
Gut-Brain Axis