To provide an updated and integrative evaluation of duloxetine as a potential therapeutic agent for irritable bowel syndrome (IBS), with emphasis on its mechanisms of action across the gut-brain axis. The review addresses the key research question: Can duloxetine, beyond its antidepressant effects, modulate neuroimmune, microbial, and pharmacogenomic factors relevant to IBS, particularly pain-predominant subtypes? This narrative review provides a targeted synthesis of selected preclinical, clinical, and translational literature addressing duloxetine as a potential gut-brain axis modulator in irritable bowel syndrome. Evidence related to neuroimmune mechanisms, microbiota-related pathways, pharmacogenomic considerations, and clinical studies was narratively summarized. Evidence indicates that duloxetine modulates serotonergic and noradrenergic neurotransmission, decreases visceral hypersensitivity, and attenuates neuroinflammation via inhibition of microglial P2X4/NF-κB signaling. Duloxetine also shifts cytokine balance toward an anti-inflammatory profile (↑ IL-10, ↓ IL-6, ↓ TNF-α). Emerging data suggest additional benefits through modulation of gut microbiota composition, enhancement of short-chain fatty acid (SCFA) production, and improvement of intestinal barrier integrity. Pharmacogenomic factors, especially CYP2D6 and CYP1A2 polymorphisms, significantly influence duloxetine metabolism and therapeutic response. Compared with TCAs and SSRIs, duloxetine shows more favorable efficacy in relieving combined gastrointestinal and psychological symptoms with fewer sexual side effects. Duloxetine exhibits multifaceted actions that extend beyond mood regulation, positioning it as a promising but still investigational GBA-directed option dual-action therapy within the gut-brain axis framework. The collective findings support the need for biomarker-guided clinical trials incorporating microbiota profiling, cytokine signatures, and pharmacogenetic testing to validate duloxetine's role in precision-medicine-based IBS management.
