Gut–Brain Axis in Comorbid Constipation and Mood Disorders: Navigating the Efficacy-Tolerability Dilemma Through Emerging Evidence and Future Directions

Mei Tu,1 Yangfeng Huang21Department of Rehabilitation Medicine, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, 621000, People’s Republic of China; 2Department of Traditional Chinese Medicine, Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, People’s Republic of ChinaCorrespondence: Yangfeng Huang, Email huangyangfeng@med.uestc.edu.cnBackground: The comorbidity of constipation and mood disorders (anxiety/depression) creates a vicious cycle of symptom superposition and treatment resistance. The persistent "efficacy-tolerability” dilemma—whereby effective treatment for one condition may exacerbate the other—remains unresolved.Methods: This narrative review is based on a systematic search of PubMed, Embase, and Cochrane Library (2015– 2026), focusing on epidemiology, gut-brain axis mechanisms, pharmacotherapy limitations, and emerging strategies. The search formula was: ("constipation” OR "functional constipation”) AND ("mood disorders” OR "anxiety” OR "depression”) AND ("gut-brain axis” OR "microbiota” OR "pharmacotherapy”).Results: Constipation and mood disorders show a bidirectional association, supported by recent Mendelian randomization studies. Pathogenesis involves central/enteric nervous system dysfunction, microbiota imbalance, and inflammatory mediators. Conventional drugs (eg, selective serotonin reuptake inhibitors [SSRIs], stimulant laxatives) may worsen one condition while treating the other. Preliminary evidence suggests gut-brain axis-targeted therapies—including 5-hydroxytryptamine type 4 (5-HT4) receptor agonists, psychobiotics, and multidisciplinary team models—may improve outcomes, but most findings remain exploratory.Conclusion: Overcoming the dilemma requires mechanism-oriented drug selection, optimized combination regimens, and individualized management. Future efforts should accelerate multi-target drug trials, multi-omics-based precision models, and multidisciplinary team implementation. The evidence base remains limited, with few large randomized controlled trials specifically targeting the comorbid population. Readers should interpret all quantitative estimates with caution, as they derive from heterogeneous study designs.Keywords: constipation, mood disorders, gut-brain axis, pharmacotherapy