Regulatory mechanisms of the gut microbiota-short chain fatty acids signalling axis in slow transit constipation and progress in multi-target interventions

Shi-hong Liu^1,2Xue Fang Yang¹Lei Liang³Bin Bin Song⁴Xue Mei Song⁵Yong Jun Yang¹MOHAMMED ABDELFATAH ALHOOT^2*

• ¹Department of Integrated Traditional Chinese and Western Medicine of Colorectal and Anal Diseases, Affiliated Hospital of North Sichuan Medical College, Nanchong, China
• ²School of Graduate Studies (SGS), Management and Science University, Shah Alam, Malaysia
• ³Department of Graduate School, Tianjin University of Traditional Chinese Medicin, Tianjin, China
• ⁴Department of Traditional Chinese Medicine, Affiliated Hospital of North Sichuan Medical College, Nanchong, China
• ⁵Department of Surgical Center, Affiliated Hospital of North Sichuan Medical College, Nanchong, China

Slow-transit constipation (STC) is an increasingly prevalent disorder that imposes a substantial health and economic burden. Mounting evidence highlights the "gut microbiota–short-chain fatty acid (SCFA)–motility" axis as a central pathophysiological link between dysbiosis and impaired colonic transit. This review synthesises current knowledge of how SCFAs, especially acetate, propionate and butyrate, shape motility through serotonergic signalling, enteric nervous system modulation, epithelial barrier integrity and immune regulation. Particular attention is devoted to the biased-signalling properties of the SCFA receptors FFAR2 and FFAR3(free fatty acid receptors 2 and 3, respectively), including emerging data on their heterodimerisation. The article then appraises recent randomised controlled trials and meta-analyses of multi-target interventions (dietary fibres, synbiotics, postbiotics, faecal microbiota transplantation, phytochemicals, and small-molecule FFAR agonists) highlighting their efficacy, safety, and translational hurdles. Finally, the authors propose a precision-medicine framework that integrates multi-omics microbiome profiling, metabolomics, and host genetics to enable phenotype-stratified therapy. Key research gaps include limited long-term safety data, heterogeneous human cohorts and the need for large multicentre trials and machine-learning-guided responder prediction. Collectively, the review provides a roadmap for shifting STC management from symptom control to mechanism-based, personalised care.