Shift Work, Circadian Disruption, and Immune Dysregulation: Molecular Links to Gastrointestinal Diseases and Occupational Health Implications

<jats:p>Background/Objectives: Shift work is an essential component of modern occupational systems but represents a major source of chronic circadian disruption associated with adverse gastrointestinal outcomes. The biological pathways underlying these associations remain incompletely integrated across circadian, neuroendocrine, immune, epithelial, and microbial domains. This narrative review aimed to synthesize current evidence linking shift work with gastrointestinal dysfunction and disease and to examine its translational implications for occupational medicine. Methods: A structured literature search was conducted in PubMed/MEDLINE, Scopus, and Web of Science, focusing primarily on studies published between January 2020 and July 2026. Recent original studies, systematic reviews, meta-analyses, and mechanistic and translational investigations were prioritized, while relevant landmark studies were retained. Evidence was synthesized within a seven-stage mechanistic framework spanning occupational exposure, circadian clock disruption, neuroendocrine misalignment, immune dysregulation, intestinal barrier dysfunction, gut microbial and metabolic alterations, and gastrointestinal disease. Results: Current evidence supports a multidirectional pathway in which chronic circadian misalignment disrupts melatonin and cortisol rhythms, autonomic regulation, and innate and adaptive immune homeostasis. Persistent inflammatory signaling and oxidative stress may subsequently impair epithelial tight junction integrity and increase intestinal permeability, thereby promoting microbial translocation and gut dysbiosis. Alterations in microbial metabolites, including short-chain fatty acids, secondary bile acids, and tryptophan derivatives, may further reinforce barrier and immune dysfunction. These interconnected mechanisms provide biological plausibility for the increased burden of disorders of gut–brain interaction, gastroesophageal reflux disease, peptic ulcer disease, and potentially inflammatory bowel disease and colorectal neoplasia among shift workers. Emerging circadian, inflammatory, intestinal barrier, microbiome, and multi-omics biomarkers may enable earlier identification of biologically susceptible individuals. Conclusions: Gastrointestinal consequences of shift work appear to arise from interacting circadian, neuroendocrine, immune, epithelial, and microbial disturbances rather than from isolated mechanisms. Integrating occupational exposure assessment with multidimensional biological profiling may support biomarker-guided surveillance, individualized prevention, and the development of Precision Occupational Medicine for shift workers. Prospective longitudinal and interventional studies are required to validate biomarkers, clarify causal pathways, and determine whether mechanism-based interventions can prevent gastrointestinal disease.</jats:p>