Shift Work, Circadian Disruption, and Immune Dysregulation: Molecular Links to Gastrointestinal Diseases and...

Shift work is an essential component of modern occupational systems but represents a major source of circadian misalignment associated with gastrointestinal symptoms and selected gastrointestinal disorders. 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 while distinguishing epidemiological associations from experimental mechanistic evidence and biologically plausible but insufficiently validated relationships. We conducted a structured literature search in PubMed/MEDLINE, Scopus, and Web of Science, focusing primarily on studies published between January 2020 and July 2026. We prioritized recent original studies, systematic reviews, meta-analyses, and mechanistic and translational investigations, while retaining relevant landmark studies. Evidence was organized within an integrative framework encompassing occupational exposure, circadian disruption, neuroendocrine alterations, immune dysregulation, intestinal barrier dysfunction, gut microbial and metabolic alterations, and gastrointestinal outcomes, with explicit consideration of differences in evidentiary strength across these proposed relationships. Human studies consistently support an association between night or rotating shift work and circadian disruption, whereas evidence for downstream neuroendocrine, immune, epithelial, and microbial pathways varies substantially in directness and strength. Experimental studies indicate that circadian disruption can alter inflammatory signaling, epithelial barrier function, and host-microbiota interactions, while microbial metabolites, including short-chain fatty acids, secondary bile acids, and tryptophan derivatives, may participate in reciprocal interactions with mucosal immunity and barrier integrity. Epidemiological evidence is strongest for disorders of gut-brain interaction, particularly irritable bowel syndrome, whereas evidence for functional dyspepsia, inflammatory bowel disease, and colorectal neoplasia is more limited, inconsistent, or unresolved. Candidate circadian, inflammatory, intestinal barrier, microbial, and metabolomic biomarkers remain investigational and are not currently validated for gastrointestinal risk prediction or routine occupational surveillance. Shift work is associated with selected gastrointestinal outcomes, while experimental evidence provides biological plausibility for interconnected circadian, neuroendocrine, immune, epithelial, and microbial mechanisms. However, the proposed framework should be regarded as integrative and hypothesis-generating rather than as an established linear causal cascade in human shift workers. Prospective longitudinal and interventional studies are required to establish temporal and causal relationships, validate candidate biomarkers, and determine whether occupational, behavioral, or mechanism-based interventions can produce clinically meaningful gastrointestinal benefits.