Inflammatory bowel disease (IBD), encompassing ulcerative colitis and Crohn's disease, is a chronic inflammatory disorder of the gastrointestinal tract characterized by symptoms such as abdominal pain, diarrhea, and bloody stools. The intestinal barrier, a critical defense system between the gut and external environment, plays a pivotal role in nutrient absorption and protection against pathogens. Damage to this barrier is a key factor in IBD pathogenesis. This review systematically explores the mechanisms of intestinal barrier dysfunction in IBD, focusing on oxidative stress, gut microbiota, and cellular autophagy, while also discussing emerging therapeutic strategies.
Introduction
The intestinal barrier maintains homeostasis by preventing harmful substances from entering systemic circulation. Its dysfunction triggers immune responses, leading to IBD. This review synthesizes current knowledge on barrier dysfunction in IBD, aiming to identify novel therapeutic targets.
Gut Barrier Composition
The intestinal barrier comprises mechanical, chemical, immune, and microbial components:
Mechanical Barrier: Consists of intestinal epithelial cells (IECs), mucus, and tight junctions (e.g., claudins, occludin). Disruption of tight junctions, as seen in ulcerative colitis, increases permeability.
Chemical Barrier: Includes mucus (e.g., Muc2) and antimicrobial peptides (AMPs) like LL-37, which defend against pathogens. Reduced Muc2 levels correlate with barrier damage.
Immune Barrier: Involves innate (e.g., TLR4, NLRs) and adaptive (e.g., GALT, SIgA) immune systems. Dysregulation exacerbates inflammation.
Microbial Barrier: Gut flora (e.g., Faecalibacterium prausnitzii) and metabolites (e.g., butyrate) maintain barrier integrity. Dysbiosis is linked to IBD progression.
Factors Influencing the Intestinal Barrier
Oxidative Stress: Excessive ROS production damages tight junctions and epithelial cells, exacerbating inflammation. The Keap1/Nrf2 pathway mitigates oxidative stress by activating antioxidant responses.
Gut Microbiota: Metabolites like butyrate enhance barrier function by upregulating Muc2 and tight junction proteins. Bile acids and LPS modulate inflammation via NF-κB and TLR4 pathways.
Autophagy: Autophagy-related proteins (e.g., ATG16L1) clear intracellular pathogens and maintain mitochondrial health. Defective autophagy contributes to IBD by impairing bacterial clearance and increasing ROS.
Other Factors: Pollutants (e.g., BPA), obesity, and NSAIDs disrupt barrier integrity by altering microbiota or tight junction expression.
Therapeutic Strategies
Conventional Drugs: Mesalazine and glucocorticoids restore tight junctions and reduce inflammation.
Fecal Microbiota Transplantation (FMT): Rebalances gut flora and reduces pro-inflammatory cytokines.
Electroacupuncture (EA): Enhances mucus secretion and tight junction protein expression via ST36 acupoint stimulation.
Vitamin Supplementation:
Vitamin A: Promotes mucosal repair and immune function.
Vitamin D: Regulates tight junction proteins and mitochondrial function via VDR, reducing inflammation.
Conclusion
IBD arises from complex interactions between genetic, environmental, and immune factors. Targeting intestinal barrier dysfunction through oxidative stress modulation, microbiota restoration, and autophagy regulation offers promising therapeutic avenues. Advances in precision medicine and microbial therapies, such as FMT and probiotics, hold potential for improving IBD management. Future research should focus on elucidating molecular mechanisms and optimizing these interventions.
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The study was recently published in the Journal of Translational Gastroenterology.
Journal of Translational Gastroenterology (JTG) dedicates to improving clinical diagnosis and treatment, advancing understanding of the molecular mechanisms, and promoting translation from bench to bedside of gastrointestinal, hepatobiliary, and pancreatic diseases. The aim of JTG is to provide a forum for the exchange of ideas and concepts on basic, translational, and clinical aspects of gastroenterology, and promote cross-disciplinary research and collaboration.
