Disruption of Intestinal Tight Junction Proteins by Giardia lamblia: Physiological Mechanisms of Barrier Dysfunction and Malabsorption

Abstract

Lamblia is a protozoan parasite causing giardiasis, characterized by diarrhea, malabsorption, and intestinal barrier dysfunction affecting over 280 million people annually. The intestinal epithelial barrier, maintained by tight junction (TJ) proteins, is critical for selective permeability and nutrient absorption. This study investigates the physiological mechanisms by which G. lamblia disrupts TJ proteins and impairs intestinal barrier function. Human intestinal epithelial cells (Caco-2) were infected with G. lamblia trophozoites, and TJ protein expression, localization, and barrier function were assessed. Transepithelial electrical resistance (TEER) decreased by 58% within 24 hours of infection (P < 0.001). Western blot analysis revealed significant reductions in claudin-1 (62%), claudin-4 (54%), occludin (71%), and ZO-1 (48%) protein levels. Immunofluorescence microscopy demonstrated redistribution of TJ proteins from cell-cell junctions to the cytoplasm. Mechanistically, G. lamblia induced activation of myosin light chain kinase (MLCK) with 3.4-fold increase in phosphorylated MLC, and caspase-3-mediated cleavage of TJ proteins. Inhibition of MLCK with ML-7 partially restored barrier function (42% recovery). Paracellular permeability to FITC-dextran increased 4.8-fold, correlating with reduced expression of nutrient transporters SGLT1 and GLUT2. These findings establish a comprehensive physiological framework for understanding Giardia-induced barrier dysfunction and identify MLCK as a potential therapeutic target for managing giardiasis-associated malabsorption.