From barrier dysfunction to immune miseducation: reprogramming of epithelial-immune circuits in chronic kidney disease

Chronic kidney disease (CKD) is accompanied by persistent systemic inflammation, intestinal dysbiosis, epithelial barrier dysfunction, and accumulation of gut-derived uremic toxins. Current gut-kidney axis models have largely emphasized passive barrier leakage and microbial translocation, yet these mechanisms alone do not fully explain the sustained immune dysregulation that accompanies CKD progression. In this Review, we propose mucosal immune miseducation as a framework for understanding how CKD may disrupt the physiological processes that normally calibrate intestinal immunity. Under homeostatic conditions, the intestinal epithelium regulates controlled antigen sampling, including goblet cell-associated antigen passages, and thereby shapes antigen-presenting cell (APC) conditioning, retinoic acid-dependent tolerogenic programs, and context-appropriate cytokine signaling. Group 3 innate lymphoid cells (ILC3s) further reinforce mucosal homeostasis through reciprocal interactions with myeloid cells and IL-22-dependent epithelial repair. In CKD, uremic toxins, dysbiosis, inflammatory signaling, and neuroimmune disturbances may converge to impair this epithelial-APC-ILC3 circuit. Candidate mechanisms include dysregulated IL6ST (gp130) signaling and region-specific cholinergic control of antigen sampling, which could reduce epithelial instructional fidelity, alter APC states, weaken retinoic acid-associated immune tolerance, and destabilize ILC3 function. We further discuss emerging but indirect evidence suggesting possible intestinal ILC3 redistribution and functional remodeling during kidney injury, together with microbiota-derived metabolic signals that may shape this process. This framework extends the gut-kidney axis beyond barrier failure by positioning the intestinal mucosa as an active immune-educational system and highlights testable therapeutic strategies aimed at restoring epithelial instruction, APC tolerance, and ILC3-mediated tissue reinforcement in CKD.