Renal failure-driven luminal ammonia production impairs gut barrier function in CKD

Chronic kidney disease (CKD) is often associated with increased intestinal permeability, commonly referred to as "leaky gut." This study aimed to investigate how uremic conditions affect gut barrier integrity using in vitro, ex vivo, and in vivo models. Caco-2 cells exposed to plasma from hemodialysis (HD) patients exhibited increased permeability. HD plasma selectively upregulated claudin-1 expression at both mRNA and protein levels, without affecting ZO-1 or occludin. Uremic toxins such as indoxyl sulfate and p-cresyl sulfate did not replicate these effects. CKD mice showed enhanced paracellular intestinal permeability, confirmed by elevated plasma levels of LBP and FD4, both in vivo and ex vivo. Claudin-1 overexpression was also observed in the colons of CKD mice. In addition, CKD mice displayed increased cecal ammonia concentrations. Exposure to ammonia, both in vitro and ex vivo, significantly disrupted epithelial barrier integrity and increased colonic permeability, supporting the hypothesis that bacterial urease activity and ammonia production contribute to gut barrier dysfunction in CKD. These findings reveal a potential mechanistic link between renal failure, luminal ammonia, and "leaky gut."