Uremic metabolites, molecules either produced by the host or from the microbiota population existing in the gastrointestinal tract that gets excreted by the kidneys into urine, have significant effects on both health and disease. Tryptophan-derived catabolites are an important group of bacteria-produced metabolites with an extensive contribution to intestinal health and, eventually, chronic kidney disease (CKD) progression. The end-metabolite, indoxyl sulfate, is a key contributor to the exacerbation of CKD via the induction of an inflammatory state and oxidative stress affecting various organ systems. Contrastingly, other tryptophan catabolites positively contribute to maintaining intestinal homeostasis and preventing intestinal inflammation—activities signaled through nuclear receptors in particular—the aryl hydrocarbon receptor (AhR) and the pregnane X receptor (PXR). This review discusses the origins of these catabolites, their effect on organ systems, and how these can be manipulated therapeutically in the future as a strategy to treat CKD progression and gut inflammation management. Furthermore, the use of biotics (prebiotics, probiotics, synbiotics) as a means to increase the presence of beneficial short-chain fatty acids (SCFAs) to achieve intestinal homeostasis is discussed.

Chronic kidney disease (CKD) is increasingly linked to intestinal barrier dysfunction, which contributes to systemic inflammation and disease progression. We investigated whether 2′-fucosyllactose (2′-FL), a human milk oligosaccharide, could modulate intestinal epithelial barrier function under uremic toxin exposure and examined the role of the aryl hydrocarbon receptor (AhR). Using wild-type (WT) and AhR knockout (AhR KO) Caco-2 cell lines, we assessed barrier function and cellular responses through transepithelial electrical resistance (TEER), paracellular permeability (Papp), tight junction (TJ) gene expression, AhR target gene activation, and metabolic assays. AhR deficiency impaired epithelial maturation, confirming its role in barrier development. Short-term exposure to uremic toxins (UTs) did not significantly affect TEER or paracellular permeability under the conditions tested. However, 2′-FL reduced paracellular permeability in both WT and AhR KO cells in the presence of FCS. These effects occurred without changes in TJ gene expression, indicating mechanisms beyond transcriptional regulation. AhR target genes were not induced by UTs, suggesting limited receptor activation, and metabolic activity was unaffected. Overall, 2′-FL reduced paracellular permeability under selected experimental conditions, while the impaired barrier development observed in AhR-deficient cells supports a role for AhR in intestinal epithelial barrier development.