Gut Barrier Disruption Exacerbates PKD and Is Ameliorated by Tributyrin Supplementation

Background: Polycystic kidney disease (PKD) is a genetic form of chronic kidney disease, wherein healthy kidney tissue is slowly replaced by large fluid-filled cysts, resulting in kidney failure. While PKD has a known genetic component, environmental factors play a significant role in disease progression to trigger immune system responses that promote cystogenesis and cyst growth. We previously demonstrated that kidney injury by tubular microcrystals potently accelerates PKD progression in rodent models, with evidence that the same occurs in humans. Other similar injury sources may exist, and we therefore hypothesized that the gut and its luminal contents, if able to transit into circulation, could constitute a significant source of kidney injury. Methods: To test this hypothesis, we treated a PKD rat model (Anks6, Cy/+) with the food additive polysorbate-80 to induce gut barrier disruption and evaluated the effect on PKD progression. We used tributyrin supplementation for intestinal delivery of butyrate to improve gut health and evaluated the effect on PKD progression in Cy/+ rats and Nestin-Cre:Pkd1 mice. Results: Following polysorbate-80 treatment, we observed signs of gut barrier disruption, including reduced markers of barrier function, increased levels of bacterial endotoxin in wild-type rats, and increased disease progression in cystic rats. Conversely, tributyrin supplementation in the Cy/+ rat and the orthologous Nestin-Cre:Pkd1 mouse led to increased intestinal barrier function and reduced cystic disease progression. Conclusion: These data suggest that disruption of intestinal barrier integrity leads to the exposure of kidneys to gut-derived compounds - such as LPS - that promote renal inflammation and progression of PKD. Conversely, promoting gut health may be a disease-modifying treatment strategy for PKD. Funding: NIDDK Support