Towards Modeling Enteric Hyperoxaluria in a Tripartite Microbiota-Gut-Kidney Microphysiological System

Hyperoxaluria is a pathological condition characterized by increased levels of oxalate in the urine, which may result in the deposition of oxalate stones, first in the kidneys, with the risk of incurring chronic kidney disease, and, in the most severe forms, systemically. Endogenous and exogenous sources linked to the hepatic metabolism of glyoxylate, the direct precursor of oxalate, and dietary intake, respectively, contribute to oxalate presence in the human circulation, ultimately removed by excretion in the urine. Disruption of oxalate homeostasis may result in hyperoxaluria, either as a primary disease (PH) in the case of genetic defects in the enzymes responsible for the hepatic metabolism of glyoxylate, or secondary to other conditions (SH), involving excessive oxalate intake or intestinal malabsorption, the latter condition also known as enteric hyperoxaluria (EH). While therapeutic strategies targeting key glyoxylate metabolic pathways have advanced the clinical management of PH, EH has lagged behind, partly because of the heterogeneity of the conditions at its basis, but also for the lack of suitable disease models. The recent development of microphysiological systems, or organ-on-a-chip, able to reproduce the physiological functions of human organs and tissues with increasing complexity and accuracy would represent a step forward in the mechanistic dissection of EH pathogenesis. In this perspective, we discuss the strategies for EH modeling in a microphysiological system, in light of the recent literature and our work, and evaluate how this implementation might be instrumental for the development of novel therapeutic strategies.