Microphysiological Systems to Recapitulate the Gut–Kidney Axis

Abstract

Gut microbiota-derived metabolites are key molecular mediators of the microbiota–host axis.The excretory capacity of the kidney is an essential part of human gut microbial symbiosis.Chronic kidney disease (CKD) is a metabolic disease in which gut microbiota-derived metabolites accumulate in the blood and adversely affect host physiological functions.Intestine-on-a-chip models have been developed that recapitulate the 3D epithelial barrier, the gut–microbiome interaction, and intercellular crosstalk with remote organs.Components of the immune system are pivotal in remote communication between the gut and kidney.The combination of engineered microphysiological systems with high-throughput multiomic analysis will provide novel insights into organ intercommunication in CKD. Chronic kidney disease (CKD) typically appears alongside other comorbidities, highlighting an underlying complex pathophysiology that is thought to be vastly modulated by the bidirectional gut–kidney crosstalk. By combining advances in tissue engineering, biofabrication, microfluidics, and biosensors, microphysiological systems (MPSs) have emerged as promising approaches for emulating the in vitro interconnection of multiple organs, while addressing the limitations of animal models. Mimicking the (patho)physiological states of the gut–kidney axis in vitro requires an MPS that can simulate not only this direct bidirectional crosstalk but also the contributions of other physiological participants such as the liver and the immune system. We discuss recent developments in the field that could potentially lead to in vitro modeling of the gut–kidney axis in CKD. Chronic kidney disease (CKD) typically appears alongside other comorbidities, highlighting an underlying complex pathophysiology that is thought to be vastly modulated by the bidirectional gut–kidney crosstalk. By combining advances in tissue engineering, biofabrication, microfluidics, and biosensors, microphysiological systems (MPSs) have emerged as promising approaches for emulating the in vitro interconnection of multiple organs, while addressing the limitations of animal models. Mimicking the (patho)physiological states of the gut–kidney axis in vitro requires an MPS that can simulate not only this direct bidirectional crosstalk but also the contributions of other physiological participants such as the liver and the immune system. We discuss recent developments in the field that could potentially lead to in vitro modeling of the gut–kidney axis in CKD. Chronic kidney disease (CKD) is the most widespread kidney disease and is characterized by the gradual loss of organ function over time, which impairs the ability to filter metabolic waste products from the blood (Box 1). The kidneys have many highly specialized functions, such as blood filtration and active secretion for the removal of metabolic waste, reabsorption of essential nutrients, maintenance of blood volume and electrolyte homeostasis, and metabolic and endocrine activity [1.Himmelfarb J. et al.The current and future landscape of dialysis.Nat. Rev. Nephrol. 2020; 16: 573-585Crossref PubMed Scopus (26) Google Scholar].Box 1Chronic Kidney Disease: Mechanism of DiseaseEpidemiologyCKD affects ~10% of the world population and has recently been classified as a major public health threat owing to its drastic rise in prevalence worldwide over recent decades. It often appears together with other comorbidities and, if left untreated, progresses to end-stage kidney disease (ESKD) [61.GBD Chronic Kidney Disease CollaborationGlobal, regional, and national burden of chronic kidney disease, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017.Lancet. 2020; 395: 709-733Abstract Full Text Full Text PDF PubMed Scopus (548) Google Scholar,62.Gajjala P.R. et al.Cellular and molecular mechanisms of chronic kidney disease with diabetes mellitus and cardiovascular diseases as its comorbidities.Front. Immunol. 2015; 6: 340Crossref PubMed Scopus (44) Google is and and kidney are the only for in [1.Himmelfarb J. et al.The current and future landscape of dialysis.Nat. Rev. Nephrol. 2020; 16: 573-585Crossref PubMed Scopus (26) Google the of and comorbidities are to a burden and systems worldwide P.R. et al.Cellular and molecular mechanisms of chronic kidney disease with diabetes mellitus and cardiovascular diseases as its comorbidities.Front. Immunol. 2015; 6: 340Crossref PubMed Scopus (44) Google et disease pathophysiology and contributions from the PubMed Scopus Google are with and and the and as advances et al.The of chronic kidney disease developed from a health a systematic 2020; PubMed Scopus Google animal and have that the of kidney can also the of and the of The of chronic and PubMed Scopus Google of is the and loss of and the in filtration that are thought to be by to the to kidney and et disease pathophysiology and contributions from the PubMed Scopus Google et diseases and tissue PubMed Scopus Google et the of chronic kidney Rev. 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It often appears together with other comorbidities and, if left untreated, progresses to end-stage kidney disease (ESKD) [61.GBD Chronic Kidney Disease CollaborationGlobal, regional, and national burden of chronic kidney disease, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017.Lancet. 2020; 395: 709-733Abstract Full Text Full Text PDF PubMed Scopus (548) Google Scholar,62.Gajjala P.R. et al.Cellular and molecular mechanisms of chronic kidney disease with diabetes mellitus and cardiovascular diseases as its comorbidities.Front. Immunol. 2015; 6: 340Crossref PubMed Scopus (44) Google is and and kidney are the only for in [1.Himmelfarb J. et al.The current and future landscape of dialysis.Nat. Rev. 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