Immunity, microbiota and kidney disease

Abstract

The recognition that intestinal microbiota exert profound effects on human health has led to major advances in our understanding of disease processes. Studies over the past 20 years have shown that host components, including components of the host immune system, shape the microbial community. Pathogenic alterations in commensal microorganisms contribute to disease manifestations that are generally considered to be noncommunicable, such as inflammatory bowel disease, diabetes mellitus and liver disease, through a variety of mechanisms, including effects on host immunity. More recent studies have shed new light on how the immune system and microbiota might also drive the pathogenesis of renal disorders. In this Review, we discuss the latest insights into the mechanisms regulating the microbiome composition, with a focus both on genetics and environmental factors, and describe how commensal microorganisms calibrate innate and adaptive immune responses to affect the activation threshold for pathogenic stimulations. We discuss the mechanisms that lead to intestinal epithelial barrier inflammation and the relevance of certain bacteria to the pathogenesis of two common kidney-based disorders: hypertension and renal stone disease. Limitations of current approaches to microbiota research are also highlighted, emphasizing the need to move beyond studies of correlation to causation.

Key points

  • The gut microbiota influences the host through reciprocal interactions with the host immune system.

  • Imbalances in the microbiota (dysbiosis) lead to epithelial barrier dysfunction and translocation of toxic compounds to the systemic circulation.

  • Hypertension and kidney stone disease might be linked to compositional or functional changes in the gut microbiome.

  • Novel research methods are being established to identify causal microorganisms that drive disease progression.

  • Understanding the crosstalk between immunity, the microbiota and the kidney has potential for the development of innovative, paradigm-shifting treatment strategies.

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Fig. 1: Regulation of gut microbial composition by host mechanisms.
Fig. 2: Microorganism-derived factors influence immunity.
Fig. 3: The gut–kidney axis in blood pressure regulation and kidney stone disease.
Fig. 4: Approaches for assessing the causality of microbiome constituents in kidney disease.

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Acknowledgements

F.K. is supported by the Deutsche Forschungsgemeinschaft (DFG; project KN 1148/2-1 and CRC 1365 Renoprotection), the Oxalosis and Hyperoxaluria Foundation and TRENAL, a thematic network grant of the Deutscher Akademischer Austauschdienst (DAAD). J.R.B. is supported by an American Cancer Society Postdoctoral Fellowship (PF-17-237-01-DMC). R.A.F. is supported by the Howard Hughes Medical Institute.

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Nature Reviews Nephrology thanks C. M. Higueras, C. Kurts, L. Nazzal and other anonymous reviewer(s) for their contribution to the peer review of this work.

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F.K. and J.R.B. researched data for the article and wrote the article. All authors contributed substantially to discussion of the article’s content and reviewed and edited the manuscript before submission.

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Correspondence to Richard A. Flavell.

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R.A.F. is a scientific consultant to GlaxoSmithKline and Zie Labs and a founder, shareholder and advisor to SMOC Therapeutics Inc. The other authors declare no competing interests.

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Glossary

Paneth cells

Epithelial cells localized in the glands of the small intestine. Microscopically, they are characterized by large eosinophilic granules that occupy the cytoplasm and contain antimicrobial compounds critical for host defence.

Enterocytes

Epithelial cells found in the small intestine. Microscopically, they are characterized by microvilli found on the apical membrane. Enterocytes are responsible for the absorption or secretion of molecules from or into the intestine.

Macrophage foam cells

Monocyte-derived macrophages that clear oxidized lipids and in this process develop into lipid-laden foam cells. These cells are components of atherosclerotic plaques and have been implicated in the pathogenesis of atherosclerotic disease.

Coprophagic animals

Animals that eat faeces, which facilitates the transmission of microbiomes between individual animals.

Goblet cells

Epithelial cells found in various organs. Goblet cells secrete mucus, a viscous fluid composed primarily of proteins called mucins.

T helper 2 (TH2) cells

Specialized population of T cells that orchestrate protective type 2 immune responses to pathogens such as parasites as well as tissue repair. TH2 cells have also been implicated in diseases such as asthma.

Pathogen-associated molecular patterns

(PAMPs). Highly conserved groups of molecular motifs detected by pattern recognition receptor (PRR)-bearing cells of the innate immune system.

Natural killer T (NKT) cells

Subset of T cells that express both a T cell receptor, a classical component of adaptive immunity, and surface receptors for natural killer cells, which are characteristic of innate immunity.

Immune exclusion

Process of clearing pathogenic microorganisms. Secretory immunoglobulin A (IgA) has a central role in this process by blocking antigens and pathogenic microorganisms from the intestinal lumen.

Vivaria

Enclosed areas for live animals in a semi-natural environment for observation or studies.

Histone deacetylases

(HDACs). Class of enzymes that remove acetyl groups. HDACs regulate access to DNA by modulating chromatin and thereby cellular processes. HDACs are also involved in immunity by, for example, regulating CD4+ T cells.

Paracellular transport

Transfer of molecules or solutes across the epithelium by passing through the intercellular space between cells. This route of transport can be enhanced if junctional proteins are displaced or have altered expression.

Transcellular transport

Transfer of molecules or solutes across the epithelium by passing through the cell. This route of transport is mediated by specialized proteins that transport from the lumen to the blood (absorption) or from the blood to the lumen (secretion).

Metagenomics

Direct genetic analysis of entire microbial communities to provide information on microbial diversity.

Metaproteomics

Characterization of all the protein samples recovered from environmental sources.

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Knauf, F., Brewer, J.R. & Flavell, R.A. Immunity, microbiota and kidney disease. Nat Rev Nephrol 15, 263–274 (2019). https://doi.org/10.1038/s41581-019-0118-7

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