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The gut microbiota and the brain–gut–kidney axis in hypertension and chronic kidney disease

Abstract

Crosstalk between the gut microbiota and the host has attracted considerable attention owing to its involvement in diverse diseases. Chronic kidney disease (CKD) is commonly associated with hypertension and is characterized by immune dysregulation, metabolic disorder and sympathetic activation, which are all linked to gut dysbiosis and altered host–microbiota crosstalk. In this Review, we discuss the complex interplay between the brain, the gut, the microbiota and the kidney in CKD and hypertension and explain our brain–gut–kidney axis hypothesis for the pathogenesis of these diseases. Consideration of the role of the brain–gut–kidney axis in the maintenance of normal homeostasis and of dysregulation of this axis in CKD and hypertension could lead to the identification of novel therapeutic targets. In addition, the discovery of unique microbial communities and their associated metabolites and the elucidation of brain–gut–kidney signalling are likely to fill fundamental knowledge gaps leading to innovative research, clinical trials and treatments for CKD and hypertension.

Key points

  • The gut microbiota has crucial roles in a variety of diseases, including hypertension and chronic kidney disease (CKD).

  • The gut microbiota communicates with the endocrine, nervous and immune systems to regulate host homeostasis, including blood pressure and kidney functions.

  • The gut–kidney axis is mediated through metabolism-dependent and immune pathways.

  • The brain–gut–kidney axis involves connections between these organs that are mediated by descending autonomic regulation from the brain and signals from the gut and the kidney, such as immune products and microbial metabolites.

  • Potential therapeutic strategies for CKD and hypertension that target the gut microbiota include dietary interventions, probiotics, prebiotics, synbiotics, faecal microbiota transplant and metabolome modulation.

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Fig. 1: The anatomy of the gut and its interactions with multiple systems.
Fig. 2: The metabolism-dependent and immune pathways of the gut–kidney axis.
Fig. 3: The brain–gut–kidney axis hypothesis for the pathogenesis of hypertension and CKD.

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T.Y. researched the data and wrote the article. M.K.R., T.Y. and E.M.R. made substantial contributions to discussions of the content. All authors reviewed and edited the manuscript before submission.

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Correspondence to Mohan K. Raizada.

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Glossary

Low-grade inflammation

A chronic systemic immune response that occurs without acute clinical symptoms.

Probiotics

A group of microorganisms with beneficial effects on human health.

Nucleus of the solitary tract

(NTS). A brainstem region that receives and integrates peripheral afferent inputs from the baroreceptors, chemoreceptors and subdiaphragmatic organs of the gastrointestinal tract. The NTS projects selectively to the paraventricular nucleus of hypothalamus or caudal ventrolateral medulla to modulate sympathetic outflow.

TH1 and TH2 responses

CD4+ T cells can be divided into two subsets on the basis of their pattern of cytokine production. The TH1 response is characterized by the production of IFNγ and is generally more effective against intracellular pathogens, whereas the TH2 response is characterized by the production of IL-4 and is generally more effective against extracellular bacteria and parasites.

Uraemic toxins

Various compounds, mainly derived from the gut microbiota, that accumulate in the blood and tissue with progression of renal failure. Some compounds exhibit high affinity for albumin and are difficult to remove by haemodialysis.

Paraventricular nucleus of hypothalamus

(PVN). An important region in the central nervous system that contributes to sympathetic nervous system efferent transmission. Stimulation of the PVN with inflammatory cytokines or angiotensin II increases sympathetic outflow.

Rostral ventrolateral medulla

(RVLM). The RVLM receives projections from the paraventricular nucleus of hypothalamus and caudal ventrolateral medulla to control sympathetic activity associated with cardiovascular functions.

Kynurenine pathway

The kynurenine pathway catabolizes approximately 95–99% of ingested tryptophan that is not utilized for protein synthesis in mammalian cells. Dysregulation of the kynurenine pathway results in overproduction of quinolinic acid, which has been implicated in inflammatory neurological diseases, such as Alzheimer and Huntington diseases.

Excitotoxin

A collection of chemical compounds that overactivate and exhaust neurons by binding to their receptors.

Prebiotics

Food ingredients that promote growth of beneficial microorganisms.

Synbiotics

Combinations of prebiotics and probiotics.

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Yang, T., Richards, E.M., Pepine, C.J. et al. The gut microbiota and the brain–gut–kidney axis in hypertension and chronic kidney disease. Nat Rev Nephrol 14, 442–456 (2018). https://doi.org/10.1038/s41581-018-0018-2

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