Linking gut microbiota to cardiovascular disease and hypertension: Lessons from chronic kidney disease

doi:10.1016/j.phrs.2018.04.023

Pharmacological Research

Volume 133, July 2018, Pages 101-107

https://doi.org/10.1016/j.phrs.2018.04.023 Get rights and content

Abstract

Bidirectional interactions exist between the kidneys and the gut. These interactions are commonly referred to as the gut-kidney axis. Chronic kidney disease (CKD) leads to disturbances of the gut ecosystem. Key features include the increase of protein fermentation at the expense of carbohydrate fermentation and a disrupted epithelial barrier. A disturbed gut ecosystem may contribute to the high burden of cardiovascular disease in patients with CKD. The present review discusses the impact of CKD on the gut microenvironment and provides an update as to how gut dysbiosis and a leaky gut may be linked to accelerated cardiovascular disease and hypertension.

Graphical abstract

Section snippets

Gut microbiota in CKD

The human intestinal tract, and especially the large intestine, is colonized by trillions of microorganisms. These microorganisms encode at least 150-fold more genes than the human genome. The combined genetic potential of the endogenous flora is referred to as the ‘microbiome’ [1]. The composition of the microbial communities shows huge inter-individual variation. This variation is driven by host factors as well as environmental influences [1]. Although the microbiota is exposed to a

Gut microbial metabolism in CKD

The gut microbial metabolism provides a significant and unique contribution towards the human metabolome [3]. The gut microbial metabolism is complex and only partly dependent on gut microbial composition. Indeed, despite variation in community structure, the metagenomic carriage of metabolic pathways has been shown to be stable, at least among healthy individuals [10].

It is generally accepted that carbohydrate and nitrogen availability is the most important determinant of colonic microbial

Intestinal barrier in CKD

The intestinal barrier is the master regulator, separating self from non-self, and coordinating all interactions between the gut microbiome and human physiology [25].

To prevent paracellular flux of luminal solutes, the intestinal epithelial cells are sealed together by apical junctional complexes, consisting of the tight junction, which is the most luminal component of the complex, and the subjacent adherens junction. The tight junction is selectively permeable and is able to discriminate

Role of increased protein fermentation

Protein fermentation results in the production of potentially toxic metabolites such as ammonia, amines, phenols and sulfides. Important representatives of these metabolites are p-cresol and indole. p-Cresol is a putrefaction metabolite of tyrosine, while indole is generated by fermentation of tryptophan. After absorption, the majority of p-cresol and indole is further metabolised and conjugated to form p-cresylsulphate (PCS) and indoxyl sulphate (IndS), respectively. Concentrations of PCS and

Treatment options

A multi-targeted approach may be required to tackle the disturbed gut ecosystem in CKD. For detailed discussion, the reader is referred to several excellent reviews discussing this topic in detail [84], [85], [86].

Future directions and conclusions

Over the last decade, it has become clear that the microbiome is involved in various aspects of the uremic syndrome. Host-microbiota interactions are bidirectional. The gut microbial composition is altered in patients with CKD, as is microbial metabolism with a shift towards a predominant proteolytic fermentation pattern. The intestinal barrier, shielding the human internal environment from the fascinating world of microbes, is disturbed in patients with CKD. These alterations contribute via

Conflict of interest

None of the authors declares a conflict of interest.

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ReviewLinking gut microbiota to cardiovascular disease and hypertension: Lessons from chronic kidney disease

Abstract

Graphical abstract

Section snippets

Gut microbiota in CKD

Gut microbial metabolism in CKD

Intestinal barrier in CKD

Role of increased protein fermentation

Treatment options

Future directions and conclusions

Conflict of interest

Kidney Int.

Am. J. Clin. Nutr.

Kidney Int. Suppl.

Curr. Opin. Biotechnol.

Am. J. Clin. Nutr.

Semin. Nephrol.

Am. J. Kidney Dis.

Am. J. Kidney Dis.

Kidney Int.

Kidney Int.

Am. J. Pathol.

Kidney Int.

Am. J. Kidney Dis.

J. Ren. Nutr.

Kindey Int.

Comp. Biochem. Physiol. B

Pharmacol. Ther.

Kidney Int.

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

Kidney Int.

Am. J. Kidney Dis.

Am. J. Kidney Dis.

Am. J. Kidney Dis.

The human microbiome project

Nature

The resilience of the intestinal microbiota influences health and disease

Nat. Rev. Microbiol.

Metabolomics analysis reveals large effects of gut microflora on mammalian blood metabolites

Proc. Natl. Acad. Sci. U. S. A.

Functional interactions between the gut microbiota and host metabolism

Nature

Gut microbiota composition correlates with diet and health in the elderly

Nature

Alteration of the gut microbiota in Chinese population with chronic kidney disease

Sci. Rep.

Uremic toxin-producing gut microbiota in rats with chronic kidney disease

Nephron

Intestinal dysbiosis, barrier dysfunction, and bacterial translocation account for CKD-Related systemic inflammation

J. Am. Soc. Nephrol.

Structure, function and diversity of the healthy human microbiome

Nature

Enumeration of human colonic bacteria producing phenolic and indolic compounds: effects of pH, carbohydrate availability and retention time on dissimilatory aromatic amino acid metabolism

J. Appl. Bact.

Influence of retention time on degradation of pancreatic enzymes by human colonic bacteria grown in a 3-stage continuous culture system

J. Appl. Bacteriol.

Expansion of urease- and uricase-containing: indole- and p-cresol-forming and contraction of short-chain fatty acid-producing intestinal microbiota in ESRD

Am. J. Nephrol.

A reduction in the butyrate producing species Roseburia spp. and Faecalibacterium prausnitzii is associated with chronic kidney disease progression

Antonie Van Leeuwenhoek

The influence of CKD on colonic microbial metabolism

J. Am. Soc. Nephrol.

The mucosal barrier at a glance

J. Cell Sci.

Impaired intestinal barrier function measured by differently sized polyethylene glycols in patients with chronic renal failure

Gut

Disintegration of colonic epithelial tight junction in uremia: a likely cause of CKD-associated inflammation

Nephrol. Dial. Transplant.

Bifidobacteria or fiber protects against diet-induced microbiota-mediated colonic mucus deterioration

Cell Host Microbe

Uremic plasma impairs barrier function and depletes the tight junction protein constituents of intestinal epithelium

Am. J. Nephrol.

The importance of the gastrointestinal system in the pathogenesis of heart failure

Eur. Heart J.

p-Cresyl sulfate and indoxyl sulfate in hemodialysis patients

Clin. J. Am. Soc. Nephrol.

p-Cresol and cardiovascular risk in mild-to-moderate kidney disease

Clin. J. Am. Soc. Nephrol.

Serum indoxyl sulfate is associated with vascular disease and mortality in chronic kidney disease patients

Review
Linking gut microbiota to cardiovascular disease and hypertension: Lessons from chronic kidney disease