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Intestinal microbiome and fitness in kidney disease

Abstract

Environmental changes can induce diversity shifts within ecosystems that affect interactions between species. Similarly, the development of kidney disease induces shifts within the ecosystem of the intestinal microbiome, affecting host physiology and fitness. Renal failure itself, together with related changes in diet and medication, alters the microbiota and its secretome of micronutrients, nutrients and regulatory metabolites towards a phenotype characterized by the production of uraemic toxins, hence contributing to the clinical syndrome of uraemia and its complications. These alterations are associated with structural changes in the intestinal wall that impair barrier function and cause leakage of bacterial metabolites, bacterial wall products and live bacteria into the circulation. Thus, the intestinal microbiota represents a new therapeutic target to improve outcomes of chronic kidney disease (CKD), including symptoms of uraemia, metabolic changes, cardiovascular complications, aberrant immunity and disease progression. Initial interventional studies have shown promising effects of unselective probiotic preparations on kidney inflammation and uraemia in patients with CKD but longer-term studies are needed. Here, we take an ecological approach to understand the role of the intestinal microbiota in determining survival fitness in kidney disease.

Key points

  • The intestinal microbiota is a highly versatile ecosystem that contributes to host physiological processes, including intestinal barrier integrity, immunological fitness and metabolic fitness, and responds dynamically to intrinsic and extrinsic challenges.

  • Crosstalk between the gut microbial ecosystem and human physiological systems is context-dependent; nutrient intake and drug therapy are the most important exogenous modifiers of this crosstalk.

  • CKD can induce changes in both the composition and metabolic activity of gut microbiota (dysbiosis), with consequences for various physiological processes.

  • CKD and related changes in the microbiota impair intestinal barrier fitness and promote translocation of bacterial components into the circulation, which impairs immunological fitness by driving persistent systemic inflammation and immune paralysis.

  • CKD and related changes in the microbiota also impair metabolic and cardiovascular fitness by secreting metabolites that favour insulin resistance, obesity, endothelial dysfunction and cardiovascular ageing.

  • Faecal transplantation, specific microorganism-targeted interventions or the use of prebiotics, probiotics or dietary interventions are potential strategies to correct or manipulate CKD-related changes in the intestinal microbiota that contribute to uraemia, as well as the progression of CKD and CKD complications.

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Fig. 1: Mutual benefits between the host and intestinal microbiota.
Fig. 2: The adaptive landscape of the gut microbial ecosystem.
Fig. 3: The symbiosis between a host and its microbiota.
Fig. 4: The intestinal barrier at the intersection between microbiome and human physiology.
Fig. 5: Effects of CKD-associated changes in intestinal flora on intestinal barrier integrity and immunological fitness.
Fig. 6: Therapeutic targeting of the intestinal microbiota.

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Acknowledgements

H.-J.A. is supported by the Heisenberg programme of the Deutsche Forschungsgemeinschaft (AN372/24-1).

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Nature Reviews Nephrology thanks J. Spence, N. Vaziri and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Microbiome

Ecological community of commensal, symbiotic or pathogenic microorganisms that reside inside and outside all multicellular organisms. A microbiome includes bacteria, archaea, meiofauna, fungi and viruses.

Archaeal microbiome

Archaea are single-cell microorganisms with metabolic and biochemical properties that distinguish them from bacteria. The archaeal microbiome is the community of archaea residing within a host.

Virome

The collection of nucleic acids (RNA and DNA) that define the viral community inside or on multicellular organisms.

Mycobiome

Fungal communities inside or on multicellular organisms.

Meiofauna

Small invertebrates including unicellular protozoa and helminthic worms (for example, Entamoeba, Trichomonas or Schistosoma).

Vertical transmission

Transmission from mother to child.

16S ribosomal RNA (rRNA) pyrosequencing

A method of DNA sequencing in which the sequencing is performed by detecting the nucleotide incorporated by a DNA polymerase, which releases pyrophosphate. This method is frequently used in microbiome genotyping.

Intestinal congestion

Oedema of the intestinal wall due to volume overload and/or vascular barrier dysfunction.

Symbiosis

A close and long-term biological interaction between two different biological organisms, the symbionts; the interaction can be mutualistic, commensalistic or parasitic.

Symbionts

Organisms that live in a symbiotic relationship with their host, for example, Escherichia coli in the human intestinal tract.

α-Diversity

Mean species diversity in a single environment (that is, within a single location).

β-Diversity

The number and variability of local niches in larger environments (for example, the diversity of species between samples taken from different locations within a single host or the diversity of species between different hosts), which contribute to species diversity at a larger scale.

Transcellular transport

Transport across cellular barriers through cells.

Paracellular transport

Transport across cellular barriers between cells.

Secretory IgA

IgA secreted by plasma cells of the gut-associated lymphoid tissue into the lumen of the intestinal tract. Secretory IgA is one of several intrinsic regulators of the intestinal microbiome.

Chordates

A large group of bilateral symmetric animals sharing the anatomical structure of a stiff rod of cartilage that extends along the inside of the body. All vertebrates are chordates, but chordates also include also non-vertebrate species such as sea squirts and lancelets.

Chitin

A long-chain polymer made of N-acetylglucosamine that is the primary component of cell walls in fungi, the exoskeleton of crustaceans and insects and the scales of fish.

Dysbiosis

Microbial imbalance or maladaptation on or inside the body, turning a previous mutual, commensal or neutral symbiosis into a harmful of dysfunctional form of symbiosis.

Pathobionts

Any potentially disease-causing organisms that, under normal circumstances, live as symbionts.

Peyer’s patches

Organized lymph follicles that are part of the gut-associated lymphoid tissue. In humans, Peyer’s patches are mainly found in the small intestine.

Metagenomic studies

Microbiome characterization by DNA sequencing.

Culturomics

High-throughput culture-based approaches to enable extensive assessment of the microbial composition.

Phase II metabolism

The metabolism of xenobiotics aims to detoxify molecules that are foreign to mammalian metabolism, for example, microbial metabolites. Phase I reactions are chemical reactions that modify the molecular structure (including oxidation, reduction and hydrolysis) and often increase the reactivity of the metabolite. Phase II reactions involve conjugation of the xenobiotic to sulfate, glucuronide or glycine, which typically reduces the reactivity of the xenobiotic.

Microbial–host co-metabolites

The transformation of microbial metabolites by phase I and II metabolism results in a wide array of derivatives. These metabolites require the combined action of both microbial and mammalian metabolism.

Hirschsprung disease

A congenital disorder characterized by the absence of nerves from parts of the intestinal tract, causing intestinal symptoms and growth retardation.

Short-chain fatty acids

(SCFAs). The end products of carbohydrate fermentation. A group of gut-flora-derived lipid metabolites with important regulatory roles in energy metabolism, hormone secretion, systemic inflammation, hypertension and cancer.

Saccharolytic fermentation

The digestion of carbohydrates under anaerobic conditions, resulting in short-chain fatty acids.

Proteolytic fermentation

The digestion of peptides and amino acids under anaerobic conditions.

Pentraxins

A conserved family of protein complexes made of five identical proteins. Pentraxins are acute phase proteins secreted from tissue cells or cells of the innate immune system that bind to and opsonize foreign particles or dead cell structures conceptually similar to antibodies.

Immune paralysis

Acquired immunodeficiency due to the long-lasting deactivation of immune cells, which can occur following a short-lasting phase of activation, for example, as described for ‘endotoxin tolerance’ that occurs upon rechallenge with bacterial endotoxin.

Type II errors

An error by which an analytical test gives a negative result although the effect is indeed present (false negative).

Myocardial stunning

Persistent dysfunction of the cardiac muscle upon a transient episode of ischaemia.

Probiotics

Live microorganisms that are intended to provide health benefits when consumed, typically by restoring the intestinal microflora.

Prebiotics

Products that are intended to restore the intestinal microflora through ingestion of nutrients that endorse the growth or activity of beneficial microorganisms.

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Meijers, B., Evenepoel, P. & Anders, HJ. Intestinal microbiome and fitness in kidney disease. Nat Rev Nephrol 15, 531–545 (2019). https://doi.org/10.1038/s41581-019-0172-1

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