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Gut microbiome studies in CKD: opportunities, pitfalls and therapeutic potential

Abstract

Interest in gut microbiome dysbiosis and its potential association with the development and progression of chronic kidney disease (CKD) has increased substantially in the past 6 years. In parallel, the microbiome field has matured considerably as the importance of host-related and environmental factors is increasingly recognized. Past research output in the context of CKD insufficiently considered the myriad confounding factors that are characteristic of the disease. Gut microbiota-derived metabolites remain an interesting therapeutic target to decrease uraemic (cardio)toxicity. However, future studies on the effect of dietary and biotic interventions will require harmonization of relevant readouts to enable an in-depth understanding of the underlying beneficial mechanisms. High-quality standards throughout the entire microbiome analysis workflow are also of utmost importance to obtain reliable and reproducible results. Importantly, investigating the relative composition and abundance of gut bacteria, and their potential association with plasma uraemic toxins levels is not sufficient. As in other fields, the time has come to move towards in-depth quantitative and functional exploration of the patient’s gut microbiome by relying on confounder-controlled quantitative microbial profiling, shotgun metagenomics and in vitro simulations of microorganism–microorganism and host–microorganism interactions. This step is crucial to enable the rational selection and monitoring of dietary and biotic intervention strategies that can be deployed as a personalized intervention in CKD.

Key points

  • Current kidney replacement therapies are insufficient for the removal of protein-bound uraemic toxins. New therapies or interventions need to be explored to reduce the accumulation of uraemic toxins in patients with chronic kidney disease (CKD).

  • Research on the composition of the gut microbiome in patients with CKD has been performed for over 10 years, but globally standardized methods have not yet been established and new techniques are being continuously implemented as technologies advance.

  • Any microbiome study of patients with CKD should include a clearly defined (control) group without CKD that is matched as closely as possible for age, body mass index, underlying comorbidities and medication use.

  • Characteristics and diet of patients with CKD can influence the composition of the microbiome at the time of sampling. Therefore, diet, transit time and medication use must be taken into account when analysing gut microbiome profiles.

  • The latest studies on the effect of dietary interventions on gut microbiome composition and improvements in kidney health show the potential of dietary interventions to change gut microbiome composition and uraemic toxin production.

  • At present, no intervention strategies with the ability to improve kidney function are available. Protocol standardization and optimization should lead to and accelerate discovery of new methods of intervention that also improve kidney function.

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Fig. 1: The gut–liver–kidney axis.
Fig. 2: Sample handling pipeline for gut microbiome studies.

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Acknowledgements

H.K., S.V. and A.-M.M. are early stage researchers who received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement no. [860329], STRATEGY-CKD.

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All authors reviewed or edited the manuscript before submission. G.G., H.K., S.V., A-M.M., S.A.O. and G.R.B.H researched data for the article. G.G., H.K., S.V., S.A.O. and G.R.B.H made substantial contributions to discussions of the content. G.G., H.K., S.V., S.A.O., G.R.B.H and J.R. wrote the article.

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Correspondence to Griet Glorieux.

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S.A.O., A-M.M., J.G. and J.v.B. are employees of Danone Nutricia Research. The other authors declare no competing interests.

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Nature Reviews Nephrology thanks M-G. Kim, S-K. Jo, A. Miller and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Related links

Anatomical therapeutic chemical code: https://www.whocc.no/atc_ddd_index/

Glossary

Bacterial translocation

The passage of bacteria from the gastrointestinal tract into systemic circulation.

Bristol Stool Form Scale

Diagnostic medical tool used to classify faeces into seven groups based on shape and consistency.

Cardiotoxins

Toxins that have effects on the heart and vessels that lead to undesirable outcomes.

Covariates

A study participant variable that might influence the results of what is being studied.

Deconfounder analysis

An analysis that is aimed at identifying which variables indirectly influence the outcome of a study and might thus introduce a confounding bias.

Dysbiosis

A compositional or functional imbalance of the gut microbiota linked to a disease state.

Functional analyses

Analyses of the metabolic potential of the gut microbiome.

Gut–kidney axis

Interplay between the gut (and the microbial community it accommodates) and the kidneys, mediated by endogenous transport mechanisms and metabolism-dependent pathways.

Microniche

A bacterial habitat offering specific conditions for optimal proliferation of one or more specific species.

Proteolytic fermentation

Bacterial degradation of (dietary) protein with production of (mostly) detrimental metabolites such as urea.

Quantitative microbial profiling

Absolute quantification of microbial taxa in complex samples.

Relative microbial profiling

Estimation of the relative frequency of microbial taxa in complex samples.

Saccharolytic fermentation

Bacterial degradation of (dietary) non-digestible carbohydrate with production of SCFAs.

Structured diet history method

Detailed assessment of daily food intake.

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Krukowski, H., Valkenburg, S., Madella, AM. et al. Gut microbiome studies in CKD: opportunities, pitfalls and therapeutic potential. Nat Rev Nephrol (2022). https://doi.org/10.1038/s41581-022-00647-z

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