# Toxic microbiome and chronic kidney disease: insights from the CKD-REIN cohort study

Sandra Wagner, Laetitia Koppe, Manolo Laiola, Islam Amine Larabi, Florence Thirion, Denis Fouque, Emmanuelle Le Chatelier, Jean-Claude Alvarez, Ziad A Massy, Dusko Stanislav, et al.

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Sandra Wagner, Laetitia Koppe, Manolo Laiola, Islam Amine Larabi, Florence Thirion, et al. Toxic microbiome and chronic kidney disease: insights from the CKD-REIN cohort study. 60th ERA CONGRESS, Jun 2023, Milan, Italie, France. [hal-04711654](https://hal.science/hal-04711654v1)

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# Toxic microbiome and chronic kidney disease:
insights from the CKD-REIN cohort study

Sandra Wagner*¹, Laetitia Koppe*²⁻³, Manolo Laiola*⁴, Islam Amine Larabi⁵, Florence Thirion⁴, Denis Fouque²⁻³, Emmanuelle Le Chatelier⁴, Jean-Claude Alvarez⁵, Ziad A. Massy⁶,⁷, Stanislav Dusko Ehrlich⁸, Bénédicte Stengel⁷

¹ Universite de Lorraine, INSERM CIC 1433, Nancy CHRU, Inserm U1116, FCRIN INI-CRCT, Nancy, France, ² Univ. Lyon, CarMeN lab, INSA-Lyon, INSERM U1060, INRA, Université Claude Bernard Lyon 1, F-69621 Villeurbanne, France, ³ Department of Nephrology, Hospices Civils de Lyon, Centre Hospitalier Lyon-Sud, Pierre-Bénite, F-69495, France, ⁴ MetaGenoPolis, INRAe, AgroParisTech, Université Paris-Saclay, Paris, France, ⁵ Department of Pharmacology and Toxicology, Inserm U-1173, UFR Simone Veil Santé UVSQ-Paris-Saclay University, Raymond Poincaré Hospital, AP-HP, 104 Boulevard Raymond Poincaré, 92380 Garches, France, ⁶ Div. of Nephrology, Ambroise Paré University Hospital, APHP, Boulogne-Billancourt/Paris, France, ⁷ Centre for Research in Epidemiology and Population Health (CESP), Paris-Saclay University, Versailles Saint Quentin University, INSERM UMRS, 1018 Villejuif, France, ⁸ Department of Clinical and Movement Neurosciences, University College London, London, UK

## INTRODUCTION

Many uremic toxins (UTs) originate from gut microbiome activity, and contribute to chronic kidney disease (CKD) progression and cardiovascular morbidity (1). In order to reduce uremic symptoms and CKD progression, patients have several dietary restrictions, which may influence gut microbiome composition, and consequently impact UTs production (2). An altered microbiota may contribute to UTs increase in those patients. However, the role of key bacterial taxa in producing UTs and the impact of diet on UTs variance in non-dialysis-dependent (NDD) patients are not well known.

## AIM

The objectives of this study were, first, to compare microbial features between CKD patients and healthy controls, and, second, to investigate cross-sectionally the features (gut microbiome, UTs or diet) associated with CKD severity.

## METHOD

This study is based on 240 NDD patients with CKD stage 3-5 from the **CKD-REIN cohort** (age: 68 ± 12 years, 71% male, eGFR: 33 ± 13 mL/min/1.73m²) (3); 78 of them were age-, sex-, and BMI-matched with healthy controls from the **Milieu Interieur** (MI) cohort (4) (age: 45 ± 14 years, 50% male, eGFR: 89 ± 13 mL/min/1.73m²).

### Measures

**Characterization of Metagenomic Species Pangenomes (MSPs)** was performed using shotgun metagenomic sequencing and the integrated Gut Catalogue 2.

Serum concentrations of 10 uremic **toxins (UTs)** and 3 **precursors** were measured by LC-MS/MS.

**Food intake** was evaluated by a validated food frequency questionnaire (5).

## RESULTS

Several MSPs were significantly contrasted between MI and CKD cohorts: **43 species were enriched in CKD patients vs 24 in controls.** Species enriched in CKD patients included several UTs producers such *Enterocloster* and *Hungatella* genera (both members of *Lachnospiraceae* family), *Dysosmobacter* – *Oscillibacter* spp., *Butyricimonas faecihominis* and *Victivallis vadensis* species. Some of them were negatively correlated with eGFR and positively correlated with the following UTs: CMPF, TMAO, and indole-3-acetic acid.

**Results from the multiomics' data integration modelling suggest a strong interplay between host characteristics, gut microbiome, UTs, and diet-related features with CKD severity**

(eGFR<30, n=110 vs eGFR ≥30 mL/min/1.73m², n=130).

<figure><img src="image_1.png" /></figure>

<figure><img src="image_2.png" /></figure>

Among taxa associated with a severe CKD, some species carrying genes for UTs production were observed, such as *Desuflovibiro fairfieldensis*, *Bacteroides clarus* and *Blautia obeum* species. along with increasing alcohol and hot drinks consumption, CRP and several UTs (kynurenic acid, 3-indoxyl sulfate and Phenylacetylglutamine) levels. In contrast, some taxa like *Faecalibacterium prausnitzii* and *Dysosmobacter welbionis* species and legume intake but not UTs were associated with a moderate CKD.

## CONCLUSIONS

Our study highlights an alteration of gut microbiome in CKD patients compared to healthy controls, with increased abundance of UTs producer species. The results of the multidimensional data integration modelling suggest a strong interplay between food intake, gut microbiome modifications, and UTs accumulation and clinical features. These findings might open to promising therapeutic strategies to reduce microbiome-related toxicity.

## ACKNOWLEDGEMENTS

We wish to acknowledge site investigators, clinical research associates, nephrologists and patients for their contribution to the CKD-REIN study. CKD-REIN is supported by a public-private partnership including the National Research Agency (ANR) through the 2010 «Cohort-Investments for the Future » program, the 2010 PHRC, and Fresenius Medical Care, GSK and Boehringer Ingelheim. This project received a grant from the ANR (ANR-19-CE17-0023).

## REFERENCES

1. Ramezani A, Massy ZA, et al. Am J Kidney Dis. 2016;67(3):483-98.

2. Koppe L, Soulage CO. Kidney Int. 2022;102(4):728-739.

3. Stengel B et al. Nephrol Dial Transplant. 2014, 29(8):1500-07.

4. Thomas S, et al. Clin Immunol. 2015;157(2):277-93.

5. Affret A, Wagner S, et al., BMC Nephrol. 2017;18(1):297.

## CONTACT INFORMATION

s.wagner2@chru-nancy.fr

<footnote>*Contributed equally</footnote>