# TOXIC MICROBIOME AND CHRONIC KIDNEY DISEASE: INSIGHTS FROM THE CKD-REIN COHORT STUDY

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Manolo Laiolaª, Sandra Wagnerᵇ, Laetitia Koppeᶜ,ᵈ, Islam Amine Larabiᵉ, Florence Thirionª, Denis Fouqueᶜ,ᵈ, Sophie Liabeufᵇ, Emmanuelle Le Chatelierª, Jean-Claude Alvarezᵉ, Ziad Massyg,ḥ, Bénédicte Stengelh, Stanislav Dusko Ehrlichª,ᵢ

## Background

Chronic kidney disease (CKD) is often associated with alterations in gut microbiome composition and functions, particularly with food-derived proteins fermentation in the colon, leading to the production of uremic toxins [1,2]. Nevertheless, the identification of the relations between the aberrant and “toxic” microbiome, the CKD severity and the potential impact of diet have not been exhaustively explored in humans.

## Aim

We investigated the associations between gut microbiome composition, blood uremic toxins, clinical metadata and food intake over a subsample of 240 patients (mean age, 68 [SD 11.6] years; 71% male) with non-dialysis CKD and an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m² from the CKD-REIN study[3]. Moreover, an observational comparison with a healthy cohort (Milieu Interieur[4], n=938) was also performed to find out microbial biomarkers characterizing the gut microbiome-related toxicity in CKD.

## Results

### 1 CKD vs Milieu Interieur

Using species level profiling, we observed that CKD patients showed a significant reduced gut microbiome health index compared to controls (left). Several CKD-related potential biomarkers were retrieved (center), like toxins producer species *Negativibacillus massiliensis* and *Victivallis vadensis* among others after adjusting for age, BMI, gender and diabetes condition as confounders (right). In addition, taxa belonging to *Enterocloster* and *Hungatella* clades (*Lachnospiraceae* family) were found negatively correlated to eGFR and positively associated with C-reactive protein (CRP) levels.

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### 2 Moderate vs Severe CKD phenotype

A supervised modelling for data integration was carried out to explore associations between multiomics' biomarkers differentiating moderate (n=130, eGFR≥ 30 mL/min) and severe (n=110, eGFR< 30 mL/min) CKD phenotypes (left). In particular, severe-related taxa carrying genes involved in the production of metabolites causing uremic toxicity were linked to serum uremic toxins as indoxyl sulphate, trimethylamine-N-oxide, phenylacetylglutamine and kynurenic acid, along with CRP levels, alcohol consumption and low vegetables intake (right).

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## Conclusions

Our study highlights the important associations of gut microbiome composition and uremic toxins accumulations with CKD severity. Moreover, the findings might open to promising therapeutic strategy to diminish microbiome-related toxicity and to potentially attenuate CKD severity, by regulating the gut microbial configuration possibly through the modulating effect of dietary intakes.

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INRA
SCIENCE & IMPACT

Centre de recherche de Jouy-en-Josas
Unité MetaGenoPolis

Contact: manolo.laiola@inrae.fr

### AFFILIATIONS

### REFERENCES

[1] Massy ZA and Drueke TB. Kidney International 99(2021):797-800.

[2] Koppe L and Soulage CO. Kidney International (2022).

[3] Stengel B et al. Nephrology Dialysis Transplantation 29(2014):1500-7.

[4] Thomas S et al. Clinical immunology 157 (2015):277-93.

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<footnote>ª MetaGenoPolis, INRAe, AgroParisTech, Université Paris-Saclay, Paris, France</footnote>

<footnote>ᵇ Université de Lorraine, INSERM CIC 1433, Nancy CHRU, Inserm U1116, FCRIN INI-CRCT, Nancy, France</footnote>

<footnote>ᶜ Department of Nephrology, Hospices Civils de Lyon, Centre Hospitalier Lyon-Sud, Pierre-Bénite, F-69495, France</footnote>

<footnote>ᵈ Univ. Lyon, CarMeN lab, INSA-Lyon, INSERM U1060, INRA, Université Claude Bernard Lyon 1, F-69621 Villeurbanne, France</footnote>

<footnote>ᵉ 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</footnote>

<footnote>f Department of Clinical Pharmacology, Pharmacoepidemiology unit Amiens University Hospital, F-80000 Amiens, France and MP3CV Laboratory, EA7517, University of Picardie Jules Verne, Amiens, F-80000 Amiens, France</footnote>

<footnote>g Div. of Nephrology, Ambroise Paré University Hospital, APHP, Boulogne-Billancourt/Paris, France</footnote>

<footnote>h Centre for Research in Epidemiology and Population Health (CESP), Paris-Saclay University, Versailles Saint Quentin University, INSERM UMRS, 1018 Villejuif, France.</footnote>

<footnote>i Department of Clinical and Movement Neurosciences, University College London, London, UK</footnote>