Targeting Gut Microbiome With Prebiotic in Patients With CKD: The TarGut-CKD Study

Pilot Studies in CKD Consortium

doi:10.1016/j.ekir.2023.12.017

Targeting Gut Microbiome With Prebiotic in Patients With CKD: The TarGut-CKD Study

Pilot Studies in CKD Consortium

Medicine, Nephrology Division

Research output: Contribution to journal › Article › peer-review

2 Scopus citations

Abstract

Introduction: Disruption of gut microbiota underpins some of the metabolic alterations observed in chronic kidney disease (CKD). Methods: In a nonrandomized, open-label, 3-phase pilot trial, with repeated measures within each phase, we examined the efficacy of oligofructose-enriched inulin (p-inulin) in changing the gut microbiome and their metabolic products in 15 patients with CKD. The stability of microbiome and metabolome was studied during the pretreatment phase (8 weeks), a p-inulin treatment phase (12 weeks), and a post treatment phase (8 weeks) of the study. Results: Study participants completed 373 of the 420 expected study visits (88.8%). Adherence to p-inulin was 83.4%. 16S rRNA sequencing was performed in 368 stool samples. A total of 1085 stool, urine, and plasma samples were subjected to untargeted metabolomic studies. p-inulin administration altered the composition of the gut microbiota significantly, with an increase in abundance of Bifidobacterium and Anaerostipes. Intersubject variations in microbiome and metabolome were larger than intrasubject variation, indicating the stability of the gut microbiome within each phase of the study. Overall metabolite compositions assessed by beta diversity in urine and stool metabolic profiles were significantly different across study phases. Several specific metabolites in stool, urine, and plasma were significant at false discovery rate (FDR) ≤ 0.1 over phase. Specifically, there was significant enrichment in microbial metabolites derived from saccharolysis. Conclusion: Results from our study highlight the stability of the gut microbiome and the expansive effect of p-inulin on microbiome and host cometabolism in patients with CKD. Findings from this study will enable rigorous design of microbiome-based intervention trials.

Original language	English (US)
Pages (from-to)	671-685
Number of pages	15
Journal	Kidney International Reports
Volume	9
Issue number	3
DOIs	https://doi.org/10.1016/j.ekir.2023.12.017
State	Published - Mar 2024

Funding

The investigators wish to thank the study participants and many individuals who made the trial possible, including: Dr. J. W. Kusek, Dr. K. C. Abbott, Dr. P. L. Kimmel (NIDDK), Dr. G. J. Beck, K. Brittain, S. Sherer, Dr. B. Hu, Mr. Larive, K. Wiggins, J. MacKrell, and V. Konig (Data Coordinating Center [Cleveland Clinic]); Dr. S. Sharma, Dr. A. Ramezani, Dr. M. Wing, C. Dr. Ping Li, Franco, A. Dumadag, and S. Andrews (George Washington University); Dr. Hostetter (Case Western). Data Safety and Monitory Board members D. Warnock, J. Bonventre, D. Coyne, L. Dworkin, R. Glassock, J. Hodges, A. Thompson, M. Leonard, M. Pahl, A.K. Singh, JR Landis, D. Bluemke. Jackson GI Medical provided the p-inulin at no cost but were not involved in designing or conducting the study, analyzing, or interpreting the data, or preparing the manuscript. This trial was sponsored by the NIDDK Pilot Clinical Trials consortium (contracts U01DK097093, U01DK099877, U01DK099924, U01DK099930, and U01DK099933). The investigators wish to thank the study participants and many individuals who made the trial possible, including: Dr. J. W. Kusek, Dr. K. C. Abbott, Dr. P. L. Kimmel (NIDDK), Dr. G. J. Beck, K. Brittain, S. Sherer, Dr. B. Hu, Mr. Larive, K. Wiggins, J. MacKrell, and V. Konig (Data Coordinating Center [Cleveland Clinic]); Dr. S. Sharma, Dr. A. Ramezani, Dr. M. Wing, C. Dr. Ping Li, Franco, A. Dumadag, and S. Andrews (George Washington University); Dr. Hostetter (Case Western). Data Safety and Monitory Board members D. Warnock, J. Bonventre, D. Coyne, L. Dworkin, R. Glassock, J. Hodges, A. Thompson, M. Leonard, M. Pahl, A.K. Singh, JR Landis, D. Bluemke. Jackson GI Medical provided the p-inulin at no cost but were not involved in designing or conducting the study, analyzing, or interpreting the data, or preparing the manuscript. This trial was sponsored by the NIDDK Pilot Clinical Trials consortium (contracts U01DK097093, U01DK099877, U01DK099924, U01DK099930, and U01DK099933). The data is available to investigators through the NIDDK biorepository. Study Design was by DSR, JJG, Dr. MFF, LFF, TI, MW, KLR, AKC, and JPM. The experiment was conducted by DSR, AP, AS, and PCV. Data analysis was by MBS, BG, JJG, and CK. Interpretation of study findings was by DSR, BG, MBS, JJG, and TI. Draft of first and subsequent versions of the manuscript was by BG and MBS. Critical revision of the manuscript was done by TI, JJG, CK, MFF, SM, AS, AP, MW, KLR, AKC, LFF, and JPM. Funding was secured by DSR, JJG, TI, AKC, and MW.

Keywords

Bifidobacterium
deoxycholic acid
indoles
metabolome
p-cresol
uremic toxin

ASJC Scopus subject areas

Nephrology

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10.1016/j.ekir.2023.12.017

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title = "Targeting Gut Microbiome With Prebiotic in Patients With CKD: The TarGut-CKD Study",

abstract = "Introduction: Disruption of gut microbiota underpins some of the metabolic alterations observed in chronic kidney disease (CKD). Methods: In a nonrandomized, open-label, 3-phase pilot trial, with repeated measures within each phase, we examined the efficacy of oligofructose-enriched inulin (p-inulin) in changing the gut microbiome and their metabolic products in 15 patients with CKD. The stability of microbiome and metabolome was studied during the pretreatment phase (8 weeks), a p-inulin treatment phase (12 weeks), and a post treatment phase (8 weeks) of the study. Results: Study participants completed 373 of the 420 expected study visits (88.8%). Adherence to p-inulin was 83.4%. 16S rRNA sequencing was performed in 368 stool samples. A total of 1085 stool, urine, and plasma samples were subjected to untargeted metabolomic studies. p-inulin administration altered the composition of the gut microbiota significantly, with an increase in abundance of Bifidobacterium and Anaerostipes. Intersubject variations in microbiome and metabolome were larger than intrasubject variation, indicating the stability of the gut microbiome within each phase of the study. Overall metabolite compositions assessed by beta diversity in urine and stool metabolic profiles were significantly different across study phases. Several specific metabolites in stool, urine, and plasma were significant at false discovery rate (FDR) ≤ 0.1 over phase. Specifically, there was significant enrichment in microbial metabolites derived from saccharolysis. Conclusion: Results from our study highlight the stability of the gut microbiome and the expansive effect of p-inulin on microbiome and host cometabolism in patients with CKD. Findings from this study will enable rigorous design of microbiome-based intervention trials.",

keywords = "Bifidobacterium, deoxycholic acid, indoles, metabolome, p-cresol, uremic toxin",

author = "{Pilot Studies in CKD Consortium} and Sohn, {Michael B.} and Bei Gao and Cynthia Kendrick and Anvesha Srivastava and Tamara Isakova and Gassman, {Jennifer J.} and Fried, {Linda F.} and Myles Wolf and Cheung, {Alfred K.} and Raphael, {Kalani L.} and Vinales, {Patricia Centron} and Middleton, {John P.} and Ana Pabalan and Raj, {Dominic S.} and Joe Ix and Susan Mendley and Flessner, {Michael F.}",

note = "Publisher Copyright: {\textcopyright} 2023 International Society of Nephrology",

year = "2024",

month = mar,

doi = "10.1016/j.ekir.2023.12.017",

language = "English (US)",

volume = "9",

pages = "671--685",

journal = "Kidney International Reports",

issn = "2468-0249",

publisher = "Elsevier Inc.",

number = "3",

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TY - JOUR

T1 - Targeting Gut Microbiome With Prebiotic in Patients With CKD

T2 - The TarGut-CKD Study

AU - Pilot Studies in CKD Consortium

AU - Sohn, Michael B.

AU - Gao, Bei

AU - Kendrick, Cynthia

AU - Srivastava, Anvesha

AU - Isakova, Tamara

AU - Gassman, Jennifer J.

AU - Fried, Linda F.

AU - Wolf, Myles

AU - Cheung, Alfred K.

AU - Raphael, Kalani L.

AU - Vinales, Patricia Centron

AU - Middleton, John P.

AU - Pabalan, Ana

AU - Raj, Dominic S.

AU - Ix, Joe

AU - Mendley, Susan

AU - Flessner, Michael F.

PY - 2024/3

Y1 - 2024/3

N2 - Introduction: Disruption of gut microbiota underpins some of the metabolic alterations observed in chronic kidney disease (CKD). Methods: In a nonrandomized, open-label, 3-phase pilot trial, with repeated measures within each phase, we examined the efficacy of oligofructose-enriched inulin (p-inulin) in changing the gut microbiome and their metabolic products in 15 patients with CKD. The stability of microbiome and metabolome was studied during the pretreatment phase (8 weeks), a p-inulin treatment phase (12 weeks), and a post treatment phase (8 weeks) of the study. Results: Study participants completed 373 of the 420 expected study visits (88.8%). Adherence to p-inulin was 83.4%. 16S rRNA sequencing was performed in 368 stool samples. A total of 1085 stool, urine, and plasma samples were subjected to untargeted metabolomic studies. p-inulin administration altered the composition of the gut microbiota significantly, with an increase in abundance of Bifidobacterium and Anaerostipes. Intersubject variations in microbiome and metabolome were larger than intrasubject variation, indicating the stability of the gut microbiome within each phase of the study. Overall metabolite compositions assessed by beta diversity in urine and stool metabolic profiles were significantly different across study phases. Several specific metabolites in stool, urine, and plasma were significant at false discovery rate (FDR) ≤ 0.1 over phase. Specifically, there was significant enrichment in microbial metabolites derived from saccharolysis. Conclusion: Results from our study highlight the stability of the gut microbiome and the expansive effect of p-inulin on microbiome and host cometabolism in patients with CKD. Findings from this study will enable rigorous design of microbiome-based intervention trials.

AB - Introduction: Disruption of gut microbiota underpins some of the metabolic alterations observed in chronic kidney disease (CKD). Methods: In a nonrandomized, open-label, 3-phase pilot trial, with repeated measures within each phase, we examined the efficacy of oligofructose-enriched inulin (p-inulin) in changing the gut microbiome and their metabolic products in 15 patients with CKD. The stability of microbiome and metabolome was studied during the pretreatment phase (8 weeks), a p-inulin treatment phase (12 weeks), and a post treatment phase (8 weeks) of the study. Results: Study participants completed 373 of the 420 expected study visits (88.8%). Adherence to p-inulin was 83.4%. 16S rRNA sequencing was performed in 368 stool samples. A total of 1085 stool, urine, and plasma samples were subjected to untargeted metabolomic studies. p-inulin administration altered the composition of the gut microbiota significantly, with an increase in abundance of Bifidobacterium and Anaerostipes. Intersubject variations in microbiome and metabolome were larger than intrasubject variation, indicating the stability of the gut microbiome within each phase of the study. Overall metabolite compositions assessed by beta diversity in urine and stool metabolic profiles were significantly different across study phases. Several specific metabolites in stool, urine, and plasma were significant at false discovery rate (FDR) ≤ 0.1 over phase. Specifically, there was significant enrichment in microbial metabolites derived from saccharolysis. Conclusion: Results from our study highlight the stability of the gut microbiome and the expansive effect of p-inulin on microbiome and host cometabolism in patients with CKD. Findings from this study will enable rigorous design of microbiome-based intervention trials.

KW - Bifidobacterium

KW - deoxycholic acid

KW - indoles

KW - metabolome

KW - p-cresol

KW - uremic toxin

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Targeting Gut Microbiome With Prebiotic in Patients With CKD: The TarGut-CKD Study

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