Original Investigation The Microbiome and p-Inulin in Hemodialysis: A Feasibility Study Dominic S. Raj, 1 Michael B. Sohn, 2 David M. Charytan, 3 Jonathan Himmelfarb, 4 T. Alp Ikizler, 5 Rajnish Mehrotra, 6 Ali Ramezani, 1 Renu Regunathan-Shenk, 1 Jesse Y. Hsu, 7 J. Richard Landis, 7 Hongzhe Li, 7 Paul L. Kimmel, 8 Alan S. Kliger, 9 and Laura M. Dember, 10 for the Hemodialysis Novel Therapies Consortium * Abstract Background The intestinal microbiome is an appealing target for interventions in ESKD because of its likely contribution to uremic toxicity. Before conducting clinical trials of microbiome-altering treatments, it is necessary to understand the within-person and between-person variability in the composition and function of the gut microbiome in patients with ESKD. Methods We conducted a multicenter, nonrandomized, crossover feasibility study of patients on maintenance hemodialysis consisting of three phases: pretreatment (8 weeks); treatment, during which the prebiotic, p-inulin, was administered at a dosage of 8 g twice daily (12 weeks); and post-treatment (8 weeks). Stool samples were collected 1–2 times per week and blood was collected weekly for 28 weeks. The gut microbiome was characterized using 16S ribosomal-RNA sequencing and metabolomic profiling. Results A total of 11 of the 13 participants completed the 28-week study. Interparticipant variability was greater than intraparticipant variability for microbiome composition (P,0.001 by UniFrac distances) and metabolomic composition (P,0.001 by Euclidean distances). p-Inulin was well tolerated by 12 of 13 participants. Adherence to the frequent sample collection and self-aliquoting of stool samples were both 96%. A change in the microbiome composition from pretreatment to post-treatment was evident by the overall shifts in weighted UniFrac distances (P50.004) and a progressive decrease in prevalence of high intraclass correlations, indicating an increase in intraparticipant microbiome diversity during and after p-inulin treatment. An effect of p-inulin on the metab- olomic profile was not evident. Conclusions The intraparticipant stability of the gut microbiome under no-treatment conditions, the tolerability of p-inulin, the signals of increased diversity of the microbiome with p-inulin treatment, and the willingness of participants to provide stool samples all support the feasibility of a larger trial to investigate interventions targeting the gut microbiome in patients with ESKD. Whether or not p-inulin has sufficient efficacy as an intervention requires evaluation in larger studies. Clinical Trial registry name and registration number: Gut Microbiome and p-Inulin in Hemodialysis, NCT02572882 KIDNEY360 2: 445–455, 2021. doi: https://doi.org/10.34067/KID.0006132020 Key Points c Analyses of repeated samples revealed greater between- person than within-person variability for both the microbiome and metabolome. c p-Inulin treatment was associated with an increase in microbial diversity, but an effect on the metabolome was not evident. c p-Inulin was well tolerated by participants. Introduction Alterations in the composition and function of the intestinal microbiome are increasingly recog- nized as potentially modifiable components of chronic conditions, such as ESKD (1,2). Processes that con- tribute to an altered, or “dysbiotic,” microbiome in ESKD include impaired protein assimilation, low di- etary fiber consumption, frequent antibiotic use, urea 1 Division of Renal Diseases and Hypertension, George Washington University School of Medicine, Washington, DC 2 Department of Biostatistics and Computational Biology, University of Rochester Medical Center, Rochester, New York 3 Division of Nephrology, Department of Medicine, New York University Grossman School of Medicine, New York, New York 4 Division of Nephrology, Department of Medicine, Kidney Research Institute, University of Washington, Seattle, Washington 5 Division of Nephrology and Hypertension, Department of Medicine, and Vanderbilt Center for Kidney Disease, Vanderbilt University Medical Center, Nashville, Tennessee 6 Division of Nephrology, Department of Medicine, Kidney Research Institute and Harborview Medical Center, University of Washington, Seattle, Washington 7 Department of Biostatistics, Epidemiology and Informatics, and Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 8 National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 9 Department of Medicine, Yale School of Medicine, New Haven, Connecticut 10 Renal-Electrolyte and Hypertension Division, Department of Medicine, and Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania Correspondence: Dr. Dominic S. Raj, Division of Kidney Diseases and Hypertension, George Washington University School of Medicine, 2150 Pennsylvania Avenue North West, Washington, DC 20037. Email: draj@mfa.gwu.edu www.kidney360.org Vol 2 March, 2021 Copyright © 2021 by the American Society of Nephrology 445