Machine Learning Identifies Microbiome and Clinical Predictors of Sustained Weight Loss Following Prolonged Fasting
Abstract
Abstract Background Prolonged fasting may improve metabolic health, but controlled data in healthy adults with longer follow-up and multi-omics profiling are limited. We investigated short- and long-term effects of a 5-day fasting intervention on body composition, gut microbiome, and circulating and fecal metabolites, and assessed whether baseline characteristics predict individual weight-loss response. Methods In a randomized, waitlist-controlled trial, 38 healthy adults completed a 5-day fasting intervention with 12-week follow-up (LEANER study). Outcomes included body mass index and body composition, gut microbiome composition, and plasma and fecal metabolites. Changes over time and between groups were evaluated using regression-based models and paired non-parametric tests, as appropriate. Additionally, permutation-based multivariate testing was performed on microbiome and metabolome data. Twelve-week body weight response was predicted using data-driven machine learning with cross-validation, followed by external validation in three independent cohorts undergoing prolonged fasting protocols. Results Fasting reduced body mass index acutely, predominantly driven by loss of fat mass, and these improvements partially persisted at 12 weeks. Fasting induced marked shifts in gut microbiome composition and in plasma and fecal metabolites. Post-fasting and longer-term changes in microbial diversity were associated with baseline microbiome diversity. A model combining baseline microbiome and clinical variables predicted body mass index response at 12 weeks; prominent predictors included an unclassified Faecalibacterium species, Oscillibacter sp. 50_27, low-density lipoprotein cholesterol, and systolic blood pressure. The model generalized to three independent cohorts, including individuals with metabolic syndrome, patients with multiple sclerosis exposed to repeated fasting, and healthy volunteers fasting for 6–12 days. Conclusions In healthy adults, a 5-day prolonged fasting intervention produces robust short-term metabolic changes with partial persistence and consistent remodeling of the gut microbiome and metabolite profiles. Baseline microbiome and clinical characteristics can help stratify expected longer-term responses, supporting the development of individualized fasting-based interventions. Trial registration ClinicalTrials.gov , NCT04452916 . Registered on June 29, 2020
Authors 20
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Max Delbrück Center · Humboldt-Universität zu Berlin · German Centre for Cardiovascular Research · Freie Universität Berlin · Charité - Universitätsmedizin Berlin
Affiliation as printed
Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
DZHK (German Centre for Cardiovascular Research), partner site Berlin, Germany
Experimental and Clinical Research Center (ECRC), a cooperation of Charité - Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine, Berlin, Germany
Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
Experimental and Clinical Research Center (ECRC), a cooperation of Charité – Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine, Berlin, Germany
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University of Oslo · Max Delbrück Center · Humboldt-Universität zu Berlin · German Centre for Cardiovascular Research · Freie Universität Berlin · Charité - Universitätsmedizin Berlin
Affiliation as printed
Centre for Ecological and Evolutionary Synthesis (CEES), Department of Biosciences, University of Oslo, Oslo, Norway
Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
DZHK (German Centre for Cardiovascular Research), partner site Berlin, Germany
Experimental and Clinical Research Center (ECRC), a cooperation of Charité - Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine, Berlin, Germany
Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
Experimental and Clinical Research Center (ECRC), a cooperation of Charité – Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine, Berlin, Germany
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Max Delbrück Center · Humboldt-Universität zu Berlin · German Centre for Cardiovascular Research · Freie Universität Berlin · Charité - Universitätsmedizin Berlin
Affiliation as printed
Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
DZHK (German Centre for Cardiovascular Research), partner site Berlin, Germany
Experimental and Clinical Research Center (ECRC), a cooperation of Charité - Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine, Berlin, Germany
Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
Experimental and Clinical Research Center (ECRC), a cooperation of Charité – Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine, Berlin, Germany
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Max Delbrück Center · Humboldt-Universität zu Berlin · German Centre for Cardiovascular Research · Freie Universität Berlin · Charité - Universitätsmedizin Berlin
Affiliation as printed
Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
DZHK (German Centre for Cardiovascular Research), partner site Berlin, Germany
Experimental and Clinical Research Center (ECRC), a cooperation of Charité - Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine, Berlin, Germany
Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
Experimental and Clinical Research Center (ECRC), a cooperation of Charité – Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine, Berlin, Germany
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Affiliation as printed
Institute of Functional Genomics, University of Regensburg, Regensburg, Germany
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Max Delbrück Center · Humboldt-Universität zu Berlin · German Centre for Cardiovascular Research · Freie Universität Berlin · Charité - Universitätsmedizin Berlin
Affiliation as printed
Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
DZHK (German Centre for Cardiovascular Research), partner site Berlin, Germany
Experimental and Clinical Research Center (ECRC), a cooperation of Charité - Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine, Berlin, Germany
Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
Experimental and Clinical Research Center (ECRC), a cooperation of Charité – Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine, Berlin, Germany
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Max Delbrück Center · Charité - Universitätsmedizin Berlin
Affiliation as printed
Experimental and Clinical Research Center (ECRC), a cooperation of Charité - Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine, Berlin, Germany
Experimental and Clinical Research Center (ECRC), a cooperation of Charité – Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine, Berlin, Germany
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Max Delbrück Center · Charité - Universitätsmedizin Berlin
Affiliation as printed
Department of Nephrology and Internal Intensive Care Medicine, Charité –Universitätsmedizin Berlin, Germany
Experimental and Clinical Research Center (ECRC), a cooperation of Charité - Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine, Berlin, Germany
Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
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Max Delbrück Center · Charité - Universitätsmedizin Berlin
Affiliation as printed
Experimental and Clinical Research Center (ECRC), a cooperation of Charité - Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine, Berlin, Germany
Experimental and Clinical Research Center (ECRC), a cooperation of Charité – Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine, Berlin, Germany
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Max Delbrück Center · Humboldt-Universität zu Berlin · German Centre for Cardiovascular Research · Freie Universität Berlin · Charité - Universitätsmedizin Berlin
Affiliation as printed
Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
DZHK (German Centre for Cardiovascular Research), partner site Berlin, Germany
Experimental and Clinical Research Center (ECRC), a cooperation of Charité - Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine, Berlin, Germany
Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
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Max Delbrück Center · Humboldt-Universität zu Berlin · Freie Universität Berlin · Charité - Universitätsmedizin Berlin
Affiliation as printed
Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
Experimental and Clinical Research Center (ECRC), a cooperation of Charité - Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine, Berlin, Germany
Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
Experimental and Clinical Research Center (ECRC), a cooperation of Charité – Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine, Berlin, Germany
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Affiliation as printed
BioStats GmbH, Nauen, Germany
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Max Delbrück Center · Humboldt-Universität zu Berlin · Freie Universität Berlin · Charité - Universitätsmedizin Berlin
Affiliation as printed
Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
Experimental and Clinical Research Center (ECRC), a cooperation of Charité - Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine, Berlin, Germany
Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
Experimental and Clinical Research Center (ECRC), a cooperation of Charité – Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine, Berlin, Germany
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Max Delbrück Center · Humboldt-Universität zu Berlin · German Centre for Cardiovascular Research · Freie Universität Berlin · Charité - Universitätsmedizin Berlin
Affiliation as printed
Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
DZHK (German Centre for Cardiovascular Research), partner site Berlin, Germany
Experimental and Clinical Research Center (ECRC), a cooperation of Charité - Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine, Berlin, Germany
Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
Experimental and Clinical Research Center (ECRC), a cooperation of Charité – Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine, Berlin, Germany
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Max Delbrück Center · Humboldt-Universität zu Berlin · Freie Universität Berlin · Charité - Universitätsmedizin Berlin
Affiliation as printed
Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
Experimental and Clinical Research Center (ECRC), a cooperation of Charité - Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine, Berlin, Germany
Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
Experimental and Clinical Research Center (ECRC), a cooperation of Charité – Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine, Berlin, Germany
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King's College London · Buchinger Wilhelmi · University of Regensburg
Affiliation as printed
Department of Nutritional Sciences, School of Life Course Sciences, Faculty of Life Sciences and Medicine, King’s College London, London, United Kingdom
Science Department, Buchinger Wilhelmi Clinic, Überlingen, Germany
Institute of Functional Genomics, University of Regensburg, Regensburg, Germany
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Max Delbrück Center · Humboldt-Universität zu Berlin · Universitätsklinikum Würzburg · German Centre for Cardiovascular Research · Freie Universität Berlin · Charité - Universitätsmedizin Berlin
Affiliation as printed
Institute of Experimental Biomedicine, University Hospital Würzburg, Germany
Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
DZHK (German Centre for Cardiovascular Research), partner site Berlin, Germany
Experimental and Clinical Research Center (ECRC), a cooperation of Charité – Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine, Berlin, Germany
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Max Delbrück Center · Humboldt-Universität zu Berlin · German Centre for Cardiovascular Research · European Molecular Biology Laboratory · University of Regensburg · Freie Universität Berlin · Charité - Universitätsmedizin Berlin
Affiliation as printed
Institute of Functional Genomics, University of Regensburg, Regensburg, Germany
Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
DZHK (German Centre for Cardiovascular Research), partner site Berlin, Germany
Experimental and Clinical Research Center (ECRC), a cooperation of Charité – Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine, Berlin, Germany
Structural and Computational Biology Unit, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany
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Hendrik Bartolomaeus corresponding
Max Delbrück Center · Universitätsklinikum Würzburg · German Centre for Cardiovascular Research
Affiliation as printed
DZHK (German Centre for Cardiovascular Research), partner site Berlin, Germany
Institute of Experimental Biomedicine, University Hospital Würzburg, Germany
Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
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Max Delbrück Center · Humboldt-Universität zu Berlin · Freie Universität Berlin · Charité - Universitätsmedizin Berlin
Affiliation as printed
Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
Experimental and Clinical Research Center (ECRC), a cooperation of Charité - Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine, Berlin, Germany
Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
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