Interindividual variability in gut microbiome mediates the efficacy of resistant starch on MASLD

37 authors, including; Xiaoxue Long; Hui Wang; Yuwei Lu; Xiaojing Gao; Yuanyuan Xiao; Mingliang Zhang; Jun Li; Weiping Jia; Rong Zeng; Yueqiong Ni; Luonan Chen; Huating Li

doi:10.1016/j.cmet.2025.10.017

Interindividual variability in gut microbiome mediates the efficacy of resistant starch on MASLD

37 authors, including
, Xiaoxue Long (Co-first Author)
, Hui Wang (Co-first Author)
, Yuwei Lu (Co-first Author)
, Xiaojing Gao (Co-first Author)
, Yuanyuan Xiao (Co-first Author)
, Mingliang Zhang (Co-first Author)
, Jun Li
, Weiping Jia^*
, Rong Zeng^*
, Yueqiong Ni^*
, Luonan Chen^*
, Huating Li^*

^*Corresponding author for this work

Department of Infectious Diseases and Public Health

Research output: Journal Publications and Reviews › RGC 21 - Publication in refereed journal › peer-review

7 Citations (Scopus)

18 Downloads (CityUHK Scholars)

Abstract

Our randomized, placebo-controlled trial showed resistant starch (RS), a type of prebiotic, has therapeutic effects in metabolic dysfunction-associated steatotic liver disease (MASLD). Here, we observed its heterogeneous efficacy, where 30% of participants exhibited limited benefits, which was replicated in a multi-center trial (ChiCTR2300074588). Multi-omics analysis and fecal microbiota transplantation identified baseline microbiota as a dominant contributor of response. Further population stratification and network analysis combined with in vitro and in vivo experiments revealed Prevotella as the key cause of low response by inhibiting RS-degrading bacteria, thereby impairing RS utilization. Conversely, Bifidobacterium pseudocatenulatum RRP01, a strain isolated from our cohort, restored RS degradation and improved Prevotella-attenuated RS response. Furthermore, we developed a predictive model integrating baseline microbial and clinical features (area under the curve [AUC] = 0.74–0.87), enabling stratification for personalized interventions. Our study indicates that gut microbiota determines the heterogeneity in RS efficacy and offers possibilities for novel microbiota-oriented precision therapeutics for MASLD. © 2025 The Author(s). Published by Elsevier Inc.

Original language	English
Pages (from-to)	2342-2361
Journal	Cell Metabolism
Volume	37
Issue number	12
Online published	20 Nov 2025
DOIs	https://doi.org/10.1016/j.cmet.2025.10.017
Publication status	Published - Dec 2025

Funding

This work has been supported by the National Key Research and Development Program of China (2022YFA1004804), the Shenzhen Medical Research Fund (C2406002), the Major Research Plan of National Natural Science Fund of China (NSFC) (92357305), the Noncommunicable Chronic Diseases-National Science and Technology Major Project (2024ZD0523200), the Excellent Young Scientists Fund of NSFC (82022012), the General Fund of NSFC (82270907), the innovative research team of high-level local universities in Shanghai (SHSMU-ZDCX20212700), and the Shanghai Municipal Key Clinical Specialty and Shanghai Research Center for Endocrine and Metabolic Diseases (2022ZZ01002) to H.L.; the National Key Research and Development Program of China (2022YFA1004800), Natural Science Foundation of China (T2341007, T2350003, 12131020, 42450084, 42450135, 12326614, and 12426310), the Science and Technology Commission of Shanghai Municipality (23JS1401300), the Zhejiang Province Vanguard Goose-Leading Initiative (2025C01114), the Hangzhou Institute for advanced study of UCAS (2024HIAS-P004), and the JST Moonshot Research and Development (JPMJMS2021) to L.C.; the Multicenter Clinical Research Project at the Shanghai Jiao Tong University School of Medicine (DLY201811), the Noncommunicable Chronic Diseases-National Science and Technology Major Project (2024ZD0523300), and the Shanghai Key Discipline of Public Health Grants Award (GWVI-11.1-20) to W.J.; the BMBF-funded “PerMiCCion” project (01KD2101A) and the EU Horizon-funded “NUTRIMMUNE” (101162457) to G.P.; the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under the Germany’s Excellence Strategy – EXC 2051 (390713860) to G.P. and Y.N.; the National Natural Science Foundation of China (82501033) and the Excellent Young Scientists Fund of the National Natural Science Foundation of China (Overseas, no. 24HAA01325) to Y.N.; the National Natural Science Foundation of China (92253304) to R. Zeng; and the Shanghai Sixth People's Hospital Clinic Research Project (ynhg202103) to Y.X.

Research Keywords

metabolic dysfunction-associated steatotic liver disease
gut microbiota
resistant starch
treatment effect heterogeneity
prebiotics
precision medicine
multi-omics

Publisher's Copyright Statement

This full text is made available under CC-BY-NC-ND 4.0. https://creativecommons.org/licenses/by-nc-nd/4.0/

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title = "Interindividual variability in gut microbiome mediates the efficacy of resistant starch on MASLD",

abstract = "Our randomized, placebo-controlled trial showed resistant starch (RS), a type of prebiotic, has therapeutic effects in metabolic dysfunction-associated steatotic liver disease (MASLD). Here, we observed its heterogeneous efficacy, where 30\% of participants exhibited limited benefits, which was replicated in a multi-center trial (ChiCTR2300074588). Multi-omics analysis and fecal microbiota transplantation identified baseline microbiota as a dominant contributor of response. Further population stratification and network analysis combined with in vitro and in vivo experiments revealed Prevotella as the key cause of low response by inhibiting RS-degrading bacteria, thereby impairing RS utilization. Conversely, Bifidobacterium pseudocatenulatum RRP01, a strain isolated from our cohort, restored RS degradation and improved Prevotella-attenuated RS response. Furthermore, we developed a predictive model integrating baseline microbial and clinical features (area under the curve [AUC] = 0.74–0.87), enabling stratification for personalized interventions. Our study indicates that gut microbiota determines the heterogeneity in RS efficacy and offers possibilities for novel microbiota-oriented precision therapeutics for MASLD. {\textcopyright} 2025 The Author(s). Published by Elsevier Inc.",

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author = "\{37 authors, including\} and Xiaoxue Long and Hui Wang and Yuwei Lu and Xiaojing Gao and Yuanyuan Xiao and Mingliang Zhang and Jingyi Guo and Jingyi Yang and Ruiqi Zhang and Qian Li and Guiyun Zhou and Ruibao Yang and Feng Chen and Qingqing Wu and Liming Sun and Chengshuang Chu and Xuexue Zhu and Zhengjun Wu and Quanlu Ren and Chunping You and Zhenmin Liu and Qian Li and Dan Liu and Di Cheng and Piao Kang and Anran Chen and Qian Wu and Qichen Fang and Li Wei and Lei Zhang and Jun Li and Gianni Panagiotou and Weiping Jia and Rong Zeng and Yueqiong Ni and Luonan Chen and Huating Li",

year = "2025",

month = dec,

doi = "10.1016/j.cmet.2025.10.017",

language = "English",

volume = "37",

pages = "2342--2361",

journal = "Cell Metabolism",

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TY - JOUR

T1 - Interindividual variability in gut microbiome mediates the efficacy of resistant starch on MASLD

AU - 37 authors, including

AU - Long, Xiaoxue

AU - Wang, Hui

AU - Lu, Yuwei

AU - Gao, Xiaojing

AU - Xiao, Yuanyuan

AU - Zhang, Mingliang

AU - Guo, Jingyi

AU - Yang, Jingyi

AU - Zhang, Ruiqi

AU - Li, Qian

AU - Zhou, Guiyun

AU - Yang, Ruibao

AU - Chen, Feng

AU - Wu, Qingqing

AU - Sun, Liming

AU - Chu, Chengshuang

AU - Zhu, Xuexue

AU - Wu, Zhengjun

AU - Ren, Quanlu

AU - You, Chunping

AU - Liu, Zhenmin

AU - Li, Qian

AU - Liu, Dan

AU - Cheng, Di

AU - Kang, Piao

AU - Chen, Anran

AU - Wu, Qian

AU - Fang, Qichen

AU - Wei, Li

AU - Zhang, Lei

AU - Li, Jun

AU - Panagiotou, Gianni

AU - Jia, Weiping

AU - Zeng, Rong

AU - Ni, Yueqiong

AU - Chen, Luonan

AU - Li, Huating

PY - 2025/12

Y1 - 2025/12

N2 - Our randomized, placebo-controlled trial showed resistant starch (RS), a type of prebiotic, has therapeutic effects in metabolic dysfunction-associated steatotic liver disease (MASLD). Here, we observed its heterogeneous efficacy, where 30% of participants exhibited limited benefits, which was replicated in a multi-center trial (ChiCTR2300074588). Multi-omics analysis and fecal microbiota transplantation identified baseline microbiota as a dominant contributor of response. Further population stratification and network analysis combined with in vitro and in vivo experiments revealed Prevotella as the key cause of low response by inhibiting RS-degrading bacteria, thereby impairing RS utilization. Conversely, Bifidobacterium pseudocatenulatum RRP01, a strain isolated from our cohort, restored RS degradation and improved Prevotella-attenuated RS response. Furthermore, we developed a predictive model integrating baseline microbial and clinical features (area under the curve [AUC] = 0.74–0.87), enabling stratification for personalized interventions. Our study indicates that gut microbiota determines the heterogeneity in RS efficacy and offers possibilities for novel microbiota-oriented precision therapeutics for MASLD. © 2025 The Author(s). Published by Elsevier Inc.

AB - Our randomized, placebo-controlled trial showed resistant starch (RS), a type of prebiotic, has therapeutic effects in metabolic dysfunction-associated steatotic liver disease (MASLD). Here, we observed its heterogeneous efficacy, where 30% of participants exhibited limited benefits, which was replicated in a multi-center trial (ChiCTR2300074588). Multi-omics analysis and fecal microbiota transplantation identified baseline microbiota as a dominant contributor of response. Further population stratification and network analysis combined with in vitro and in vivo experiments revealed Prevotella as the key cause of low response by inhibiting RS-degrading bacteria, thereby impairing RS utilization. Conversely, Bifidobacterium pseudocatenulatum RRP01, a strain isolated from our cohort, restored RS degradation and improved Prevotella-attenuated RS response. Furthermore, we developed a predictive model integrating baseline microbial and clinical features (area under the curve [AUC] = 0.74–0.87), enabling stratification for personalized interventions. Our study indicates that gut microbiota determines the heterogeneity in RS efficacy and offers possibilities for novel microbiota-oriented precision therapeutics for MASLD. © 2025 The Author(s). Published by Elsevier Inc.

KW - metabolic dysfunction-associated steatotic liver disease

KW - gut microbiota

KW - resistant starch

KW - treatment effect heterogeneity

KW - prebiotics

KW - precision medicine

KW - multi-omics

U2 - 10.1016/j.cmet.2025.10.017

DO - 10.1016/j.cmet.2025.10.017

M3 - RGC 21 - Publication in refereed journal

SN - 1550-4131

VL - 37

SP - 2342

EP - 2361

JO - Cell Metabolism

JF - Cell Metabolism

IS - 12

ER -

Interindividual variability in gut microbiome mediates the efficacy of resistant starch on MASLD

Abstract

Funding

Research Keywords

Publisher's Copyright Statement

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