iProXProteomicsRong ZengHomo Sapienshttp://www.iprox.org/page/project.html?id=IPX0011457000zengrong@shanghaitech.edu.cnShanghai Clinical Research and Trial CenteriProXOur 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.Interindividual variability in gut microbiome mediates the efficacy of resistant starch on MASLD.Long Xiaoxue X, Wang Hui H, Lu Yuwei Y, Gao Xiaojing X, Xiao Yuanyuan Y, Zhang Mingliang M, Guo Jingyi J, Yang Jingyi J, Zhang Ruiqi R, Li Qian Q, Zhou Guiyun G, Yang Ruibao R, Chen Feng F, Wu Qingqing Q, Sun Liming L, Chu Chengshuang C, Zhu Xuexue X, Wu Zhengjun Z, Ren Quanlu Q, You Chunping C, Liu Zhenmin Z, Li Qian Q, Liu Dan D, Cheng Di D, Kang Piao P, Chen Anran A, Wu Qian Q, Fang Qichen Q, Wei Li L, Zhang Lei L, Li Jun J, Panagiotou Gianni G, Jia Weiping W, Zeng Rong R, Ni Yueqiong Y, Chen Luonan L, Li Huating HfalseSerum proteomics of individuals with MASLD under resistance starch interventionSearching for baseline proteins that contribute to the individual response to RS interventionWed Sep 24 00:00:00 BST 2025PXD068798960641270737