Interindividual variability in gut microbiome mediates the efficacy of resistant starch on MASLD
Xiaoxue Long, Hui Wang, Yuwei Lu, Xiaojing Gao, Yuanyuan Xiao, Mingliang Zhang, Jingyi Guo, H. J. Yang, Ruiqi Zhang, Qian Li, Guiyun Zhou, Ruibao Yang, Feng Chen, Qingqing Wu, Liming Sun, Chengshuang Chu, Xuexue Zhu, Zhengjun Wu, Quanlu Ren, Chunping You, Zhenmin Liu, Qian Li, Dan Liu, Di Cheng, Piao Kang, Anran Chen, Qian Wu, Qichen Fang, Wei Li, Lei Zhang, Jun Li, Gianni Panagiotou, Weiping Jia, Rong Zeng, Yueqiong Ni, Luonan Chen, Huating Li
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.