Strain-level genetic heterogeneity and colonization dynamics drive microbiome therapeutic efficacy

Kai Chen; Yina Liu; Jie Rong; Ningbin Dai; Caihua Xu; Heng Li; Ling Zhong; Baoyan Wang; Zhen Ji; Shichang Xie; Yangzuo Xu; Fulin Yang; Jing Wang; Dapeng Li; Yulan Gu; Xiumin Zhou; Yan Li; Minbin Chen; Yanan Chen; Wei Li; Zaixiang Tang; Jun Cai; Jiancheng Xu; Shuting Xia; Qimin Zhan; Zhemin Zhou

doi:10.1016/j.chom.2026.02.002

Strain-level genetic heterogeneity and colonization dynamics drive microbiome therapeutic efficacy

Cell Host Microbe. 2026 Mar 11;34(3):393-405.e5. doi: 10.1016/j.chom.2026.02.002. Epub 2026 Feb 25.

Authors

Kai Chen¹, Yina Liu², Jie Rong², Ningbin Dai³, Caihua Xu¹, Heng Li⁴, Ling Zhong², Baoyan Wang⁵, Zhen Ji⁵, Shichang Xie², Yangzuo Xu², Fulin Yang², Jing Wang², Dapeng Li¹, Yulan Gu⁶, Xiumin Zhou¹, Yan Li⁷, Minbin Chen⁸, Yanan Chen⁹, Wei Li¹, Zaixiang Tang¹⁰, Jun Cai¹¹, Jiancheng Xu¹², Shuting Xia¹³, Qimin Zhan¹⁴, Zhemin Zhou¹⁵

Affiliations

¹ Department of Oncology, The First Affiliated Hospital of Soochow University, Cancer Institute, Suzhou Medical College, Soochow University, Suzhou, Suzhou 215127, China.
² Suzhou Key Laboratory of Precision Medicine in Oncology, MOE Key Laboratory of Geriatric Diseases and Immunology, Cancer Institute, Suzhou Medical College, Soochow University, Suzhou, Suzhou 215127, China; National Center of Technology Innovation for Biopharmaceuticals, Suzhou Biomedical Industry Innovation Center, Suzhou 215127, China.
³ Suzhou Key Laboratory of Pathogenic Microorganisms for New and Emerging Major Infectious Diseases, Suzhou Biobank, Suzhou Center for Disease Control and Prevention, Suzhou 215131, China.
⁴ Department of Microbiology, School of Basic Medical Sciences, Suzhou Medical College, Soochow University, Suzhou, Suzhou 215123, China.
⁵ Suzhou Health Information Center, Suzhou Health Commission, Suzhou 215006, China; Suzhou Healthcare Digital Intelligence Innovation Laboratory, Suzhou 215006, China.
⁶ Department of Oncology, Changshu Second People's Hospital, Suzhou 215500, China.
⁷ Department of Oncology, Suzhou Ninth People's Hospital, Suzhou 215200, China.
⁸ Department of Oncology, Kunshan First People's Hospital, Suzhou 215300, China.
⁹ Department of Oncology, Zhangjiagang First People's Hospital, Suzhou 215600, China.
¹⁰ Department of Biostatistics, School of Public Health, Suzhou Medical College of Soochow University, Suzhou, Suzhou 215123, China.
¹¹ Shanbai Biotechnology Co, Ltd., Suzhou 215000, China.
¹² Suzhou Key Laboratory of Precision Medicine in Oncology, MOE Key Laboratory of Geriatric Diseases and Immunology, Cancer Institute, Suzhou Medical College, Soochow University, Suzhou, Suzhou 215127, China; National Center of Technology Innovation for Biopharmaceuticals, Suzhou Biomedical Industry Innovation Center, Suzhou 215127, China. Electronic address: jcxu@suda.edu.cn.
¹³ Suzhou Key Laboratory of Precision Medicine in Oncology, MOE Key Laboratory of Geriatric Diseases and Immunology, Cancer Institute, Suzhou Medical College, Soochow University, Suzhou, Suzhou 215127, China; National Center of Technology Innovation for Biopharmaceuticals, Suzhou Biomedical Industry Innovation Center, Suzhou 215127, China. Electronic address: stxia@suda.edu.cn.
¹⁴ Suzhou Key Laboratory of Precision Medicine in Oncology, MOE Key Laboratory of Geriatric Diseases and Immunology, Cancer Institute, Suzhou Medical College, Soochow University, Suzhou, Suzhou 215127, China; National Center of Technology Innovation for Biopharmaceuticals, Suzhou Biomedical Industry Innovation Center, Suzhou 215127, China. Electronic address: zhanqimin@bjmu.edu.cn.
¹⁵ Department of Oncology, The First Affiliated Hospital of Soochow University, Cancer Institute, Suzhou Medical College, Soochow University, Suzhou, Suzhou 215127, China; Suzhou Key Laboratory of Precision Medicine in Oncology, MOE Key Laboratory of Geriatric Diseases and Immunology, Cancer Institute, Suzhou Medical College, Soochow University, Suzhou, Suzhou 215127, China; National Center of Technology Innovation for Biopharmaceuticals, Suzhou Biomedical Industry Innovation Center, Suzhou 215127, China; National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing 102207, China. Electronic address: zmzhou@suda.edu.cn.

PMID: 41747725
DOI: 10.1016/j.chom.2026.02.002

Abstract

Fecal microbiota transplantation (FMT) has shown immunotherapeutic promise, yet its efficacy in non-small-cell lung cancer (NSCLC) remains unclear. We demonstrate that FMT improves anti-PD-1 efficacy and progression-free survival in a single-arm trial of advanced PD-L1-negative NSCLC. Analyzing over 2,000 metagenomes from diverse disease cohorts and healthy controls via a high-resolution strain-tracking framework, we reveal that phylogenetically distinct strains within identical species exert opposing therapeutic effects, resolving prior inconsistencies. We identify conserved ecological principles where engraftment relies on species-intrinsic metabolic and immune evasion traits. Crucially, successful colonization by specific beneficial strain variants correlates with positive clinical outcomes. Finally, we identify 38 priority species with robust engraftment potential and significant heterogeneity as candidates for precision therapeutics. These findings establish a strain-function-efficacy paradigm, elucidating the mechanistic basis of variable outcomes and guiding next-generation microbiome drug development.

Keywords: FMT; HSIM score; NSCLC; fecal microbiota transplantation; healthy strain in microbiome score; immune therapy; non-small-cell lung cancer; strain tracking; ucgMLST.

MeSH terms

Bacteria / classification
Bacteria / genetics
Carcinoma, Non-Small-Cell Lung* / microbiology
Carcinoma, Non-Small-Cell Lung* / therapy
Fecal Microbiota Transplantation* / methods
Female
Gastrointestinal Microbiome* / genetics
Genetic Heterogeneity*
Humans
Lung Neoplasms* / microbiology
Lung Neoplasms* / therapy
Male
Metagenome
Microbiota* / genetics
Phylogeny
Treatment Outcome