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This study aimed to systematically evaluate the potential associations among gut microbiota, metabolic profiles, and clinical outcomes in patients with MSI-H advanced colorectal cancer (CRC) treated with immunotherapy. Twenty advanced CRC patients receiving immunotherapy were enrolled and categorized into clinical benefit response (CBR) and non-benefit (NCB) groups based on treatment efficacy. Fecal samples were analyzed using metagenomic sequencing and untargeted metabolomics. The results revealed significant enrichments of\n                    <jats:italic>s_Clostridium unclassified<\/jats:italic>\n                    and metabolites such as guanosine, 3-carboxy-4-methyl-5-propyl-2-furanpropionic acid, and quercetin 3-(6\u201d-malonyl-glucoside) in the CBR group, suggesting their potential positive predictive value for immunotherapy response. Conversely, the NCB group showed significant enrichments of\n                    <jats:italic>s_Roseburia hominis, s_Marseilla massiliensis<\/jats:italic>\n                    , and metabolites including pyrophosphate, riboflavin, and PC(22:5(4Z,7Z,10Z,13Z,16Z)\/14:0), indicating a possible association with treatment resistance. By integrating fecal metagenomics and metabolomics, this study reveals distinctive \u201cflora-metabolite\u201d interactions linked to therapeutic response in advanced CRC patients undergoing immunotherapy. Specific microbial and metabolic profiles were positively or negatively correlated with immunotherapy outcomes, highlighting their potential not only as predictive biomarkers but also as a theoretical foundation for developing individualized immunotherapy strategies based on microecological modulation.\n                  <\/jats:p>","DOI":"10.33073\/pjm-2026-016","type":"journal-article","created":{"date-parts":[[2026,8,6]],"date-time":"2026-08-06T14:05:19Z","timestamp":1786025119000},"page":"168-194","source":"Crossref","is-referenced-by-count":0,"title":["Distinct Gut Microbiome and Metabolome Profiles Associate with Differential Responses to Immunotherapy in Colorectal Cancer"],"prefix":"10.33073","volume":"75","author":[{"given":"Fang","family":"Liang","sequence":"first","affiliation":[{"name":"Department of Oncology, Zhengzhou Central Hospital Affiliated to Zhengzhou University , Zhengzhou , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Oncology, Zhengzhou Central Hospital Affiliated to Zhengzhou University , Zhengzhou , China"},{"name":"Medical Key Laboratory for Diagnosis and Treatment of Colorectal Cancer in Henan Province , Zhengzhou , China"},{"name":"Zhengzhou Key Laboratory for Diagnosis, Treatment and Research of Colorectal Cancer , Zhengzhou , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingkun","family":"Yue","sequence":"additional","affiliation":[{"name":"Department of Oncology, Zhengzhou Central Hospital Affiliated to Zhengzhou University , Zhengzhou , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaxin","family":"Pan","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary and Pancreatic Surgery, People\u2019s Hospital of Henan University , Zhengzhou , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenyu","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Oncology, Zhengzhou Central Hospital Affiliated to Zhengzhou University , Zhengzhou , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Duo","family":"Cheng","sequence":"additional","affiliation":[{"name":"Department of Oncology, Zhengzhou Central Hospital Affiliated to Zhengzhou University , Zhengzhou , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Oncology, Zhengzhou Central Hospital Affiliated to Zhengzhou University , Zhengzhou , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kunkun","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Zhengzhou Central Hospital Affiliated to Zhengzhou University , Zhengzhou , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feifei","family":"Chu","sequence":"additional","affiliation":[{"name":"Medical Key Laboratory for Diagnosis and Treatment of Colorectal Cancer in Henan Province , Zhengzhou , China"},{"name":"Zhengzhou Key Laboratory for Diagnosis, Treatment and Research of Colorectal Cancer , Zhengzhou , China"},{"name":"Department of Gastroenterology, Zhengzhou Central Hospital Affiliated to Zhengzhou University , Zhengzhou , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huili","family":"Wu","sequence":"additional","affiliation":[{"name":"Medical Key Laboratory for Diagnosis and Treatment of Colorectal Cancer in Henan Province , Zhengzhou , China"},{"name":"Zhengzhou Key Laboratory for Diagnosis, Treatment and Research of Colorectal Cancer , Zhengzhou , China"},{"name":"Department of Gastroenterology, Zhengzhou Central Hospital Affiliated to Zhengzhou University , Zhengzhou , China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"18083","published-online":{"date-parts":[[2026,6,30]]},"reference":[{"key":"2026081913073867654_j_pjm-2026-016_ref_001","doi-asserted-by":"crossref","unstructured":"Alsaafeen BH, Ali BR, Elkord E. 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