肠道微生物失调与结肠直肠癌（CRC）的发生有关，但肠道微生物基础分层与临床分子特征和预后的关系仍需阐明。本研究采用细菌16S rRNA基因测序对423例I-IV期患者的肿瘤和正常粘膜进行了分析。肿瘤分为微卫星不稳定性（MSI）、CpG岛甲基转移酶表型（CIMP）、APC、BRAF、KRAS、PIK3CA、FBXW7、 SMAD4和TP53基因突变类型，其中可分为染色体不稳定性（CIN）、突变签名和一致性分子亚型（CMS）子组。微生物聚类分类法在293例II/III期肿瘤的独立队列中得到验证。 肿瘤得出三种不同的癌基因微生物群落亚型（OCS），具有显著的特征：OCS1（口腔病原微生物，蛋白酶，21％）、位于右侧，高度分化、MSI高、CIMP阳性、CMS1、BRAF V600E和FBXW7突变；OCS2（Firmicutes/Bacteroidetes，糖类，44％）和OCS3（Escherichia/Pseudescherichia/Shigella，脂肪酸β-氧化，35％）均位于左侧且显示CIN。OCS1与MSI相关的突变标记（SBS15、SBS20、ID2和ID7）有关，而OCS2和OCS3与由反应性氧化物造成的损害有关的SBS18有关。在II/III期患者中，相对于OCS2，OCS1和OCS3对于微卫星稳定肿瘤（多元HR分别为1.85，95％ CI为1.15-2.99，P = 0.012和HR = 1.52，95％ CI为1.01-2.29，P = 0.044）和左侧肿瘤（多元HR分别为2.66，95％ CI为1.45-4.86，P = 0.002和HR = 1.76，95％ CI为1.03-3.02，P = 0.039）的总体生存率较差。OCS分类法将CRC分为三种不同的亚群，具有不同的临床分子特征和结果。我们的研究成果为肠道微生物基础分层提供了框架，能够改进预后，并指导肠道微生物应用的干预措施的开发。版权所有©2023 AGA研究所。由Elsevier Inc.出版。保留所有权利。

Dysbiosis of gut microbiota is linked to the development of colorectal cancer (CRC). However, microbiota-based stratification of CRC tissue and how this relates to clinico-molecular characteristics and prognosis remains to be clarified.Tumour and normal mucosa from 423 stage I-IV patients were profiled by bacterial 16S rRNA gene sequencing. Tumours were characterised for microsatellite instability (MSI), CpG island methylator phenotype (CIMP), APC, BRAF, KRAS, PIK3CA, FBXW7, SMAD4 and TP53 mutations; subsets for chromosome instability (CIN), mutation signatures and consensus molecular subtypes (CMS). Microbial clusters were validated in an independent cohort of 293 stage II/III tumours.Tumours reproducibly stratified into three onco-microbial community subtypes (OCS) with distinguishing features: OCS1 (Fusobacterium/oral pathogens, proteolytic, 21%), right-sided, high-grade, MSI-high, CIMP-positive, CMS1, BRAF V600E and FBXW7 mutated; OCS2 (Firmicutes/Bacteroidetes, saccharolytic, 44%) and OCS3 (Escherichia/Pseudescherichia/Shigella, fatty acid beta-oxidation, 35%) both left-sided and exhibiting CIN. OCS1 was associated with MSI-related mutation signatures (SBS15, SBS20, ID2 and ID7), OCS2 and OCS3 with SBS18 related to damage by reactive oxygen species. Among stage II/III patients, both OCS1 and OCS3 had poorer overall survival as compared to OCS2 for microsatellite stable tumours (multivariate HR 1.85, 95% CI 1.15-2.99, P=0.012 and HR=1.52, 95% CI 1.01-2.29, P=0.044, respectively) and left-sided tumours (multivariate HR 2.66, 95% CI 1.45-4.86, P=0.002 and HR=1.76, 95% CI 1.03-3.02, P=0.039, respectively).OCS classification stratified CRCs into three distinct subgroups with different clinico-molecular features and outcomes. Our findings provide a framework for a microbiota-based stratification of CRC to refine prognostication and to inform the development of microbiota-targeted interventions.Copyright © 2023 AGA Institute. Published by Elsevier Inc. All rights reserved.