Objective: Here, we systematically investigated alterations in the bacteriome and mycobiome of CRC patients in tumours and matched adjacent mucosa resulting in the identification of microbiome-based subtypes associated with host clinico-pathological and molecular characteristics. Design: Diversity and composition of bacteriome and mycobiome of tumour and adjacent mucosa, resulting subtypes were computationally deconvoluted from RNA sequencing, using >10000 samples from in-house and publically available patient cohorts. Results: The bacteriome of tumours had higher dominance and lower α-diversity compared to matched adjacent local and distant mucosa. Tumours were enriched with Proteobacteria (Gammaproteobacteria class), Fusobacteria (including Fusobacterium Nucleatum species) and Basidiomycota fungi (Malasseziaceae family). Tumours were depleted of Bacteroidetes (Bacteroidia class), Firmicutes (Clostridia class) and Ascomycota (Sordariomycetes and Saccharomycotina). Tumours and adjacent mucosa samples were classified into 4 microbial subtypes, termed C1 to C4, based on the bacteriome and mycobiome composition. The bacterial Propionibacteriaceae, Enterobacteriaceae, Fusobacteriaceae, Bacteroidaceae and Ruminococcaceae and the fungal Malasseziaceae, Saccharomycetaceae and Aspergillaceae were among the key families driving the microbial subtyping. Microbial subtypes were associated with distinct tumour histology and patient phenotypes and served as an independent prognostic marker for disease-free survival. Key associations between microbial subtypes and alterations in host immune response and signalling pathways were validated in the TCGA pan-cancer cohort. The microbial subtyping demonstrated stratification value in the pan-cancer settings beyond merely representing differences in survival by cancer type. Conclusions: This study demonstrates the translational potential of microbial subtyping in CRC patient stratification, and provides avenues to design tailored microbiota modulation therapy to further precision oncology.

中文翻译：

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结直肠癌患者肿瘤和邻近黏膜组织中四种细菌和真菌生物亚型的鉴定和表征

目的：在这里，我们系统地研究了 CRC 患者在肿瘤和匹配的邻近粘膜中的细菌组和真菌组的变化，从而确定了与宿主临床病理学和分子特征相关的基于微生物组的亚型。设计：肿瘤和邻近粘膜的细菌组和真菌组的多样性和组成，使用来自内部和公开可用的患者队列的 >10000 个样本，从 RNA 测序中对产生的亚型进行计算解卷积。结果：与匹配的邻近局部和远处粘膜相比，肿瘤的细菌组具有更高的优势和更低的α多样性。肿瘤富含变形菌（Gammaproteobacteria类），梭杆菌属（包括核梭杆菌属）和担子菌门真菌（马拉色菌科）。肿瘤中的拟杆菌门（拟杆菌门）、厚壁菌门（梭菌门）和子囊菌门（Sordariomycetes和Saccharomycotina）均已耗尽。根据细菌组和真菌组的组成，肿瘤和邻近粘膜样本被分为 4 种微生物亚型，称为 C1 至 C4。细菌丙酸杆菌科、肠杆菌科、梭杆菌科、拟杆菌科和瘤胃球菌科以及真菌马拉色菌科、酵母菌科和曲霉科是推动微生物分型的关键科。微生物亚型与不同的肿瘤组织学和患者表型相关，并作为无病生存的独立预后标志物。微生物亚型与宿主免疫反应和信号通路改变之间的关键关联在 TCGA 泛癌队列中得到验证。微生物亚型在泛癌环境中表现出分层价值，而不仅仅是代表癌症类型的生存差异。结论：这项研究证明了微生物亚型在 CRC 患者分层中的转化潜力，并为设计定制的微生物群调节疗法以进一步精准肿瘤学提供了途径。