Institute of Digestive Disease, Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Shenzhen Research Institute, Sha Tin, New Territories, Hong Kong.
Institute for Microbial Ecology, School of Medicine, Xiamen University, Department of Gastroenterology, Zhongshan Hospital, Xiamen University, Xiamen, China.
Gastroenterology. 2021 Jun;160(7):2395-2408. doi: 10.1053/j.gastro.2021.02.020. Epub 2021 Feb 11.
BACKGROUND & AIMS: Gut microbial dysbiosis has pivotal involvement in colorectal cancer (CRC). However, the intratumoral microbiota and its association with CRC progression remain elusive. We aimed to determine the microbial community architecture within a neoplasia (CRC or adenoma) and its contribution to colorectal carcinogenesis.
We collected 436 tissue biopsies from patients with CRC (n = 36) or adenoma (n = 32) (2-6 biopsies from a neoplasia plus 2-5 biopsies from adjacent normal tissues per individual). Microbial profiling was performed using 16S ribosomal RNA gene sequencing with subsequent investigation of microbiota diversities and heterogeneity. The correlation between microbial dysbiosis and host genetic alterations (KRAS mutation and microsatellite instability) in all neoplasia biopsies was also analyzed.
We discovered that intra-neoplasia microbial communities are heterogeneous. Abundances of some CRC-associated pathobionts (eg, Fusobacterium, Bacteroides, Parvimonas, and Prevotella) were found to be highly varied within a single neoplasia. Correlation of such heterogeneity with CRC development revealed alterations in microbial communities involving microbes with high intra-neoplasia variation in abundance. Moreover, we found that the intra-neoplasia variation in abundance of individual microbes changed along the adenoma-carcinoma sequence. We further determined that there was a significant difference in intra-neoplasia microbiota between biopsies with and without KRAS mutation (P < .001) or microsatellite instability (P < .001), and illustrated the association of intratumoral microbial heterogeneity with genetic alteration.
We demonstrated that intra-neoplasia microbiota is heterogeneous and correlated with colorectal carcinogenesis. Our findings provide new insights on the contribution of gut microbiota heterogeneity to CRC progression.
肠道微生物失调与结直肠癌（CRC）密切相关。然而，肿瘤内微生物群及其与 CRC 进展的关系仍不清楚。本研究旨在确定肿瘤内微生物群落结构及其在结直肠癌变中的作用。
我们收集了 36 例 CRC 患者和 32 例腺瘤患者的 436 份组织活检样本（每位患者从肿瘤中采集 2-6 份活检样本，从相邻正常组织中采集 2-5 份活检样本）。采用 16S 核糖体 RNA 基因测序进行微生物谱分析，随后研究微生物多样性和异质性。还分析了所有肿瘤活检样本中微生物失调与宿主遗传改变（KRAS 突变和微卫星不稳定性）之间的相关性。
我们发现肿瘤内微生物群落存在异质性。某些与 CRC 相关的病原体（如梭菌、拟杆菌、小帕氏菌和普雷沃氏菌）在单个肿瘤内的丰度存在很大差异。这种异质性与 CRC 发展的相关性表明，微生物群落的改变涉及到丰度具有高肿瘤内变异性的微生物。此外，我们发现单个微生物在肿瘤内的丰度变化沿着腺瘤-癌序列发生改变。我们进一步确定，KRAS 突变（P <.001）或微卫星不稳定（P <.001）的活检样本之间，以及无 KRAS 突变或微卫星不稳定的活检样本之间，肿瘤内微生物群存在显著差异，并且说明了肿瘤内微生物异质性与遗传改变之间的关联。
我们证明了肿瘤内微生物群是异质的，并与结直肠癌变相关。我们的研究结果为肠道微生物群异质性对 CRC 进展的贡献提供了新的见解。
