Gastric microbiome profile throughout gastric carcinogenesis: beyond helicobacter

Gastric dysbiosis has been hinted as a potential cause of gastric cancer. However, changes in microbiome throughout the major stages of gastric carcinogenesis remain mostly unknown. To describe gastric microbiome at different stages, analysing for the first time dysbiosis specifically in patients with early gastric cancer (EGC). Cross-sectional study including patients (<i>n</i> = 77) with endoscopically and histologically confirmed normal stomachs (controls; <i>n</i> = 25), advanced atrophic gastritis with intestinal metaplasia (IM; <i>n</i> = 18) and EGC (<i>n</i> = 34). Endoscopic biopsies from antrum and corpus (<i>n</i> = 154) were analyzed. Next-generation sequencing was performed characterizing microbial communities down to the species level based on full-length 16SrRNA gene profiling. Significant differences were found in the microbiome profile between the groups. Firmicutes were more frequent (<i>p</i> = .012) and Proteobacteria were less frequent (<i>p</i> = .04) both in the IM and EGC when comparing to controls. Relative frequency of <i>Helicobacter pylori</i>, when present, was much higher in the controls (83%) when comparing to the other groups (IM 1%, EGC 27%; <i>p</i> = .006), being the dominant bacteria only in the controls. Dysbiosis was present already and more significantly at the IM stage, with two bacteria progressively increasing from controls to IM then to cancer: <i>Gemella</i> from 1.48 to 3.9% (<i>p</i> = .014); and <i>Streptococcus</i> from 19.3 to 33.7% (<i>p</i> = .04), being the EGC dominant bacteria. Our results confirm <i>Helicobacter pylori</i> dominancy in non-atrophic stomachs and progressive dysbiosis throughout gastric carcinogenesis. <i>Gemella</i> but particularly <i>Streptococcus</i> is significantly increased in patients with EGC. Specific modulation of these bacteria may change gastric cancer risk.

胃部微生态失调（gastric dysbiosis）被认为是胃癌的潜在致病因素之一，但目前学界对胃癌发生主要阶段的微生物组动态变化仍大多未被阐明。为阐明不同阶段胃部的微生物组特征，本研究首次针对早期胃癌（early gastric cancer, EGC）患者的微生态失调情况开展专项分析。本研究为横断面研究，共纳入77例受试者，其中经内镜及组织病理学确认的胃黏膜正常者作为对照（n=25）、伴肠上皮化生的进展性萎缩性胃炎患者（intestinal metaplasia, IM；n=18）以及早期胃癌（EGC）患者（n=34）。本研究对采集自胃窦与胃体的154份内镜活检标本进行了分析，基于全长16S rRNA基因测序，通过二代测序技术对微生物群落进行物种水平的鉴定与表征。各组间的微生物组谱存在显著差异：厚壁菌门（Firmicutes）在IM组与EGC组中的相对丰度均显著高于对照组（p=0.012），而变形菌门（Proteobacteria）的相对丰度则显著低于对照组（p=0.04）。幽门螺杆菌（Helicobacter pylori）在阳性感染者中的相对丰度在对照组中显著更高（83%），其余两组分别为1%（IM组）与27%（EGC组，p=0.006），且仅在对照组中为优势菌群。早在肠上皮化生阶段即已出现微生态失调，且该失调程度在该阶段更为显著：有两种细菌的相对丰度从对照组到IM组再到胃癌组呈渐进式上升——孪生球菌属（Gemella）从1.48%升至3.9%（p=0.014），链球菌属（Streptococcus）从19.3%升至33.7%（p=0.04），其中链球菌属在EGC组中成为优势菌群。本研究结果证实，幽门螺杆菌在非萎缩性胃黏膜中占据优势地位，且胃癌发生全过程中存在渐进式的微生态失调。孪生球菌属，尤其是链球菌属，在早期胃癌患者体内的相对丰度显著升高。对上述细菌进行特异性调控或可改变胃癌发病风险。