Salivary Microbiota for Gastric Cancer Prediction: an exploratory study. Salivary Microbiota for Gastric Cancer Prediction: an exploratory study

Abstract: To characterize the salivary microbiota in patients at different progressive histological stages of gastric carcinogenesis and identify microbial markers for detecting gastric cancer. Two hundred and ninety-three patients were grouped into superficial gastritis (SG; n=101), atrophic gastritis (AG; n=93), and gastric cancer (GC; n=99) according to their histology. 16S rRNA gene sequencing was used to access the salivary microbiota profile. A random forest model was constructed to classify gastric histological types based on the salivary microbiota compositions. A distinct salivary microbiota was observed in patients with GC when comparing with SG and AG, which was featured by an enrichment of putative proinflammatory taxa including Corynebacterium and Streptococcus. Among the significantly decreased oral bacteria in GC patients including Haemophilus, Neisseria, Parvimonas, Peptostreptococcus, Porphyromonas, and Prevotella, Haemophilus and Neisseria are known to reduce nitrite, which may consequently result in an accumulation of carcinogenic N-nitroso compounds. We found that GC can be distinguished accurately from patients with AG and SG (AUC=0.91) by the random forest model based on the salivary microbiota profiles, and taxa belonging to unclassified Streptophyta and Streptococcus have potential as diagnostic biomarkers for GC. Remarkable changes in the salivary microbiota functions were also detected across three histological types, and the upregulation in the isoleucine and valine is in line with a higher level of these amino acids in the gastric tumor tissues that reported by other independent studies. Conclusively, Bacteria in the oral cavity may contribute gastric cancer and become new diagnostic biomarkers for GC, but further evaluation against independent clinical cohorts are required. The potential mechanisms of salivary microbiota in participating the pathogenesis of GC may include an accumulation of proinflammatory bacteria and a decline in those reducing carcinogenic N-nitroso compounds.

摘要：旨在阐明胃癌发生进展不同组织学阶段患者的唾液微生物群特征，并筛选可用于胃癌检测的微生物标志物。本研究共纳入293例患者，根据组织学检测结果分为浅表性胃炎（superficial gastritis, SG；n=101）、萎缩性胃炎（atrophic gastritis, AG；n=93）及胃癌（gastric cancer, GC；n=99）三组。采用16S rRNA基因测序技术分析唾液微生物群的组成谱。基于唾液微生物群构成构建随机森林（random forest）模型，以区分胃部组织学类型。
与浅表性胃炎及萎缩性胃炎患者相比，胃癌患者的唾液微生物群结构存在显著差异，表现为棒杆菌属（Corynebacterium）、链球菌属（Streptococcus）等潜在促炎性类群的富集。胃癌患者体内显著减少的口腔细菌包括嗜血杆菌属（Haemophilus）、奈瑟菌属（Neisseria）、小单胞菌属（Parvimonas）、消化链球菌属（Peptostreptococcus）、卟啉单胞菌属（Porphyromonas）及普雷沃菌属（Prevotella），其中嗜血杆菌属与奈瑟菌属可还原亚硝酸盐，其丰度下降可能导致致癌性N-亚硝基化合物的积累。
基于唾液微生物群特征构建的随机森林模型可准确区分胃癌患者与萎缩性胃炎、浅表性胃炎患者（曲线下面积（Area Under Curve, AUC）=0.91），未分类链形植物门（Streptophyta）类群及链球菌属有望成为胃癌诊断的生物标志物。三组患者的唾液微生物群功能亦存在显著变化，其中异亮氨酸与缬氨酸代谢通路上调，与此前独立研究报道的胃癌组织中这些氨基酸水平升高的结果一致。
综上，口腔细菌可能参与胃癌的发生过程，可作为胃癌新型诊断标志物，但仍需在独立临床队列中开展进一步验证。唾液微生物群参与胃癌发病的潜在机制可能包括促炎性细菌富集，以及可还原致癌性N-亚硝基化合物的细菌丰度降低。