Gastric cancer is the third most common cause of death from cancer in the world and infection with Helicobacterpylori (H. pylori) is the main cause of gastric cancer. In addition to Helicobacter infection, the overall stomach microbiota has recently emerged as a potential factor in gastric cancer progression. Previously we had established that mice deficient in myeloid differentiation primary response gene 88 (MyD88, Myd88^−/−) rapidly progressed to neoplasia when infected with H. felis. Thus, in order to assess the role of the microbiota in this fast-progressing gastric cancer model we investigated changes of the gastric microbiome in mice with different genotypic backgrounds: wild type (WT), MyD88-deficient (Myd88^−/−), mice deficient in the Toll/interleukin-1 receptor (TIR) domain-containing adaptor-inducing interferon-β (TRIF, Trif^Lps2), and MyD88- and TRIF-deficient (Myd88^−/−/Trif^Lps2, double knockout (DKO)) mice. We compared changes in alpha diversity, beta diversity, relative abundance, and log-fold differential of relative abundance ratios in uninfected and Helicobacter infected mice and studied their correlations with disease progression to gastric cancer in situ. We observed an overall reduction in microbial diversity post-infection with H. felis across all genotypes. Campylobacterales were observed in all infected mice, with marked reduction in abundance at 3 and 6 months in Myd88^−/− mice. A sharp increase in Lactobacillales in infected Myd88^−/− and DKO mice at 3 and 6 months was observed as compared to Trif^Lps2 and WT mice, hinting at a possible role of these bacteria in gastric cancer progression. This was further reinforced upon comparison of Lactobacillales log-fold differentials with histological data, indicating that Lactobacillales are closely associated with Helicobacter infection and gastric cancer progression. Our study suggests that differences in genotypes could influence the stomach microbiome and make it more susceptible to the development of gastric cancer upon Helicobacter infection. Additionally, increase in Lactobacillales could contribute to faster development of gastric cancer and might serve as a potential biomarker for the fast progressing form of gastric cancer.

中文翻译：

---

快速和缓慢进展的胃癌小鼠模型中的微生物组特征及其对胃癌发生的贡献

胃癌是全世界癌症和感染死亡的第三个最常见的原因幽门螺旋杆菌（幽门螺旋杆菌）是胃癌的主要原因。除了幽门螺杆菌感染外，整体胃微生物群最近已成为胃癌进展的潜在因素。先前我们已证实，在髓样分化初级应答基因缺陷小鼠88（MyD88的，MYD88 ^{- / - ）}与感染时迅速进展到瘤H.蚤. 因此，为了评估微生物群在这种快速进展的胃癌模型中的作用，我们研究了具有不同基因型背景的小鼠胃微生物组的变化：野生型 (WT)、MyD88 缺陷型 ( Myd88 ^-/- )、小鼠缺乏 Toll/白细胞介素-1 受体 (TIR) 域包含适配器诱导干扰素-β (TRIF, Trif ^Lps2 ), 和 MyD88- 和 TRIF 缺陷 ( Myd88 ^-/- / Trif ^Lps2 , 双敲除 (DKO))老鼠。我们比较了未感染和螺杆菌的α 多样性、β 多样性、相对丰度和相对丰度比的对数倍差的变化感染小鼠并原位研究它们与疾病进展为胃癌的相关性。我们观察到在所有基因型中，H. felis感染后微生物多样性总体下降。在所有受感染的小鼠中均观察到弯曲杆菌属，Myd88 ^-/-小鼠在第 3 个月和第 6 个月时丰度显着降低。与Trif ^Lps2相比，在第 3 个月和第 6 个月时观察到受感染的Myd88 ^-/-和 DKO 小鼠中乳酸杆菌的急剧增加和 WT 小鼠，暗示这些细菌在胃癌进展中的可能作用。通过将乳酸杆菌对数倍数差异与组织学数据进行比较，这一点得到进一步加强，表明乳酸杆菌与螺杆菌感染和胃癌进展密切相关。我们的研究表明，基因型的差异可能会影响胃微生物组，使其更容易在幽门螺杆菌感染后发展为胃癌。此外，乳酸杆菌的增加可能有助于胃癌的更快发展，并可能作为胃癌快速进展形式的潜在生物标志物。