Microbiome Signatures in a Fast- and Slow-Progressing Gastric Cancer Murine Model and Their Contribution to Gastric Carcinogenesis

Abstract

Gastric cancer is the third most common cause of death from cancer in the world and infection with <i>Helicobacter</i> <i>pylori</i> (<i>H. pylori</i>) is the main cause of gastric cancer. In addition to <i>Helicobacter</i> 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, <i>Myd88^-/- </i>) rapidly progressed to neoplasia when infected with <i>H. felis</i>. 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 (<i>Myd88^-/- </i>), mice deficient in the Toll/interleukin-1 receptor (TIR) domain-containing adaptor-inducing interferon-β (TRIF, <i>Trif</i> ^Lps2), and MyD88- and TRIF-deficient (<i>Myd88^-/- </i>/<i>Trif</i> ^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 <i>Helicobacter</i> infected mice and studied their correlations with disease progression to gastric cancer <i>in situ</i>. We observed an overall reduction in microbial diversity post-infection with <i>H. felis</i> across all genotypes. Campylobacterales were observed in all infected mice, with marked reduction in abundance at 3 and 6 months in <i>Myd88^-/- </i> mice. A sharp increase in Lactobacillales in infected <i>Myd88^-/- </i> and DKO mice at 3 and 6 months was observed as compared to <i>Trif</i> ^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 <i>Helicobacter</i> 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 <i>Helicobacter</i> 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.