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Abstract
Gastric cancer is the third most common cause of death from cancer in the world and infection with Helicobacter pylori (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, TrifLps2), and MyD88- and TRIF-deficient (Myd88−/−/TrifLps2, 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 TrifLps2 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.
Highlights
Gastric cancer is the sixth most common cancer and third most common cause of cancer mortality in the world [1]
Infection with H. felis resulted in a decreased diversity index (statistically significant for WT at 6 months (p < 0.05); Myd88−/− at 1 month (p < 0.05) and 3 months (p < 0.01); Trif Lps2 at 3 months (p < 0.05); and double knockout (DKO) at 3 months (p < 0.01)
Our study suggests that differences in genotypes help define the stomach microbiome diversity as different genotypes have significantly dissimilar communities
Summary
Gastric cancer is the sixth most common cancer and third most common cause of cancer mortality in the world [1]. By far the largest risk factor for gastric cancer development is the presence of the carcinogenic microbe Helicobacter pylori [2]. Infection with H. pylori leads to development of premalignant lesions that progress from gastric atrophy to metaplasia, dysplasia, and to gastric adenocarcinoma. While H. pylori infects almost 50% of the global population, only 1–3% of the infected individuals develop gastric cancer [3]. Several other factors contribute to gastric cancer progression, such as Helicobacter strains, environmental factors, external factors like alcohol consumption [4] and host immune response. Studies have revealed that thrombosis can be one of the reasons for fatality in gastric cancer patients [5]
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