The role of microbiota in the development and treatment of gastric cancer

Abstract

The stomach was once considered a sterile organ until the discovery of Helicobacter pylori (HP). With the application of high-throughput sequencing technology and macrogenomics, researchers have identified fungi and fivemajor bacterial phyla within the stomachs of healthy individuals. These microbial communities exert regulatory influence over various physiological functions, including energy metabolism and immune responses. HP is a well-recognized risk factor for gastric cancer, significantly altering the stomach's native microecology. Currently, numerous studies are centered on the mechanisms by which HP contributes to gastric cancer development, primarily involving the CagA oncoprotein. However, aside from exogenous infections such as HP and EBV, certain endogenous dysbiosis can also lead to gastric cancer through multiple mechanisms. Additionally, gut microbiota and its metabolites significantly impact the development of gastric cancer. The role of microbial therapies, including diet, phages, probiotics and fecal microbiota transplantation, in treating gastric cancer should not be underestimated. This review aims to study the mechanisms involved in the roles of exogenous pathogen infection and endogenous microbiota dysbiosis in the development of gastric cancer. Also, we describe the application of microbiota therapy in the treatment and prognosis of gastric cancer.

Keywords: Epstein-Barr virus (EBV); Helicobacter pylori (HP); gastric cancer; immunotherapy; microbiota.

Figure 1

Factors affecting gastric microecological dysbiosis and potential mechanisms underlying microecological dysbiosis causing gastric carcinogenesis. A multitude of microorganisms resides in the stomach, creating normal gastric microecology. Normal microecology plays a vital role in various physiological activities such as energy metabolism, nutrient absorption, immune response, and nervous system regulation. High-fat diet, antibiotics, genetic variation, and exogenous infections can all dysregulate normal gastric microecology, turning the normal microenvironment into the tumor microenvironment and eventually leading to gastric cancer development. Exploring the mechanism of gastric cancer progression from the perspective of gastric microecology is essential for early diagnosis, treatment, and prognosis of gastric cancer. HP, Helicobacter pylori; EBV, Epstein-Barr virus; HBV, Hepatitis B virus; JCV, John Cunningham virus, F. nucleatum, Fusobacterium nucleatum; Th, helper T cell; CTL, Cytotoxic T lymphocyte. Created with BioRender.com. (accessed on 17 May 2023).

Figure 2

Pathogens and probiotics have effects on anti-tumor immunity. Pathogens correlated with gastric carcinogenesis comprise Helicobacter pylori, F. nucleatum, and Candida albicans, all of which can suppress immune cell function, stimulate tumor cell proliferation and hinder apoptosis, thereby fostering tumor advancement. Helicobacter pylori upregulate PD-L1 expression in gastric epithelial cells, consequently inducing T cell apoptosis. Helicobacter pylori additionally activate MDSCs, reducing DCs and macrophage function while enhancing Treg cell activity. The F. nucleatum virulence factor Fap2 obstructs tumor elimination by immune cells via binding and interacting with TIGIT on NK cells or lymphocytes. Candida albicans infection leads to heightened expression of the inflammatory factor PGE2. PGE2 diminishes cytokine levels such as IL-1, IL-12, and TNF-α, which restrain DC and NK cell activity and function, obstruct CTL activation, and promote Treg cell maturation, ultimately suppressing tumor immunity. Furthermore, PGE2 facilitates MDSC migration to TME, thus promoting tumor immune escape. Probiotics like Bifidobacterium and B. fragilis elicit robust immune responses, enhance anti-tumor immunity, and impede tumor progression. Bifidobacterium directly stimulates DC maturation and fosters immune response production by T cells. B. fragilis induces macrophage polarization toward the M1 phenotype and enhances macrophage phagocytic capacity. In summary, microbial pathogens associated with gastric carcinogenesis suppress anti-tumor immunity. However, probiotics can potentially enhance anti-tumor immunity, which has significant implications for the treatment and prognosis of gastric cancer. F. nucleatum, Fusobacterium nucleatum; B. fragilis, Bacteroides fragilis; MDSCs, myeloid-derived suppressor cells; Treg cells, regulatory T cells; TIGIT, T cell immunoreceptors with IG and ITIM domains; DC, Dendritic cell; TME, Tumor microenvironment. Created with BioRender.com. (accessed on 17 May 2023).