The interplay between Helicobacter pylori and the gut microbiota: An emerging driver influencing the immune system homeostasis and gastric carcinogenesis

Abstract

The human gut microbiota are critical for preserving the health status because they are required for digestion and nutrient acquisition, the development of the immune system, and energy metabolism. The gut microbial composition is greatly influenced by the colonization of the recalcitrant pathogen Helicobacter pylori (H. pylori) and the conventional antibiotic regimens that follow. H. pylori is considered to be the main microorganism in gastric carcinogenesis, and it appears to be required for the early stages of the process. However, a non-H. pylori microbiota profile is also suggested, primarily in the later stages of tumorigenesis. On the other hand, specific groups of gut microbes may produce beneficial byproducts such as short-chain fatty acids (acetate, butyrate, and propionate) that can modulate inflammation and tumorigenesis pathways. In this review, we aim to present how H. pylori influences the population of the gut microbiota to modify the host immunity and trigger the development of gastric carcinogenesis. We will also highlight the effect of the gut microbiota on immunotherapeutic approaches such as immune checkpoint blockade in cancer treatment to present a perspective for further development of innovative therapeutic paradigms to prevent the progression of H. pylori-induced stomach cancer.

Keywords: Helicobacter pylori; gastric carcinogenesis; gut microbiota; immune system homeostasis; immunotherapy; probiotics.

Figure 1

The interplay between H. pylori and the gut microbiota. Infection with H. pylori causes and maintains an inflammatory response in the gastric mucosa, which leads to the loss of acid-secreting parietal cells and an elevation in gastric pH in certain infected people. H. pylori colonization declines in this changing environment and bacteria from other parts of the gut colonize the gastric niche, resulting in gut dysbiosis. Non-H. pylori bacteria promote gastric carcinogenesis through their own characteristics and microbial metabolites, such as N-nitroso compounds and lactate. The main putative mechanisms include induction of inflammatory response, modulation of the immune response, induction of DNA damage, and development of carcinogenesis.

Figure 2

Potential mechanisms for microbiota-mediated immunomodulation in tumor cells. SCFAs, which primarily consist of acetate, butyrate, and propionate can act as an HDAC inhibitor and influencing directly on cancer cells. By interacting with particular GPCRs including GPR41, GPR43 and GPR109A, SCFAs can have an effect on the immune system, leading to upregulation of immunosuppressive IL-10 and transforming growth factor-beta (TGF-β), downregulation of pro-inflammatory cytokines in macrophages and neutrophils, and inhibition of differentiation towards T helper type 17 (Th17) cells, thereby suppressing inflammation and carcinogenesis. SCFAs activate the inflammasome and the PPAR-γ pathway, promoting mucin production and improving epithelial integrity. SCFAs were also shown to activate the NLR family pyrin domain containing 3 (NLRP3) inflammasome, modulating the production of IL-18, which protects epithelial integrity. Significantly, SCFAs, in particular butyrate, may alter CD8⁺ T cell antitumor responses by influencing DC signaling pathways involving IL-12, IL-27, and IFN- β, all of which have an impact on tumor combination therapy. In this figure, the role of PD-1 and CTLA-4 in the priming and effector phases of anti-tumor immune responses is shown. Anti-CTLA-4 blocking antibodies may thereby restore T cell priming in lymph nodes, whereas PD-1 signaling inhibition may allow T cells to operate as tumor effectors. Other cell types in the tumor microenvironment, such as DCs, may also express PD-1 and hence be impacted by PD-1 inhibition. Blocking PD-1 and CTLA-4 may influence T helper cell profiles directly or indirectly by changing the microbiota. HDAC, Histone deacetylase; PD-L, Programmed death-ligand; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; PPAR-γ, peroxisome proliferator-activated receptor-γ; GPCRs, G-protein-coupled receptors.