Gastric Cancer, Immunotherapy, and Nutrition: The Role of Microbiota

Abstract

Immune checkpoint inhibitors (ICI) have revolutionized the treatment of gastric cancer (GC), which still represents the third leading cause of cancer-related death in Western countries. However, ICI treatment outcomes vary between individuals and need to be optimized. Recent studies have shown that gut microbiota could represent a key influencer of immunotherapy responses. At the same time, the nutritional status and diet of GC patients are also predictive of immunotherapy treatment response and survival outcomes. The objective of this narrative review is to gather recent findings about the complex relationships between the oral, gastric, and gut bacterial communities, dietary factors/nutritional parameters, and immunotherapy responses. Perigastric/gut microbiota compositions/functions and their metabolites could be predictive of response to immunotherapy in GC patients and even overall survival. At the same time, the strong influence of diet on the composition of the microbiota could have consequences on immunotherapy responses through the impact of muscle mass in GC patients during immunotherapy. Future studies are needed to define more precisely the dietary factors, such as adequate daily intake of prebiotics, that could counteract the dysbiosis of the GC microbiota and the impaired nutritional status, improving the clinical outcomes of GC patients during immunotherapy.

Keywords: H. pylori; ICI; diet; gastric cancer; gut microbiota; immunotherapy; immunotherapy response; malnutrition; muscle mass; nutrition; nutritional status.

Figure 1

High-fat diet leads to an increase in Firmicutes, Bacteroides, and Enterobacteriaceae, which cause dysbiosis by increasing LPS (1), decreasing SCFAs, and increasing the expression of claudin-1 and occludin (2). These events, associated with altered permeability of the gut barrier, are important triggers for LPS translocation, which activates TLR4 (3). The binding of LPS to TLR4 causes the release of many cytokines and ROS that induce the inflammatory response. Abbreviations: LPS: lipopolysaccharides; SFCAs: short-chain fatty acids; TLR4: Toll-like receptor 4; ROS: Reactive Oxygen Species; TNF-α: Tumor Necrosis Factor-alpha; IL-1β: Interleukin 1-beta; IL-6: Interleukin-6; IL-1: Interleukin 1.

Figure 2

Impact of nutritional intervention through microbiota in immunotherapy in gastric cancer. Section (A): Caloric restriction and intake of fermentable oligosaccharides, disaccharides, and monosaccharides are associated with enhancement of A. muciniphila, which is associated with a positive systemic effect on immune homeostasis and favorable outcome checkpoint blockade in cancer immunotherapy. Section (B): Fiber intakes enhance the presence of Faecalibacterium prausnitzii and Roseburia spp. and the metabolism of SCFAs, which can promote a clinical response to immunotherapy. Section (C): Vitamin D can modulate and favor homeostasis of the immune system through the regulation of PD-1 and CTLA-4 expression and reduction in Th1, Th17, and inflammatory cytokines, with a positive impact on immunotherapy response. Section (D): Prebiotics improve alpha diversity and increase the abundance of Bifidobacterium and Lactobacillus in the gut microbiota, enhancing immunomodulatory effects. Section (E): Probiotics like Bifidobacterium and Lactobacillus spp. can enhance the production of INFγ, which can stimulate NK cells; moreover, LPS-TLR4 binding induces macrophages and the production of inflammatory cytokines. Finally, they lead to enhanced CD8+ T cell priming and accumulation in the tumor microenvironment, promoting antitumor immunity. Abbreviations: CTLA-4: anti-cytotoxic T-lymphocyte antigen 4; anti-PD-1: anti-programmed death cell-1; IFN γ: interferon gamma; IL-1β: interleukin beta; LPS: lipopolysaccharides; NK: natural killer; SCFAs: short-chain fatty acids; TLR4: Toll-like receptor 4; TNF: tumor necrosis factor.