Gut microbiome-derived butyrate inhibits the immunosuppressive factors PD-L1 and IL-10 in tumor-associated macrophages in gastric cancer

Abstract

Early detection and surgical treatment are essential to achieve a good outcome in gastric cancer (GC). Stage IV and recurrent GC have a poor prognosis. Therefore, new treatments for GC are needed. We investigated the intestinal microbiome of GC patients and attempted to reverse the immunosuppression of the immune and cancer cells of GC patients through the modulation of microbiome metabolites. We evaluated the levels of programmed death-ligand 1 (PD-L1) and interleukin (IL)-10 in the peripheral blood immunocytes of GC patients. Cancer tissues were obtained from patients who underwent surgical resection of GC, and stained sections of cancer tissues were visualized via confocal microscopy. The intestinal microbiome was analyzed using stool samples of healthy individuals and GC patients. Patient-derived avatar model was developed by injecting peripheral blood mononuclear cells (PBMCs) from advanced GC (AGC) patients into NSG mice, followed by injection of AGS cells. PD-L1 and IL-10 had higher expression levels in immune cells of GC patients than in those of healthy controls. The levels of immunosuppressive factors were increased in the immune and tumor cells of tumor tissues of GC patients. The abundances of Faecalibacterium and Bifidobacterium in the intestinal flora were lower in GC patients than in healthy individuals. Butyrate, a representative microbiome metabolite, suppressed the expression levels of PD-L1 and IL-10 in immune cells. In addition, the PBMCs of AGC patients showed increased levels of immunosuppressive factors in the avatar mouse model. Butyrate inhibited tumor growth in mice. Restoration of the intestinal microbiome and its metabolic functions inhibit tumor growth and reverse the immunosuppression due to increased PD-L1 and IL-10 levels in PBMCs and tumor cells of GC patients.

Gut microbiome alterations during gastric cancer: evidence assessment of case–control studies

“…Although direct research linking Rothia with gastric cancer is limited, it is important to note that Rothia is part of the core microbiota in the stomachs of healthy individuals ( Nardone and Compare, 2015 ). The gut microbiota can produce butyrate, a short-chain fatty acid that has been shown to suppress the expression of PD-L1 and IL-10 in immune cells and demonstrate tumor growth inhibition potential in mouse models ( Lee et al, 2024 ). It is speculated that Rothia may influence the progression of gastric cancer through its metabolic products.…”

Oral administration of Manuka honey induces IFNγ-dependent resistance to tumor growth that correlates with beneficial modulation of gut microbiota composition

“…Although much remains to be elucidated, there is evidence for individual metabolites acting to either improve responses to cancer therapy, such as indole-3-acetic acid ( 85 ), or mitigate against high-fat-diet-mediated progression of intestinal tumors, such as butyrate ( 86 ). Moreover, butyrate was shown to inhibit gastric tumors by reducing the expression of immunosuppressive factors, such as PD-L1 and IL-10 ( 87 ). In the context of colorectal cancer, a recent study demonstrated that oral administration of Lactobacillus plantarum CBT could effectively inhibit the growth of colorectal cancer in noth orthotopic as well as ectopic preclinical mouse models ( 88 ).…”

Stomach microbiota in gastric cancer development and clinical implications

“…68 Butyrate also decreases the levels of immunosuppressive PD-L1 and interleukin (IL)-10 in tumour-associated macrophages, thereby restraining GC tumour growth (figure 2). 64…”

“…For example, microbes-derived butyrate suppresses the expression of PD-L1 and IL-10 in tumour-associated macrophages in mouse models of GC. 64 Butyrate could also enhance the function of CD8 + T cells in the microenvironment of GC through GPR109A/HOPX pathway (figure 2). 68 Nevertheless, it is important to pinpoint that the role of microbes in immunotherapy for GC, especially at cellular and molecular levels, remains massively unclear.…”