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. 2024 Jan-Dec;16(1):2300846.
doi: 10.1080/19490976.2023.2300846. Epub 2024 Jan 10.

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

Seung Yoon Lee  1   2   3 , JooYeon Jhun  1   2   3 , Jin Seok Woo  1   2 , Kun Hee Lee  1   2   3 , Sun-Hee Hwang  1   2 , Jeonghyeon Moon  4 , Goeun Park  5 , Sun Shim Choi  5 , So Jung Kim  6 , Yoon Ju Jung  7 , Kyo Young Song  6 , Mi-La Cho  1   2   3   8
Affiliations

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

Seung Yoon Lee et al. Gut Microbes. 2024 Jan-Dec.

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.

Keywords: Faecalibacterium prausnitzii; Gastric cancer; IL-10; PD-L1; avatar model; butyrate; microbiome.

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Conflict of interest statement

No potential conflict of interest was reported by the author(s).

Figures

Figure 1.
Figure 1.
Increased levels of immunosuppressive markers in the PBMCs of AGC patients.
Figure 2.
Figure 2.
Increased levels of immunosuppressive markers in the tumor mucosa of AGC patients.
Figure 3.
Figure 3.
Gut microbiota profile of patients with GC.
Figure 4.
Figure 4.
Differential microbial abundance in GC patients.
Figure 5.
Figure 5.
Reduction of PD-L1 and IL-10 levels by butyrate.
Figure 6.
Figure 6.
Inhibition of tumor cell growth by butyrate.
See this image and copyright information in PMC

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