Combination of Sodium Butyrate and Immunotherapy in Glioma: regulation of immunologically hot and cold tumors via gut microbiota and metabolites
BackgroundRecent studies have highlighted the importance of cross-talk along the gut-brain axis in regulating inflammatory nociception, inflammatory responses, and immune homeostasis. The gut microbiota, particularly its bacterial composition, plays a crucial role in the development and function of...
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Frontiers Media S.A.
2025-04-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1532528/full |
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| author | Sui Li Sui Li Li Wang MingYu Han Huali Fan Hailin Tang Huile Gao Guobo Li Zheng Xu Zhaokai Zhou JunRong Du Cheng Peng Fu Peng Fu Peng |
| author_facet | Sui Li Sui Li Li Wang MingYu Han Huali Fan Hailin Tang Huile Gao Guobo Li Zheng Xu Zhaokai Zhou JunRong Du Cheng Peng Fu Peng Fu Peng |
| author_sort | Sui Li |
| collection | DOAJ |
| description | BackgroundRecent studies have highlighted the importance of cross-talk along the gut-brain axis in regulating inflammatory nociception, inflammatory responses, and immune homeostasis. The gut microbiota, particularly its bacterial composition, plays a crucial role in the development and function of the immune system. Moreover, metabolites produced by the gut microbiota can significantly impact both systemic immune responses and central nervous system (CNS) immunity. Sodium butyrate is a key metabolite produced by the gut microbiota and, as a histone deacetylase inhibitor, can enhance the anti-tumor immunity of cytotoxic CD8+ T cells. However, it remains unclear whether sodium butyrate treatment can enhance the efficacy of PD-1 blockade in glioma therapy. In this research, the effect and underlying mechanism of combination of gut microbiota metabolites and anti-mouse PD-1 mAb on glioma has been investigated.MethodsRNA-seq assay in glioma cell and biomedical databases, including ONCOMINE, GEPIA and TCGA were incorporated. Subsequently, the inhibitory effect of sodium butyrate on glioma cells and its related mechanisms were assessed through Counting Kit-8 (CCK-8), Flow Cytometry, Western blot (WB), reverse transcription-quantitative polymerase chain reaction (RT-qPCR), and other in vitro experiments. In vitro, an orthotopic mouse glioma model was established. MRI imaging, Immunohistochemistry, and Immune cell flow cytometry were used to investigate the therapeutic effects of combined sodium butyrate and PD-1 inhibitor treatment on glioma-bearing mice.ResultsWe discovered that deacetylation-associated gene expression is significantly increased in glioma patients and affects patient survival time. Moreover, we found sodium butyrate promoted glioma cell apoptosis, disrupted the cell cycle, and inhibited tumor growth. Additionally, sodium butyrate may upregulate PD-L1 expression in glioma cells by modulating the PI3K/AKT pathway. The experimental results demonstrated that this combination therapy significantly reduced tumor volume and prolonged survival in an orthotopic murine glioma model. Moreover, combination therapy led to an increase in the proportion of probiotic bacteria in the mouse gut microbiota, resulting in elevated levels of antitumor metabolites and a decrease in metabolites that affect immune cell function. |
| format | Article |
| id | doaj-art-6da5d16c8d2849b1bd6cf4c61fe3b6e9 |
| institution | OA Journals |
| issn | 1664-3224 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Immunology |
| spelling | doaj-art-6da5d16c8d2849b1bd6cf4c61fe3b6e92025-08-20T02:17:09ZengFrontiers Media S.A.Frontiers in Immunology1664-32242025-04-011610.3389/fimmu.2025.15325281532528Combination of Sodium Butyrate and Immunotherapy in Glioma: regulation of immunologically hot and cold tumors via gut microbiota and metabolitesSui Li0Sui Li1Li Wang2MingYu Han3Huali Fan4Hailin Tang5Huile Gao6Guobo Li7Zheng Xu8Zhaokai Zhou9JunRong Du10Cheng Peng11Fu Peng12Fu Peng13West China School of Pharmacy, Sichuan University, Chengdu, ChinaState Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, ChinaBioinformatics Department, Jiangsu Sanshu Biotechnology Co., Ltd., Nantong, ChinaWest China School of Pharmacy, Sichuan University, Chengdu, ChinaWest China School of Pharmacy, Sichuan University, Chengdu, ChinaState Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center, Guangdong, ChinaWest China School of Pharmacy, Sichuan University, Chengdu, ChinaWest China School of Pharmacy, Sichuan University, Chengdu, ChinaState Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, ChinaDepartment of Urology, The First Affiliated Hospital of Zhengzhou University, Department of Clinical Medicine, Zhengzhou University, Henan, ChinaWest China School of Pharmacy, Sichuan University, Chengdu, ChinaState Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, ChinaWest China School of Pharmacy, Sichuan University, Chengdu, ChinaKey Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, ChinaBackgroundRecent studies have highlighted the importance of cross-talk along the gut-brain axis in regulating inflammatory nociception, inflammatory responses, and immune homeostasis. The gut microbiota, particularly its bacterial composition, plays a crucial role in the development and function of the immune system. Moreover, metabolites produced by the gut microbiota can significantly impact both systemic immune responses and central nervous system (CNS) immunity. Sodium butyrate is a key metabolite produced by the gut microbiota and, as a histone deacetylase inhibitor, can enhance the anti-tumor immunity of cytotoxic CD8+ T cells. However, it remains unclear whether sodium butyrate treatment can enhance the efficacy of PD-1 blockade in glioma therapy. In this research, the effect and underlying mechanism of combination of gut microbiota metabolites and anti-mouse PD-1 mAb on glioma has been investigated.MethodsRNA-seq assay in glioma cell and biomedical databases, including ONCOMINE, GEPIA and TCGA were incorporated. Subsequently, the inhibitory effect of sodium butyrate on glioma cells and its related mechanisms were assessed through Counting Kit-8 (CCK-8), Flow Cytometry, Western blot (WB), reverse transcription-quantitative polymerase chain reaction (RT-qPCR), and other in vitro experiments. In vitro, an orthotopic mouse glioma model was established. MRI imaging, Immunohistochemistry, and Immune cell flow cytometry were used to investigate the therapeutic effects of combined sodium butyrate and PD-1 inhibitor treatment on glioma-bearing mice.ResultsWe discovered that deacetylation-associated gene expression is significantly increased in glioma patients and affects patient survival time. Moreover, we found sodium butyrate promoted glioma cell apoptosis, disrupted the cell cycle, and inhibited tumor growth. Additionally, sodium butyrate may upregulate PD-L1 expression in glioma cells by modulating the PI3K/AKT pathway. The experimental results demonstrated that this combination therapy significantly reduced tumor volume and prolonged survival in an orthotopic murine glioma model. Moreover, combination therapy led to an increase in the proportion of probiotic bacteria in the mouse gut microbiota, resulting in elevated levels of antitumor metabolites and a decrease in metabolites that affect immune cell function.https://www.frontiersin.org/articles/10.3389/fimmu.2025.1532528/fullanti-tumor immunitygut microbiota and metabolitesgliomasodium butyratePD-1/PD-L1PI3K/Akt signaling pathway |
| spellingShingle | Sui Li Sui Li Li Wang MingYu Han Huali Fan Hailin Tang Huile Gao Guobo Li Zheng Xu Zhaokai Zhou JunRong Du Cheng Peng Fu Peng Fu Peng Combination of Sodium Butyrate and Immunotherapy in Glioma: regulation of immunologically hot and cold tumors via gut microbiota and metabolites Frontiers in Immunology anti-tumor immunity gut microbiota and metabolites glioma sodium butyrate PD-1/PD-L1 PI3K/Akt signaling pathway |
| title | Combination of Sodium Butyrate and Immunotherapy in Glioma: regulation of immunologically hot and cold tumors via gut microbiota and metabolites |
| title_full | Combination of Sodium Butyrate and Immunotherapy in Glioma: regulation of immunologically hot and cold tumors via gut microbiota and metabolites |
| title_fullStr | Combination of Sodium Butyrate and Immunotherapy in Glioma: regulation of immunologically hot and cold tumors via gut microbiota and metabolites |
| title_full_unstemmed | Combination of Sodium Butyrate and Immunotherapy in Glioma: regulation of immunologically hot and cold tumors via gut microbiota and metabolites |
| title_short | Combination of Sodium Butyrate and Immunotherapy in Glioma: regulation of immunologically hot and cold tumors via gut microbiota and metabolites |
| title_sort | combination of sodium butyrate and immunotherapy in glioma regulation of immunologically hot and cold tumors via gut microbiota and metabolites |
| topic | anti-tumor immunity gut microbiota and metabolites glioma sodium butyrate PD-1/PD-L1 PI3K/Akt signaling pathway |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1532528/full |
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