肠道菌群代谢物丁酸盐通过组蛋白去乙酰化酶抑制调控结肠癌免疫微环境的机制与研究进展综述
Review on Mechanism and Research Progress of Gut Microbiota Metabolite Butyrate Regulating Colorectal Cancer Immune Microenvironment via Histone Deacetylase Inhibition
DOI: 10.12677/wjcr.2026.163024, PDF,   
作者: 曾令翰, 钟岳霖, 欧展瑜:广西医科大学肿瘤医学院,广西 南宁;杨通艳:桂林医科大学第二临床医学院,广西 桂林
关键词: 丁酸盐组蛋白去乙酰化酶抑制结肠癌免疫微环境肠道菌群免疫治疗Butyrate Histone Deacetylase Inhibition Colorectal Cancer Immune Microenvironment Gut Microbiota Immunotherapy
摘要: 结肠癌作为全球高发恶性肿瘤,其发生发展与肠道菌群失调密切相关。丁酸盐作为肠道菌群发酵膳食纤维产生的主要短链脂肪酸,在维持肠道稳态和抑制结肠癌进展中发挥关键作用。近年来研究揭示,丁酸盐通过抑制组蛋白去乙酰化酶活性,调控免疫细胞功能及肿瘤微环境,从而影响结肠癌的免疫逃逸与抗肿瘤免疫应答。然而,现有研究多聚焦于单一细胞类型或信号通路,缺乏对丁酸盐调控结肠癌免疫微环境整体机制的整合性分析。基于此,文章系统综述了丁酸盐的代谢来源、组蛋白去乙酰化酶抑制机制及其对结肠癌免疫微环境中T细胞、巨噬细胞、树突状细胞等多种免疫细胞的调控作用,并探讨了基于丁酸盐的免疫治疗策略及未来研究方向,旨在为结肠癌的精准治疗提供理论依据。
Abstract: Colorectal cancer is a highly prevalent malignant tumor worldwide, and its occurrence and progression are closely associated with gut microbiota dysbiosis. Butyrate, a major short-chain fatty acid produced by gut microbiota fermenting dietary fiber, plays a vital role in maintaining intestinal homeostasis and restraining colorectal cancer development. Recent studies have demonstrated that butyrate modulates immune cell functions and tumor microenvironment by inhibiting histone deacetylase activity, thereby regulating tumor immune escape and anti-tumor immune responses in colorectal cancer. Nevertheless, most current research focuses on individual cell types or signaling pathways, lacking a comprehensive analysis of the overall mechanism underlying butyrate-mediated regulation of the colorectal cancer immune microenvironment. This paper systematically reviews the metabolic origin of butyrate, its histone deacetylase inhibitory effect, as well as its regulatory impacts on multiple immune cells, including T cells, macrophages, and dendritic cells within the colorectal cancer immune microenvironment. It also discusses butyrate-based immunotherapeutic strategies and future research prospects, aiming to provide theoretical references for the precise treatment of colorectal cancer.
文章引用:曾令翰, 钟岳霖, 杨通艳, 欧展瑜. 肠道菌群代谢物丁酸盐通过组蛋白去乙酰化酶抑制调控结肠癌免疫微环境的机制与研究进展综述[J]. 世界肿瘤研究, 2026, 16(3): 232-244. https://doi.org/10.12677/wjcr.2026.163024

参考文献

[1] Kaźmierczak-Siedlecka, K., Marano, L., Merola, E., Roviello, F. and Połom, K. (2022) Sodium Butyrate in Both Prevention and Supportive Treatment of Colorectal Cancer. Frontiers in Cellular and Infection Microbiology, 12, Article ID: 1023806. [Google Scholar] [CrossRef] [PubMed]
[2] Mederle, A.L., Semenescu, A., Drăghici, G.A., Dehelean, C.A., Vlăduț, N. and Nica, D.V. (2025) Sodium Butyrate: A Multifaceted Modulator in Colorectal Cancer Therapy. Medicina, 61, Article No. 136. [Google Scholar] [CrossRef] [PubMed]
[3] Sanaei, M. and Kavoosi, F. (2022) Effect of Sodium Butyrate on P p16INK4a, p14ARF, p15INK4b, Class I HDACs (HDACs 1, 2, 3) Class II HDACs (HDACs 4, 5, 6), Cell Growth Inhibition and Apoptosis Induction in Pancreatic Cancer AsPC-1 and Colon Cancer HCT-116 Cell Lines. Asian Pacific Journal of Cancer Prevention, 23, 795-802. [Google Scholar] [CrossRef] [PubMed]
[4] Klepinina, L., Klepinin, A., Truu, L., Chekulayev, V., Vija, H., Kuus, K., et al. (2021) Colon Cancer Cell Differentiation by Sodium Butyrate Modulates Metabolic Plasticity of Caco-2 Cells via Alteration of Phosphotransfer Network. PLOS ONE, 16, e0245348. [Google Scholar] [CrossRef] [PubMed]
[5] Ma, X., Zhou, Z., Zhang, X., Fan, M., Hong, Y., Feng, Y., et al. (2020) Sodium Butyrate Modulates Gut Microbiota and Immune Response in Colorectal Cancer Liver Metastatic Mice. Cell Biology and Toxicology, 36, 509-515. [Google Scholar] [CrossRef] [PubMed]
[6] Han, B., Chai, Q., Chen, Q., Liu, M., Wang, T., Zhang, Y., et al. (2025) Sodium Butyrate Inhibits Colorectal Cancer Development by Reducing M2 Macrophage Polarization and PD-L1 Expression. mSystems, 10, e0069225. [Google Scholar] [CrossRef
[7] Wang, X., Fang, Y., Liang, W., Wong, C.C., Qin, H., Gao, Y., et al. (2024) Fusobacterium nucleatum Facilitates Anti-PD-1 Therapy in Microsatellite Stable Colorectal Cancer. Cancer Cell, 42, 1729-1746.e8. [Google Scholar] [CrossRef] [PubMed]
[8] Makowski, Z., Lipiński, K. and Mazur-Kuśnirek, M. (2022) The Effects of Sodium Butyrate, Coated Sodium Butyrate, and Butyric Acid Glycerides on Nutrient Digestibility, Gastrointestinal Function, and Fecal Microbiota in Turkeys. Animals, 12, Article No. 1836. [Google Scholar] [CrossRef] [PubMed]
[9] Wu, Q.L., Fang, X.T., Wan, X.X., et al. (2024) Fusobacterium nucleatum-Induced Imbalance in Microbiome-Derived Butyric Acid Levels Promotes the Occurrence and Development of Colorectal Cancer. World Journal of Gastroenterology, 30, 2018-2037. [Google Scholar] [CrossRef] [PubMed]
[10] Alrafas, H.R., Busbee, P.B., Chitrala, K.N., Nagarkatti, M. and Nagarkatti, P. (2020) Alterations in the Gut Microbiome and Suppression of Histone Deacetylases by Resveratrol Are Associated with Attenuation of Colonic Inflammation and Protection against Colorectal Cancer. Journal of Clinical Medicine, 9, Article No. 1796. [Google Scholar] [CrossRef] [PubMed]
[11] Wang, J., Zhao, Q., Zhang, S., Liu, J., Fan, X., Han, B., et al. (2026) Microbial Short Chain Fatty Acids: Effective Histone Deacetylase Inhibitors in Immune Regulation (Review). International Journal of Molecular Medicine, 57, Article No. 5687. [Google Scholar] [CrossRef
[12] Wang, H., Chen, J., Chen, X., Liu, Y., Wang, J., Meng, Q., et al. (2024) Cancer-Associated Fibroblasts Expressing Sulfatase 1 Facilitate VEG-FA-Dependent Microenvironmental Remodeling to Support Colorectal Cancer. Cancer Research, 84, 3371-3387. [Google Scholar] [CrossRef] [PubMed]
[13] He, Y., Ling, Y., Zhang, Z., Mertens, R.T., Cao, Q., Xu, X., et al. (2023) Butyrate Reverses Ferroptosis Resistance in Colorectal Cancer by Inducing c-Fos-Dependent xCT Suppression. Redox Biology, 65, Article ID: 102822. [Google Scholar] [CrossRef] [PubMed]
[14] Zhang, Y., Zhang, Y., Shen, C., Li, J., Wang, H., Hamad, A., et al. (2026) Preoperative Exercise Induces Anti-Tumor Kupffer Cells to Prevent Surgical Stress-Promoted Colorectal Cancer Liver Metastasis. Cell Reports Medicine, 7, Article ID: 102589. [Google Scholar] [CrossRef
[15] Hou, H., Chen, D., Zhang, K., Zhang, W., Liu, T., Wang, S., et al. (2022) Gut Microbiota-Derived Short-Chain Fatty Acids and Colorectal Cancer: Ready for Clinical Translation? Cancer Letters, 526, 225-235. [Google Scholar] [CrossRef] [PubMed]
[16] Song, L., Sun, Q., Zheng, H., Zhang, Y., Wang, Y., Liu, S., et al. (2022) Roseburia hominis Alleviates Neuroinflammation via Short‐Chain Fatty Acids through Histone Deacetylase Inhibition. Molecular Nutrition & Food Research, 66, e2200164. [Google Scholar] [CrossRef] [PubMed]
[17] Mowat, C., Dhatt, J., Bhatti, I., Hamie, A. and Baker, K. (2023) Short Chain Fatty Acids Prime Colorectal Cancer Cells to Activate Antitumor Immunity. Frontiers in Immunology, 14, Article ID: 1190810. [Google Scholar] [CrossRef] [PubMed]
[18] Kim, Y.D., Park, S.M., Ha, H.C., et al. (2020) HDAC Inhibitor, CG-745, Enhances the Anti-Cancer Effect of Anti-PD-1 Immune Checkpoint Inhibitor by Modulation of the Immune Microenvironment. Journal of Cancer, 11, 4059-4072. [Google Scholar] [CrossRef] [PubMed]
[19] Yuan, Y., Li, B., Kuang, Y., Ni, S., Zhuge, A., Yang, J., et al. (2020) The Fiber Metabolite Butyrate Reduces gp130 by Targeting TRAF5 in Colorectal Cancer Cells. Cancer Cell International, 20, Article No. 212. [Google Scholar] [CrossRef] [PubMed]
[20] Liang, R., Ding, D., Li, Y., Lan, T., Ryabtseva, S., Huang, S., et al. (2024) HDACi Combination Therapy with IDO1i Remodels the Tumor Microenvironment and Boosts Antitumor Efficacy in Colorectal Cancer with Microsatellite Stability. Journal of Nanobiotechnology, 22, Article No. 753. [Google Scholar] [CrossRef] [PubMed]
[21] Gong, L., Tian, L., Li, H., Zhou, K., He, H., Xiao, S., et al. (2025) FK228 Reshapes Tumor Microenvironment to Enhance Anti-PD-L1 Efficacy. Oncogene, 44, 3665-3678. [Google Scholar] [CrossRef
[22] Shi, Y., Fu, Y., Zhang, X., Zhao, G., Yao, Y., Guo, Y., et al. (2020) Romidepsin (FK228) Regulates the Expression of the Immune Checkpoint Ligand PD-L1 and Suppresses Cellular Immune Functions in Colon Cancer. Cancer Immunology, Immunotherapy, 70, 61-73. [Google Scholar] [CrossRef] [PubMed]
[23] Chen, C., Lim, D., Cai, Z., Zhang, F., Liu, G., Dong, C., et al. (2023) HDAC Inhibitor HPTA Initiates Anti-Tumor Response by CXCL9/10-Recruited CXCR3+CD4+T Cells against PAHs Carcinogenicity. Food and Chemical Toxicology, 176, Article ID: 113783. [Google Scholar] [CrossRef] [PubMed]
[24] de Lazari, M.G.T., Pereira, L.X., Orellano, L.A.A., Scheuermann, K., Machado, C.T., Vasconcelos, A.C., et al. (2020) Sodium Butyrate Downregulates Implant-Induced Inflammation in Mice. Inflammation, 43, 1259-1268. [Google Scholar] [CrossRef] [PubMed]
[25] Jin, L., Duan, W., Cai, Z., Lim, D. and Feng, Z. (2021) Valproic Acid Triggers Radiation-Induced Abscopal Effect by Modulating the Unirradiated Tumor Immune Microenvironment in a Rat Model of Breast Cancer. Journal of Radiation Research, 62, rrab037. [Google Scholar] [CrossRef] [PubMed]
[26] Sun, Z., Xu, C., Cheng, J., Yang, Z., Liu, T., Deng, B., et al. (2024) Discovery of Novel HDAC3 Inhibitors with PD-L1 Downregulating/Degrading and Antitumor Immune Effects. Journal of Medicinal Chemistry, 67, 13067-13088. [Google Scholar] [CrossRef] [PubMed]
[27] Spadotto, V., Ripamonti, C., Ghiroldi, A., Galbiati, E., Pozzi, P., Noberini, R., et al. (2025) HDAC6 Inhibition by ITF3756 Modulates PD-L1 Expression and Monocyte Phenotype: Insights for a Promising Immune Checkpoint Blockade Co-Treatment Therapy. Frontiers in Immunology, 16, Article ID: 1546939. [Google Scholar] [CrossRef] [PubMed]
[28] Han, R., Zhou, H., Peng, B., Yu, S., Zhu, J. and Chen, J. (2025) Synergistic Integration of HDAC Inhibitors and Individualized Neoantigen Therapy (INT): A Next-Generation Combinatorial Approach for Cancer Immunotherapy. Vaccines, 13, Article No. 550. [Google Scholar] [CrossRef] [PubMed]
[29] Gagliano, T., Kerschbamer, E., Baccarani, U., Minisini, M., Di Giorgio, E., Dalla, E., et al. (2024) Changes in Chromatin Accessibility and Transcriptional Landscape Induced by HDAC Inhibitors in TP53 Mutated Patient-Derived Colon Cancer Organoids. Biomedicine & Pharmacotherapy, 173, Article ID: 116374. [Google Scholar] [CrossRef] [PubMed]
[30] Moufarrij, S., Srivastava, A., Gomez, S., Hadley, M., Palmer, E., Austin, P.T., et al. (2020) Combining DNMT and HDAC6 Inhibitors Increases Anti-Tumor Immune Signaling and Decreases Tumor Burden in Ovarian Cancer. Scientific Reports, 10, Article No. 3470. [Google Scholar] [CrossRef] [PubMed]
[31] Yang, Z., Chu, B., Tu, Y., Li, L., Chen, D., Huang, S., et al. (2024) Dual Inhibitors of DNMT and HDAC Remodels the Immune Microenvironment of Colorectal Cancer and Enhances the Efficacy of Anti-PD-L1 Therapy. Pharmacological Research, 206, Article ID: 107271. [Google Scholar] [CrossRef] [PubMed]
[32] Yan, M., Cao, H., Tao, K., Xiao, B., Chu, Y., Ma, D., et al. (2023) HDACs Alters Negatively to the Tumor Immune Microenvironment in Gynecologic Cancers. Gene, 885, Article ID: 147704. [Google Scholar] [CrossRef] [PubMed]
[33] Chen, Z., Yang, X., Chen, Z., Li, M., Wang, W., Yang, R., et al. (2023) A New Histone Deacetylase Inhibitor Remodels the Tumor Microenvironment by Deletion of Polymorphonuclear Myeloid-Derived Suppressor Cells and Sensitizes Prostate Cancer to Immunotherapy. BMC Medicine, 21, Article No. 402. [Google Scholar] [CrossRef] [PubMed]
[34] Wang, L., Shannar, A.A.F., Wu, R., Chou, P., Sarwar, M.S., Kuo, H., et al. (2022) Butyrate Drives Metabolic Rewiring and Epigenetic Reprogramming in Human Colon Cancer Cells. Molecular Nutrition & Food Research, 66, e2200028. [Google Scholar] [CrossRef] [PubMed]
[35] Serpa, J., Caiado, F., Carvalho, T., Torre, C., Gonçalves, L.G., Casalou, C., et al. (2010) Butyrate-Rich colonic Microenvironment Is a Relevant Selection Factor for Metabolically Adapted Tumor Cells. Journal of Biological Chemistry, 285, 39211-3923. [Google Scholar] [CrossRef
[36] Donohoe, D.R., Collins, L.B., Wali, A., Bigler, R., Sun, W., Bultman, S.J., et al. (2012) The Warburg Effect Dictates the Mechanism of Butyrate-Mediated Histone Acetylation and Cell Proliferation. Molecular Cell, 48, 612-626. [Google Scholar] [CrossRef] [PubMed]
[37] Han, A., Bennett, N., Ahmed, B., Whelan, J. and Donohoe, D.R. (2018) Butyrate Decreases Its Own Oxidation in Colorectal Cancer Cells through Inhibition of Histone Deacetylases. Oncotarget, 9, 27280-27292. [Google Scholar] [CrossRef] [PubMed]
[38] Arpaia, N., Campbell, C., Fan, X., Dikiy, S., van der Veeken, J., deRoos, P., et al. (2013) Metabolites Produced by Commensal Bacteria Promote Peripheral Regulatory T-Cell Generation. Nature, 504, 451-455. [Google Scholar] [CrossRef] [PubMed]
[39] Salvi, P.S. and Cowles, R.A. (2021) Butyrate and the Intestinal Epithelium: Modulation of Proliferation and Inflammation in Homeostasis and Disease. Cells, 10, Article No. 1775. [Google Scholar] [CrossRef] [PubMed]
[40] Wang, C., Qiu, M., Wang, S., Luo, J., Huang, L., Deng, Q., et al. (2024) Gut-Microbiota-Derived Butyric Acid Overload Contributes to Ileal Mucosal Barrier Damage in Late Phase of Chronic Unpredictable Mild Stress Mice. International Journal of Molecular Sciences, 25, Article No. 12998. [Google Scholar] [CrossRef] [PubMed]
[41] Zhao, Z.H., Wang, Z.X., Zhou, D., Han, Y., Ma, F., Hu, Z., et al. (2021) Sodium Butyrate Supplementation Inhibits Hepatic Steatosis by Stimulating Liver Kinase B1 and Insulin-Induced Gene. Cellular and Molecular Gastroenterology and Hepatology, 12, 857-871. [Google Scholar] [CrossRef] [PubMed]
[42] Rebeck, O.N., Wallace, M.J., Prusa, J., Ning, J., Evbuomwan, E.M., Rengarajan, S., et al. (2025) A Yeast-Based Oral Therapeutic Delivers Immune Checkpoint Inhibitors to Reduce Intestinal Tumor Burden. Cell Chemical Biology, 32, 98-110.e7. [Google Scholar] [CrossRef] [PubMed]
[43] Li, N., Niu, L., Liu, Y., Wang, Y., Su, X., Xu, C., et al. (2024) Taking SCFAs Produced by Lactobacillus reuteri Orally Reshapes Gut Microbiota and Elicits Antitumor Responses. Journal of Nanobiotechnology, 22, Article No. 241. [Google Scholar] [CrossRef] [PubMed]
[44] Liu, X., Jin, G., Tang, Q., Huang, S., Zhang, Y., Sun, Y., et al. (2022) Early Life Lactobacillus rhamnosus GG Colonisation Inhibits Intestinal Tumour Formation. British Journal of Cancer, 126, 1421-1431. [Google Scholar] [CrossRef] [PubMed]
[45] Chen, Y., Ma, W., Zhao, J., Stanton, C., Ross, R.P., Zhang, H., et al. (2024) Lactobacillus plantarum Ameliorates Colorectal Cancer by Ameliorating the Intestinal Barrier through the CLA-PPAR-γ Axis. Journal of Agricultural and Food Chemistry, 72, 19766-19785. [Google Scholar] [CrossRef] [PubMed]
[46] Khonthun, C. and Surangkul, D. (2023) Butyrate-Mediated Resistance to Trichostatin A Accompanied by Elevated Expression of Glucose Transporter 3 (GLUT3) in Human Colorectal Carcinoma HCT116 Cells. Asian Pacific Journal of Cancer Prevention, 24, 4085-4092. [Google Scholar] [CrossRef] [PubMed]
[47] Linnekamp, J.F., Kandimalla, R., Fessler, E., de Jong, J.H., Rodermond, H.M., van Bochove, G.G.W., et al. (2021) Pre-operative Decitabine in Colon Cancer Patients: Analyses on WNT Target Methylation and Expression. Cancers, 13, Article No. 2357. [Google Scholar] [CrossRef] [PubMed]
[48] Tomita, Y., Ikeda, T., Sakata, S., Saruwatari, K., Sato, R., Iyama, S., et al. (2020) Association of Probiotic Clostridium butyricum Therapy with Survival and Response to Immune Checkpoint Blockade in Patients with Lung Cancer. Cancer Immunology Research, 8, 1236-1242. [Google Scholar] [CrossRef
[49] Lübbert, M. and Kuendgen, A. (2022) Clinical Challenges of Combining DNMT and HDAC Inhibitors with Short-Chain Fatty Acid Butyrate: Biomarker Stratification, Dose Scheduling and Overlapping Toxicities in Colorectal Cancer Translational Design. Clinical Epigenetics, 14, Article No. 156.
[50] Heydarian, R., Divsalar, A., Kouchesfehani, H.M. and Rasouli, M. (2025) Folic Acid-Targeted β-Lactoglobulin Nanocarriers for Enhanced Delivery of 5-Fluorouracil and Sodium Butyrate in Colorectal Cancer Treatment. International Journal of Pharmaceutics, 671, Article ID: 125262. [Google Scholar] [CrossRef] [PubMed]
[51] Wang, T., Yin, Q., Huang, H.Y., Wang, Z., Song, H. and Luo, X. (2025) Probiotic Escherichia coli Nissle 1917 Propelled Micro-Robot with pH Sensitivity for Hypoxia Targeted Intestinal Tumor Therapy. Colloids and Surfaces B: Biointerfaces, 225, Article ID: 113277. [Google Scholar] [CrossRef] [PubMed]
[52] Thananimit, S., Pahumunto, N. and Teanpaisan, R. (2022) Characterization of Short Chain Fatty Acids Produced by Selected Potential Probiotic Lactobacillus Strains. Biomolecules, 12, Article No. 1829. [Google Scholar] [CrossRef] [PubMed]
[53] Liu, M., Xie, W., Zhang, X., Wu, W., Li, G. and Wang, L. (2025) Sodium Butyrate Regulates Macrophage Polarization by TGR5/β-Arrestin2 in Vitro. Molecular Medicine, 31, Article No. 31. [Google Scholar] [CrossRef] [PubMed]