The effects of microbiota-derived short-chain fatty acids on T lymphocytes: From autoimmune diseases to cancer

IF 2.5 3区医学 Q2 ONCOLOGY

Seminars in oncology Pub Date : 2025-08-19 DOI:10.1016/j.seminoncol.2025.152398

Mohamed J. Saadh , Omer Qutaiba B. Allela , Suhas Ballal , Morug Salih Mahdi , Mamata Chahar , Rajni Verma , Rouaida Kadhim A Al-hussein , Mohaned Adil , Mahmood Jasem Jawad , Ali M. Ali Al-Nuaimi

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引用次数: 0

Abstract

Short-chain fatty acids (SCFAs), acetate, propionate, and butyrate, are the microbial metabolites that have significant functions in host immune modulation, especially T lymphocyte function. Implication by recent evidence indicates SCFAs regulate T-cell growth, differentiation, metabolism, effector function, and apoptosis through histone deacetylase (HDAC) inhibition, G-protein-coupled receptor (GPCR) signaling, and metabolic reprogramming processes. Butyrate, for example, enhances regulatory T cell (Treg) and Interleukin 10 (IL-10)-producing T helper 1 (Th1) cell differentiation as well as context-dependent regulation on T helper 17 (Th17) cell development. SCFAs also impact cytotoxic CD8+ T cells through augmented production of IFN-γ and memory formation, which enhances antiviral and antitumor immunity. SCFAs reprogram T-cell metabolism through enhanced acetyl-CoA, mechanistic target of rapamycin (mTOR) signaling, and fatty acid oxidation (FAO), thus promoting the unique metabolic requirements of effector and memory T-cell subsets. In addition, SCFAs induce apoptosis of activated T cells through the Fas upregulation by inhibiting HDAC1. SCFA dysregulation plays a role in disease and autoimmune disorders like type 1 diabetes and rheumatoid arthritis, whereas therapeutic supplementation reduces inflammation and immune tolerance. SCFAs also amplify the antitumor effect of immune checkpoint inhibitors (eg, anti-programmed cell death protein 1 (anti-PD-1)) in cancer by driving CD8+ T-cell activation, infiltration, and Interferon gamma (IFNγ) production, partially through the transcriptional regulator Inhibitor of DNA binding 2 (ID2). Significantly, tissue- and disease-specific differential expression and functional implication of SCFA receptors (eg, GPR43, GPR41, GPR109A) emphasize the complexity of SCFA-mediated signaling. In conclusion, the current review emphasizes the multifunctional role of microbiota-derived SCFAs in T lymphocyte biology and their therapeutic potential in cancer, infection, and autoimmune diseases.

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微生物源性短链脂肪酸对T淋巴细胞的影响：从自身免疫性疾病到癌症

短链脂肪酸（SCFAs），醋酸酯、丙酸酯和丁酸酯是在宿主免疫调节，特别是T淋巴细胞功能中具有重要功能的微生物代谢物。最近的证据表明，SCFAs通过抑制组蛋白去乙酰化酶（HDAC）、g蛋白偶联受体（GPCR）信号传导和代谢重编程过程调节t细胞的生长、分化、代谢、效应功能和凋亡。例如，丁酸盐可以增强调节性T细胞（Treg）和产生白细胞介素10 （IL-10）的辅助性T细胞1 （Th1）细胞的分化，以及对辅助性T细胞17 （Th17）细胞发育的环境依赖性调节。SCFAs还通过增加IFN-γ的产生和记忆形成来影响细胞毒性CD8+ T细胞，从而增强抗病毒和抗肿瘤免疫。SCFAs通过增强乙酰辅酶a、雷帕霉素（mTOR）信号传导机制靶点和脂肪酸氧化（FAO）来重编程t细胞代谢，从而促进效应t细胞亚群和记忆t细胞亚群独特的代谢需求。此外，SCFAs通过抑制HDAC1而上调Fas，诱导活化的T细胞凋亡。SCFA失调在1型糖尿病和类风湿性关节炎等疾病和自身免疫性疾病中发挥作用，而治疗性补充可减少炎症和免疫耐受。SCFAs还通过驱动CD8+ t细胞活化、浸润和干扰素γ (IFNγ)的产生，部分通过转录调节因子DNA结合2抑制剂（ID2），增强了免疫检查点抑制剂（例如抗程序性细胞死亡蛋白1 (anti-PD-1)）在癌症中的抗肿瘤作用。值得注意的是，组织和疾病特异性的SCFA受体（如GPR43、GPR41、GPR109A）的差异表达和功能意义强调了SCFA介导的信号传导的复杂性。总之，本综述强调了微生物来源的SCFAs在T淋巴细胞生物学中的多功能作用及其在癌症、感染和自身免疫性疾病中的治疗潜力。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Seminars in oncology 医学-肿瘤学

CiteScore

6.60

自引率

0.00%

发文量

审稿时长

104 days

期刊介绍： Seminars in Oncology brings you current, authoritative, and practical reviews of developments in the etiology, diagnosis and management of cancer. Each issue examines topics of clinical importance, with an emphasis on providing both the basic knowledge needed to better understand a topic as well as evidence-based opinions from leaders in the field. Seminars in Oncology also seeks to be a venue for sharing a diversity of opinions including those that might be considered "outside the box". We welcome a healthy and respectful exchange of opinions and urge you to approach us with your insights as well as suggestions of topics that you deem worthy of coverage. By helping the reader understand the basic biology and the therapy of cancer as they learn the nuances from experts, all in a journal that encourages the exchange of ideas we aim to help move the treatment of cancer forward.