| 唐杰,王俊杰,李春晓.肠道菌群代谢物异丁酸/异戊酸对结直肠癌荷瘤小鼠X射线照射后CD8+ T细胞功能的影响[J].中华放射医学与防护杂志,2026,46(9):818-825.Tang Jie,Wang Junjie,Li Chunxiao.The influence of gut microbiota metabolites isobutyric acid and isovaleric acid on the function of CD8+ T cells following X-ray irradiation in colorectal cancer-bearing mice[J].Chin J Radiol Med Prot,2026,46(9):818-825 |
| 肠道菌群代谢物异丁酸/异戊酸对结直肠癌荷瘤小鼠X射线照射后CD8+ T细胞功能的影响 |
| The influence of gut microbiota metabolites isobutyric acid and isovaleric acid on the function of CD8+ T cells following X-ray irradiation in colorectal cancer-bearing mice |
| 投稿时间：2026-03-01 |
| DOI：10.3760/cma.j.cn112271-20260301-00072 |
| 中文关键词: 异丁酸 异戊酸 肠道菌群 放射 T细胞 |
| 英文关键词:Isobutyric acid Isovaleric acid Gut microbiota Radiotherapy T cell |
| 基金项目:国家自然科学基金（82473246，82573446）；北京市自然科学基金（7232207）；北京大学第三医院重点项目（人才A类：BYSY2022044） |
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| 中文摘要: |
| 目的 探讨肠道菌群代谢物异丁酸/异戊酸（IBA/IVA）对结直肠癌放疗后机体CD8+ T细胞功能及抗肿瘤效应的影响。方法 采用雌性C57BL/6N小鼠，共20只，构建MC38结直肠癌皮下荷瘤模型，根据随机数字表将小鼠随机分为对照组、IBA/IVA组、照射组及照射联合IBA/IVA组，每组5只。单次10 Gy X射线照射，照射后给予IBA/IVA混合物灌胃处理，1次/2 d，共计7次。灌胃总剂量为38.05 mg/kg，其中IBA 17.6 mg/kg，IVA 20.45 mg/kg。21 d后取脾脏和肿瘤引流淋巴结（dLNs），采用流式细胞术检测效应CD8+ T细胞（CD44hiCD62Llo）的比例、CD8+ T细胞中颗粒酶B（GZMB）、干扰素γ（IFN-γ）、肿瘤坏死因子α（TNF-α）以及T淋巴细胞免疫球蛋白黏蛋白3（TIM-3）的表达水平，并取肿瘤组织进行体积和质量评估。结果 与对照组相比，照射显09著提高了dLNs [（5.12±0.53）% vs.（6.68±0.48）%，q=10.76，P < 0.05]和脾脏[（3.56±0.53）% vs.（6.20±0.72）%，q=11.97，P < 0.05]中效应CD8+ T细胞的比例，但IBA/IVA处理显著抑制了dLNs [照射组vs. 照射联合IBA/IVA组=（6.68±0.48）% vs. （4.22±0.25）%，q=16.96，P < 0.05]和脾脏[照射组vs. 照射联合IBA/IVA组=（6.20±0.72）% vs. （4.46±0.35）%，q=7.89，P < 0.05]中效应CD8+ T细胞的比例。同时，照射组脾脏（q=14.00、14.86、4.24、7.36，P < 0.05）与dLNs（q=11.22、21.66、11.58、9.36，P < 0.05）中CD8+ T细胞的GZMB、IFN-γ及TNF-α表达较对照组显著升高，TIM-3表达水平降低。而照射联合IBA/IVA组脾脏（q=12.24、16.31、7.42、13.93，P < 0.05）与dLNs（q=11.47、21.96、13.71、23.78，P < 0.05）中，GZMB、IFN-γ及TNF-α表达水平均较照射组显著下降，TIM-3表达水平增高。相较于照射组，照射联合IBA/IVA组小鼠的肿瘤生长明显加速，第21天肿瘤体积[（185.08±34.90）mm3 vs. （813.15±112.85）mm3，q=7.33，P < 0.05]和质量[（0.20±0.04）g vs. （0.89±0.12）g，q=7.57，P < 0.05]显著增大。结论 IBA/IVA可抑制照射诱导的CD8+ T细胞活化及效应功能，减少效应CD8+ T细胞比例和GZMB、IFN-γ和TNF-α等抗肿瘤细胞因子的表达，上调TIM-3的表达，从而削弱照射的抗肿瘤效应并促进肿瘤进展，对调控放疗期间的肠道代谢环境具有潜在的临床意义。 |
| 英文摘要: |
| Objective To investigate how the gut microbial metabolites isobutyric acid and isovaleric acid (IBA/IVA) influence CD8+ T cell function and the antitumor efficacy of irradiation (IR) in a murine colorectal cancer model.Methods A subcutaneous MC38 colorectal cancer model was established in 20 female C57BL/6N mice, which were randomly assigned using a random number table to four groups: Vehicle, IBA/IVA, IR, and IR combined with IBA/IVA (n=5 in each group). A single dose of 10 Gy radiation was administered to the tumors. Post-irradiation, mice were treated with an IBA/IVA mixture via oral gavage every other day for a total of 7 administrations. The total dosage was 38.05 mg/kg, comprising 17.6 mg/kg of IBA and 20.45 mg/kg of IVA. At 21d post-irradiation, spleens and draining lymph nodes (dLNs) were collected. Flow cytometry was used to quantify the proportion of effector CD8+ T cells (CD44hiCD62Llo), and the expression of granzyme B (GZMB), interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), and T cell immunoglobulin domain and mucin domain-3 (TIM-3) in CD8+ T cells. Tumor volume and weight were also evaluated. Comparisons between two groups were performed using the independent-samples t-test.Results Compared with the Vehicle group, IR markedly increased the proportion of effector CD8+ T cells in the dLNs [(5.12 ± 0.53)% vs. (6.68 ± 0.48)%, q=10.76, P < 0.05] and spleen [(3.56 ± 0.53)% vs. (6.20 ± 0.72)%, q=11.97, P < 0.05]; however, IBA/IVA treatment significantly inhibited the increase in dLNs [IR vs. IR + IBA/IVA = (6.68 ± 0.48)% vs. (4.22 ± 0.25)%, q=16.96, P < 0.05] and spleen [IR vs. IR + IBA/IVA = (6.20 ± 0.72)% vs. (4.46 ± 0.35)%, q=7.89, P < 0.05]. In the IR group, the expression of GZMB, IFN-γ, and TNF-α in CD8+ T cells from both spleens (q=14.00、14.86、4.24、7.36, P < 0.05) and dLNs (q=11.22, 21.66, 11.58, 9.36, P < 0.05）was significantly upregulated, while TIM-3 expression was downregulated compared with Vehicle group. Conversely, in the IR + IBA/IVA group, the expression levels of GZMB, IFN-γ, and TNF-α were significantly lower, whereas TIM-3 expression level was higher, compared with the IR group in both spleens (q=12.24, 16.31, 7.42, 13.93，P < 0.05) and dLNs (q=11.47, 21.96, 13.71, 23.78, P < 0.05). In addition, the IR + IBA/IVA group exhibited accelerated tumor growth compared with the IR group, with significantly greater tumor volume [(813.15 ± 112.85) mm3 vs. (185.08 ± 34.90) mm3, q=7.33, P < 0.05] and weight [(0.89 ± 0.12) g vs. (0.20 ± 0.04) g, q=7.57, P < 0.05] at 21d (P < 0.05).Conclusions IBA/IVA impair the IR-induced activation and effector function of CD8+ T cells, reducing the proportion of effector CD8+ T cells and the expression of anti-tumor cytokines (GZMB, IFN-γ, TNF-α), and promoting TIM-3 expression. These findings suggest that modulation of the intestinal metabolic environment during IR may help preserve radiotherapy-induced antitumor immunity. |
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