肠道基石菌——酪酸梭菌在结直肠癌防治中的研究进展
鹿凤娇1王凯2杨蓉3王蒙4
1 青岛市医用与食用微生态制品研发重点实验室，医用微生态制品开发国家地方联合工程研究中心，清华大学医学院北京协和医学院
2 中国医药教育协会微生态与健康专业委员会常委，《中国微生态学杂志》审稿专家，《中西医结合肿瘤临床研究》研究生规划教材（第2版）副主编
3 陕西省第二人民医院科教科
4 陕西中医药大学
摘要：
结直肠癌发病率与死亡率持续上升，现有手术及放化疗等治疗手段存在复发转移、耐药及不良反应等局限，亟需从源头探索新的防治策略。肠道微生态失衡，特别是肠道基石菌酪酸梭菌的缺失，与结直肠癌的发生发展密切相关。本综述系统总结酪酸梭菌在结直肠癌防治中的临床研究进展，并总结酪酸梭菌如何通过修复肠屏障、预防肿瘤细胞癌变、激活抗肿瘤免疫、调节肠道菌群、抑制肠道炎症等机制防治结直肠癌。目前，我国已实现酪酸梭菌CGMCC0313-1的产业化，为临床结直肠癌的防治指明了新方向。
关键词：结直肠癌；酪酸梭菌；丁酸；肠道基石菌
Research Progress of Clostridium Butyricum,the Keystone Species of the Gut Microbiota, in the Prevention and Treatment of Colorectal Cancer
Abstract
In recent years, the incidence and mortality of colorectal cancer continues to rise. However, current therapeutic modalities, including surgery, chemotherapy, and radiotherapy, are limited by recurrence, metastasis, drug resistance, and adverse reactions, raisingan urgent need to explore new prevention and treatment strategies targeting the root causes. Gut dysbiosis, particularly the deficiency of the keystone species of the gut microbiota, Clostridium butyricum, is closely associated with the development and progression of colorectal cancer. This review systematically summarizes the clinical research progress of Clostridium butyricumin the prevention and treatment of colorectal cancer, and delineates the mechanisms by which Clostridium butyricumcombats colorectal cancer, including restoring the intestinal barrier, preventing tumorigenesis, activating antitumor immunity, modulating gut microbiota, and suppressing intestinal inflammation. Currently, the industrialization of the Clostridium butyricumstrain CGMCC0313-1 has been achieved in China, pointing to a new direction for the clinical prevention and treatment of colorectal cancer.
Keywords: Colorectal cancer; Clostridium butyricum; Butyrate; Keystone species of the gut microbiota
1、引言：结直肠癌的治疗现状与治疗挑战
目前，结直肠癌（Colorectal Cancer，CRC）是严重威胁人类健康的消化道恶性肿瘤，其疾病负担在全球范围内持续上升：在全球范围内，结直肠癌的发病率高居所有恶性肿瘤第三位，死亡率位列第二，给各国医疗系统带来了沉重负担[1]。中国国家癌症中心（National Cancer Center，NCC）发布的数据指出，结直肠癌是我国发病率第二位的恶性肿瘤，患者基数众大[2]。据国际癌症研究机构预测，这一增长趋势仍将持续，预计到2050年，我国每年新增发病人数将在现有基础上增长60%以上[3]。
然而，目前结直肠癌的防治仍面临巨大挑战。目前，手术是临床结直肠癌治疗的主要手段，但大量患者术后仍面临复发和转移，需联合化疗、放疗、靶向治疗、免疫治疗等多种方案，长期应用易产生耐药性，并导致严重不良反应，严重影响患者生存质量[4-7]。因此，找到从源头上防治结直肠癌的措施已十分迫切。
近年来，多篇研究指出，酪酸梭菌（Clostridium butyricum）缺失、肠道微生态失衡、肠屏障受损是结直肠癌高发的关键原因[8-11]，补充酪酸梭菌对结直肠癌的防治具有重要意义。酪酸梭菌又称丁酸梭菌，能够大量产生丁酸（酪酸），为肠上皮细胞提供能量，从而保护肠黏膜屏障的完整性[12-13]。本综述系统总结基石菌酪酸梭菌在临床结直肠癌防治中的应用，并解析酪酸梭菌如何通过构筑完整的肠屏障、抑制肿瘤细胞增殖、促进肿瘤细胞清除、调控肠道菌群、抑制炎症反应等多种机制防治结直肠癌，为临床结直肠癌的防治提供理论依据。
2、酪酸梭菌防治结直肠癌的临床研究进展
酪酸梭菌在结直肠癌中的防治作用，已成为近年国际微生态学领域的研究热点。近年来，多篇研究通过大量16S rRNA测序及宏基因组研究，发现酪酸梭菌匮乏、肠道微生态失衡与结直肠癌发生发展密切相关[8-11]：一项针对中国、奥地利、美国、德国和法国五个国家高达536个临床样本的大规模研究发现：结直肠癌患者肠道中的酪酸梭菌丰度均显著低于健康人群[14]。此外，多篇研究发现，直接补充酪酸梭菌，能够有效防治结直肠癌：
2.1 预防腺瘤复发：结直肠腺瘤息肉在切除后常复发，是结直肠癌的高危因素[15]。研究发现，腺瘤切除后的患者，每日补充酪酸梭菌，能够有效降低腺瘤息肉复发率，且无明显不良反应[16]。
2.2. 减轻化疗毒副作用：化疗在杀灭肿瘤细胞的同时，往往带来严重的毒副作用。研究发现，补充酪酸梭菌活菌片（CGMCC0313-1），能够降低化疗引起的恶心呕吐、肢端麻木、白细胞减少、肝功能异常等毒副作用的发生率，并降低血清中的肿瘤标志物水平，显著提升了患者生活质量[17]。
2.3 促进术后康复：临床研究证实，肠癌患者术后补充酪酸梭菌活菌胶囊（CGMCC0313-1），能够显著促进伤口愈合，加速康复进程[18]。
3、酪酸梭菌防治结直肠癌的分子机制
近年来，多篇研究指出，酪酸梭菌能够通过多重机制，防治结直肠癌：
图1基石菌酪酸梭菌通过多种机制防治结直肠癌
3.1 构筑完整的肠屏障
肠屏障受损、肠黏膜通透性增加是结直肠癌发生的根本原因[19]。肠屏障（包括黏液层、肠上皮细胞及紧密连接、肠道菌群、黏膜免疫系统）受损后，肠黏膜通透性增加，发生“肠漏”，细菌及其产物（如脂多糖LPS）发生易位，从而触发慢性炎症反应，驱动结直肠癌的发生与发展[19-20]。最新研究指出，以酪酸梭菌为代表的产丁酸菌是肠道基石菌，在保护完整的肠屏障、调控免疫、维持机体健康中发挥核心作用[21,22]。酪酸梭菌能够产生丁酸，促进受损的肠上皮细胞的修复，并上调紧密连接蛋白的表达，从而有效保护肠黏膜屏障的完整性[22]，从源头上预防结直肠癌的发生。
3.2 产生丁酸，直接抑制肿瘤：酪酸梭菌产生的丁酸，能够作为组蛋白去乙酰化酶（Histone Deacetylase，HDAC）抑制剂，抑制组蛋白去乙酰化酶活性，调控多个肿瘤相关信号通路，诱导肿瘤细胞周期停滞、促进细胞凋亡和分化，从而直接抑制结直肠癌[23-25]。在小鼠结直肠癌模型中，酪酸梭菌与右旋糖酐组成的抗癌制剂能显著抑制结直肠癌，且没有明显不良反应[26]；此外，研究发现补充酪酸梭菌能够通过蛋白酶体依赖途径促进MYC的泛素化降解，从而降低化疗药物5-FU的耐药性、增强免疫疗法的抗肿瘤疗效[27]。
3.3 激活抗肿瘤免疫，促进肿瘤细胞清除：多篇研究表明，酪酸梭菌及丁酸能够直接增强CD8+T细胞活性，促进CD8+T细胞杀伤肿瘤：丁酸能够通过其组蛋白去乙酰化酶活性，抑制T细胞组蛋白去乙酰化，上调转录因子ID2的表达，而ID2能够进一步促进IL-12受体的表达、增强IL-12/IL-12R信号，从而增强CD8+T细胞的抗肿瘤效果[28]；此外，酪酸梭菌能够通过其表面蛋白secD，结合宿主细胞表面的受体GRP78，靶向肠癌细胞，进入肿瘤内部，抑制肿瘤细胞PI3K-AKT-NF-κB信号通路，通过抑制IL-6的产生，重新激活CD8+T细胞，发挥抗肿瘤作用[29]。
3.4 调控肠道菌群：健康的肠道微生态系统对防治结直肠癌至关重要。“细菌驾驶员-乘客模型”指出，有害菌过度增殖是驱动肠癌发生的关键风险因素[30]。一旦肠道菌群紊乱、肠道微生态失衡，会导致有害菌异常增殖，进而诱发肠道炎症，长期的慢性炎症环境会加剧DNA损伤、染色体突变以及特定代谢产物的改变，从而加速肿瘤进展[31-32]。酪酸梭菌能够通过促进形成肠道内酸性厌氧环境、交叉喂养、竞争性抑制等方式增加有益菌（如多种产丁酸菌）的丰度，降低艰难梭菌、沙门氏菌等有害菌的丰度，从而恢复肠道菌群平衡[33-35]。
3.5抑制肠道炎症：长期的慢性炎症是结直肠癌的诱发因素[31-32,36]。研究表明，在葡聚糖硫酸钠（DSS）诱导的实验性结肠炎小鼠模型中，酪酸梭菌可通过TLR2/MyD88通路，促进肠道巨噬细胞产生抑炎因子IL-10[37]；此外，酪酸梭菌能够通过抑制TLR-4/NF-κB/MAPK信号通路，抑制多种炎症因子TNF-α、IL-1β、IL-6 的表达[38]；丁酸还能促进调节性T细胞（Tregs）的生成，抑制过度的炎症反应，维持肠道免疫稳态，从而抑制结直肠癌的发生发展[39-40]。
4、总结与展望
综上所述，作为肠道核心基石菌，酪酸梭菌可通过产生丁酸，构筑完整的肠道屏障、抑制肿瘤细胞增殖、促进肿瘤细胞清除、调控肠道菌群、抑制炎症反应，在结直肠癌的防治中发挥重要作用。目前，已有临床研究证明补充酪酸梭菌能够有效预防腺瘤复发、减轻化疗毒副作用、促进肠癌术后康复[16-18]，为后续结直肠癌的防治指明了新方向。
目前，在国家863项目的支持下，医用微生态制品开发国家地方联合工程研究中心已经筛选出了高活性的酪酸梭菌菌株CGMCC0313-1，并在高密度发酵、微囊化制剂工艺上取得突破，成功实现基石菌酪酸梭菌的产业化，相关技术已获得中国、美国等多国专利授权（如ZL 200610086642.3、US 7785581B2等）。凭借其良好的疗效和安全性，酪酸梭菌被国家药品监督管理局批准为绿标OTC国药准字药品（S20040084，S20040088）[41-42]，广泛应用于腹泻、肠易激综合征等肠道疾病的临床治疗[43-45]，为进一步推进结直肠癌防治相关的临床研究奠定了坚实的基础。
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