修回日期: 2024-09-26
接受日期: 2024-10-21
在线出版日期: 2024-12-28
胃肠道疾病在全球范围内影响着数百万人, 尤其是胃肠道炎症与肿瘤, 严重影响个体健康和生活质量. 近年来, 随着相关研究的不断呈现, 胃肠道疾病诊疗手段有了极大进展. 但是, 传统疗法仍然可能存在疗效欠佳、副作用等缺点. 抗菌肽作为机体固有免疫的一部分, 不仅具有广谱抗菌活性及免疫调节功能, 能协助维持胃肠道内稳态, 而且可以特异性杀伤肿瘤细胞, 在胃肠道疾病的治疗中展现出良好的前景. 本文将就近十余年抗菌肽在各胃肠道疾病中发挥作用的相关研究、应用前景及所面临的挑战进行简要论述.
核心提要: 抗菌肽通过抑菌活性、调节免疫及抗肿瘤活性参与胃肠道疾病的发生发展, 并具有应用于胃肠道疾病治疗的潜力, 然而其结构特性使其应用面临挑战, 仍需要不断优化改进.
引文著录: 顼霞, 于岩波. 抗菌肽在胃肠道疾病中作用的研究进展. 世界华人消化杂志 2024; 32(12): 865-871
Revised: September 26, 2024
Accepted: October 21, 2024
Published online: December 28, 2024
Gastrointestinal diseases, especially gastrointestinal inflammation and tumors, affect millions of people world-wide, adversely affecting the health and quality of life of individuals. In recent years, with the continuous advances of relevant research, the diagnosis and treatment of gastrointestinal diseases have made great progress. However, traditional therapies still have drawbacks such as poor efficacy and side effects. Antimicrobial peptides, as part of the innate immune defense of many organisms, not only have broad-spectrum antibacterial activity and immune modulating function, which can assist in maintaining homeostasis within the gastrointestinal tract, but also can specifically kill tumor cells, showing good prospects in the treatment of gastrointestinal diseases. In this review, we briefly outline the related studies on the role of antimicrobial peptides in gastrointestinal diseases in the last decade, and discuss the application potential and challenges that they face.
- Citation: Xu X, Yu YB. Role of antimicrobial peptides in gastrointestinal diseases: Recent advances. Shijie Huaren Xiaohua Zazhi 2024; 32(12): 865-871
- URL: https://www.wjgnet.com/1009-3079/full/v32/i12/865.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v32.i12.865
抗菌肽(antimicrobial peptides, AMPs)是一类重要的天然分子, 广泛存在于植物、昆虫、动物及人类中. 在人体中, AMPs分别在肠上皮细胞、潘氏细胞和免疫细胞中以组成或诱导的方式表达. 它们作为宿主防御肽, 在宿主的先天免疫中发挥着关键作用.
AMPs的结构和功能具有高度的多样性. 不同的AMPs可能具有不同的抗微生物谱和作用机制. 目前, AMPs根据其结构组成与氨基酸序列被分为: 防御素, 组织蛋白酶抑制素[1], 肝杀菌肽, 富组蛋白肽和鱼特异性抗菌肽五大家族[2]. 其中, 人及哺乳动物AMPs主要包括组织蛋白酶抑制素和防御素两大类[3]. 这种多样性与特异性使得它们能够针对不同类型的靶点, 也为AMPs的研究和应用提供了广阔的前景, 尤其是在新型抗生素的开发方面[4,5].
AMPs的最主要功能是直接杀灭细菌、病毒、真菌和寄生虫等微生物. 一般认为, 在其抗菌作用过程中, 机体细胞与病原体细胞膜组成的差异是AMPs特异性靶向病原体的基础[6,7]. AMPs通常带有正电荷, 可以与带负电荷的病原体细胞膜结合, 形成孔洞或破坏膜结构, 使细胞内容物泄漏. 这使得AMPs在宿主的先天免疫中成为重要的防御因子[4,8]. 目前已有几种模型被构建用于解释AMPs破坏病原体细胞膜的过程, 包括桶壁模型[9]、环形孔模型[10]、无序环形孔模型[11]、地毯模型[12]等. 除膜作用机制外, 一些AMPs还能够作用于细胞内靶点, 通过干扰细菌的核酸合成或蛋白质合成、中断细胞壁生物合成或细胞分裂, 影响其增殖能力, 从而发挥抑菌活性[13]. 例如, 吲哚杀啶[14], 组织蛋白酶抑制素家族成员之一, 是一种从牛中性粒细胞胞质颗粒中分离得到的天然AMPs, 即可通过抑制核酸合成相关酶的活性来发挥作用.
而肠道中的AMPs不仅能够抑制有害微生物的生长, 还能同时促进有益微生物的繁殖, 调节菌群组成, 维持肠道微生物群的平衡, 从而维护肠道健康. 这对于防止肠道疾病的发生至关重要[5,15].
除了直接的抗微生物作用, AMPs还参与调节宿主的免疫反应. 它们可以刺激免疫细胞的活性, 例如单核细胞和巨噬细胞, 影响细胞因子的释放, 从而调节炎症反应. 这种免疫调节作用有助于在感染初期迅速调动机体的免疫系统, 提高对病原体的抵抗力[5,16]. 人源抗菌肽LL-37是人类体内唯一的组织蛋白酶抑制素家族抗菌肽成员[3]. Marin等[17]研究发现LL-37通过调节Toll样受体-4(toll-like receptor 4, TLR4)和促炎因子白细胞介素-1β的基因表达, 帮助早期结肠上皮抵抗肠型鼠伤寒沙门氏菌.
AMPs在创面愈合过程中也发挥着重要作用. 研究表明[18], 局部应用AMPs能显著促进角质形成细胞和成纤维细胞的迁移, 还能影响细胞的分化和功能[19]. 这对于修复损伤的组织尤其重要, 例如胃肠道的上皮组织. 此外, 其抑菌抗炎作用, 也为创面愈合创造良好的微环境[20]. 如人β-防御素2(hBD-2), 已被证明能够刺激肠道创面的愈合[21]. 这种抑菌抗炎和直接影响细胞活动从而促进肠道上皮的修复与再生的双重作用使AMPs成为胃肠道愈合的潜在治疗选择.
研究表明, 某些AMPs具有抗肿瘤的潜力. 其正电荷在中性条件下使其能有效识别和结合肿瘤细胞膜, 通过诱导凋亡、自噬、破坏细胞膜、阻止细胞周期、抑制转移和破坏细胞骨架等抗肿瘤机制, 抑制肿瘤细胞的生长和增殖及抑制肿瘤血管生成, 以发挥抗癌作用, 而对正常细胞的损伤很小[22-24]. AMPs的这些特性使其在癌症治疗中成为一种有前景的研究方向[4,25]. 如LL-37已被证实对结直肠癌、胃癌、肝癌细胞均有较强的抗肿瘤活性[26].
AMPs作为一种重要的生物分子, 具有广泛的研究价值和应用潜力. 其中, 胃肠道AMPs作为效应器位于人体屏障前线, 其表达可能会影响胃肠道疾病发生或被胃肠道疾病所影响. 近年来, 有关AMPs和胃肠道健康的研究逐渐增多, 特别是在炎症性肠病和胃肠道肿瘤方面, 提示AMPs在胃肠道疾病的发生中可能发挥重要作用[27]. 这也使其成为胃肠道疾病监控及治疗的新靶点.
2.1.1 胃肠道感染: 作为机体先天免疫的重要组成部分, AMPs在机体的免疫防御中发挥着关键作用, 尤其是在胃肠道健康和感染防治方面. 天蚕素AD对胃肠道致病菌如大肠杆菌具有显著的抑制作用, 可以有效减轻由此引起的肠炎症状[28]. 而哺乳动物中两种主要的AMPs: 人α防御素-5(human α-defensin 5, HD5)[29]、组织蛋白酶抑制素相关AMPs[30], 以及蜜蜂源性AMPs Abaecin都显示出调节炎症信号通路与肠道微生物组成来缓解结肠炎的潜力. 这表明[31], AMPs不仅通过直接杀菌作用, 还可以通过改善胃肠道微生物群落构成来改善炎症, 促进肠道健康. 此外, 有研究表明[32], 在有中度坏死性小肠结肠炎临床症状的婴儿中, 粪便中的hBD-2水平显著升高, 相反, 在严重的NEC病例中, 低hBD-2表达与TLR4/骨髓分化蛋白-2表达减少相关, 这意味着对腔内细菌的反应不足, 说明较低的hBD-2水平表明对肠道细菌的反应不足, 可能增加婴儿对坏死性小肠结肠炎发展或加重的易感性, 呈现了粪便中人hBD-2作为免疫系统不成熟的指标的可行性.
2.1.2 耐药菌感染: 相较于传统抗菌药物, AMPs的一个优势是微生物对其产生耐药性的倾向较低, 这可能归因于其在质膜上的独特作用方式, 即其具有疏水性、阳离子性及两亲性, 使其折叠成特征性三维两亲性结构, 通过静电力与带负电荷的致病菌膜相互作用, 造成细菌细胞膜的破坏, 使细菌死亡. 从而使AMPs成为治疗耐药细菌(包括所谓的危险多重耐药MDR细菌)的有利选择[33].
在AMPs治疗耐药菌领域, Wu等[34]发现一种源自人类唾液蛋白组蛋白5的AMPs P-113的非天然氨基酸取代衍生物bip-P-113对万古霉素耐药的屎肠球菌、金黄色葡萄球菌和野生型大肠杆菌具有显著的抗菌活性和与万古霉素的协同活性. Tian等[35]研究了MR-22对耐药大肠杆菌的抑菌动力学与抑菌机制, 发现其在高温、10% FBS和Ca2+条件下具有稳定的抑菌活性, 在耐药大肠杆菌中通过刺激活性氧(reactive oxygen species, ROS)和诱导三磷酸腺苷(adenosine triphosphate, ATP)减少来破坏膜的完整性. 在小鼠腹膜炎模型中, MR-22在体内表现出较强的抗菌活性. 这些结果表明MR-22是一种潜在的抗耐药大肠杆菌的候选药.
在炎症性肠病(inflammatory bowel disease, IBD)患者中, AMPs的表达水平和功能可能受到了损害, 这导致肠道防御机制的降低, 进而引发炎症反应. 研究发现IBD患者的肠道内AMPs的缺乏与肠道炎症发生发展以及肠道有害微生物过度生长相关.
嗜中性多肽(human neutrophil peptides 1, HNP-1)是α-防御素家族中的成员, 其在炎症性肠病发病中的作用机制正在被探索. 一项对照研究[36,37]发现腹腔注射高剂量HNP-1(100 μg/天)会加重小鼠葡聚糖硫酸钠(dextran sulfate sodium salt, DSS)诱导的结肠炎, 表明高浓度HNP可能具有促炎作用, 相反的, 腹腔注射低剂量HNP-1可减轻DSS诱导的结肠炎, 并导致小鼠结肠中促炎细胞因子的表达降低. 轻度转基因过表达HNP-1则可降低小鼠对DSS诱导的结肠炎的易感性. 与野生型小鼠相比, HNP-1转基因小鼠不仅结肠组织损伤更小, 疾病活动指数(DAI)评分也显著降低. 这两项结果可能与其抗菌活性和诱导巨噬细胞产生细胞因子的生理功能相关.
除此之外, 某些AMPs(如HD5/HD6、HNP1-3、hBD-2等)已经被研究肯定于鉴别溃疡性结肠炎和克罗恩病与其他疾病以及区分疾病处于活跃与静止状态[38,39]. 与此同时, 组织蛋白酶抑制素、乳铁蛋白等AMPs已显示出作为IBD复发、并发症风险和治疗反应的预测指标的前景[40,41].
癌症是是发展中国家的第二大死亡原因, 消化道肿瘤在其中占据极大比例[42]. AMPs作为一种新兴的抗癌治疗药物, 近年来受到了广泛关注, 特别是在治疗消化道肿瘤方面.
2.3.1 食管癌: 食管癌是最常见的恶性肿瘤之一, 常通过手术结合放化疗治疗. LvHemB1是由虾的血清素衍生的一种AMPs, 有研究表明[43]其对食管癌细胞具有抗增殖作用, 并可引起癌细胞线粒体功能障碍, 以及增加ROS水平和促凋亡蛋白的表达对食管癌产生选择性毒性, 而对非癌细胞系的增殖无显著影响. 而天蚕素XJ则可诱导微管解聚、肌动蛋白聚合等促细胞骨架破坏, 调控细胞骨架蛋白基因表达, 对食管癌Eca109细胞产生细胞毒性[44]. 可能成为未来治疗食管癌的潜在药物.
2.3.2 胃癌: 胃癌作为消化道常见癌症, 目前, 已有十余种AMPs被研究或可用于胃癌的治疗, 包括蜂毒素[45]、牛乳铁蛋白B[46]、9聚二聚体防御素样肽CopA3[47]、HD-5[48]、LL-37[49]、Cecropin[50]等. 其中蜂毒素通过抑制胃癌AGS细胞的增殖, 同时抑制AGS细胞(一种人胃癌细胞系)的迁移和侵袭治疗转移性胃癌[45]. 而HD-5则通过抑制B淋巴瘤Mo-MLV插入区-1转录活性, 增加细胞周期蛋白依赖激酶抑制剂p16和p19的表达来抑制细胞增殖, 从而发挥其抗肿瘤特性[48].
2.3.3 结直肠癌: 结直肠癌是世界范围内第四大癌症类型[51]. 既往众多实验均证明AMPs作为抗结直肠癌新型疗法的潜力. 乳链菌肽是一种阳离子抗菌多肽, 可以靶向结肠癌细胞内的下调转移基因CEA、CEAM6等诱导凋亡[52]. 而天蚕素B已被证明在小鼠腹水型结肠腺癌细胞系中具有有效的抗肿瘤活性[53]. 此外, 通过观察蜂毒素(melittin, Mel)、天蚕素A和天蚕素A-蜂毒素杂交肽(cecropin A-melittin hybrid, CA-Mel)对两种人类结直肠癌衍生球体(HT-29和HCT-116)的影响, Răileanu等[54]发现通过膜渗透和ATP水平的消耗, 三种AMPs均降低了癌细胞的活力, 其中Mel和CA-Mel肽的结果最为显著. 这亦为开发新的抗癌疗法及改善其局限性提供了新思路.
AMPs在胃肠道疾病的发病机制中扮演着重要角色, 既往研究可得, 内源性AMPs的缺失可能与胃肠道疾病的发生相协同, 而外源性AMPs的补充则可在一定程度上缓解疾病发展. 其抗菌、免疫调节、抗肿瘤等作用可能为胃肠道疾病的治疗提供新的思路.
由于AMPs的独特作用机制和较低的耐药风险, AMPs在未来的胃肠道疾病治疗中具有广阔的应用前景. 研究人员正在积极探索其在胃肠道疾病、特别是肠炎和肠道肿瘤中的潜在应用. 迄今为止, 已有超过3000种AMPs被发现, 其中七种已获得美国食品药品监督管理局的批准, 用于治疗严重的细菌感染, 主要用于局部用药, 但一些也被用于注射以治疗全身性感染[55]. 如多粘菌素是芽孢杆菌产生的一组抗菌多肽[56]. 其中, 多粘菌素B和多粘菌素E(粘菌素)已商业化并应用于临床, 对多重耐药革兰氏阴性杆菌有较好的疗效[57,58]. 此外, 大量AMPs已进入临床试验, 如满足上市条件的被证实可有效缓解肠道感染的瘤胃球菌蛋白C1[59], 以及可用于肠道艰难梭菌感染的索托霉素[60], 虽然在进行三期临床后停止了研发, 但因其较低的复发风险, 在临床研究与应用中仍有一定的价值.
尽管AMPs在临床应用上展现出广阔前景, 其开发和应用过程中仍面临诸多挑战: AMPs在体内的稳定性较差, 受到酶解和代谢的影响, 易被裂解并迅速通过肾脏排出, 或者因与白蛋白等蛋白质结合等而降低抗菌活性[61], 这意味着它们在进入循环系统后可能很快失去活性, 从而影响治疗效果[62,63]; 尽管AMPs普遍被认为对宿主细胞的毒性较低, 但研究发现数种AMPs在抗菌浓度下可引起溶血和/或细胞毒性作用, 这限制了其临床剂量的提升与更广泛的应用[63], 如多粘菌素在抗菌浓度下可能引起肾毒性和神经毒性[64]; AMPs的生物利用度较低, 尤其是在肠道应用中, 可能受到胃肠道环境(如pH值和酶的影响)的限制, 因此, 提高AMPs的吸收, 是当前研究的重点之一[63]; 在临床相关环境中, AMPs的抗菌活性较低, 如在生理盐条件下, 由于AMPs和细胞膜之间的静电相互作用的丧失, AMPs可能失去其杀菌活性[65]; AMPs的合成和提纯成本相对较高, 产量少, 耗时长、操作复杂等都在一定程度上限制了其大规模应用, 寻找高效的生产方法和降低成本是推动AMPs商业化的关键因素[63]. 此外, AMPs可能引起机体的免疫反应导致过敏或其他免疫相关问题、AMPs对于肠道有益菌群的影响以及高频率应用AMPs后可能出现的耐药情况等也需要被考虑. 目前已有关于多黏菌素的耐药性和对AMPs的交叉耐药性研究的相关报道[66]. 如此种种结构缺陷与研发困难, 使得许多有潜在应用实力的AMPs未能进入临床试验或被停止研发, 如Friulimicin B, 放线菌Actinoplanes friuliensis中分离得到的一种AMPs, 在健康志愿者中的Ⅰ期临床试验因其不良的药代动力学特征而终止. 而这些问题的解决需要深化对AMPs作用机制的理解, 并优化其化学结构以提高活性, 改善不足.
目前大多用于临床研究的AMPs都是天然AMPs及其正电荷类似物, 并仅限于局部注射或静脉应用, 而AMPs的疗效则极大程度上取决于其分布以及稳定性, 因此研究者们探索了不同的策略, 包括化学修饰(环化[67]、肽烃吻合器[68]、末端疏水性修饰[69]等)和现代技术(如药物递送), 以获得更安全有效的AMPs作为潜在的治疗剂[70]. 例如Ito等[71]发现在消化酶靶向的可切割位点加入特定的非蛋白质原性氨基酸有助于开发具有增强化学稳定性的生物活性肽; 在抗蛋白水解AMPs D1的n端标记非天然氨基酸(Nal)可显著提高抗菌活性和抗菌稳定性, 且不产生毒性[69]. 通过附着于材料表面递送或与纳米载体、水凝胶组装等递送系统运输AMPs不仅可以靶向运送AMPs提高其特异性并控制释放从而降低细胞毒性, 还能保护AMPs免受酶解, 有效提高AMPs的生物利用度[72]. Xin-Miao Lan团队[73]便开发了四种自组装AMPs, 并通过不同的实验对其化学结构与抗菌活性之间的关系进行探讨, 为精确可控AMP的优化设计提供了新的见解和思路. 而研究者们也试图通过研究替代肽合成方法和超短和/或截短的AMPs的生产降低生产成本, 如Du等[74]通过改变疏水氨基酸的数量和正电荷, 设计并合成了一系列序列简单、短序列的AMPs, 从而改善其抗菌活性并降低生产成本, 择出能降低鼠伤寒沙门氏菌感染小鼠腹腔感染及减少脏器损伤的最佳构型.
AMPs作为生物体固有免疫的基本组成部分, 虽然天然AMPs的有效性、稳定性和毒性等局限性制约了AMPs的综合利用, 使其临床应用面临诸多挑战, 但凭借其独特的结构与抗菌活性、免疫调节、抗肿瘤活性等生理功能, 其在治疗肠道疾病及胃肠道肿瘤方面的潜力仍然巨大. 如今, 对天然AMPs及其类似物的结构优化与对各种来源的新型AMPs的检测研究正在不断进行. 同时, 计算方法逐渐被引入到AMPs的研究中, 以预测结构修饰对AMPs的理化性质、稳定性和活性的影响. 因此, 未来的研究可能集中在以下几个方面: 通过计算机辅助药物设计和基因编辑技术, 开发出更具靶向性和安全性的AMPs[75,76]; 结合水凝胶和纳米技术等新型递送系统, 提高AMPs在体内的稳定性和生物利用度[75,77]; 在临床应用中, 建立长期监测机制, 以评估AMPs的安全性及其对肠道微生物群的影响, 从而优化使用策略.
除了AMPs本身的限制, AMPs的研发涉及生物化学、药理学、微生物学等多个学科, 目前的研究却往往局限于单一学科, 缺乏有效的跨学科合作[78]; 针对AMPs的评估标准和方法尚未统一, 不同研究使用的评价体系可能导致结果的不一致性, 在一定程度上影响了对AMPs临床有效性的评价; 临床设计较复杂, 临床病人认知与接受度较低等都可能限制AMPs的进一步研究与应用. 技术的进步为AMPs的开发带来新的机遇, 使AMPs的研究与开发处于一个快速发展的阶段, 而解决研究方法的瓶颈却需要所有研究者共同努力.
随着对AMPs研究的不断深入以及结构的不断改善优化, AMPs在新药研发、临床治疗及其他领域的应用将不断扩大. 而作为一种新兴的治疗手段, AMPs也在治疗胃肠道疾病中具有广阔的应用前景, 有望在未来成为胃肠道疾病治疗的重要组成部分.
学科分类: 胃肠病学和肝病学
手稿来源地: 山东省
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