修回日期: 2022-08-22
接受日期: 2022-10-20
在线出版日期: 2022-11-08
炎症性肠病(inflammatory bowel disease, IBD)的发生受到环境因素的影响. 饮食作为重要的环境因素, 与肠道生态的联系最为密切, 在IBD的病理过程中扮演了重要角色. 本文综述了饮食中主要营养成分在IBD发病中的作用以及目前的研究进展, 为IBD的预防和治疗提供参考.
核心提要: 饮食因素与炎症性肠病(inflammatory bowel disease, IBD)的病理过程密切相关, 明确饮食中不同营养成分在IBD中的作用, 对于临床上IBD的预防和治疗具有重要意义. 本文综合近年来临床调查和动物基础研究的结果, 对食物营养成分在IBD发病中的作用进行了综述.
引文著录: 谭艳丽, 赵豫鄂. 食物营养成分对炎症性肠病疾病影响的研究进展. 世界华人消化杂志 2022; 30(21): 921-927
Revised: August 22, 2022
Accepted: October 20, 2022
Published online: November 8, 2022
The occurrence of inflammatory bowel disease (IBD) is influenced by environmental factors. Diet, as an important environmental factor, is closely associated with intestinal ecology and plays a critical role in the pathological process of IBD. This review summarizes the role of major dietary nutrients in the pathogenesis of IBD, with an aim to provide clues for the prevention and treatment of IBD.
- Citation: Tan YL, Zhao YE. Advances in understanding of effects of dietary nutrients in inflammatory bowel disease patients. Shijie Huaren Xiaohua Zazhi 2022; 30(21): 921-927
- URL: https://www.wjgnet.com/1009-3079/full/v30/i21/921.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v30.i21.921
炎症性肠病(inflammatory bowel disease, IBD)是一种慢性的肠道炎性疾病, 包括克罗恩病(Crohn's disease, CD)和溃结性肠炎(ulcerative colitis, UC)两种类型. 流行病学调查显示, 2017年全球IBD患者有680万人, 发病率为84.3/10万, 且IBD的发病率在全球范围内快速增加[1]. 最新研究认为, IBD的发病与易感宿主对肠道菌群的不适当免疫反应有关[2]. IBD患者肠道菌群的多样性和丰富度大幅度降低, 其最佳稳态和代谢失调[3]. 肠道菌群对维持机体正常的生理功能和新陈代谢具有重要作用, 其功能包括: 协助机体获取食物中无法消化的营养成分、合成维生素、通过调节肠道的分泌和运动功能促进肠道稳态、通过激活肠道免疫系统来诱导肠粘膜的耐受性等[4]. 目前饮食偏好已被证明是决定肠道微生物组成的关键因素之一[5,6]. 因此IBD患者的饮食被越来越多的临床和科研工作者所关注[7,8]. 考虑到饮食对肠道菌群的重要影响, 笔者希望通过探讨饮食中的碳水化合物、脂肪、蛋白质、微量营养素和一些食品添加剂在IBD发病中的作用, 为预防IBD的发生或者改善IBD的症状提供参考.
碳水化合物可根据其聚合度分为: (1)单糖; (2)双糖(葡萄糖、果糖、蔗糖); (3)低聚糖(低聚果糖、低聚半乳糖); (4)多糖(淀粉、纤维素、菊粉等). 其中, 单糖、双糖和淀粉能够被小肠水解和吸收. 菊粉、低聚果糖、低聚半乳糖等, 在小肠中不能被水解吸收, 但是能够被大肠中微生物群酵解. 膳食纤维是一类复杂碳水化合物, 既包括可溶性的, 也包括不溶性的, 非水溶性纤维能够完整的通过消化道, 增加肠道内容物的体积, 具有通便作用[9].
在IBD患者中, 大量摄入葡萄糖、蔗糖、乳糖或果糖等碳水化合物, 可能会超过肠道的吸收能力, 破坏肠道的吸收机制, 增加肠内糖含量和渗透负荷, 引起各种胃肠症状, 同时肠道内糖浓度增加, 还会导致肠道中的细菌过度生长[10]. 在小鼠模型中, 高糖摄入已经被证实会促进肠道失调以及病原性细菌的扩增, 同时增加肠道的通透性和炎症[11]. 临床证据表明, IBD患者通常伴有果糖吸收不良或乳糖不耐受, 这也是目前一些复杂碳水化合物限制饮食(如SCD、FODMAPs)的理论依据[12].
此外, 通过前瞻性的调查和系统性的回顾分析发现, 较高的膳食纤维摄入能够降低CD发生的风险, 但不能降低UC发生的风险[13,14]. 在1619例IBD患者参与的一项前瞻性研究中, 膳食纤维摄入量高的CD患者比纤维摄入量低的CD患者病情复发的机率更小, 可惜UC患者中没有发现这种现象[15]. 主要原因可能在于, 膳食纤维等碳水化合物聚合物能被肠道微生物降解和发酵成单糖以及各种副产品, 如人体可吸收的短链脂肪酸, 如醋酸盐、丙酸盐和丁酸盐等[16], 这些肠道微生物副产物可以调节宿主免疫系统和肠道屏障功能, 在肠道稳态中发挥重要作用[17]. 确有调查发现[18], IBD患者肠道内厚壁菌门和拟杆菌门的丰度大幅度降低, 而这些细菌能够将膳食纤维发酵成短链脂肪酸, 这类肠道菌群结构改变可引起抗炎产物以及免疫调节代谢产物的水平降低(尤其是丁酸盐). 因此对于症状缓解以及肠道无狭窄的IBD患者, 不需要限制膳食纤维的摄入[19]. 在小鼠UC模型中, 在炎症发生之前摄入膳食纤维能够起到保护作用[20], 这可能是由于膳食纤维所介导的保护作用使肠道黏液层在疾病活动性期间不被破坏[21], 在膳食纤维缺乏的情况下, 肠道微生物群会将黏液层糖蛋白作为营养来源, 导致结肠黏液屏障的侵蚀破坏[22].
脂类大致包括四种类型: (1)饱和脂肪(主要来自动物, 如乳制品和肉类); (2)单不饱和脂肪酸(橄榄、菜籽和花生中富含); (3)多不饱和脂肪酸(油菜、亚麻籽油和鱼类中富含); (4)反式脂肪(黄油、氢化食物中富含).
有证据指出, 过量的脂肪摄入与IBD的发病机制有关, 高脂饮食增加IBD发生的风险, 可能是由于肠道菌群的改变和肠黏膜通透性的增加所致. 事实上, 大多数健康受试者在高脂饮食一个月后血浆内毒素水平升高, 提示这些受试者可能出现肠道致病菌群以及肠黏膜通透性的增加, 即使他们没有发生炎症[23]. 高脂饮食和IBD的关系, 最早是在欧洲的研究中发现人造黄油的大量摄入导致CD的发病率增加[24], 后续在日本的研究中发现脂肪摄入与CD和UC的发生率密切相关[25]. 原因可能在于, ω-3多不饱和脂肪酸具有抗炎作用, ω-6多不饱和脂肪酸具有促炎作用. 而作为人体内无法自己合成的脂肪酸, ω-3与ω-6脂肪酸必须通过饮食摄取. 一项大型前瞻性研究表明, 高摄入量的ω-3多不饱和脂肪酸(二十二碳六烯酸)可预防UC的发生[26], 保持ω-3/ω-6多不饱和脂肪酸的比值平衡对维持肠道稳态至关重要的.
一项针对儿童群体(<20岁)的病例对照研究发现, 饮食中较高的ω-3/ω-6脂肪酸比值能够降低CD发生的风险[27]. Uchiyama等[28]建议IBD患者增加ω-3多不饱和脂肪酸的摄入, 并减少ω-6多不饱和脂肪酸的摄入, 在随后的12 mo中, IBD患者红细胞膜上的ω-3/ω-6脂肪酸比值显著提高, 并且病情缓解的患者比病情反复的患者比值提高更加显著. 尽管这些研究表明ω-3脂肪酸在预防和治疗IBD中具有积极作用, 但是Matsunaga等[29]的研究结果则认为ω-3脂肪酸会加重小鼠溃疡性结肠炎症状.
Hou等[14]对流行病学数据进行系统性分析, 发现饮食中总脂肪、总多不饱和脂肪酸以及ω-6脂肪酸摄入量过高会增加CD和UC发生的风险. 大量研究表明, 高脂肪饮食改变了肠道菌群的构成, 损害了肠道屏障功能, 导致肠道和全身炎症, 并且高脂肪/高糖饮食还会促进一种与IBD相关的侵袭性大肠杆菌的定植[30]. 其它一些脂肪, 例如, 长链甘油三酯能够促进肠道淋巴细胞增殖、上调促炎介质, 从而增加IBD发生的风险, 而中等链长的甘油三酯则通过抑制IL-8的产生在IBD中发挥保护作用[31].
有研究表明[32], 蛋白质的摄入量(尤其是动物蛋白)与IBD的发生呈正相关. 还有一项前瞻性研究的结果表明[33], 高蛋白质摄入还会增加UC患者疾病复发的风险. 然而, Spooren等[34]通过系统性回顾分析发现, 大部分的研究中(8/10)关于高蛋白质摄入会导致IBD发生风险增加的结论并不具备显著性.
尽管蛋白质在IBD发病机制的作用仍不明确, 但考虑到其对肠道稳态的作用, 特别是对结肠微菌群和黏膜的作用, 高蛋白质摄入可能会影响IBD的发病. 肠道菌群对氨基酸分解会产生多种多样的代谢产物, 这些产物对结肠黏膜上皮细胞的更新和肠道屏障功能等方面有些是有益的(如丁酸、吲哚等), 而有些是有害的(如氨、硫化氢等), 这些不利的后果可能与IBD的发病机制有关[35]. 在动物研究中, 接受高蛋白饮食的大鼠大肠中普拉梭菌的数量显著减少, 这种肠道共生菌在小鼠UC模型表现出抗炎特性, 并且在IBD患者肠道中明显减少[36,37]. 高蛋白-低纤维的减肥套餐能够减少粪便中抗癌代谢物, 增加有害代谢产物, 同时还减少了肠道中直肠杆菌的数量, 这类细菌能够产生对结肠黏膜有益的化合物丁酸盐[38]. IBD患者肠黏膜中的丁酸盐转运不足[39], UC患者被检测到肠道菌群结构发生改变同时伴有丁酸盐种类显著减少[40], 此外, 高蛋白饮食还降低了猪肠黏膜上的丁酸转运体的表达[41].
有研究推测, 蛋白质在肠道中的降解产物能够为肠道菌群提供的底物, 从而改变肠道菌群结构, 引起IBD相关病原菌的扩增, 或改变短链脂肪酸的形成, 来调节肠上皮细胞的功能. 不同来源的高蛋白质摄入量, 包括红肉、鱼、鸡蛋、牛奶、奶酪、坚果等, 也可能会引起IBD发病的改变[31], 并且高蛋白饮食对于肠道菌群和肠道屏障的影响可能在屏障功能受损的个体中被进一步放大, 这也能够解释为什么高蛋白质摄入会导致IBD患者的复发风险增加[33].
人体必需的微量营养素包含了维生素和矿物质, 维生素与矿物质在体内发挥了重要的功能, 这些功能主要包括: 作为辅助因子或者辅酶参与代谢、控制遗传基因表达以及机体抗氧化[42]. 对IBD来说, 维生素和矿物质在控制遗传基因表达和抗氧化方面的作用, 对于预防IBD的发生或缓解IBD的症状十分重要.
1.4.1 维生素: 维生素A、B和E参与调节肠道内的免疫反应和稳态, 抑制炎症细胞因子的释放, 促进调节性T淋巴细胞(regulatory T cells, Treg)向辅助性T淋巴细胞(T helper cell 17, Th17)的分化. 维生素A、C、E作为活性抗氧化物质和辅酶(需要锌、硒参与)能够清除机体产生的活性氧簇(reactive oxygen species, ROS)[43]. 在IBD患者中, 一方面, 免疫失调和炎症导致ROS的产生增加, 而微量营养素具有抗炎和清除ROS的功能, 因此对于缓解IBD的进展有积极的作用; 另一方面, 部分患者在疾病进展过程表现出微量营养素匮乏(包括多种维生素和铁、锌、硒等微量元素), 但是由于难以通过饮食成分来确定个体微量营养素的水平, 因此目前尚不能确定患者体内微量营养素水平下降与IBD发生的因果关系[44].
维生素D在IBD中的作用涉及到多个方面, 包括调节钙稳态和骨骼代谢、调节免疫系统、保护正常菌群和维持肠道黏膜完整性[45]. 维生素D可以通过促进紧密连接蛋白的表达来保护并恢复上皮屏障功能, 它还能抑制树突状细胞的成熟, 减少共刺激分子的产生来降低效应T细胞的活化, 以及通过促进抗菌肽的分泌保护正常菌群. 动物研究证实, 给小鼠喂食缺乏维生素D食物, 小鼠患溃疡性结肠炎的风险增加[46], 并且在小鼠IBD模型中, 补充维生素D能够改善症状, 而缺乏维生素D则加重症状[47,48]. IBD患者经常出现维生素D的缺乏, 有研究表明, 57.7%的CD患者存在维生素D的缺乏[49]. 而IBD患者维生素D的缺乏会导致疾病复发增加、病情更加严重以及住院需求的增多, 同时也会增加骨质疏松、患癌以及手术的风险[50,51]. 一项前瞻性研究显示, 较高的血浆维生素D预测水平可显著降低女性发生CD的风险, 但不能显著降低UC的风险[52]. 然而在另一项长达15.7年研究中, 血清维生素D缺乏与IBD发生并没有明显的相关性[53].
此外, 由于IBD患者肠道功能的紊乱以及屏障功能被破坏, 一方面使得肠道对营养成分的吸收减少, 另一方面也导致体内营养成分的流失增加, 因此, 其它一些维生素在IBD患者体内也表现出缺乏的状态; 并且一些研究也证实了补充维生素对IBD的益处, 补充维生素B、C、E和K等能够缓解IBD的症状或减轻一些IBD相关的并发症, 但是如何合理补充维生素仍需进一步的研究来确定[44].
1.4.2 微量元素: 锌作为辅助因子, 在免疫调节中发挥着重要的作用, 体内缺锌引起促炎细胞因子IL-6分泌增多[54]. 编码锌指蛋白A20的基因Tnfaip3出现特定的突变会引起多种炎症, 增加IBD发生的风险. 在小鼠肠道上皮细胞中, Tnfaip3的缺失导致小鼠对葡聚糖硫酸钠(dextran sulfate sodium salt, DSS)诱导的溃疡性结肠炎的敏感性增加[55]. 锌还通过抑制还原型辅酶Ⅱ(nicotinamide adenine dinucleotide phosphate, NADPH)氧化酶和作为超氧化物歧化酶的辅助因子发挥抗氧化作用[56]. 对170756名女性进行的为期26年的前瞻性研究发现, 锌的摄入量增加会显著降低CD发生的风险[57]. 约有15.2%-65%的IBD患者体内缺锌, 缺锌导致IBD患者的住院治疗、手术和并发症增加, 当锌升高到正常水平, 这些不良的后果也相应降低到正常范围[58].
与锌一样, 硒也参与到免疫功能的调节, 谷胱甘肽过氧化物酶(GPx)能够利用硒来清除ROS, 在小鼠IBD模型中, GPx蛋白的编码基因缺失导致IBD症状加重, 缺硒导致疾病的严重性增加以及促炎细胞因子TH1的上调[59]. 有研究报道, 约30.9%的IBD患者缺硒[60]. 在动物实验中, 补充硒能够改善环氧化酶依赖的炎症的发生[61].
铁是血液形成的必需元素, IBD患者中缺铁性贫血和相关疲劳的发生率达到了36%-76%, 因此补充铁对IBD患者缺铁性贫血的干预具有积极意义[62].
食品添加剂常用于延长食品保存时间、提高食品质量和改善加工食品的味道, 主要包括防腐剂、膨松剂、增稠剂、着色剂、增味剂、香料等, 近年来, 人们开始关注食品添加剂在IBD中的作用.
乳化剂(如羧甲基纤维素和聚山梨醇酯-80)能够增强食物的质地和稳定性. 研究表明, 乳化剂能够破坏了宿主-微生物的相互作用, 促进了肠道炎症和结肠癌的发生. 在小鼠模型中, 乳化剂导致肠道粘液厚度的减少、细菌与黏膜层的距离的缩小、细菌种类结构的改变(如拟杆菌门的减少)以及促炎细胞因子的增加, 并且还能引起结肠炎遗传易感小鼠的易感性增加[63]. 麦芽糖糊精, 常用作填充剂或增稠剂, 能够影响肠道微生物群, 损害肠道黏液层[64]. 人工甜味剂会诱发肠道生态失调和粘膜炎症, 在动物模型中, 人工甜味剂的摄入促进了小鼠回肠变形菌门的扩张, 增加了细菌对回肠固有层的渗透[65]. 食用着色剂(如二氧化钛和抗菌剂), 已被证明会诱发肠道炎症并增加小鼠的氧化应激, 破坏肠道微绒毛和肠道上皮细胞屏障[66]. 这些研究表明, 许多食品添加剂可能会增加IBD的发生风险.
长期以来, 遗传因素都是研究人员探讨IBD发病机制的重点方向, 有超过200个基因位点与IBD的发生有关[67], 但实际上仅有26%的CD病人和19%的UC病人存在遗传变异[68], 因此IBD的发生还存在其它重要的因素. 环境因素被认为是IBD发生的另一个重要诱因, 而在肠道疾病中, 饮食作为最为重要环境因素, 被越来越多的研究者所关注. 饮食与肠道稳态之间的关系非常复杂, 它受到宿主免疫、肠道上皮细胞和肠道菌群之间相互作用的影响. 目前的研究已经证实, 饮食能够直接影响肠道菌群构成, 这可能是诱发IBD的重要原因. 因此, 探讨饮食中营养成分在IBD中的作用, 对于疾病的预防和治疗具有重要意义.
从流行病学结果来看, 膳食纤维、ω-3多不饱和脂肪酸、维生素D和锌是IBD发病的保护因素; 而高糖、高脂肪、高蛋白以及一些食品添加剂则是IBD发生的危险因素. 但是仍有不少研究持有不同的意见, 比如: Matsunaga等[29]认为ω-3脂肪酸会加重小鼠溃疡性结肠炎症状; Spooren等[34]认为大部分研究得出的高蛋白质摄入会增加IBD发生风险的结论并不具备显著性. 因此, 相关的研究有必要在更严格的条件控制下做进一步的探讨. 此外, 未来的研究需要进一步阐明饮食中营养成分、易感基因、肠道菌群以及宿主免疫反应之间的整体联系, 为预防或治疗IBD的饮食精细化管理提供理论依据.
学科分类: 胃肠病学和肝病学
手稿来源地: 湖北省
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科学编辑:张砚梁 制作编辑:张砚梁
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