膳食纤维调节肠道菌群的作用机制研究进展

2020-02-22 07:29:26 中国现代医生 2020年36期

李丽娟 师凤华 谭木秀 刘凤鸣

[摘要] 肠道菌群失调与多种系统疾病的发生发展密切相关,研究证明膳食纤维在肠道菌群结构和功能方面具有重要调节作用,有利于维持肠道菌群动态平衡。膳食纤维为肠道菌群提供生长代谢底物,且优化了菌群代谢,肠道菌群通过酵解在小肠中不能被消化吸收的膳食纤维,产生的代谢产物参与机体多种信号调节机制,从而影响宿主生理病理改变。本文将对近段时间关于膳食纤维调节肠道菌群的作用机制进行综述,以期为更有效利用膳食纤维,优化肠道菌群代谢,防治疾病提供更多的参考依据。

[关键词] 膳食纤维;肠道菌群;短链脂肪酸;机制

[中图分类号] R151          [文献标识码] A          [文章编号] 1673-9701(2020)36-0188-05

[Abstract] Intestinal flora imbalance is closely related to the occurrence and development of a variety of systemic diseases. Studies have shown that dietary fiber plays an important regulatory role in the structure and function of intestinal flora, which is conducive to maintaining the dynamic balance of intestinal flora. Dietary fiber provides growth and metabolism substrate for intestinal flora, and optimizes its metabolism. Intestinal flora produces dietary fiber that cannot be digested and absorbed in the small intestine through fermentation, and the metabolites produced participate in various signal regulation mechanisms of the body, thus affecting physiological and pathological changes of the host. This paper will review the mechanism of dietary fiber regulating intestinal flora in recent years to provide more references for more effective use of dietary fiber, optimize intestinal flora metabolism, and provide more references for disease prevention and treatment.

[Key words] Dietary fiber; Intestinal flora; Short-chain fatty acids; Mechanism

冠心病、腦卒中、糖尿病等慢性疾病是影响人群健康的主要因素,虽然药物、手术等治疗手段在不断进步,能在一定程度上延缓疾病发展,但其过程所消耗的人力财力物力是影响人们生活水平、造成经济负担和心理负担的主要原因[1-2],因此,提高人们未病先防的意识,以及寻找治疗疾病经济有效的方法具有深远意义,而从膳食层面干预是一种行之有效的方法[3-4]。膳食纤维作为膳食结构的重要组成部分,被称为“第七类营养素”,有益于健康以及疾病防治,膳食纤维抗内源性酶的特性,需要通过肠道菌群的代谢作用来影响宿主的健康状态,但目前膳食纤维对肠道菌群的作用机制仍未完全明了,通过对两者具体作用机制进行深入研究,可为促进健康、防治疾病特别是慢性疾病提供更多科学有效的方案。

1 膳食纤维调节肠道菌群在疾病中的作用

膳食纤维是具有10个或以上单体单位的碳水化合物聚合物,且不能被内源性酶水解。研究表明,增加膳食纤维的摄入有利于降低患病风险[5-6],辅助药物提高疾病治疗效果[7],还能减轻抑郁症状[8]等。膳食纤维摄入作为一种可改变的干预因素,对身心健康的有利影响,主要依赖于肠道菌群的中介作用。肠道菌群是寄居在肠道内的微生物群,肠道菌群的组成除受宿主遗传基因型的影响外,后天生活方式是影响肠道菌群组成和代谢的主要因素,又以膳食结构影响显著。以肠道菌群为干预靶点,在疾病的治疗方面也取得了积极效果,如改善慢性放射性肠炎患者的肠道症状[9],辅助抗击癌细胞[10],以及在药物治疗疾病中增强药效[11],降低毒副作用和减少不良反应等[12-13]。而越来越多的研究证明了膳食纤维通过调节肠道菌群代谢发挥防治疾病的作用。通过补充膳食纤维可以调节高脂饮食(High-fat diet,HFD)小鼠肠道菌群和脂肪酸代谢,预防肥胖[14];膳食纤维还可通过调节大鼠肠道菌群组成和提高肠道短链脂肪酸(Short-Chain Fatty Acids,SCFAs)含量来减轻肠道炎症[15]。膳食纤维通过调节肠道菌群代谢还有利于预防肺部炎症和哮喘发作[16]、抑制肥胖[17]、提高2型糖尿病(Type 2 Diabetes Mellitus,T2DM)治疗效果[18]、降低血压[19]、改善尿毒症透析患者症状和合并症[20]等。

2 膳食纤维调节肠道菌群的作用机制

2.1 膳食纤维对肠道菌群结构、多样性的影响

肠道中约90%的菌群由硬壁菌属和拟杆菌属构成,且硬壁菌属与拟杆菌属的比值被作为肠道菌群平衡与否的标志。膳食纤维为菌群生长代谢提供底物,有利于肠道菌群多样性和(或)丰度的增加[21],So等[22]荟萃分析发现,膳食纤维干预,特别是涉及果聚糖和低聚半乳糖的干预,增加了双歧杆菌和乳酸杆菌属等肠道益生菌的丰度。Zhai等[14]也发现了同时补充不溶性纤维和可溶性纤维混合物可显著增加肠道菌群的相对丰度和多样性,调节HFD小鼠的脂肪酸代谢,从而预防肥胖。菊粉是一种可溶性膳食纤维,研究发现[23],与正常对照大鼠相比,糖尿病大鼠中硬壁菌的比例升高,拟杆菌的比例降低,而对照组和菊粉处理组大鼠肠道菌群特征相似,此外,乳酸杆菌和产生SCFAs的菌群在菊糖治疗的糖尿病组中显著多于未治疗的糖尿病组,说明菊粉治疗可使糖尿病大鼠肠道菌群结构趋于平衡,且增加肠道益生菌数量。因此,膳食纤维可优化肠道菌群结构,增加菌群多样性,有利于代谢平衡。

2.2 膳食纤维对肠道菌群代谢产物的影响

膳食纤维经肠道菌群酵解后,主要的代谢产物是SCFAs,包括乙酸盐、丙酸盐、丁酸盐等,SCFAs能为宿主肠壁细胞提供能量来源,也可通过门静脉转运至外周循环,作为信号分子,调节宿主体内多种信号机制[24],高膳食纤维饮食对健康的益处,很大程度上与肠道菌群代谢的SCFAs作用机制有关。Lin等[25-26]的研究发现,與正常对照组相比,结直肠癌患者粪便代谢产物中如乙酸盐、丁酸盐、丙酸盐等物质水平降低,而增加膳食纤维摄入提高了肠道菌群的产丁酸盐活性,提供大量丁酸盐,降低结直肠癌风险[27]。因此,通过补充富含膳食纤维的食物,调节SCFAs产量及组分,是改善宿主健康状态的有效途径,特别是增加丁酸盐含量,来改善大鼠的肥胖前事件,包括肝脂肪变性、血清总胆固醇水平升高等[28]。果胶是一种重要的水溶性膳食纤维,存在于水果和蔬菜的细胞壁中,研究发现[29],与单独使用长双歧杆菌BB-46干预相比,长双歧杆菌BB-46和果胶结合干预的大鼠,在增加丁酸盐产生菌方面更有效。而果胶发酵产生的丁酸盐可以抑制载脂蛋白E缺乏小鼠肠道胆固醇吸收以及动脉粥样硬化的进展[30]。肠道菌群的另一种主要代谢产物是三甲胺氮氧化物(Trimethylamine N-oxide,TMAO),循环中TMAO水平升高被认为是多种疾病的危险因素,如癌症[31]、糖尿病[32]、心血管疾病[33]等。虽然TMAO不是直接由膳食纤维经肠道菌群酵解而来,但通过膳食纤维调节肠道菌群和胆碱利用途径,可降低循环TMAO浓度。Li等[34]发现,可溶性膳食纤维通过调节肠道菌群减少了三甲胺代谢,抑制TMAO产生。β-葡聚糖是一种可溶性纤维,添加β-葡聚糖的饮食可降低慢性肾脏疾病患者血清TMAO浓度,且安全有效[35]。TMAO是由胆碱类化合物转化而来,但膳食纤维的调节作用或许比胆碱本身的转化作用更显著,Leal-Witt等[36]在研究中观察到,TMAO水平变化与胆碱摄入量的差异不相关,但与纤维摄入量呈负相关。因此,膳食纤维通过调节肠道菌群多种代谢产物的水平,有利于维持机体动态平衡,防治疾病。

3 SCFAs对细胞信号通路的调节机制

3.1 乙酸盐

乙酸盐也称醋酸盐,是最丰富的SCFAs,乙酸盐可通过影响脂质代谢和葡萄糖稳态在体重控制和胰岛素敏感性中发挥重要调节作用[37]。乙酸盐在调节宿主免疫功能的相关机制也被日益挖掘,炎症小体是免疫稳态的关键组成部分,其失调可导致各种炎症反应,Xu等[38]研究发现,乙酸盐通过与短链脂肪酸受体(G protein-coupled receptor 43,GPR43)结合,降低Ca2+动员,进而促进Nod样受体蛋白3(Nod-like receptor protein 3,NLRP3)炎症小体泛素化,并最终通过自噬诱导NLRP3降解,从而减轻NLRP3炎症小体相关炎症反应。在体内研究中,乙酸盐可保护小鼠免受NLRP3炎性小体依赖性腹膜炎和脂多糖诱导的内毒素血症的侵害;还降低了促炎性细胞因子和趋化因子的水平,下调肺组织中丝裂原活化蛋白激酶(Mitogen-activated protein kinase,MAPK)磷酸化水平,通过其抗炎和抗氧化活性作用,保护小鼠免受脂多糖诱导的急性肺损伤[39]。肿瘤微环境中,免疫细胞T细胞与肿瘤细胞竞争葡萄糖,使T细胞的代谢受到限制,导致其在癌症期间的低反应性,有利于肿瘤的发展[40]。Qiu等[41]的研究发现,低反应性T细胞可以被乙酸盐表观遗传重塑和激活,提高其产生干扰素-γ(Interferon-γ,IFN-γ)能力,增强抗肿瘤能力。另外,Pandey等[42]发现,乙酸盐干预肿瘤细胞后,可升高细胞存活调节因子以及细胞胞浆细胞色素c的表达,抑制肿瘤细胞的存活。

3.2 丙酸盐

丙酸盐已被证明与肝脂肪变性和糖异生有关[43,44]。腺苷酸活化蛋白激酶(AMP-activated protein kinase,AMPK)是肝糖代谢的主要调节因子,丙酸盐与肝脏GPR43受体结合,通过增加细胞内的Ca2+浓度,诱导钙离子/钙调蛋白依赖性蛋白激酶激酶β(Ca2+/calmodulin-dependent protein kinase kinaseβ,CaMKKβ)依赖性的AMPK激活,下调葡萄糖-6-磷酸酶(Glucose-6-phosphatase,G6Pase)和磷酸烯醇式丙酮酸羧激酶(phosphoenolpyruvate carboxyl kinase,PEPCK)表达,抑制糖异生[45]。丙酸盐还有抑制肥胖的潜力,Wang等[46]研究发现,使用菊粉和丙酸盐处理小鼠后,其空肠和回肠甘油三酯含量降低,脂解基因表达升高,其体外研究证明,丙酸盐通过激活AMPK和赖氨酸特异性组蛋白去甲基化酶1(Lysine specific demethylase 1,LSD1)的磷酸化,升高肠上皮细胞脂肪甘油三酯脂肪酶、激素敏感脂肪酶、溶酶体酸性脂肪酶等脂解基因表达,促进脂肪分解和代谢。丙酸盐也参与癌细胞的信号调控,生存素(Survivin)是一种抗凋亡蛋白,在多种癌症中高表达,Survivin基因敲除通过增加Bcl-2相关细胞死亡因子(Bcl-2 related cell death factor,Bad)和Bcl-2相关X蛋白(Bcl-2 related X protein,Bax)的表达及诱导G2/M期阻滞致细胞凋亡[47],Kim等[48]研究发现,丙酸钠处理后,分别下调和上调Survivin和细胞周期抑制因子p21(cell cycle inhibitor p21,p21)的表达诱导H1299和H1703肺癌细胞G2/M期阻滞和细胞凋亡,抑制肺癌细胞株的生长。

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(收稿日期:2020-06-04)