双歧杆菌与肠道疾病及糖尿病的研究进展

摘    要：

肠道菌群失调会对人体能量代谢、免疫调节、消化吸收等生理过程产生负面影响,成为多种疾病的推动力量,研究表明肠道菌群在多种疾病的治疗中发挥着重要作用。双歧杆菌是肠道内的重要细菌,在肠道功能和营养等方面有着重要意义。双歧杆菌保持相对稳定对于发挥肠道正常功能及人体健康是至关重要的。一旦双歧杆菌失调,可能会引发疾病。文章就双歧杆菌与肠道疾病(炎性肠病和肠易激综合征)及糖尿病的关系和研究进展进行综述,为基于肠道菌群调控的上述疾病及其并发症的治疗提供理论依据。

 

关键词：

双歧杆菌 肠易激综合征 炎性肠病 糖尿病 综述

 

Research progress of bifidobacterium and enteropatia and diabetes

Tan Feifei Zhou Zhongyin

Department of Gastroenterology,Renmin Hospital of Wuhan University,Hubei Key Laboratory of Digestive System;

Abstract：

Intestinal flora imbalance will have a negative impact on physiological processes such as energy metabolism, immune regulation, digestion and absorption, and become a driving force for a variety of diseases. Moreover, studies have shown that intestinal flora plays an important role in the treatment of a variety of diseases. Bifidobacterium is an important bacteria in the intestinal tract, which plays an important role in intestinal function and nutrition. Bifidobacterium remains relatively stable, which is crucial for normal intestinal function and human health. Once the bifidobacterium becomes dysregulated, it may cause diseases. This paper reviewed the relationship between bifidobacterium and enteropatia(inflammatory bowel disease and irritable bowel syndrome), diabetes, and its research progress, so as to provide theoretical basis and reference for the treatment of these diseases and their complications based on the regulation of intestinal flora.

 

Keyword：

Bifidobacterium; Inflammatory bowel disease; Irritable bowel syndrome; Diabetes; Review;

 

近年来,肠道菌群对营养相关疾病的影响引起了人们的极大关注。人体肠道中菌群的密度比其他任何器官都高,因此,肠道菌群又被称作肠道内的“微生物器官”,并被认为是调节人体健康的“第二大基因组”。据估计,人体的肠道菌群总共包括1 000多种细菌,共同构成了100万亿个细胞与2 kg肠道的质量,可以认为它是一个重要的与人体共生的生态系统,一旦失调,就可能导致多种疾病的发生及发展[1]。相关基础及临床研究表明,肠道菌群及其代谢物的紊乱会对人体能量代谢、免疫调节、消化吸收等生理过程产生负面影响,成为多种疾病的推动力量,并且研究表明肠道菌群在多种疾病的治疗中发挥着重要作用[2]。肠道菌群主要分为3个门:厚壁菌门、拟杆菌门和放线菌门,双歧杆菌属于放线菌门,且是放线菌门中最主要的一种[3]。双歧杆菌是由法国学者首次分离出的一种革兰阳性厌氧杆菌, 末端常常分叉, 因此称为双歧杆菌。它在特定时期内保持相对稳定,对于发挥肠道正常功能以及人体健康是至关重要的,一旦失调,可能会引发疾病[4]。双歧杆菌是肠道内的重要细菌,目前已经发现并测序出72种双歧杆菌亚种, 其中长双歧杆菌、短双歧杆菌、两歧双歧杆菌、假长双歧杆菌和青春双歧杆菌等已被证明是存在于哺乳动物消化道内的主要双歧杆菌亚种,在肠道功能乃至人体稳态方面发挥着重要作用[5]。现就双歧杆菌与肠道疾病(炎性肠病和肠易激综合征)及糖尿病的关系和研究进展进行综述。

 

1 双歧杆菌与炎性肠病(IBD)

炎性肠病(inflammatory bowel disease,IBD)是一种病因不明的慢性复发性非特异性肠道炎性疾病,以终身治疗和无法治愈为特征,症状包括腹痛、腹泻、直肠出血、体质量减轻、营养不良和发热等,包括两种主要的临床类型:克罗恩病(Crohn disease,CD)和溃疡性结肠炎(ulcerative colitis,UC)[6]。据流行病学调查显示,目前我国IBD的发病率呈逐年上升的趋势[7]。但IBD的病因和发病机制尚未完全明确,疾病的易感基因,如NOD2、ATG16L1和IRGM等都与其发病机制有关[8]。然而,IBD发病率的迅速增加不能仅通过遗传因素来解释,越来越多的证据表明,环境因素通过引起肠道菌群失调从而触发了基因易感宿主的异常免疫应答,从而在IBD的发生中发挥关键作用[9]。肠道菌群移植(FMT)是提取健康人群的肠道菌移植到患者的肠道内,改善患者失调的肠道菌群,重建正常肠道微生态的一种新兴治疗手段[10]。越来越多的研究发现,FMT对IBD有潜在治疗作用,并证明肠道微生态在炎性肠病发生发展中的重要作用[11]。但FMT在IBD的应用仍处在科研阶段,粪便的制备、移植途径、适应证等诸多问题仍未达成共识[12]。

 

1.1 双歧杆菌与UC

UC是一种慢性复发性结肠炎,其病因和发病机制目前尚不明确。然而,大量研究表明,肠道菌群失调、上皮屏障完整性破坏和肠道免疫失调均对其发生及发展起着重要作用[13]。日本研究表明,活动性UC患者双歧杆菌数量减少,补充长双歧杆菌536(BB536)可以缓解症状[14-15];且维持肠道内双歧杆菌菌群稳定对于保持UC缓解非常重要。因此,UC发病与肠道双歧杆菌数量减少相关,且增加肠道中双歧杆菌数量有助于治疗轻中度UC。这将为UC的临床诊断及治疗提供新的思路和方向。

 

1.2 双歧杆菌与CD

CD是一种慢性复发性胃肠道炎性疾病,其发病率在全球范围内呈上升趋势,病程可分为活动期和缓解期,其特征在于活动期反复发作,且伴有腹痛和腹泻症状,病程因个人而异,而且病程的可预测性较差,这会影响临床的诊断和治疗,CD尤其是活动期的CD会对患者的生活质量产生重大影响,尽管确切原因尚不清楚,但目前普遍接受的假设是CD是由遗传易感宿主中针对共生细菌的异常免疫反应产生的[16]。研究发现[17],CD患者总肠道菌群种类减少,其中有益菌数量及种类减少而有害菌增多。双歧杆菌作为肠道内最为常见的有益菌之一,目前有关其与CD的研究[17-21],结果大多相互矛盾,且缺乏临床试验证实CD患者补充双歧杆菌是否有助于病情的缓解或导致病情恶化,故无法确定CD发病与双歧杆菌是否存在相互关系,随着肠道微生物宏基因组学计划及临床研究的开展,相信双歧杆菌与CD的关系将更加明确。

 

2 双歧杆菌与肠易激综合征(IBS)

肠易激综合征(irritable bowel syndrome,IBS)是一种功能性肠道疾病,其特征在于反复发作的腹痛及内脏痛觉的改变,且发作的同时会伴随排便频率和/或大便形式的改变,其发病机制至今尚未完全阐明[22]。IBS 是全球范围内的流行病,在全世界流行率为5%～6%[23]。除严重影响生活质量外, IBS还给社会和家庭造成了沉重的经济压力[24]。研究发现,IBS与双歧杆菌失调之间存在密切联系,2015年Shukla等[25]通过16S rRNA的方法测定了IBS患者的粪便肠道菌群, 发现与正常组相比,IBS患者双歧杆菌数量显著减少;2019年Mazzawi等[26]研究了IBS患者的粪便样本微生物组成, 同样发现IBS患者的双歧杆菌水平显著降低;2019年Liang等[27]Meta分析发现,IBS患者粪便中双歧杆菌的数量显著减少。多年来,大量研究发现双歧杆菌及其相关制剂能够缓解IBS患者疼痛,改善症状, 对于治疗IBS疗效确切且不良反应发生率低[28];富含双歧杆菌的粪便供体可能是IBS患者成功进行FMT的积极预测指标[29]。双歧杆菌类益生菌及制剂在IBS的治疗中具有积极作用, 其发挥作用的机制可能是[4]:(1)通过调节宿主肠道内的细菌, 改善肠道菌群组成和稳定性; (2)通过与肠道上皮细胞结合,抑制病原菌的结合;(3) 通过增加黏蛋白的产生增强肠道上皮的屏障作用, 预防病原菌对上皮组织的损害,降低细胞通透性;(4)通过肠道内容物的发酵, 产生短链脂肪酸, 降低肠道pH, 酸化肠道, 抑制病原菌的生长; (5) IBS患者常常具有免疫紊乱现象, 而双歧杆菌类益生菌能够调节免疫系统;(6) 双歧杆菌类益生菌及制剂还能改善IBS患者的肠道蠕动性, 增强患者的肠道运动。因此, 利用双歧杆菌及其制剂治疗IBS具有较强的可行性, 将给IBS患者的康复带来新的希望。

 

3 双歧杆菌与糖尿病

2017年,第八版国际糖尿病联合会(IDF)糖尿病图谱显示,全球约有4.25亿糖尿病患者[30]。IDF报道,到2045年全世界将有6.3亿人患有糖尿病,糖尿病主要分为3种类型:1型糖尿病(T1DM)、2型糖尿病(T2DM)和妊娠糖尿病(GDM)[31]。我国糖尿病发病率约为10%,糖尿病患者已达1.14亿,占全球糖尿病患者总数的1/3。糖尿病目前不可以被治愈,而其长期的发展会导致严重的并发症(如血管疾病、糖尿病肾病),甚至死亡,这极大的影响了生活质量且给家庭带来了沉重的负担[32-33]。因此,迫切需要研究糖尿病的病理机制和有效防治的方法。近年来,越来越多的研究证明,糖尿病与肠道菌群失调有关,尤其是双歧杆菌的变化有关,双歧杆菌或可成为未来糖尿病治疗的新靶点[34-37]。

 

3.1 双歧杆菌与2型糖尿病(T2DM)

T2DM是世界上最常见的代谢性疾病,占糖尿病的90%[31]。T2DM是一组代谢综合征,表现为胰岛素分泌的绝对或相对不足,靶器官对胰岛素的敏感性下降[33]。虽然目前病因及发病机制未明,但一些研究表明[38-39],双歧杆菌能通过饱食信号、肠道完整性和胰腺细胞的抗氧化作用来调节血糖,葡萄糖代谢受损与产生丁酸盐的细菌水平降低有关(丁酸调节血糖代谢的机制为刺激胰高血糖素样肽、增加餐后胰岛素分泌、调节肠道糖异生和葡萄糖摄取)。多项研究均证实[40-42],T2DM患者肠道内双歧杆菌数量减少,而双歧杆菌是丁酸盐产生最主要的肠道细菌之一,故可以推断T2DM的发生可能与双歧杆菌数量减少密切相关。吴玉文等[43]研究发现,对T2DM患者在常规二甲双胍治疗的基础上,给予达格列净联合双歧杆菌三联活菌胶囊治疗,能够改善糖脂代谢功能,缓解胰岛素抵抗,提高胰岛素敏感性,还能够增加肠道内双歧杆菌的数量;张燕等[44]临床研究显示,对新诊断的T2DM患者,在常规给予胰岛素治疗基础上再给予双歧杆菌三联活菌制剂,不仅能增加患者肠道双歧杆菌的数量,而且能改善胰岛素抵抗,并且有利于血糖和糖化血红蛋白达标。因此有理由认为双歧杆菌与T2DM发病存在密切联系,且增加肠道菌群中双歧杆菌数量对于治疗T2DM有帮助。

 

3.2 双歧杆菌与1型糖尿病(T1DM)

T1DM是除T2DM外最常见的一种糖尿病。T1DM 是一种器官特异性的自身免疫性疾病,因为胰岛β细胞破坏或功能衰竭导致胰岛素分泌不足,是遗传、免疫、环境等多种因素共同作用的结果,但具体机制目前尚不清楚[45]。当前的研究表明[46],肠道菌群和免疫系统之间的相互作用可能是影响T1DM发生发展的主要因素,并且发现肠道菌群的改变会通过一系列反应引起促炎反应并刺激遗传易感人群中的β细胞发生自身免疫导致T1DM的发生。研究发现[47-48], T1DM患者中双歧杆菌数量减少;丁酸盐可能通过对抗胰岛细胞自身抗体起作用,从而对胰岛细胞具有保护作用;增加患者双歧杆菌的数量有助于其血糖的控制。综上,T1DM患者补充双歧杆菌可能有助于其病情的控制,但目前缺乏大样本的临床试验,且关于双歧杆菌与T1DM的相关试验较少,因此未来需要开展相关研究工作来证实该假设的正确性。

 

此外,Kuang等[49]研究发现,GDM患者肠道中双歧杆菌数量减少,故推测双歧杆菌在GDM的发生发展中也存在一定作用。

 

4 小结与展望

虽然目前关于双歧杆菌与IBD、IBS及糖尿病发病的关系尚不十分明确,但双歧杆菌失调在上述疾病的发生发展中起着不可忽视的作用,且给患者补充双歧杆菌有助于其病情的缓解。当然,双歧杆菌的研究不仅仅局限于上述疾病,它还与癌症及多发性硬化症等一些目前无法治愈的疾病及焦虑和抑郁等情绪障碍相关,这为进一步阐明相关疾病的发病机制、病理过程、治疗及预防提供了新的研究思路,同时也为研究双歧杆菌在人体中的作用提供新的方向。相信未来随着科学技术的不断发展,会发现更多疾病的发生及发展与双歧杆菌相关,同时也为更多目前无法根治的疾病的治疗提供新方向。

 

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