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肠黏膜屏障在1型糖尿病中的作用研究进展

更新时间:2021-06-23 08:47点击:

摘    要:1型糖尿病(Diabetes mellitus type 1,T1DM)是儿童和青少年常见以胰岛β细胞破坏和胰岛素缺乏为特征的自身免疫性疾病。近期研究表明,肠道菌群失衡和肠黏膜屏障变化与1型糖尿病的发生发展有关,但其确切机制尚不清楚。本文就近年来肠道菌群、肠黏膜屏障在T1DM中的研究作一综述,并探讨孕期治疗、粪菌移植、益生菌、短链脂肪酸治疗维持健康肠黏膜屏障改善T1DM的研究现状,为T1DM的防治提供新的思路与方法。
 
关键词: 1型糖尿病; 肠黏膜屏障;肠道菌群;防治;综述;
 
 
Research progress on the role of intestinal mucosal barrier in type 1 diabetes
SONG Chao-jie
ZHANG Xiao-li
CHEN Huan-huan TANG Cong
Henan University of Chinese Medicine
 
 
Abstract:Type 1 diabetes is a common autoimmune disease in children and adolescents characterized by destruction of islet β-cells and lack of insulin. Recent studies have shown that the imbalance of intestinal flora and changes in the intestinal mucosal barrier are related to the occurrence and development of type 1 diabetes, but the exact mechanism is still unclear. This article reviews rencent studies on intestinal flora and intestinal mucosal barrier in T1DM, and discusses the current research status of treatment during pregnancy, fecal bacteria transplantation, probiotics, and short-chain fatty acid therapy to maintain healthy intestinal mucosal barrier and improve T1DM. Prevention and treatment provide new ideas and methods.
 
Keyword:Diabetes mellitus type 1; intestinal mucosal barrier; intestinal flora; preventive treatment; review;
 
T1DM是一种自身免疫性疾病,好发于儿童和青少年,其发病与遗传和环境因素密切相关。根据全球糖尿病地图(IDF Diabetes Atlas)第9版显示,T1DM发病率呈逐年上升趋势,2019年中国儿童和青少年(0~19岁)T1DM患者近5万,位居世界第四[1]。因此,研究T1DM的发病机制、寻求防治T1DM的有效方法尤为重要。DIABIMMUNE研究表明[2],HLA(人类白细胞抗原)编码位点是T1DM易感性最重要的位点,约70% T1DM患者携带HLA等位基因,各种 HLA 基因型可能会影响新生儿的微生物定植。近年来,肠道菌群失调是认为是引发T1DM的重要环境因素[3,4]。研究表明,肠道菌群失衡可引起肠道通透性增加,使条件致病菌及内毒素易位至胰腺淋巴结,进而引发T1DM[5,6]。调控肠道菌群、改善肠黏膜屏障可显著改善T1DM[7,8,9,10]。
 
1 肠黏膜屏障
肠黏膜屏障主要由免疫屏障、机械屏障、化学屏障、微生物屏障四部分组成,这些功能分别有相应的结构基础,以上任何一方面损害均可能造成细菌、内毒素移位,引发肠道炎症。
 
1.1 肠黏膜免疫屏障
肠道是人体最大的免疫器官,约占外周免疫细胞的70%。肠粘膜免疫屏障包括肠相关淋巴组织(gut-associated lymphoid tissue, GALT)和弥散淋巴细胞。肠相关淋巴组织主要指分布于肠道集合淋巴小结,是免疫应答的诱导和活化部位。弥散淋巴细胞是肠黏膜免疫的效应部位。肠道免疫系统的效应部分包括树突状细胞(DC)、M细胞、肠巨噬细胞、黏膜层淋巴细胞(LPL)、肠上皮内淋巴细胞和分泌IgA的浆细胞。其中分泌性IgA是胃肠道和黏膜表面的主要免疫效应分子,对肠黏膜免疫其起重要作用,是防御致病菌在肠黏膜粘附和定植的第一道防线。
 
1.2 肠黏膜机械屏障
肠黏膜机械屏障作为第一道屏障能防止肠道毒性物质进入全身循环,由肠上皮细胞、上皮细胞间紧密连接及覆盖在上皮细胞表面的粘液层共同构成。肠上皮细胞由五种不同的细胞组成:吸收细胞、产生黏液的杯状细胞、分泌激素的肠内分泌细胞、呈递抗原的潘氏细胞和M细胞组成。潘氏细胞位于肠道隐窝基底部,分泌抗菌素(如防御素和cathelicidins抗菌肽)。细胞间紧密连主要由紧密连接蛋白组成,包括咬合蛋白(occludin)、闭合蛋白(Claudin)、带状闭合蛋白(Zonula occludens,ZO)家族,连接黏附因子等。
 
1.3 肠黏膜化学屏障
肠黏膜化学屏障由胃肠道分泌的胃酸、胆汁、黏液、各种酶、黏多糖等化学物质组成。肠黏液与浆细胞分泌的IgA相结合,用于肠道细菌的免疫选择[11],并且抑制病原微生物定植到肠上皮[12]。脂肪酸合酶(FAS)是一种由杯状细胞分泌的调节黏蛋白2的合成酶,在保护肠上皮细胞中发挥重要作用。
 
1.4 肠黏膜微生物屏障
人体肠道内微生物种类有500~1000种,数量约1013~1014个,其中以革兰氏阴性菌为主的拟杆菌门和以革兰氏阳性菌为主的厚壁菌门为优势菌群[13]。肠道菌群按功能功能可分为三类:益生菌、致病菌和条件性致病菌。正常菌群在人体肠道内黏附、定植和繁殖,形成一层“菌膜屏障”,抵抗并排斥病原菌的定植、入侵,以维护机体内环境稳定。若肠道菌群失衡,可引发机体免疫失调、代谢紊乱及炎症性疾病等。
 
2 肠黏膜屏障参与T1DM的可能作用机制
研究表明[14]肠道菌群失调,尤其是肠道中革兰阴性菌增加,其细胞壁结构中的脂多糖 (LPS) 释放,产生大量内毒素,破坏肠道黏膜,造成肠壁渗漏,并可吸收入血,进一步刺激免疫细胞分泌炎症因子如肿瘤坏死因子α(TNF-α)、白细胞介素17 (IL-17) 等。Sofi等[15]研究表明T1DM患者血浆中LPS表达升高,其原因可能是T1DM患者肠道通透性增加,LPS通过受损的肠黏膜屏障入血所致。目前广泛认为T1DM患者肠道免疫屏障、机械屏障、化学屏障、微生物屏障功能受损与肠道菌群失衡密切相关,但其确切机制未明。
 
肠黏膜屏障完整性不仅对胃肠道健康发挥作用,而且对其他组织器官的正常功能也至关重要[16]。研究发现[5,6]NOD小鼠及STZ诱导的T1DM小鼠胰腺淋巴结中发现易位的肠道细菌,其可能作用机制为肠黏膜屏障功能受损促进细菌由肠道向胰腺淋巴结转移。此外,这些易位的细菌激活了位于胰腺淋巴结内的CD11b+髓细胞内的NLR家族成员核苷酸结合寡聚化结构域2(NOD2)受体,从而促进致病性T辅助细胞1(T-helper type 1,Th1)和T辅助细胞17(T-helper type 17,Th17)的分化,参与T1DM发病过程[6]。
 
3 T1DM患者及动物模型中肠黏膜屏障的改变
3.1 T1DM中肠黏膜免疫屏障改变
Miranda 等[5]研究发现4~6周龄非肥胖糖尿病(NOD)小鼠结肠IgA水平下降,明显出现肠黏膜屏障功能缺陷。研究发现[17]缺乏TLR接头分子髓样分化因子88(MyD88-/-)的非肥胖糖尿病(nonobese diabetic,NOD)小鼠在无特定病原体(specific pathogen-free,SPF)环境下,可免于糖尿病侵袭。Macpherson等[18]将MyD88-/-NOD小鼠的肠道菌群移植给NOD小鼠,可触发肠道调节性免疫反应,并增加IgA和TGF-β表达,改善肠黏膜屏障功能障碍保护NOD小鼠免于T1DM发生。
 
3.2 T1DM中肠黏膜机械屏障改变
通过乳果糖-甘露糖渗透实验测定肠道渗透性,Bosi 等发现T1DM患者的肠道渗透性均大于正常人群[19]。动物模型以及临床试验进一步得知,T1DM个体肠道中紧密连接蛋白 Zo-1、Claudin、Occuludin 等含量有不同程度的下降,肠绒毛长度、黏液厚度及隐窝深度也有不同程度的下降[13,20]。McGuckin等[21]发现T1DM患者潘氏细胞数量正常,但其杀菌活性降低,这表明T1DM与潘氏细胞活性降低有关,而非细胞数量变化。易患糖尿病生物繁殖型糖尿病(DP-BB)大鼠是一种自发性发展为T1DM的模型,Visser等[22]研究发现DP-BB大鼠结肠中Claudin-1、Claudin-2、Occludin水平降低,且肠道通透性增高。
 
3.3 T1DM中肠黏膜化学屏障改变
Wei等[23]研究表明FAS水平降低与STZ诱导的T1DM小鼠黏液厚度减少及肠道炎症有关。Miranda等[5]研究发现与非肥胖糖尿病抗性(NOR)小鼠相比,非肥胖糖尿病(NOD)小鼠肠黏液分泌减少,分泌型IgA水平降低,这些肠道改变大多发生在T1DM发作之前。
 
3.4 T1DM中肠黏膜微生物屏障改变
大量研究表明,T1DM 患者和动物模型中存在肠道菌群失调,主要表现在结构和功能上,如菌群多样性下降、拟杆菌门/厚壁菌门比升高、乳杆菌属和双歧杆菌属数量减少、产丁酸盐的细菌如 Roseburia faecis和 Faecalibacterium prausnitzii显著减少等[10,24,25]。表1总结了涉及T1DM患者及动物模型中肠道菌群变化的研究。
 
表1 T1DM患者肠道菌群变化
 
4保护肠黏膜屏障改善T1DM
4.1 孕期治疗改善后代肠道菌群
Needell等[7]在孕前T1DM大鼠饮用水中加入SCFAs(甲酸、丙酸、丁酸)补充剂,发现子代大鼠肠道菌群中双歧杆菌、梭状芽胞杆菌丰度降低,推测SCFAs通过调节肠道菌群进而减轻胰岛炎症、降低T1DM发生率。相反,从断奶开始服用SCFAs饮水的大鼠不能避免T1DM的发生。孕期和哺乳期给与雌性NOD小鼠无麸质饮食,可明显降低其后代T1DM发病率,后代肠道菌群丰度增加,尤其是Akkermansia菌和Proteobacteria菌,此外,与普通饮食比,无麸质饮食小鼠后代肠道Treg细胞数增加,而胰腺CD11b+树突细胞减少[35]。以上研究表明孕前或哺乳期给与T1DM孕鼠特殊饮食可通过改变子代肠道菌群组成减缓T1DM发生。
 
4.2 菌群移植改善T1DM
粪便微生物菌群移植(Fecal microbiota transplantation ,FMT)是有效治疗T1DM的方法,粪菌移植已用于多种疾病的防治,如克罗恩病[36],2型糖尿病[3],溃疡性结肠炎[37]。将MyD88缺陷型NOD小鼠粪便菌群移植给野生型NOD小鼠可减少胰岛炎病延缓T1DM发作[34]。乳酸杆菌和梭菌为肠道益生菌,其数量增加可降低T1DM发病率。向NOD小鼠移植Akkermansia muciniphila可延迟T1DM发展,肠黏液和Treg细胞数量增加,血清细菌内毒素水平和胰岛TLR表达降低[38]。Valladares等[39] 从抗糖尿病的大鼠肠道中分离出约翰逊氏乳杆菌N6.2移植给DP-BB大鼠,可减轻T1DM。
 
4.3 补充益生菌改善T1DM
益生菌是一种活的微生物,以单独或多种形式应用时,可维持宿主健康。研究表明益生菌对肠黏膜屏障完整性具有调节作用。益生菌通过多种机制发挥作用,包括抑制病原菌生长,增加黏液产生,改善肠道上皮完整性,调节菌群紊乱和免疫系统等方面。
 
益生菌通过改善胰岛整体功能和肠道-胰腺免疫调节,进而调控T1DM发生发展。2004年至2014年,TEDDY在美国和欧洲对8676名有T1DM遗传风险的婴儿进行了一项前瞻性研究,自婴儿出生27天通过饮食补充剂和/或通过强化婴儿配方食品服用益生菌,其胰岛自身免疫风险降低,可能是益生菌可重塑肠道菌群影响对环境暴露的免疫反应,进而降低T1DM的发病率[40]。每天补充酪酸梭状芽孢杆菌CGMCC0313.1可延缓T1DM发作,这与肠道中Treg细胞向胰腺迁移及肠道、胰腺淋巴结、胰腺中Th1,Th2和Th17细胞水平降低有关[41]。Groele 等[42]给与T1DM儿童补充鼠李糖乳杆菌GG和乳酸双歧杆菌Bb12组成的混合益生菌,可恢复T1DM患儿肠道菌群失衡,调节免疫细胞并保持胰岛细胞的数量和增殖,进而改善T1DM。这些发现表明益生菌在控制T1DM方面有很好的作用。
 
4.4 补充短链脂肪酸改善T1DM
肠道菌群和胰腺之间的相互作用也通过菌群代谢产物短链脂肪酸(SCFAs)发挥作用[43]。用特殊饲料喂养的NOD小鼠可产生大量的SCFAs,保护NOD小鼠免于T1DM发生[44]。与对照组儿童比,患有胰岛自身免疫和T1DM的儿童产SCFAs的细菌丰度下降[45]。研究发现,由胰岛β细胞特异性表达的Cathelicidin抗菌肽(CAMP)与T1DM密切相关[46],并受SCFAs影响[47]。经丁酸盐(SCFAs的一种)干预的NOD小鼠,可通过重塑肠道菌群改善T1DM[48]。且有研究表明,丁酸盐干预8天后,NOD小鼠胰腺淋巴结及脾脏中Treg细胞数增加,胰腺CAMP的表达升高[49],说明肠道菌群及其代谢产物与胰岛在糖尿病保护中的重要作用。十二指肠淋巴结与胰腺淋巴结存在淋巴连接,有学者认为这是内分泌与外周肠源性相交的通道,由于胰腺淋巴结能排出乳糜微粒吸收肠道的抗原,因此肠道菌群改变及肠屏障功能障碍均可能引发T1DM[50]。
 
5展望
T1DM是一种胰岛β细胞被定向破坏导致胰岛素分泌不足的自身免疫性慢性疾病。现有研究认为,肠道菌群作为环境因素更多的参与到T1DM发病过程。最近研究发现,肠屏障功能紊乱与T1DM患者自身免疫增加有关。肠道菌群失衡与T1DM密切相关,表现为肠道菌群丰度及多样性变化,肠道免疫系统过度活化和肠道上皮通透性改变,肠腔内抗原、微生物易位至其他组织器官,包括胰腺和胰腺淋巴结。但是,尚不清楚菌群失衡、肠黏膜屏障受损可能导致T1DM发病的机制。
 
调节肠道菌群是改善T1DM的新方法,致力于改善肠道菌群丰度和多样性的方法仍在不断探索。婴儿在早期生活增加益生菌摄入、将健康供体肠道微生物群移植给有T1DM倾向的个体、给予益生菌补充或修复缺失的细菌是很有前途的T1DM治疗方法。然而,这些治疗方法面临许多挑战,包括在菌群移植过程中某些疾病传播的可能性,在准备过程中益生菌与其他菌污染的可能性。需要继续研究肠道菌群在胰岛自身免疫性疾病发展中的作用,这将有助于提供更好地防治T1DM的新治疗方法。
 
参考文献
[1] International Diabetes Federation.IDF DIABETES ATLAS Ninth edition 2019 [EB/OL] 。[2020-01-19] 。https://www.idf.org/elibrary/epidemi
[2] Peet A, Kool P, llonen J, et al. Birth weight in newborn infants with diferent diabetes. associated HL A genotypes in three neighbouring countries: Finland, Estonia and Russian Karelia[J]. Diabetes Metab Res Rev, 2012, 28(5): 455- 461. Dol: 10. 1002/dmrr.2303
[3] De OliveiraGL v, Leite AZ, Higuchi B s, et al. Intestinal dysbiosis and probiotic applications in autoimmune diseases[J]. Immunology, 2017,152(): 1-12. DOl: 1111/11m.12765
[4] Vatanen T, Franzosa E A, Schwager R, et al. The human gut microbiome in early-onset type 1 diabetes from the TEDDY study[J]. Nature, 2018, 562(7728): 589-594. DOl: 10. 1038/s41586 018-0620-2
[5] Miranda MC G, Oliveira R P, Torres L, et al. Frontine Science: Abnormalities in the gut mucosa of non-obese diabetic mice precede the onsetof type 1 diabetes[J]. J Leukoc Biol, 2019, 106(3): 513-529. DOl: 10.1002/JLB. 3H10119-024RR
[6] CostaF R, Francozo M C, de Oliveira G G, et al. Gut microbiota translocation to the pancreatic lymph nodes triggers NOD2 activation and contributes to T1D onset[J]. J Exp Med, 2016, 213(7): 1223- 1239. Dol: 10. 1084/jem.20150744
[7] Needell JC, Ir D, Robertson c E, et al. Maternal treatment with short-chain fatty acids modulates the intestinal microbiota and immunity and ameliorates type 1 diabetes in the offspring[J]. PLoS One, 2017. 12(9): e0183786. DOI: 10.1371/jourmal.pone 0183786
[8]Wuc, PanL L, Niu w, et al. Modulation of Gut Microbiota by Low MethoxyI Pectin Attenuates Type 1 Diabetes in Non-obese Diabetic Mice[J].Front Immunol, 2019, 10: 1733. Dol: 10 3389/immu 2019.01733
[9] HansenC HF, Larsen C s, Petersson H O, et al. Targeting gut microbiota and barrier function with prebiotics to alleviate autoimmune manifestations in NOD mice[J]. Diabetologia, 2019, 62(9): 1689-1700. DOl: 10.1007/s00125-019-4910-5
[10] Ho J, NicolucciA C, Virtanen H, et al. Effect of Prebiotic on Microbiota, Intestinal Permeabil
, and Glycemic Control in Children With Type 1Diabetes[J.」Clin Endocrinol Metab, 2019, 104(10): 4427-4440. Dol: 10. 1210/jc.2019-00481
[11] ouwerkerk J P, de Vos W M. Belzer C. Glycobiome: bacteria and mucus at the epithelial interfacel[J]. Best Pract Res Clin Gastroenterol, 2013, 27(1): 25-38. DOI: 10. 1210/jC.2019-00481
[12] Cormick s, Tawiah A. Chadee K. Roles and regulation of the mucus barrier in the gut[J. Tissue barriers, 2015, 3(1-2): e982426. DOI: 10.4161/21688370 .2014. 982426
[13] Boerner B P, Sarvetnick N E. Type 1 diabetes. role of intestinal microbiome in humans and micel[I. Ann N Y Acad Sci, 2011, 1243: 103-118.DOI: 111.17496632 2011. 06340.x
[14]章常华,马广强,邓永兵,等.葛根芩连汤对KK-Ay糖尿病小鼠血浆中LPS、TNF-a、 1L-6及 肠道菌群的影响[J].中草药, 2017, 48(8). 1611-1616. D0l:10.7501.issn.0253-2670.2017 .08.020
[15] Sofi M H, JohnsonB M, Gudi R R, et al. Polysaccharide A-Dependent opposing Effects of Mucosal and Systemic Exposures to Human Gut Commensal Bacteroides fragilis in Type 1 Diabetes[J]. Diabetes, 2019, 68(10): 1975-1989. DOl: 10 2337/db19-0211
[16] Knip M. ijander H. The role of the intestinal microbiota in type 1 diabetes mellitus[J]. Nat Rev Endocrinol, 2016, 12(3): 154-167. DOL: 10.1038/nrendo. 2015.218
[17] WenL, Ley R E, Volchkov P Y, et al. Innate immunity and intestinal microbiota in the development of Type 1 diabetes[J]. Nature, 2008, 455(7216): 109-1113. DOl: 10.1038/nature07336
[18] Macpherson A J, Uhr T. Induction of protective lgA by intestinal dendritic cells carrying commensal bacteria[]. Science (New York, NY), 2004, 303(5664): 1662- 1665. Dol: 10. 1038/nature07336
[19] Bosi E, Molteni L, Radaeli M G, et al. Increased intestinal permeability precedes clinical onset of type 1 diabetes [凹. Diabetologia, 2006, 49(12): 2824-2827. DOI: 10. 1007/s00125-006-0465-3
[20] Tanca A. Palomba A, Fraumene c, et al. Clostridial Butyrate Biosynthesis Enzymes Are significantly Depleted in the Gut Microbiota of Nonobese Diabetic Mice[J]. mSphere, 2018, 3(5). DOI: 10.1128/mSphere .00492-18
[21] McGuckin M A. Linden s K, Sutton P, et al. Mucin dynamics and enteric pathogens[J]. Nat. Rev. Microbiol, 2011, 9(4): 265-278. DOI: 10.1038/nmicro2538
[22] visser Jτ, Lammers K, Hoogendijk A, et al. Restoration of impaired intestinal barrier function by the hydrolysed casein diet contributes to theprevention of type 1 diabetes in the diabetes- prone BioBreeding rat[J]. Diabetologia, 2010, 53(12): 2621-2628. DOI: 10. 1007/s00125-010-1903-9
[23] Weix, YangZ, ReyF E, et al. Fatty acid synthase modulates intestinal barrier function through palmitoylation of mucin 2[J]. Cell Host Microbe, 2012, 11(2): 140-152. DO!: 10.1016/. chom.2011.12 006
[24] Patterson E, Marques T M, O'Sullivan O, et al. Streptozotocin-induced type -1-diabetes disease onset in Sprague- Dawley rats is associated with an altered gut microbiota composition and decreased diversity[J]. Microbiology, 2015, 161(Pt 1): 182-193. DOI: 10.1099/mic 0.082610-0
[25]朱华,郭亚茜,杜晓鹏,等.链脲佐菌素诱导糖尿病大鼠模型肠道菌群变化[J].中国实验动物学报, 2018, 26(3): 349-356. DOI: 10.3969/j. ssn.1005-484
[26] Biassoni R, Di Marco E, Squllario M, et al. Gut Microbiota in T1DM-Onset Pediatric Patients: Machine-Learning Algorithms to Classify Microorganisms as Disease Linked[J]. J Clin Endocrinol Metab, 2020, 105(9). DOl: 10.1210/clinem/dgaa407
[27] Demirci M, Bahar Tokman H, Taner z, et al. Bacteroidetes and Firmicutes levels in gut microbiota and effects of hosts TLR2/TLR4 gene expression levels in adult type 1 diabetes patients in Istanbul, Turkey[J]. J Diabetes Complications, 2020, 34(2): 107449. DOI: 10.1016/j.jdiacomp 2019. 107449
[28] Murri M, Leiva 1, Gomez- Zumaquero J M, et al. Gut microbiota in children with type 1 diabetes differs from that in healthy children: a case-control study[J]. BMC Med, 2013, 11: 46. DOl: 10.1186/1741-7015-11-46
[29] Soyucen E, Gulcan A. Aktuglu-Zeybek AC, et al. Differences in the gut microbiota of healthy children and those with type 1 diabetes[J]. Pediatr Int, 2014. 56(3): 336 -343. DOl: 1111/ped0 12243
[30] Pinto E, Anselmo M, Calha M, et al. The intestinal proteome of diabetic and control children is enriched with diferent microbial and host proteins[J]. Microbiology, 2017, 163(2): 161-174. DOl: 10.1099/mic 0.000412
[31] De Goffau M C. Luopajarvi K, Knip M, et al. Fecal microbiota composition difters between children with β-cell autoimmunity and those without
[1. Diabetes. 2013. 62(4): 1238-1244. DO: 10. 23371db12 -0526
[32] Qic J, Zhang Q, Yu M, et al. Imbalance of Fecal Microbiota at Newly Diagnosed Type 1 Diabetes in Chinese Children[J]. Chin Med J (Eng),2016, 129(11): 1298-1304. DOl: 10.4103/0366 6999.182841
[33] HuangY, Lis C, Hu J, et al. Gut microbiota profling in Han Chinese with type 1 diabetes[J]. Diabetes Res Clin Pract, 2018, 141: 256-263. Dol: 10.1016/] diabres 2018.04 032
[34] Ma Q, LiY, Wang J, et al. Investigation of gut microbiome changes in type 1 diabetic mellitus rats based on high-throughput sequencing[J]. Biomed Pharmacother, 2020, 124: 109873. DOI: 10.1016/j.biopha .2020.109873
[35] Hansen C H, Krych L, Buschard K, et al. A matermal gluten-free diet reduces inflammation and diabetes incidence in the offspring of NOD micel[J. Diabetes. 2014. 63(8): 2821-2832. DO: 10.2337/db13-1612
[36] Gutin L, Piceno Y, Fadrosh D, et al. Fecal microbiota transplant for Crohn disease: A study evaluating safety, fficacy, and microbiome profile
[J] United European GastroenterolJ, 2019, 7(6): 807-814. DOl: 10.117712050640619845986
[37] Chibbar. Dieleman. The Gut Microbiota in Celiac Disease and probiotics[J]. Nutients, 2019, 11(10):2375. DOl: 10. 390/11102375
[38] ZhugeA, LiB,Yuan Y,et al. Lactobailus salivarius L101 encapsulated in alginate- pectin microgels ameliorates D-galactosamine-inducedacute liver injury in rats[J]. Appl Microbiol Biotechnol, 2020, 104(3). DOl: 10. 1007/s00253-020-10749-Y
[39] Valladares R, Sankar D, Li N, et al. Lactobacillus jonsonii N6. 2 mitigates the development of type 1 diabetes in BB-DP rats[J]. PLoS One, 2010. 5(5): e10507. DOI: 10. 1371/joumnal pone, 0010507
[40] Uusitalo U, Liu x, Yang J, et al. Association of Early Exposure of Probiotics and Islet Autoimmunity in the TEDDY Study[J]. JAMA Pediatr, 2016, 170(1): 20-28. DOI: 10. 1001/jamapediatrics .2015.2757
[41] JiaL, ShanK, PanL L, et al. Clostridium butyricum CGMCC0313.1 Protects against Autoimmune Diabetes by Modulating Intestinal ImmuneHomeostasis and Inducing Pancreatic Regulatory T Csl[J Front Immunol, 2017, 8: 1345. DOl: 10 39/immu 2017.01345
[42] Groele L, szajewska H, szypowska A. Effects of L actobacillus rhamnosus GG and Bifidobacterum lactis Bb12 on beta-cell function in children with newly diagnosed type 1 diabetes: protocol of a randomised controlled trial[J]. BMJ Open, 2017. 7(10): e017178. DOl: 10.1136/bmjopen-2017-017178
[43] Brugman s, Klatter F A, Visser J T, et al. Antibiotic treatment partially protects against type 1 diabetes in the Bio- Breeding diabetes-prone rat Is the gut flora involved in the development of type 1 diabetes?[J]. Diabetologia, 2006, 49(9); 2105-2108. Do: 10 1007/s00125 006-0334-0
[44] Pearson JA, Tai N, Ekanayake Alper D K, et al. Norovirus Changes suscepibility to Type 1 Diabetes by Altering Intestinal Microbiota and Immune Cell Functins[J]. Front Immunol, 2019, 10: 2654. DOl: 10.3389/immu 2019.02654
[45] Machate D J, Figueiredo P s. Fatty Acid Diets: Regulation of Gut Microbiota Compostion and Obesity and Its Related Metabolic Dysbiosis
[J].2020. 21<11): 4093. Dol: 10. 390/jm521114093
[46] Roy R, Nguyen-Ngo C. Lappas M. Short-chain fatty acids as novel therapeutcs for gestational diabetes[J]. J Mol Endocrinol, 2020, 65(2): 21-34. DO: 10.1530/JME 20-0094
[47] ZhouC,LiL,LiT, et al. SCFAS induce autophagy in intestinal epithelial clls and relieve coltis by stabilizing HIF- 1a[J]. Journal of Molecular Medicine, 2020, 98(501- 523). pol: 10 1007/s00109 020-01947-2
[48] Mario E, Richards J L, McLeod K H, et al. Gut microbial metabolites limit the frequency of autoimmune T cells and protect against type 1 diabetes[J]. 2017, 18(5): 552-562. DOl: 10 1038/i.3713
[49] Healey G, Murphy R. Butts C. et al. Habitual dietary fibre intake influences gut microbiota response to an nuintype fructan prebiotic: a randomised. doubdouble- blind, placebo. contolleda, cross over, human intevention study[J]. Br J Nutr, 2018. 119(2): 176- 189. DOl: 10.1700071145170
[50] Chen K, Chen H, Faas M M, et al. Specific inulin-type fructan fibers protect against autoimmune diabetes by modulating gut immunity, barrierfunction, and microbiota homeostasis[J]. Mol Nutr Food Res, 2017, 61(8)- DOl: 10.1002/mfr. 201601006
 
 

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