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Volume 42 Issue 5
May  2024
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XU Fei, CHEN Jin, LU Yuhan, LI Zhiyong. Research progress on the mechanism of gut microbiota participating in diabetes nephropathy[J]. Journal of Pharmaceutical Practice and Service, 2024, 42(5): 181-184, 197. doi: 10.12206/j.issn.2097-2024.202312023
Citation: XU Fei, CHEN Jin, LU Yuhan, LI Zhiyong. Research progress on the mechanism of gut microbiota participating in diabetes nephropathy[J]. Journal of Pharmaceutical Practice and Service, 2024, 42(5): 181-184, 197. doi: 10.12206/j.issn.2097-2024.202312023

Research progress on the mechanism of gut microbiota participating in diabetes nephropathy

doi: 10.12206/j.issn.2097-2024.202312023
  • Received Date: 2023-12-09
  • Rev Recd Date: 2024-01-17
  • Available Online: 2024-05-22
  • Publish Date: 2024-05-25
  • With the increasing prevalence of diabetes, the prevention and treatment of diabetes nephropathy have become a worldwide problem. The molecular mechanism of the occurrence and development of diabetes nephropathy is still unclear, but many studies in recent years have shown that gut microbiota plays an important role in the progress on diabetes nephropathy. The research progress on the mechanism of gut microbiota participating in diabetes nephropathy was reviewed in this article.
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Research progress on the mechanism of gut microbiota participating in diabetes nephropathy

doi: 10.12206/j.issn.2097-2024.202312023

Abstract: With the increasing prevalence of diabetes, the prevention and treatment of diabetes nephropathy have become a worldwide problem. The molecular mechanism of the occurrence and development of diabetes nephropathy is still unclear, but many studies in recent years have shown that gut microbiota plays an important role in the progress on diabetes nephropathy. The research progress on the mechanism of gut microbiota participating in diabetes nephropathy was reviewed in this article.

XU Fei, CHEN Jin, LU Yuhan, LI Zhiyong. Research progress on the mechanism of gut microbiota participating in diabetes nephropathy[J]. Journal of Pharmaceutical Practice and Service, 2024, 42(5): 181-184, 197. doi: 10.12206/j.issn.2097-2024.202312023
Citation: XU Fei, CHEN Jin, LU Yuhan, LI Zhiyong. Research progress on the mechanism of gut microbiota participating in diabetes nephropathy[J]. Journal of Pharmaceutical Practice and Service, 2024, 42(5): 181-184, 197. doi: 10.12206/j.issn.2097-2024.202312023
  • 据估计,2017 年全球有 4.51 亿(18~99 岁)糖尿病(DM)患者,预计到 2045 年,这一数字将增至 6.93 亿[1]。糖尿病肾病(DKD)是DM的一种严重并发症,是世界范围内终末期肾病(ESRD)的主要病因[2, 3]。DKD的发生率与DM的发病率和病死率增加密切相关[4]。在美国,开始接受ESRD治疗的DM患者数量从2000年的4万多人显著增加到2014年的5万多人[5]。在我国,DKD的发病率在过去10年中显著增加,2013年的一项调查结果显示,中国DKD患者数量估计达到2 430万[6]。当前,DM患病率持续上升,如果DKD的临床预防策略没有改善,预计DKD的患病率也会随之增加[7, 8]。然而目前除了控制血糖、血压等手段外,临床上尚无其他有效预防DKD的方案。DKD的发病机制复杂,其分子机制还没有得到全面阐明。近年来,越来越多的研究发现,肠道菌群在DKD的发生发展中发挥了重要作用,本文围绕DKD的肠道菌群参与情况,综述其研究进展。

    肠道菌群是一个由微生物菌落组成的复杂生态系统,包括至少1 000个不同物种的数万亿细菌,另外还有其他共生生物,如古细菌、病毒、真菌和原生生物。肠道菌群失调的主要特征是细菌和真菌的多样性和丰度下降[9]。近年来,人们对肠道菌群与宿主相互作用产生极大兴趣,众多证据表明,肠道菌群在人类健康和疾病中发挥重要作用,菌群失调已被证明与动脉粥样硬化、高血压、心力衰竭、慢性肾病(CKD)、肥胖和2型糖尿病(T2DM)等疾病有关[10]。肠道菌群有能力产生一系列代谢产物,包括短链脂肪酸(SCFAs)、N-氧化三甲胺(TMAO)、胆汁酸(BA)、蛋白质结合的尿毒症毒素(PBUT)、支链氨基酸(BCAAs)和一些其他未知代谢产物。肠道微生物产生的代谢产物被认为是微生物与宿主之间交流的媒介,对人体的生物活性和代谢有重要影响[11]。近年来,许多研究调查了DM、肥胖和代谢综合征等代谢性疾病患者肠道微生物群的多样性和功能的变化。有研究发现,这些患者的肠道微生物群落发生了显著变化,并导致肠道微生物群失调和肠漏综合征,肠道屏障功能障碍,肠道通透性增加[12]。多种肠道微生物群代谢产物被释放到血液中,如SCFAs、TMAO、脂多糖(LPS)和尿毒症毒素,再通过多种信号通路进一步导致疾病表型的变化[13, 14]

    • DKD是DM患者的主要微血管并发症,尽管DKD发病机制相当复杂,但最近的研究表明,肠道菌群也参与了DKD的进展。一项研究通过16s rDNA测序分析了DKD患者和健康志愿者之间粪便样本,发现与健康志愿者相比,DKD患者肠道细菌丰富度和多样性显著下降,而许多常见病原体在DKD和DM患者中均富集,如拟杆菌门、毛梭菌门、双歧杆菌门、乳杆菌门、罗斯氏菌门和粪杆菌门。其中,巨球菌属、厌氧菌属和嗜血菌属等属在DKD中的丰富度远高于DM中的丰富度。几个特征属,如巨球菌属、韦荣球菌属、埃希氏菌属、志贺氏菌属、厌氧菌属和嗜血杆菌属则可能是DKD新的潜在微生物标志物[15]。有研究发现,中国人和欧洲女性DM患者中的哈氏梭菌增加,而罗斯伯里氏菌减少,研究者推测这与DM的发展有关[16, 17]。另一项研究则把DKD患者与DM患者进行比较,发现与DM患者相比,DKD患者肠道疣微菌门和梭杆菌门的水平显著升高,二者都属于G-菌,而LPS可通过加速巨噬细胞/单核细胞和中性粒细胞的活化而诱发炎症,导致DKD进展[18]。CKD患者常出现肠道菌群失调、细菌代谢产物累积、肠道屏障功能破坏和慢性炎症,大多数CKD患者肠道细菌过度生长,但细菌多样性下降,如梭杆菌属等在ESRD 患者体内显著富集,而产生SCFAs的细菌,尤其是产生丁酸的细菌丰度随着 ESRD 的恶性进展而逐渐下降,SCFAs通常被认为在维持人类健康方面发挥着多种重要作用[19, 20]

      以上研究表明,健康的肾脏通过细胞和分子信号与肠道微生物群沟通,以确保肠道微生物群的正常稳态。肠道菌群的失衡将导致这种平衡被破坏,肠道菌群多样性下降、特定菌群种类变化可能在DKD的发展中发挥重要作用。

    • 肠道的黏液层和上皮结构是肠道屏障最重要的结构,肠道上皮是有正常上皮细胞和几种具有特定功能的细胞组成,包括潘氏细胞、杯状细胞等[21]。潘氏细胞可分泌溶菌酶和防御素等抗菌肽,防止有害细菌定植,杯状细胞通过分泌黏蛋白来维持黏膜层。上皮细胞通过顶端连接复合体连接,该复合体由紧密连接(TJ)和黏附连接组成。TJ由TJ蛋白Claudin、Occludin和连接黏附蛋白分子 A (JAM-A) 以及细胞内斑块蛋白组成[22]。肠道屏障将肠腔中的微生物与内部环境分隔开来,许多微生物系统通过肠壁与内部环境相互作用。DKD患者肠道微生物群组成和功能的改变会导致肠上皮屏障受损和肠道通透性增加[23]。一方面,由于DKD患者肾脏滤过减少,大量尿素水解导致氨重吸收增加,随后肝脏重新合成尿素,导致跨上皮电阻(TER)显著下降,关键TJ蛋白如Claudin-1、Occludin 和ZO-1丢失[24]。另一方面,DKD肠道菌群失调引起相应代谢产物发生变化。肠道菌群代谢会产生多种类型的SCFAs。Nathan等在一项小鼠骨髓移植研究中发现,丁酸盐通过为肠上皮细胞提供能量来维持结肠细胞健康,这可能有助于肠上皮的完整性[25]。Huang等发现,丁酸盐还可能通过改变肠道Claudin-2水平来抑制细胞因子诱导的屏障功能障碍[26]。此外,一些动物研究表明,乙酸盐可直接激活核苷酸结合寡聚物肠上皮细胞中的炎症结构域3(NLRP3)炎症小体,导致IL-18释放,进而通过激活小鼠上皮细胞上的IL-18受体来促进肠屏障的完整性[27]。丙酸盐还可以抑制小鼠结肠组织中 ZO-1、Occludin 和上皮钙黏蛋白(E-cadherin) 下调改善由葡聚糖硫酸钠(DSS)引起的高肠通透性[28]。体外实验中,乙酸盐、丙酸盐和丁酸盐已被证明可以通过改变肠道上皮TJ蛋白的表达促进细胞内通透性,包括体外的 ZO-1[29]。综上所述,SFCAs 被认为是维持肠道屏障的关键因素。

    • BA由肝细胞中的胆固醇在肝脏中合成。初级BA可以通过肠道微生物群转化并分解为次级 BA。肠道微生物群通过初级BA的解结合、脱氢和二羟基化来调节 BA 代谢过程[30]。BA 是G蛋白偶联胆汁酸受体 (TGR5)和核激素受体法尼醇X受体(FXR)的配体。BA与TGR5结合,通过胰高血糖素样肽-1 (GLP-1)提高胰岛素敏感性,并调节肌肉或棕色脂肪组织的能量消耗[31]。FXR的激活会减少脂肪生成和肝脏糖异生,并通过产生抗菌肽来抑制细菌过度生长和易位[32]。Wang等在链脲霉素诱导小鼠糖尿病实验中发现, FXR和TGR5通过调节肾脏信号通路在DM和肥胖相关肾脏疾病中发挥肾脏保护作用[33]。另一项体外实验证明,龙胆苦苷通过 TGR5 激活抑制 NF-κB 信号通路,从而减轻DKD中的炎症和纤维化[34]。熊去氧胆酸(UDCA)是一种继发性BA,已被发现可减轻DKD大鼠肾内质网应激引起的肾功能障碍、足细胞凋亡和氧化应激。给予牛磺酸脱氧胆酸(TUDCA)可以减轻 DM大鼠的肾小球和肾小管损伤,这部分是通过抑制内质网介导的[35]

    • SCFAs 是肠道菌群代谢的主要产物之一,主要包括由拟杆菌门产生的乙酸盐、丙酸盐和厚壁菌门产生的丁酸盐。丁酸盐通过介导miR7a-5p/P311/TGF-β1通路缓解DKD进展, 转化生长因子-β1(TGF-β1)是触发纤维化信号级联的初始因子[36]。丁酸钠(NaB)是一种已知的核因子E2相关因子2(NRF2)激活剂,具有预防DKD的作用。研究发现,未接受NaB治疗的DM小鼠表现出明显的肾脏病理变化,如氧化损伤、炎症、细胞凋亡、纤维化。NaB 通过激活NRF2抑制组蛋白去乙酰化酶(HDAC)活性改善DKD[37]。Gasdermin D (GSDMD)是一种新发现的焦亡关键执行蛋白,可被炎症性半胱氨酸天冬氨酸酶(caspase)裂解。高糖可增加碘化丙啶(PI)阳性细胞水平,促进乳酸脱氢酶(LDH)、IL-1β、IL-18的释放,并伴有caspase-1水平升高。NaB通过NF-κB/IκB-α信号通路的caspase 1-GSDMD 经典焦烧死亡途径改善了高葡萄糖诱导的肾小球内皮细胞焦亡[37-39]。由以上研究可见,丁酸盐在高糖刺激的肾损伤中发挥重要作用,并可能作为有效的治疗靶点。此外,SCFAs改变导致肠上皮TJ的破坏,进而引起肠道通透性增加,肠腔内微生物代谢物及其他有害物质穿过肠道屏障进入体内循环,如甲酚、吲哚分子、LPS等。LPS会持续浸润门静脉,导致代谢性内毒素血症和炎症细胞因子水平升高,从而加速DKD的进展[40]。 LPS 是G-菌的表面抗原,通过 TLR2 和 TLR4 相关途径介导宿主炎症[41]。TLR2和TLR4通过诱导肿瘤坏死因子-α(TNF-α)、IL-1和IL-1β等促炎细胞因子的释放, NF-κB介导的炎症级联反应,参与DKD的持续炎症反应过程[42]

      其他SCFAs在DKD中的作用仍存在争议,在一项微生物移植治疗DM大鼠的研究中发现,乙酸盐可能会加剧 DKD的疾病进展, 如肠道微生物群产生过量的乙酸盐,通过激活G蛋白偶联受体43(GPR43)破坏胆固醇稳态,导致肾脏出现肾小管间质损伤[43]。另一项动物研究发现,肠道微生物群失调可能与早期DKD肾内肾素-血管紧张素系统(RAS)激活有关,血浆醋酸盐水平与肾内血管紧张素Ⅱ蛋白表达呈正相关,推测醋酸盐也可能参与早期DKD的肾损伤[44]

    • TMAO主要来源于肠道菌群氧化三甲胺(TMA)。肠道微生物从摄入的卵磷脂和胆碱等营养物质中代谢并产生TMA,这些营养物质通过门静脉循环进入肝脏,并被黄素单加氧酶3或其他黄素单加氧酶氧化,产生TMAO。TMAO水平升高与CKD患者死亡风险增加相关[45]。TMAO及其前体胆碱水平的增加与信号转导蛋白SMAD3和TGF-β信号的磷酸化增强有关,从而加重高脂饮食(HFD)喂养小鼠的肾胶原沉积和肾小管间质纤维化。饮食诱导的肥胖小鼠模型中,TMAO水平升高还与NADPH氧化酶和炎症细胞因子的升高有关,而补充 TMA 形成抑制剂可改善 HFD 诱导的肾损伤纤维化并降低小鼠肾损伤分子-1(KIM-1)和促炎细胞因子的表达[46]。这些研究表明,高水平的TMAO可能是CKD进展的致病介质。近年来,研究发现TMAO在DKD发展中也发挥重要作用。TMAO可激活DKD患者的NF-κB通路,进一步加重体内微炎症,导致DKD恶化[47]。与无肾脏疾病的 T2DM 患者以及健康个体相比,DKD患者表现出更高浓度的TMAO,这与尿白蛋白肌酐比值(UACR) 呈正相关[48]。在一项动物研究中,喂食TMAO的DKD大鼠表现出更严重的肾功能衰退和肾纤维化,该研究证明TMAO可以通过激活NLRP3炎症小体并最终导致IL-1β和IL-18的释放来加速肾脏炎症[49]

      由此可见,肠道微生物群衍生的代谢物,是肠道菌群影响DKD进展的重要参与者,肠道微生物及其代谢物与肾脏之间存在相互作用,称为肠肾轴。

    • 肠道微生物群与肾脏疾病相关,已有众多研究证实了肠肾轴的存在。肠道微生物群通过产生无数代谢物来参与宿主体内平衡,这些代谢物充当代谢反应的关键信号分子和底物。基于肠道微生物群的治疗可能是未来预防和治疗DKD的一种有前景的策略。饮食结构的改变有助于改善肠道菌群失调,肠道菌群移植也有望在安全、规范的条件下发挥恢复DKD微生物群生态的作用,宏基因组学和代谢组学的结合有助于研究肠道菌群失调与代谢紊乱之间的关系[49]。然而,目前大部分数据仅限于动物模型,需要更可靠的临床试验来阐明DKD发病机制的关键途径和特定菌株。

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