·综述·
子痫前期(pre-eclampsia,PE)是指妊娠20周后出现以高血压、蛋白尿或母体脏器功能不良的一种特殊疾病,是造成孕产妇和围产儿患病及死亡率升高的主要原因之一[1]。目前,PE发病机制尚未阐明,可能与子宫螺旋动脉重塑障碍、氧化应激、内皮细胞受损及母胎界面免疫失衡等有关[2]。全球范围内PE发病率为2%~8%[3],是孕产妇和胎儿死亡的主要原因之一。
肠道菌群是寄居在人体肠道内微生物群,在肠道内进行着复杂的代谢活动,不仅为其自身提供了生长和繁殖的能量和营养,也产生了大量的代谢产物进入到人体内[4]。在妊娠期间肠道菌群会发生显著变化,并在母体和胎儿健康中发挥重要作用[5]。目前已知的肠道菌群代谢产物有氧化三甲胺(trimethylamine oxide,TMAO)、短链脂肪酸(short-chain fatty acids,SCFAs)、脂多糖(lipopolysaccharides,LPS)和胆汁酸(bile acids,BAs)等。近期研究发现肠道菌群失调与PE发展密切相关,肠道微生物群通过“肠-胎盘轴”参与PE发生及发展[6-7]。肠道菌群失调所导致的代谢产物变化通过免疫耐受、炎症反应、糖脂代谢异常及氧化应激等参与PE发病[8]。本文重点阐述肠道菌群代谢产物在PE中的作用,以期为临床诊疗提供新思路。
氧化三甲胺(TMAO)是一种肠源性菌群代谢产物,由摄入含有膳食磷脂酰胆碱和肉碱的食物在肠道菌群的作用下产生其前体三甲胺(trimethylamine,TMA),后被吸收到门静脉循环中,通过肝脏中的含黄素单加氧酶(flavin monooxygenases,FMOs)氧化产生[9-10]。TMAO可通过多种机制潜在影响PE的发生。研究显示PE患者血浆中存在含量较高的TMAO,其可促使炎症过度激活和血管内皮细胞损伤导致PE[11]。Chen等[12]研究发现TMAO通过抑制SIRT3/SOD2/ROS途径激活核苷酸结合寡聚化结构域样受体蛋白3(nucleotide-binding oligomerization domain-Like Receptor Protein 3,NLRP3)炎症小体从而促进IL-1β分泌。Sun等[13]研究发现TMAO通过TXNIP/NLRP3途径诱导IL-β和IL-8等炎症因子的释放,并抑制一氧化氮产生,促进PE发生。对减少子宫灌注压(reduced uterine perfusion pressure,RUPP)构建的PE大鼠模型研究发现,血浆TMAO可通过下调IL-10促进血管炎症和氧化应激,导致PE大鼠血管内皮损伤[14]。Chang等[15]研究发现TMAO通过NADPH途径可增加滋养 细胞中可溶性酪氨酸激酶-1(solubleFms-like tyrosine kinase-1,sFlt-1)的产生,sFlt-1能够抑制胎盘生长因子和血管内皮生长因子的活性,加速血管内皮损伤,抑制血管新生,进而参与PE的发病。此外还有研究发现重度PE组血浆TMAO明显高于健康对照组和轻度PE组,表明TMAO加速PE的进展[16]。以上研究提示,TMAO可通过调节炎症因子,影响炎症免疫过度激活和血管内皮受损,参与PE的病理生理过程,并加速PE的发生及发展,有望成为预测PE的新型标志物。
短链脂肪酸(SCFAs)是由盲肠和结肠中的厌氧肠道细菌发酵膳食纤维或多糖产生的主要细菌代谢产物,主要包括丁酸盐、乙酸盐和丙酸盐[17]。SCFAs可以维持肠黏膜免疫细胞的活性和肠上皮细胞的完整性,降低结肠的pH值,抑制细菌生长,调节能量代谢,从而在高血压、糖尿病、癌症及免疫代谢疾病中发挥重要作用[18]。研究表明,肠道微生物调控血压的机制之一是通过SCFAs发挥作用。SCFAs可以直接与受体结合,如G蛋白偶联受体(如GPR41、GPR43)和嗅觉受体78(olfr78),进而影响血压,但结合的受体不同对血压的影响也不同[19]。Ye等[20]研究发现SCFAs通过激活雷帕霉素靶蛋白信号通路(mammalian target of rapamycin,mTOR) 促进核因子-κB(NF-κB) 表达,NF-κB可增加促炎细胞因子的产生,进而导致内皮细胞功能损伤,加速 PE 的病理生理过程。Li等[21]研究发现,PE孕妇血清中丙酸盐表达高于正常孕妇,且丙酸盐随着PE病情加重表达增强,可能与丙酸盐与O1fr78受体结合有关。研究还发现,SEFAs可诱导炎症和氧化环境,进一步降低胎盘中过氧化物体增殖物激活受体γ(Peroxisome proliferator-activated receptor γ,PPARγ)的表达,促进PE发生[22]。常艳玲等[23]发现SCFAs与肠道菌群可能在PE的发展中起同步作用。Liu等[24]研究发现SCFAs可下调辅助性T淋巴细胞17(T helper cell 17,Th17)和调节性T淋巴细胞(regulatory T cell,Treg)的表达,继而延缓高血压的进展。Yong等[25]用丁酸盐处理PE大鼠,发现丁酸盐可改善母胎界面免疫失衡,还可调节胎盘血管生成因子和抗血管生成因子的平衡来降低血压及炎症因子水平。以上研究表明,SCFAs可通过多种途径参与PE的发生发展,且还可能通过调节炎症因子,进而减轻PE的进展,但其具体机制仍需进一步深入研究。
脂多糖(LPS)是革兰阴性细菌细胞壁的一种成分,主要由脂质和多糖构成。研究表明,PE动物模型及患者均存在肠道菌群失调,菌群失调会损伤肠道黏膜损伤,LPS入血与Toll样受体(toll-like receptors,TLR)结合促进炎症因子,如白细胞介素 6(interleukin-6,IL-6)、肿瘤坏死因子-α(tumor necrosis factor-α,TNF-α)释放进而诱发炎症反应[26-27]。TLR是模式识别受体之一,在免疫应答中起关键作用,在免疫细胞和非免疫细胞(如胎盘滋养细胞和蜕膜细胞)中表达。Xue等[28]研究发现LPS通过激活滋养细胞转录因子激活蛋白1(activator protein 1,AP-1)下调基质金属蛋白酶-2(matrix metalloproteinase-2,MMP-2)的表达,抑制滋养细胞的侵袭与迁移,从而促进PE的发展。Tang等[29]在体外实验中发现LPS通过上调lncRNA BC030099 与NF-κB的表达来加速滋养细胞侵袭和迁移。以上研究提示,LPS可引起滋养细胞表达的细胞因子改变,直接或间接参与PE的发病,因此,LPS可以构建出与PE患者病理相似的PE动物模型,为研究PE的发病机制提供了合适的动物模型。
胆汁酸(BAs)是由肝脏细胞产生并由胆管分泌到肠道的两亲性脂质分子,肠道菌群参与其代谢及合成。据报道,BAs作为信号分子,通过激活核受体类法尼醇X受体(farnesoid X receptor,FXR)、维生素 D 受体(vitamin D receptor,VDR)、孕烷 X 受体(pregnane X receptor,PXR)、组成型雄甾烷受体(Constitutive androstane receptor,CAR)以及 G 蛋白偶联受体(G protein-coupled receptors,GPCRs)途径来影响心血管健康[30]。研究发现BAs蓄积可增加促炎细胞因子和趋化因子在胎盘和母体外周器官中的表达,通过激活NF-κB通路导致氧化应激发生,介导PE的发生发展。研究发现[31-32]BAs可上调sFlt-1/PLGF的比值,导致胎盘功能障碍,严重时会造成孕产妇及胎儿死亡。Deng等[33]研究发现母体血清BAs与PE的严重程度呈正相关,还发现与胎儿生长受限风险有关。以上研究表明,BAs在PE的发病过程中扮演了重要角色,但确切的机制仍有待阐明,尤其是BAs是如何加速PE的进展可能成为未来研究PE的新靶点。
综上所述,TMAO、SCFAs、LPS及BAs等不同肠道菌群代谢产物通过介导血管因素、母胎界面免疫失衡及全身炎症反应参与PE的发生及发展,提示肠道菌群代谢产物可成为预测PE的新靶点,也为PE的预防和治疗提供了新视角。随着基因组学、蛋白组学、转录组学及代谢组学研究的开展,肠道菌群与PE的关系将会得到更深入地阐明。然而,目前肠道菌群代谢产物对PE调控的深层机制研究很少,今后需更多的动物、体内外实验及临床研究来进一步探索,为 PE的基础研究和临床治疗提供充分的理论依据。
1 Wang M,Pan W,Xu Y,et al.Microglia-Mediated Neuroinflammation:A Potential Target for the Treatment of Cardiovascular Diseases.J Inflamm Res,2022,15:3083-3094.
2 Cheng K,Cui J,Wang Y.miRNA-141-5p Affects the Levels of Neutrophil Elastase in Preeclampsia by Regulating MAPK1.Matern Fetal Med,2022,4:238-244.
3 Qi J,Wu B,Chen X,et al.Diagnostic biomolecules and combination therapy for pre-eclampsia.Reprod Biol Endocrinol,2022,20:136.
4 Ananthakrishnan AN,Singal AG,Chang L.The Gut Microbiome and Digestive Health-A New Frontier.Clin Gastroenterol Hepatol,2019,17:215-217.
5 Di Simone N,Santamaria Ortiz A,Specchia M,et al.Recent Insights on the Maternal Microbiota:Impact on Pregnancy Outcomes.Front Immunol,2020,11:528202.
6 赵诚,王伽略,赵扬玉.肠道菌群与子痫前期相关性的研究进展.中华围产医学杂志,2018,21:479-482.
7 Chen X,Li P,Liu M,et al.Gut dysbiosis induces the development of pre-eclampsia through bacterial translocation.Gut,2020,69:513-522.
8 Zhao Y,Wang B,Zhao X,et al.Corrigendum:The effect of gut microbiota dysbiosis on patients with preeclampsia.Front Cell Infect Microbiol,2023,13:1138934.
9 Meyer KA.Population studies of TMAO and its precursors may help elucidate mechanisms.Am J Clin Nutr,2020,111:1115-1116.
10 Chang QX,Chen X,Yang M,et al.Trimethylamine N-Oxide increases solublefms-like tyrosine Kinase-1 in human placenta via NADPH oxidase dependent ROS accumulation.Placenta,2021,103:134-140.
11 Wen Y,Peng L,Xu R,et al.Maternal serum trimethylamine-N-oxide is significantly increased in cases with established preeclampsia.Pregnancy Hypertens,2019,15:114-117.
12 Chen ML,Zhu XH,Ran L,et al.Trimethylamine N-OxideInduces Vascular Inflammationby Activatingthe NLRP3 Inflammasome Throughthe SIRT3-SOD2 mtROSSignaling Pathway.J Am Heart Assoc,2017,6:e002238.
13 Sun X,Jiao X,Ma Y,et al.Trimethylamine N-oxide induces inflammation and endothelial dysfunction in human umbilical vein endothelial cells via activating ROS-TXNIP-NLRP3 inflammasome.Biochem Biophys Res Commun,2016,481:63-70.
14 Chen H,Li J,Li N,et al.Increased circulating trimethylamine N-oxide plays a contributory role in the development of endothelial dysfunction and hypertension in the RUPP rat model of preeclampsia.Hypertens Pregnancy,2019,38:96-104.
15 Chang QX,Chen X,Yang M,et al.Trimethylamine N-Oxide increases solublefms-like tyrosine Kinase-1 in human placenta via NADPH oxidase dependent ROS accumulation.Placenta,2021,103:134-140.
16 Huang X,Li Z,Gao Z,et al.Association between risk of preeclampsia and maternal plasma trimethylamine-N-oxide in second trimester and at the time of delivery.BMC Pregnancy Childbirth,2020,20:302.
17 Martin-Gallausiaux C,Marinelli L,Blottière HM,et al.SCFA:mechanisms and functional importance in the gut.Proc Nutr Soc,2021,80:37-49.
18 He J,Zhang P,Shen L,et al.Short-Chain Fatty Acids and Their Association withSignalling Pathways in Inflammation,Glucose and Lipid Metabolism.Int J Mol Sci,2020,21:6356.
19 Hu T,Wu Q,Yao Q,et al.Short-chain fatty acid metabolism and multiple effects on cardiovascular diseases.Ageing Res Rev,2022,81:101706.
20 Ye Z,Wang S,Zhang C,et al.Coordinated Modulation of Energy Metabolism and Inflammation by Branched-Chain Amino Acids and Fatty Acids.Front Endocrinol(Lausanne),2020,11:617.
21 Li J,Wang L,Chen H,et al.The Diagnostic Potential of Gut Microbiota-Derived Short-Chain Fatty Acids in Preeclampsia.Front Pediatr,2022,10:878924.
22 Ganss R.Maternal Metabolism and Vascular Adaptation in Pregnancy:The PPAR Link.Trends Endocrinol Metab,2017,28:73-84.
23 常艳玲.伴随肠道微生物改变的短链脂肪酸促进子痫前期高血压发生的研究.上海交通大学,2020.
24 Liu YJ,Tang B,Wang FC,et al.Parthenolide ameliorates colon inflammation through regulating Treg/Th17 balance in a gut microbiota-dependent manner.Theranostics,2020,10:5225-5241.
25 Yong W,Zhao Y,Jiang X,et al.Sodium butyrate alleviates pre-eclampsia in pregnant rats by improving the gut microbiota and short-chain fatty acid metabolites production.J Appl Microbiol,2022,132:1370-1383.
26 Fitzgerald KA,Kagan JC.Toll-like Receptors and the Control of Immunity.Cell,2020,180:1044-1066.
27 Chen X,Li P,Liu M,et al.Gut dysbiosis induces the development of pre-eclampsia through bacterial translocation.Gut,2020,69:513-522.
28 Xue P,Fan W,Diao Z,et al.Up-regulation of PTEN via LPS/AP-1/NF-κB pathway inhibits trophoblast invasion contributing to preeclampsia.Mol Immunol,2020,118:182-190.
29 Tang R,Xiao G,Jian Y,et al.The Gut Microbiota Dysbiosis in Preeclampsia Contributed to Trophoblast Cell Proliferation,Invasion,and Migration via lncRNA BC030099/NF-κB Pathway.Mediators Inflamm,2022,2022:6367264.
30 Collins SL,Stine JG,Bisanz JE,et al.Bile acids and the gut microbiota:metabolic interactions and impacts on disease.Nat Rev Microbiol,2023,21:236-247.
31 Biberoglu E,Kirbas A,Daglar K,et al.Role of inflammation in intrahepatic cholestasis of pregnancy.J Obstet Gynaecol Res,2016,42:252-257.
32 Frampton GK,Jones J,Rose M,et al.Placental growth factor(alone or in combination with solublefms-like tyrosine kinase 1) as an aid to the assessment of women with suspected pre-eclampsia:systematic review and economic analysis.Health Technol Assess,2016,20:1-160.
33 Deng W,Zhang L,Du Q,et al.The association of serum total bile acid with new-onset hypertension during pregnancy.BMC Pregnancy Childbirth,2022,22:879.