Research Progress of Akkermansia Muciniphila and Obesity-related Metabolic Diseases
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摘要: 肠道微生物群在调节宿主免疫和能量代谢等方面起着至关重要的作用，与肥胖、糖尿病以及心血管疾病等疾病的发生有关。目前，多种动物模型和人体研究证明，嗜黏蛋白阿克曼菌（Akkermansia muciniphila/A. muciniphila）水平与肥胖、糖尿病、肥胖性肝病、动脉粥样硬化等代谢性疾病的发生呈负相关。A. muciniphila通过增加肠道黏液层厚度、减轻全身炎症、改善糖耐量和胰岛素抵抗，在治疗代谢紊乱方面具有广阔前景，被认为是新一代的治疗药物。就A. muciniphila与代谢性疾病及宿主之间相互作用的基本机制作系统性综述。Abstract: The intestinal microbiota plays a vital role in regulating host immunity and energy metabolism, and is related to the occurrence of obesity, diabetes, and cardiovascular diseases. At present, various animal models and human studies have proved that Akkermansia muciniphila （Akkermansia muciniphila/A. muciniphila） levels are negatively correlated with the occurrence of metabolic diseases such as obesity, diabetes, obese liver disease, and atherosclerosis. A. muciniphila has broad prospects in the treatment of metabolic disorders by increasing the thickness of the intestinal mucus layer, reducing systemic inflammation, improving glucose tolerance and insulin resistance, and is considered to be a new generation of therapeutic drugs. This article systematically reviews the basic mechanism of the interaction between A. muciniphila and metabolic diseases and hosts.
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Key words:
- Akkermansia muciniphila /
- Intestinal barrier /
- Systemic inflammation /
- Insulin resistance
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妊娠期间由于其特殊的代谢状态，孕妇存在不同程度的胰岛素抵抗，多数妊娠期糖尿病（gestational diabetes mellitus，GDM）孕妇处于前期糖尿病状态或存在慢性胰岛素抵抗，随妊娠进展，获得性胰岛素抵抗加重，而孕前肥胖、孕期过度增重、孕期高胆固醇血症均是引起GDM胰岛素抵抗的高危因素[1]。孕期脂肪的堆积伴随着大量脂肪因子的分泌，更加剧脂代谢紊乱，尤其网膜脂肪组织的增加对孕期胰岛素抵抗的影响尤为显著[2]，加剧胰岛素抵抗。
Chemerin为视黄酸受体反应蛋白2，是一种新型的14 kDa趋化剂蛋白，是一种前趋化素。这种非活性前体通过凝血和炎性丝氨酸蛋白酶[3]转化为活性分子。Chemerin及其受体几乎只在白色脂肪组织[4]中表达和合成。具有广泛生物活性的Chemerin不仅参与脂肪细胞的成熟分化，参与慢性炎症反应、具有旁分泌和内分泌作用影响机体的糖脂代谢、胰岛素抵抗、参与高血压进展[5-6]。孕期血清中Chemerin参与了GDM的高血脂改变，孕前及产前BMI > 28 kg/m2的孕妇血清中Chemerin水平增高更为显著[7]。Chemerin可调节胰岛素的敏感性[8]，为进一步探讨Chemerin与GDM胰岛素抵抗的关系，本文拟从网膜脂肪组织中Chemerin的表达变化与经典胰岛素信号传导通路的关系来探讨Chemerin引起胰岛素抵抗的作用。
1. 资料与方法
1.1 研究对象
选择2013年4月至2014年6月期间在昆明医科大学第一附属医院产科规律产检并分娩的单胎妊娠孕妇，按下列条件分别纳入病例组和对照组。
1.1.1 GDM的普査和管理
具有GDM高危因素的孕妇首诊时（< 12周）即接受75 g口服葡萄糖耐量试验（oral glucose tolerance test，OGTT），若血糖结果正常再于妊娠24～28周复查该试验。对其余不具备高危因素的孕妇于妊娠24～28周直接进行75gOGTT试验。
GDM的诊断参照IADPSG的GDM诊断标准[9]：24～28周时行75 g OGTT试验，服糖前空腹8 h，抽取第1次空腹血后立即口服75 g 葡萄糖，分别于服糖后1 h及2 h分别抽取静脉血测血糖，如有1项或1项以上大于或等于临界值则诊断为GDM（OGTT诊断临界值：0 h 5.1 mmol/L，1 h 10.0 mmol/L，2 h 8.5 mmol/L）。对诊断为GDM的患者按国际标准给予饮食、运动控制，分娩方式均为孕足月因产科指征剖宫产。
1.1.2 对照组的选择
同期选择与每个GDM病例均为首产、分娩孕周接近（±1周）并在同年分娩的NGT孕妇作为本研究的对照组，GDM组30例，NGT组24例。
纳入本研究的病例组和对照组均符合[9]：（1）本次妊娠前无高血压、肾脏、心血管、肝脏或糖尿病等疾病者；（2）未曾服用过可能干扰糖、脂代谢药物者（如消炎痛、酚妥拉明、速尿、噻嗪类利尿剂、苯妥英钠、可的松等）；（3）无内分泌疾病（如甲亢、甲减、柯兴氏综合征）；（4）非吸烟者。本研究经医院医学伦理委员会批准，研究方案符合医学伦理道德规范，研究对象签署知情同意书后纳入研究。
1.2 方法
1.2.1 研究对象
选择2013年4月至2014年6月期间在昆明医科大学第一附属医院产科规律产检并分娩的单胎妊娠孕妇，按下列条件分别纳入病例组24例和对照组22例。
1.2.2 组织标本收集
在剖宫产手术分娩时收集网膜脂肪组织约2 g，分为两部分，无菌PBS液反复洗涤至无血液，转置无菌、无RNA酶的EP管中（内预留1 mL Trizol液，Invitrogen公司）中混匀充分匀浆，一部分不加任何溶液，处理完毕后立即-80 ℃保存。
1.2.3 Western blot
检测大网膜脂肪组织中Chemerin、IRS-1的表达 免疫共沉淀法检测IRS-1酪氨酸磷酸化水平。蛋白质相对表达的计算：Image J 图像分析软件计算目的蛋白灰度值/内参蛋白灰度值即为目的蛋白相对表达量。
1.2.4 qPCR
检测大网膜脂肪组织中Chemerin、IRS-1的mRNA表达 加入 TＲIzol 裂解液的标本充分裂解后在依次用氯仿、异丙醇、75% 酒精依次萃取沉淀洗涤总ＲNA，取 1 μg 总 ＲNA，进行逆转录 （ Thermo，Ｒevert AidTM H Minus First Strand cDNA Synthesis Kit，K1632） 。合成 cDNA 后予以3倍稀释后取1 μL cDNA进行PCＲ。3次重复以消除孔间操作误差。计算各样品相对拷贝值。
1.3 统计学处理
用Spss21.0软件对数据进行统计学处理。正态分布的计量资料以（
$\bar x \pm s $ ）表示，采用独立样本的t检验进行分析；非正态分布的计量资料以中位数表示，采用Mann-Whitney U检验；P < 0.05为差异有统计学意义。Spearman或Pearson相关性分析各指标间关系。2. 结果
2.1 GDM组孕妇及对照组一般临床资料比较
GDM组孕妇在孕前BMI高于NGT组，诊为GDM后给予指导饮食、运动治疗，空腹及餐后2 h血糖控制良好。GDM孕妇产前BMI与NGT组无差异，2组孕妇TG、TC、HDL、LDL、FFA等脂代谢指标差异无统计学意义（P > 0.05），见表1。
表 1 GDM组孕妇与对照组一般临床资料比较Table 1. Comparison of general clinical data between GDM group and control group一般项目 GDM组（n = 30） NGT组（n = 24） t P 年龄（岁） 30.23 ± 4.40 28.77 ± 4.76 1.142 0.259 孕周（d） 266 ± 3.42 266 ± 5.31 −0.125 0.872 孕前BMI（kg/m2） 22.03 ± 4.24 20.64 ± 2.24* −2.068 0.042 产前BMI（kg/m2） 27.62 ± 3.37 26.93 ± 2.76 −1.165 0.253 OGTT0h（mmol/L） 4.90 ± 0.84 4.29 ± 0.50* −4.430 0.000 OGTT2h（mmol/L） 8.37 ± 1.69 6.06 ± 1.05* −8.367 0.000 TC（mmol/L） 5.98 ± 0.93 5.69 ± 0.70 0.588 TG（mmol/L） 3.33（1.78，5.97） 3.70（1.71，11.89） 0.989 HDL（mmol/L） 1.57 ± 0.24 1.70 ± 0.32 0.283 LDL（mmol/L） 3.44 ± 0.82 3.01 ± 1.17 0.428 与GDM组比较，*P < 0.05 2.2 网膜脂肪组织中Chemerin mRNA及蛋白表达
实时定量PCR结果显示GDM孕妇网膜脂肪组织中Chemerin mRNA的表达与正常对照组无统计学差异。Chemerin蛋白质[2.99 （0.04，7.90） vs 2.21（0.02，13.30），P = 0.010]在GDM组的表达有统计学意义，见图1。
图 1 网膜脂肪组织中Chemerin蛋白的相对表达Figure 1. The relative expression of Chemerin in omental adipose tissue2.3 网膜脂肪组织中IRS-1的表达
IRS-1mRNA[5.47（4.00，5.61）vs 3.41（2.17，4.24），P = 0.027]及蛋白[ 2.79（2.06，3.49）vs 1.76（0.23，2.11），P = 0.024]在GDM孕妇大网膜脂肪组织中的表达明有统计学意义，见图2。
图 2 网膜脂肪组织中IRS-1mRNA及蛋白的表达Figure 2. The relative expression of IRS-1 mRNA and protein in omental adipose tissue2.4 网膜脂肪组织中IRS-1酪氨酸磷酸化水平
免疫沉淀发现，GDM患者大网膜脂肪组织中IRS-1酪氨酸磷酸化显著降低[0.60（0.01，1.74） vs 4.06（0.06，54.41），P = 0.012]，2者比较有统计学意义，见图3。
图 3 网膜脂肪组织中IRS-1酪氨酸磷酸化表达Figure 3. The tyrosine phosphorylation of IRS-1 in omental adipose tissue2.5 网膜脂肪组织中Chemerin、IRS-1蛋白表达及IRS-1酪氨酸磷酸化电泳图
WB检测网膜脂肪组织中Chemerin的表达，发现GDM组的相对表达显著增高，IRS-1的表达降低，经免疫共沉淀后发现IRS-1的酪氨酸磷酸化水平低于NGT组，差异有统计学意义，见图4。
图 4 网膜脂肪组织中Chemerin、IRS-1及酪氨酸磷酸化表达1，2列是 GDM；3，4 列 NGT。Figure 4. The relative expression of Chemerin，IRS-1 and tyrosine phosphorylation in omental adipose tissue2.6 网膜脂肪组织中Chemerin的表达与IRS-1及IRS-1酪氨酸磷酸化水平的相关性分析
Spearman或Pearson相关性分析Chemerin与IRS-1及IRS-1酪氨酸磷酸化水平发现，Spearman相关性分析发现Chemerin 蛋白表达与OGTT 2 h血糖（r = 0.453，P = 0.002）密切相关；Chemerin mRNA与产前BMI（r = 0.645，P = 0.000）密切相关；Chemerin蛋白表达与IRS-1蛋白（r = 0.762，P = 0.000）正相关；IRS-1酪氨酸磷酸化水平与OGTT 0 h PG（r = -0.351，P= 0.014）、OGTT 2 h PG（r = -0.313，P = 0.034）密切相关。
3. 讨论
妊娠期间脂肪组织的增加，尤其是腹部内脏脂肪组织的增加严重影响糖脂代谢的平衡[10]。网膜脂肪组织分泌的Chemerin是血清Chemerin的主要来源之一[11]，Chemerin可提高脂肪组织的胰岛素敏感性，改善胰岛素的抵抗[8]。Chemerin与脂肪量的相关性取决于葡萄糖代谢状态[12]及血清胰岛素水平[13]。脂肪的蓄积及脂肪细胞体积的增大可使脂肪细胞Chemerin的合成及分泌增多，Chemerin可促进脂肪细胞的分化成熟及脂代谢，如此反复可引起更高水平Chemerin的表达，肥胖及Chemerin的高表达促进系统性炎症的发生，加剧肥胖及脂代谢紊乱的发生，高TG则可促进脂肪组织分泌更高水平Chemerin[14]。不同剂量Chemerin不同时期 3T3-L1细胞对胰岛素刺激下的葡萄糖的摄取及IRS-1的酪氨酸磷酸化不同[8]，高胰岛素水平可增强脂肪组织中的chemerin的分泌，在体外和动物研究中，趋化素影响胰岛素的传递和葡萄糖降解，导致脂肪细胞和骨骼肌中的胰岛素抵抗[15]。在本研究中发现IRS-1的酪氨酸磷酸化水平降低与空腹血糖及餐后血糖密切相关，餐后血糖的升高与网膜脂肪组织中Chemerin的表达密切相关，GDM孕妇网膜脂肪组织中Chemerin的表达显著高于正常糖耐量孕妇，由此提示GDM网膜脂肪组织中Chemerin的高表达是引起餐后糖耐量异常的原因之一。
肥胖与胰岛素抵抗是血清中Chemerin升高的协同因素[7]，且Chemerin水平与睡眠时间长，红肉和含糖饮料摄入量高及乳制品摄入量低呈线性关系[16]。孕期热量来源低于58%碳水化合物的性摄入对于降低GDM孕妇血糖管控有一定促进作用[17]。因此，妊娠期间合理饮食，积极体重控制不仅可以保持健康的体态，更重要的是降低GDM的胰岛素抵抗状态，改善母儿不良预后。
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