Response of gut microbiota to serum metabolome changes in intrahepatic cholestasis of pregnant patients

BACKGROUNDIntrahepatic cholestasis in pregnancy (ICP) is the most common liver disease during pregnancy, and its exact etiology and course of progression are still poorly understood.AIMTo investigate the link between the gut microbiota and serum metabolome in ICP patients.METHODSIn this study, a total of 30 patients were recruited, including 15 patients with ICP (disease group) and 15 healthy pregnant patients (healthy group). The serum nontarget metabolomes from both groups were determined. Amplification of the 16S rRNA V3-V4 region was performed using fecal samples from the disease and healthy groups. By comparing the differences in the microbiota and metabolite compositions between the two groups, the relationship between the gut microbiota and serum metabolites was also investigated.RESULTSThe Kyoto Encyclopedia of Genes and Genomes analysis results showed that the primary bile acid biosynthesis, bile secretion and taurine and hypotaurine metabolism pathways were enriched in the ICP patients compared with the healthy controls. In addition, some pathways related to protein metabolism were also enriched in the ICP patients. The principal coordination analysis results showed that there was a distinct difference in the gut microbiota composition (beta diversity) between the ICP patients and healthy controls. At the phylum level, we observed that the relative abundance of Firmicutes was higher in the healthy group, while Bacteroidetes were enriched in the disease group. At the genus level, most of the bacteria depleted in ICP are able to produce short-chain fatty acids (e.g., Faecalibacterium, Blautia and Eubacterium hallii), while the bacteria enriched in ICP are associated with bile acid metabolism (e.g., Parabacteroides and Bilophila). Our results also showed that specific genera were associated with the serum metabolome.CONCLUSIONOur study showed that the serum metabolome was altered in ICP patients compared to healthy controls, with significant differences in the bile, taurine and hypotaurine metabolite pathways. Alterations in the metabolization of these pathways may lead to disturbances in the gut microbiota, which may further affect the course of progression of ICP.     

垂盆草苷对幼龄肝内胆汁淤积大鼠的作用机制

研究垂盆草苷(sarmentosin,SA)对幼龄肝内胆汁淤积大鼠的干预和调节作用。将48只SD幼龄大鼠随机分为正常组(Control)、α-萘异硫氰酸酯(ANIT)组(Model)、熊去氧胆酸(UDCA)阳性对照组、垂盆草苷低、中、高剂量组,每组8只,除正常组外,各组大鼠连续1周分别灌胃给予相应药物,每日1次。在第5 d灌胃给予80 mg/kg ANIT造模。在造模后48 h测定大鼠的胆汁流量;测定大鼠血清中丙氨酸转氨酶(ALT)、天冬氨酸转氨酶(AST)、碱性磷酸酶(ALP)的活性和总胆红素(TBIL)、直接胆红素(DBIL)、总胆汁酸(TBA)的含量;检测肝脏组织病理变化和组织匀浆中丙二醛(MDA)、超氧化物歧化酶(SOD)、谷胱甘肽过氧化物酶(GSH-Px)的含量;测定血清中肿瘤坏死因子(TNF-α)、γ-干扰素(INF-γ)、白细胞介素1β(IL-1β)的表达;Western blot法分析胆汁酸转运蛋白与合成蛋白。与正常组相比,模型组胆汁流量受到明显的抑制;大鼠肝组织出现明显的病理损伤;血清中ALT、AST、ALP、TBIL、DBIL、TBA水平显著升高;组织匀浆中MDA含量显著升高,SOD和GSH-Px含量显著降低;炎症因子TNF-α、IFN-γ、IL-1β的表达升高(P<0.05,P<0.01);FXR、SHP-1、SHP-2、MREP2、BSEP、NTCP蛋白表达下降,CYP7A1、CYP27A1蛋白表达升高。与模型组相比,垂盆草苷各剂量组大鼠的胆汁流量呈现不同程度的增加;大鼠肝脏组织的病理损伤有所改善;血清中ALT、AST、ALP、TBIL、DBIL、TBA水平降低;肝脏组织匀浆中MDA的含量降低,SOD、GSH-Px的含量升高(P<0.05,P<0.01);TNF-α、IFN-γ、IL-1β的表达降低(P<0.05,P<0.01);结果表明垂盆草苷对于胆汁淤积有一定的治疗效果,其中垂盆草苷高剂量的作用效果与UDCA组相当,同时垂盆草苷可上调FXR、SHP-1、SHP-2、MREP2、BSEP、NTCP蛋白表达,下调CYP7A1、CYP27A1蛋白表达,说明垂盆草苷通过调控相关蛋白发挥作用。垂盆草苷对ANIT所致的SD幼龄大鼠肝内胆汁淤积有明显的干预和调节作用。可能是通过参与胆汁酸的转运与合成发挥其治疗作用。     

妊娠肝内胆汁淤积症孕妇围生期母婴结局与TBil和DBil水平及其比值变化的研究

目的 探究血清总胆红素（TBil）和直接胆红素（DBil）比值变化与妊娠肝内胆汁淤积孕妇围生期母婴结局的关系。方法 选取2012年1月—2017年8月在中国医科大学附属盛京医院进行治疗的妊娠合并肝内胆汁淤积的孕妇100例作为研究对象。根据孕妇体内DBil和TBil的比值,分为观察Ⅰ组（0.50～0.75）和观察Ⅱ组（>0.75）,每组50例。以同期50例健康孕妇作为对照组,观察各组患者体内TBil、DBil和胆汁酸（TBA）水平及各组母婴并发症及结局情况。结果 观察Ⅱ组血清TBA、TBil和DBil水平高于观察Ⅰ组和对照组（P?<0.05）,观察I组的血清TBA、TBil和DBil水平高于对照组（P?<0.05）;两组孕妇的结局,观察I组的剖宫产分娩发生率、产后出血发生率均低于观察Ⅱ组,产后出血量少于观察Ⅱ组（P?<0.05）;新生儿结局（早产、胎儿窘迫、羊水污染、新生儿窒息和出生体重）,观察Ⅰ组均优于观察Ⅱ组（P?<0.05）。结论 血清TBil和DBil可反映妊娠妇女早期肝内胆汁淤积情况,通过血清DBil和TBil的比值可以及早判断病情,及时干预,在改善围生期母婴结局上具有一定意义。     

血清学检测对妊娠合并肝内胆汁淤积症病人病情严重程度的评估价值

探讨血中总胆汁酸(TBA),血清抑制素A(INH-A)及可溶性细胞间黏附因子-1(sICAM-1)水平对妊娠合并肝内胆汁淤积症(ICP)病人病情严重程度的评估价值,选取本院100例ICP患者作为观察组,50例健康体检者作为对照组。结果显示,与对照组比较,观察组患者TBA,INH-A,sICAM-1显著增高,其中,重度组显著高于轻度组;联合TBA、INH-A、sICAM-1检测对诊断ICP病情程度进行诊断的敏感度、特异度及AUC均高于各指标单独诊断(P<0.05)。结果提示,TBA、INH-A、sICAM-1联合检测可作为评估ICP患者病情严重程度的重要指标。     

多烯磷脂酰胆碱联合谷胱甘肽治疗妊娠期肝内胆汁淤积症患者的效果及对围产结局的影响

目的探讨多烯磷脂酰胆碱联合谷胱甘肽治疗妊娠期肝内胆汁淤积症(ICP)患者的效果及对围产结局的影响。方法选取2015年1月～2018年12月ICP患者124例,随机分为两组。两组均予以卧床休息、间断吸氧、高渗葡萄糖、维生素C及能量合剂等治疗。对照组在此基础上予以多烯磷脂酰胆碱针15 mL静脉滴注,1次/d;观察组在对照组基础上再加谷胱甘肽针2.4 g静脉滴注,1次/d。两组均连用2周。观察两组治疗后临床症状及血清生化指标改善情况,并比较其围产结局。结果治疗2周后,两组瘙痒评分均较治疗前显著下降(P0.01或P0.05),且观察组下降幅度较对照组更明显(P0.05);观察组黄疸和瘙痒消失时间明显少于或短于对照组(P0.05)。治疗2周后,两组血清ALT、TBA和AST水平均较治疗前明显下降(P0.01或P0.05),且观察组下降幅度较对照组更明显(P0.05)。同时观察组宫内窘迫、早产和新生儿窒息发生率明显低于对照组,分娩出血量明显少于对照组,新生儿体重明显大于对照组(P0.05)。结论多烯磷脂酰胆碱联合谷胱甘肽治疗ICP患者不仅能明显改善其临床症状,降低肝酶指标与胆汁酸水平,而且能降低发生不良围产结局,有利于母婴安全。     

Potential of ileal bile acid transporter inhibition as a therapeutic target in Alagille syndrome and progressive familial intrahepatic cholestasis

Alagille syndrome (ALGS) and progressive familial intrahepatic cholestasis (PFIC) are rare, inherited cholestatic liver disorders that manifest in infants and children and are associated with impaired bile flow (ie cholestasis), pruritus and potentially fatal liver disease. There are no effective or approved pharmacologic treatments for these diseases (standard medical treatments are supportive only), and new, noninvasive options would be valuable. Typically, bile acids undergo biliary secretion and intestinal reabsorption (ie enterohepatic circulation). However, in these diseases, disrupted secretion of bile acids leads to their accumulation in the liver, which is thought to underlie pruritus and liver‐damaging inflammation. One approach to reducing pathologic bile acid accumulation in the body is surgical biliary diversion, which interrupts the enterohepatic circulation (eg by diverting bile acids to an external stoma). These procedures can normalize serum bile acids, reduce pruritus and liver injury and improve quality of life. A novel, nonsurgical approach to interrupting the enterohepatic circulation is inhibition of the ileal bile acid transporter (IBAT), a key molecule in the enterohepatic circulation that reabsorbs bile acids from the intestine. IBAT inhibition has been shown to reduce serum bile acids and pruritus in trials of paediatric cholestatic liver diseases. This review explores the rationale of inhibition of the IBAT as a therapeutic target, describes IBAT inhibitors in development and summarizes the current data on interrupting the enterohepatic circulation as treatment for cholestatic liver diseases including ALGS and PFIC.     

丁二磺酸腺苷蛋氨酸对胆汁淤积性肝炎的疗效观察

[目的]评估丁二磺酸腺苷蛋氨酸(SAMe)治疗胆汁淤积性肝炎的效果及不良反应。[方法]68例胆汁淤积性肝炎患者被随机分为治疗组(38例)和对照组(30例)。2组均予常规保肝治疗,治疗组加用SAMe针剂1.0g/d静脉滴注,对照组加用苦黄针剂30ml/d静脉滴注,2组疗程均为4周。观察2组治疗前后临床症状与体征、生化指标[总胆红素(TBil)、直接胆红素(DBil)、谷丙转氨酶(ALT)、谷草转氨酶(AST)、γ-谷氨酸转肽酶("-GT)、总胆汁酸(TBA)]、疗效及不良反应。[结果]治疗后治疗组TBil、DBil、"-GT及TBA下降程度明显高于对照组(P0.05或P0.01);其灰白便和皮肤瘙痒改善率也明显高于对照组(P0.05或P0.01);治疗组总有效率为84.2%,明显高于对照组的60.0%(P0.05)。2组患者耐受性良好,均无严重不良反应发生。[结论]SAMe治疗胆汁淤积性肝炎有确切的疗效,且安全性好。     

Cavernous Transformation of the Portal Vein Causing Jaundice,Presenting in the Form of Wilson’s Disease

The following is a case review of portal vein cavernous malformation presenting with intermittent cholestasis and jaundice in a 4 year old child. Correct assessment was supported by radiology, later laparoscopy, yet hindered by histopathology representative Wilson’s disease and elevated urinary copper excretion. During surgical procedure the stenosis of the common bile duct secondary to extremely dilated portal vein reticulation was solved by Roux-en-Y choledochojejunostomy. After a one-year follow up the child remains asymptomatic.