WO2022068076A1 - 罗伊氏乳杆菌在制备治疗急性肝衰竭药物中的用途 - Google Patents

罗伊氏乳杆菌在制备治疗急性肝衰竭药物中的用途 Download PDF

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WO2022068076A1
WO2022068076A1 PCT/CN2020/136274 CN2020136274W WO2022068076A1 WO 2022068076 A1 WO2022068076 A1 WO 2022068076A1 CN 2020136274 W CN2020136274 W CN 2020136274W WO 2022068076 A1 WO2022068076 A1 WO 2022068076A1
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lactobacillus reuteri
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liver failure
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陈智
周琦惠
朱海红
连雯雯
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Zhejiang University
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    • A—HUMAN NECESSITIES
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    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
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    • A61K35/744—Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
    • A61K35/747—Lactobacilli, e.g. L. acidophilus or L. brevis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

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  • the invention relates to the use of Lactobacillus reuteri in preparing medicines for treating acute liver failure.
  • AHF Acute hepatic failure
  • AHF refers to a group of severe clinical syndromes in which a large number of liver cell necrosis and severe liver function damage occur in a short period of time without basic liver diseases, and hepatic encephalopathy is caused. Its clinical features are no history of chronic liver disease, sudden onset, rapid onset of jaundice, liver failure, bleeding and neuropsychiatric symptoms. Multiple organ dysfunction syndrome can be combined in the short term. This disease has a high fatality rate and is one of the critical illnesses, and there is currently no effective treatment.
  • Antiviral therapy can be used for acute liver failure caused by viral hepatitis.
  • drugs that may cause liver damage should be discontinued first; patients with acetaminophen poisoning can be given intravenous infusion of N-acetylcysteine and oral activated charcoal therapy.
  • immunomodulators can reduce inflammation, regulate immune function, and reduce complications such as infection.
  • Commonly used drugs are thymosin, immunoglobulin, glucocorticoid and so on.
  • hepatocyte growth factor and prostaglandin E2 can be used as appropriate; N-acetylcysteine and reduced glutathione can be used as appropriate to improve hepatic microcirculation.
  • Cerebral edema and pulmonary edema limit the amount and speed of fluid input, supplement albumin and plasma, and use dehydrating agents and diuretics as appropriate.
  • Artificial liver refers to a treatment method that removes various harmful substances, supplements essential substances, improves the internal environment, and temporarily replaces part of the function of the failing liver through external mechanical, physical, chemical or biological devices.
  • plasma exchange blood perfusion, hemofiltration and so on.
  • Orthotopic liver transplantation is currently the most effective method for the treatment of liver failure.
  • Lactobacillus reuteri as a probiotic component, can reduce intestinal permeability, reduce intestinal inflammation, repair damaged epidermis, and promote the recovery of inflammatory bowel disease by linking with intestinal immune cells.
  • systemic organ failure is prone to occur at the same time.
  • the present application provides new uses of Lactobacillus reuteri.
  • Lactobacillus reuteri Use of Lactobacillus reuteri in the manufacture of a medicament for reducing serum IL-17 levels.
  • the inventors of the present application conducted in-depth research for the purpose of alleviating inflammation in the liver and intestinal tract, and divided the research objects into a blank control group, a positive control group and a Lactobacillus reuteri supplementation group.
  • RESULTS In the Lactobacillus reuteri supplementation group, liver transaminase levels, the inflammatory factor IL-17, and inflammatory cells in the liver decreased. That is, prophylactic daily supplementation with Lactobacillus reuteri can reduce liver and intestinal inflammation in the event of acute liver failure. In this context, it is expected to reduce liver and intestinal inflammation by prophylactic supplementation of Lactobacillus reuteri in healthy populations.
  • Figure 1 shows the serum transaminase and total bilirubin indexes of the blank control group, the positive control group and the Lactobacillus reuteri supplementation group (**, P ⁇ 0.01; *, P ⁇ 0.05).
  • the levels of alanine aminotransferase, aspartate aminotransferase and total bilirubin in the positive control group and the Lactobacillus reuteri supplementation group were higher than those in the blank control group, but were lower in the Lactobacillus reuteri supplementation group than in the positive control group.
  • Lactobacillus reuteri supplementation can relieve liver inflammation.
  • Figure 2 shows the immunohistochemical images of HE and tight junction protein in the intestinal tissue of the blank control group, the positive control group and the Lactobacillus reuteri supplementation group.
  • Intestinal histopathology was the most serious in the positive control group, and the Lactobacillus reuteri supplementation group was less severe than the positive control group.
  • the content of intercellular tight junction protein was also the least in the positive control group, while the content in the supplemented Lactobacillus reuteri group was higher than that in the positive control group.
  • Figure 3 is the western blot of intestinal tight junction proteins in the blank control group, the positive control group and the Lactobacillus reuteri supplementation group.
  • the content of intercellular tight junction protein was the least in the positive control group, while the content in the supplemented Lactobacillus reuteri group was higher than that in the positive control group.
  • Figure 4 shows the levels of intestinal permeability LPS-binding protein LBP in the blank control group, the positive control group and the Lactobacillus reuteri supplementation group (**, P ⁇ 0.01).
  • the LBP level in the positive control group was higher than that in the Lactobacillus reuteri supplementation group, indicating that the latter can reduce intestinal permeability.
  • Figure 5 shows the serum IL-17 levels in the blank control group, the positive control group and the Lactobacillus reuteri supplementation group (**, P ⁇ 0.01; *, P ⁇ 0.05).
  • the serum IL-17 level was highest in the positive control group, while the Lactobacillus reuteri supplementation group was lower than the positive control group, indicating that the latter had reduced liver inflammation.
  • Rats were divided into 3 groups: the Lactobacillus reuteri supplementation group (ie, Lactobacillus reuteri, and galactosamine for modeling), the positive control group (ie, the same amount of PBS, and galactose). amine modeling), blank control group (ie, no probiotics, nor galactosamine modeling).
  • Lactobacillus reuteri supplementation group ie, Lactobacillus reuteri, and galactosamine for modeling
  • the positive control group ie, the same amount of PBS, and galactose
  • amine modeling blank control group (ie, no probiotics, nor galactosamine modeling).
  • Lactobacillus reuteri gavage Dissolve Lactobacillus reuteri in sterile PBS solution, and gavage at 1*10E9CFU/ml/only/day. The model group was given continuous gavage for 14 days. At the same time, the control group was given PBS solution for 14 days.
  • liver failure After fasting for 12 hours, liver failure was induced by intraperitoneal injection of galactosamine 1.1 g/kg body weight in the control group and the model group, respectively.

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Abstract

本发明涉及罗伊氏乳杆菌在制备治疗急性肝衰竭药物中的用途。本申请发明人以减轻肝脏和肠道炎症为目的进行了深入研究，对研究对象分为空白对照组，阳性对照组和补充罗伊氏乳杆菌组。结果发现补充罗伊氏乳杆菌组，肝脏转氨酶水平、炎症因子IL‐17以及肝内炎症细胞降低。即预防性每日补充罗伊氏乳杆菌可以在发生急性肝衰竭时，使肝脏和肠道炎症减轻。在这样的背景下，期望通过在健康人群中预防性地补充罗伊氏乳杆菌，减轻肝脏和肠道炎症。

Description

罗伊氏乳杆菌在制备治疗急性肝衰竭药物中的用途 技术领域
本发明涉及罗伊氏乳杆菌在制备治疗急性肝衰竭药物中的用途。
背景技术
急性肝功能衰竭(acute hepatic failure.AHF)是指在原来无肝脏基础性疾病而短时间内发生大量肝细胞坏死及严重肝功能损害，并引起肝性脑病的一组严重临床综合征。其临床特点是以往无慢性肝病史，骤然起病，迅速出现黄疸、肝功能衰竭、出血和神经精神症状等。短期内可合并多器官功能障碍综合征。本病病死率高，属于危重病症之一，目前无特效治疗方法。
目前的治疗方法包括：
1.病因治疗
针对病毒性肝炎所致的急性肝功能衰竭可以采用抗病毒疗法。对于药物性肝功能衰竭，应首先停用可能导致肝损害的药物；对乙酰氨基酚中毒所致者可给予N‐乙酰半胱氨酸静脉滴注及活性炭口服治疗。
2.免疫凋节治疗
使用免疫调节剂能够减少炎症反应、调节机体免疫功能、减少感染等并发症。常用药物有胸腺肽类、免疫球蛋白、糖皮质激素等。
3.促肝细胞生长和改善肝脏微循环
为减少肝细胞坏死，促进肝细胞再生，可酌情使用肝细胞生长因子和前列素E2；改善肝脏微循环可酌情使用N‐乙酰半胱氨酸和还原型谷胱甘肽治疗。
4.防治并发症
(1)肝性脑病去除诱因，限制蛋白质的摄入，清除肠道内的积食、积血或其他含氮物质。
(2)脑水肿和肺水肿限制液体输入量和速度，补充白蛋白和血浆，酌情使用脱水剂和利尿药。
(3)急性肾功能衰竭预防和消除诱发肾功能衰竭的因素，如不适当的抽取腹水、利尿、使用肾毒性药物，监测并维持足够的有效血容量。
5.人工肝治疗
人工肝是指通过体外的机械、物理、化学或生物装置，清除各种有害物质，补充必需物质，改善内环境，暂时替代衰竭肝脏部分功能的治疗方法。目前常用的有血浆置换、血液灌注、血液滤过等。
6.肝移植
原位肝移植是目前治疗肝功能衰竭最有明确效果的方法。
在炎症性肠病中，肠道表皮尤其是固有层免疫细胞相互作用失调是其首发因素，肠道菌群紊乱促进因素之一。罗伊氏乳杆菌作为一种益生菌成分，通过与肠道免疫细胞发生关联而降低肠道通透性，减轻肠道炎症，修复受损表皮，促进炎症性肠病恢复。在急性肝衰竭患者中，易同时并发全身器官衰竭。目前尚不清楚预防性补充罗伊氏乳杆菌是否能改善肝衰竭患者受损肠道屏障及肝脏炎症，以及通过何种方式改善；另外，急性肝衰竭除了人工肝以及对症治疗外，尚缺乏全面的微生态辅佐治疗方案。
发明内容
本申请提供了罗伊氏乳杆菌的新用途。
罗伊氏乳杆菌在制备治疗急性肝衰竭药物中的用途。
罗伊氏乳杆菌在制备肝脏炎症减轻药物中的用途。
罗伊氏乳杆菌在制备肠道炎症减轻药物中的用途。
罗伊氏乳杆菌在制备降低血清中IL‐17水平的药物中的用途。
本申请发明人以减轻肝脏和肠道炎症为目的进行了深入研究，对研究对象分为空白对照组，阳性对照组和补充罗伊氏乳杆菌组。结果发现补充罗伊氏乳杆菌组，肝脏转氨酶水平、炎症因子IL‐17以及肝内炎症细胞降低。即预防性每日补充罗伊氏乳杆菌可以在发生急性肝衰竭时，使肝脏和肠道炎症减轻。在这样的背景下，期望通过在健康人群中预防性地补充罗伊氏乳杆菌，减轻肝脏和肠道炎症。
附图说明
图1为空白对照组，阳性对照组和补充罗伊氏乳杆菌组血清转氨酶和总胆红素指标(**，P＜0.01；*，P＜0.05)。谷丙转氨酶、谷草转氨酶以及总胆红素在阳性对照组和补充罗伊氏乳杆菌组较空白对照组均升高，但补充罗伊氏乳杆菌组比阳性对照组低。说明补充罗伊氏乳杆菌能缓解肝脏炎症。
图2为空白对照组，阳性对照组和补充罗伊氏乳杆菌组肠道组织HE和紧密连接蛋白的免疫组化图。肠道组织病理在阳性对照组最严重，补充罗伊氏乳杆菌组较阳性对照组减轻。而细胞间紧密连接蛋白含量也是在阳性对照组最少，而补充罗伊氏乳杆菌组含量较阳性对照 组增高。
图3为空白对照组，阳性对照组和补充罗伊氏乳杆菌组肠道紧密连接蛋白的western blot图。细胞间紧密连接蛋白含量在阳性对照组最少，而补充罗伊氏乳杆菌组含量较阳性对照组增高。
图4为空白对照组，阳性对照组和补充罗伊氏乳杆菌组肠道通透性LPS结合蛋白LBP水平(**，P＜0.01)。LBP水平在阳性对照组比补充罗伊氏乳杆菌组升高，说明后者能降低肠道通透性。
图5为空白对照组，阳性对照组和补充罗伊氏乳杆菌组血清IL‐17水平(**，P＜0.01；*，P＜0.05)。血清中IL‐17水平在阳性对照组中最高，而补充罗伊氏乳杆菌组较阳性对照组降低，说明后者肝脏炎症减轻。
具体实施方式
1.实验分组及处理情况：
大鼠分组：共分3组，分别为补充罗伊氏乳杆菌组(即予罗伊氏乳杆菌，并予半乳糖胺造模)，阳性对照组(即予等量PBS，并予半乳糖胺造模)，空白对照组(即不予益生菌，也不予半乳糖胺造模)。
罗伊氏乳杆菌灌胃：将罗伊氏乳杆菌溶于无菌PBS溶液，以1*10E9CFU/ml/只/天灌胃。模型组连续灌胃14天。同时予对照组14天PBS溶液。
诱导肝衰竭：禁食12小时后，分别予对照组和模型组半乳糖胺1.1g/kg体重腹腔注射诱导肝衰竭。
2.罗伊氏乳杆菌对半乳糖胺诱导急性肝衰竭大鼠肝脏炎症的改善作用
诱导肝衰竭24小时后，取下腔静脉血检测血清ALT、AST、TBil等水平；取新鲜肝脏组织，进行HE染色。发现转氨酶和总胆红素在补充罗伊氏乳杆菌组较阳性对照组降低，说明补充罗伊氏乳杆菌能减轻肝脏炎症。
3.罗伊氏乳杆菌对半乳糖胺诱导急性肝衰竭大鼠肠道屏障功能、肠道炎症的改善
在诱导肝衰竭后24小时，取新鲜小肠组织。检测小肠组织紧密连接蛋白如ZO‐1、occludin的mRNA表达和蛋白质水平；检测血清中LPS/LBP、IL‐17水平。发现小肠组织的HE染色结果提示，补充罗伊氏乳杆菌组小肠炎症减轻；紧密连接ZO‐1的免疫组化和WB结果提示，补充罗伊氏乳杆菌组ZO‐1较阳性对照组表达高，说明补充罗伊氏乳杆菌能改善肝衰竭大鼠小肠紧密连接表达。血清LBP结果提示，补充罗伊氏乳杆菌能改善小肠通透性。另外，补充罗伊氏乳杆菌能降低血清中IL‐17水平，降低炎症水平。

Claims (4)

  1. 罗伊氏乳杆菌在制备治疗急性肝衰竭药物中的用途。
  2. 罗伊氏乳杆菌在制备肝脏炎症减轻药物中的用途。
  3. 罗伊氏乳杆菌在制备肠道炎症减轻药物中的用途。
  4. 罗伊氏乳杆菌在制备降低血清中IL‐17水平的药物中的用途。
PCT/CN2020/136274 2020-09-30 2020-12-14 罗伊氏乳杆菌在制备治疗急性肝衰竭药物中的用途 Ceased WO2022068076A1 (zh)

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