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Article(id=1210518236060324143, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1210518228766421884, articleNumber=null, orderNo=null, doi=10.16438/j.0513-4870.2022-0908, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1658678400000, receivedDateStr=2022-07-25, revisedDate=1661443200000, revisedDateStr=2022-08-26, acceptedDate=null, acceptedDateStr=null, onlineDate=1766539637817, onlineDateStr=2025-12-24, pubDate=1670774400000, pubDateStr=2022-12-12, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1766539637817, onlineIssueDateStr=2025-12-24, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1766539637817, creator=13701087609, updateTime=1766539637817, updator=13701087609, issue=Issue{id=1210518228766421884, tenantId=1146029695717560320, journalId=1189982191388893191, year='2022', volume='57', issue='12', pageStart='0', pageEnd='3698', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1766539636078, creator=13701087609, updateTime=1766539730802, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1210518626109624560, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1210518228766421884, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1210518626109624561, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1210518228766421884, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=3524, endPage=3534, ext={EN=ArticleExt(id=1210518236978876736, articleId=1210518236060324143, tenantId=1146029695717560320, journalId=1189982191388893191, language=EN, title=Dengzhan Shengmai inhibits nonalcoholic fatty liver disease via regulating intestinal microenvironment, columnId=1210518233132692356, journalTitle=Acta Pharmaceutica Sinica, columnName=Special Reports: Therapeutic Modulation of Gut Immune and Microbiota Homeostasis by Chinese Medicine, runingTitle=null, highlight=null, articleAbstract=

The aim of this study was to investigate the efficacy and mechanism of Dengzhan Shengmai (DZSM) against nonalcoholic fatty liver diseases (NAFLD). The animal experiment program was reviewed and approved by the Ethics Committee of Institute of Materia Medica, Chinese Academy of Medical Sciences. The NAFLD model of Syrian golden hamsters was established by high fat diets. After 6 weeks of DZSM treatment, the serum lipid, hepatic lipid accumulation, liver function and inflammatory response were determined. The regulations of gut microbiota and short-chain fatty acids were detected by 16S rRNA gene sequencing and gas chromatography-mass spectrometry method, respectively. The gut barrier function was evaluated by enzyme linked immunosorbent assay (ELISA), reverse transcription-quantitative polymerase chain reaction (RT-qPCR), Western blot and histopathological methods and further verified in HepG2 cells. The results showed that the efficacy of DZSM against NAFLD was remarkably reduced after removal of the gut microbiota. The study of mechanism showed that DZSM significantly regulated the composition of gut microbiota, promoted the production and absorption of intestinal short-chain fatty acids, then leading to the reduction of hepatic lipid accumulation. Moreover, after DZSM treatment, the decreased lipopolysaccharide (LPS) level by improving the intestinal barrier function significantly inhibited the hepatic inflammation through down-regulating Toll like receptor 4 (TLR4)-nuclear factor kappa B (NFKB) signaling pathway. These results indicate that DZSM inhibits NAFLD via regulating intestinal microenvironment.

, correspAuthors=Lu-lu WANG, Yan-xing HAN, authorNote=null, correspAuthorsNote=null, copyrightStatement=Copyright ©2022 Acta Pharmaceutica Sinica. All rights reserved., copyrightOwner=null, extLink=null, articleAbsUrl=null, sourceXml=null, magXml=null, pdfUrl=null, pdf=null, pdfFileSize=null, pdfExtLink=null, richHtmlUrl=null, mobilePdfUrl=null, reviewReport=null, pdfFirstPage=null, abstractGraph=null, abstractGraphContent=null, abstractVideo=null, citation=null, cebUrl=null, magXmlContent=null, mapNumber=null, authorCompany=null, fund=null, authors=null, authorsList=Hui-hui GUO, Hao-ran SHEN, Hong-juan ZHANG, Lu-lu WANG, Yan-xing HAN, Jian-dong JIANG), CN=ArticleExt(id=1210518238602072479, articleId=1210518236060324143, tenantId=1146029695717560320, journalId=1189982191388893191, language=CN, title=灯盏生脉通过调节肠道微环境抑制非酒精性脂肪肝进程, columnId=1210518233338213258, journalTitle=药学学报, columnName=专题报道：肠道黏膜免疫及菌群稳态与中医药调控, runingTitle=null, highlight=null, articleAbstract=

本研究旨在探讨灯盏生脉(Dengzhan Shengmai, DZSM) 对高脂饮食引起的非酒精性脂肪肝病(non-alcoholic fatty liver diseases, NAFLD) 的改善作用及机制。动物实验方案由中国医学科学院药物研究所伦理委员会审核并批准。高脂饮食建立叙利亚金黄地鼠的NAFLD模型, DZSM治疗6周后测定各组动物的血脂、肝脂、肝功能、炎症反应等指标; 采用16S rRNA基因测序技术和气相-质谱联用技术检测给药后对肠道菌群及短链脂肪酸(short-chain fatty acids, SCFAs) 的调节作用; 采用ELISA (enzyme linked immunosorbent assay)、RT-qPCR (reverse transcription-quantitative polymerase chain reaction)、Western blot及组织病理学方法检测肠屏障功能; 并在体外HepG2细胞中进行验证和机制研究。结果发现, DZSM改善NAFLD的作用在抗生素处理杀灭肠道菌群后明显减弱。进一步的机制研究表明, DZSM可明显调节肠道菌群结构和组成, 促进肠道内SCFAs产生和吸收进入肝脏, 从而减轻肝细胞内的脂质堆积; 而且DZSM通过改善肠屏障功能减少肠内毒素脂多糖(lipopolysaccharide, LPS) 进入机体, 抑制LPS激活的Toll样受体4 (Toll like receptor 4, TLR4)-核因子KB (nuclear factor kappa B, NFKB) 信号通路, 减轻肝脏炎症反应。以上结果表明, DZSM可通过调节肠道微环境改善NAFLD进程。

, correspAuthors=王璐璐, 韩燕星, authorNote=null, correspAuthorsNote=
*王璐璐, Tel: 86-10-63017906, E-mail: ;
韩燕星, E-mail:
, copyrightStatement=版权所有©《药学学报》编辑部2022, copyrightOwner=null, extLink=null, articleAbsUrl=null, sourceXml=EHWDr8oh0nzI6tFx7hH/9A==, magXml=Pdecao2ONAN0CxZ5hET45g==, pdfUrl=null, pdf=PUYUmWdheHmzRtEa45JOZg==, pdfFileSize=7403980, pdfExtLink=null, richHtmlUrl=null, mobilePdfUrl=null, reviewReport=null, pdfFirstPage=null, abstractGraph=YPAK+s6A7xcBYMVCnGFz6w==, abstractGraphContent=null, abstractVideo=null, citation=null, cebUrl=null, magXmlContent=CQLUJynFrvKJOH36BKhBCw==, mapNumber=null, authorCompany=null, fund=null, authors=

#共同第一作者.

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High fatty diet (HFD)-fed hamsters were treated with DZSM (720 mg·kg<sup>-1</sup>·d<sup>-1</sup>), DZSM+ antibiotics (AB) (720 mg·kg<sup>-1</sup>·d<sup>-1</sup> DZSM + 50 mg·kg<sup>-1</sup>·d<sup>-1</sup> amoxicillin + 25 mg·kg<sup>-1</sup>·d<sup>-1</sup> clarithromycin + 25 mg·kg<sup>-1</sup>·d<sup>-1</sup> ofloxacin) or solvent (0.25% sodium carboxymethylcellulose) for 6 weeks. Hamsters fed with normal chow diet were used as control (NCD). A: Serum cholesterol (CHO), low-density lipoprotein cholesterol (LDL-c) and triglyceride (TG) levels; B: Hepatic TG level; C: Serum alanine aminotransferase (ALT) and aspartate transaminase (AST) levels; D: Representative photographs of hematoxylin eosin (H & E) stained liver sections; E: The histological score of H & E stained liver sections; F: Representative photographs of oil red stained liver sections. Scale bar: 100 μm. <i>n</i> = 7-10, <span class="mag-xml-inline-formula">$ \overline{x} $</span> ± standard error of mean (SEM). <sup>*</sup><i>P</i> < 0.05, <sup>**</sup><i>P</i> < 0.01, <sup>***</sup><i>P</i> < 0.001 , figureFileSmall=g4s0Cn9WAcGpTlMO7YHbHw==, figureFileBig=YPAK+s6A7xcBYMVCnGFz6w==, tableContent=null), ArticleFig(id=1210518248647430915, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1210518236060324143, language=EN, label=null, caption=null, figureFileSmall=p3SCLtI4HFm1IAk/zuopcg==, figureFileBig=XfWYHc8lD8IXY1Cd57H+OA==, tableContent=null), ArticleFig(id=1210518248739705611, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1210518236060324143, language=CN, label=Figure 2, caption= Modulation of gut microbiota by DZSM in HFD-fed hamsters. A: Microbiota community analysis based on principal components analysis (PCA) and principal coordinate analysis (PCoA) score plots; B: Community abundance profiling of the gut microbiota at the phylum, family and genus levels; C: The mean proportion of multiple differentiated gut microbiota on the family (left) and genus (right) levels using Kruskal-Wallis H test analysis. <sup>**</sup><i>P</i> < 0.01, <sup>***</sup><i>P</i> < 0.001. OTU: Operational taxonomic unit , figureFileSmall=p3SCLtI4HFm1IAk/zuopcg==, figureFileBig=XfWYHc8lD8IXY1Cd57H+OA==, tableContent=null), ArticleFig(id=1210518248873923355, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1210518236060324143, language=EN, label=null, caption=null, figureFileSmall=c7GrR9mvXCP++CqYbBlgHQ==, figureFileBig=yLZLmCWx5UfX4u4LA+pfbw==, tableContent=null), ArticleFig(id=1210518250098660126, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1210518236060324143, language=CN, label=Figure 3, caption= Effect of DZSM on the production and absorption of intestinal short-chain fatty acids (SCFAs) in HFD-fed hamsters. A: SCFA levels in cecal (left) and colonic (right) contents of drug treated hamsters; B: The mRNA expression of the <i>Mct1</i> gene in colonic tissues; C: SCFA levels in plasma; D: The mRNA expression of the <i>Mct1</i> gene in liver tissues; E: SCFA levels in liver tissues. <i>n</i> = 8-10, <span class="mag-xml-inline-formula">$ \overline{x} $</span> ± SEM. <sup>*</sup><i>P</i> < 0.05, <sup>**</sup><i>P</i> < 0.01, <sup>***</sup><i>P</i> < 0.001 , figureFileSmall=c7GrR9mvXCP++CqYbBlgHQ==, figureFileBig=yLZLmCWx5UfX4u4LA+pfbw==, tableContent=null), ArticleFig(id=1210518250220294955, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1210518236060324143, language=EN, label=null, caption=null, figureFileSmall=J0Xq0fAUD6ISMzpslQh5+g==, figureFileBig=TeCjaUxdIIbW/9Y/ADU9zQ==, tableContent=null), ArticleFig(id=1210518250333541169, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1210518236060324143, language=CN, label=Figure 4, caption= The amelioration of lipid accumulation by DZSM or butyrate in HepG2 cells. HepG2 cells were incubated with oleic acid (OA, 500 μmol·L<sup>-1</sup>) and lipopolysaccharide (LPS, 5 μg·mL<sup>-1</sup>) for 24 h in the absence or presence of DZSM (125, 250, 500 μg·mL<sup>-1</sup>) or sodium butyrate (50, 100, 200 μmol·L<sup>-1</sup>). Untreated HepG2 cells were used as control group. A: Lipid droplets in HepG2 cells was determined by oil red O staining assay; B: The relative quantitative results of oil red O staining in HepG2 cells. Scale bar: 100 μm. <i>n</i> = 3, <span class="mag-xml-inline-formula">$ \overline{x} $</span> ± SEM. <sup>**</sup><i>P</i> < 0.01, <sup>***</sup><i>P</i> < 0.001. Con: Control , figureFileSmall=J0Xq0fAUD6ISMzpslQh5+g==, figureFileBig=TeCjaUxdIIbW/9Y/ADU9zQ==, tableContent=null), ArticleFig(id=1210518250446787384, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1210518236060324143, language=EN, label=null, caption=null, figureFileSmall=dwFep32TO0HTtGW7c+KApw==, figureFileBig=mP89lp4lcBbkKocu5mbuYw==, tableContent=null), ArticleFig(id=1210518250547450687, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1210518236060324143, language=CN, label=Figure 5, caption= Effect of DZSM on intestinal barrier in HFD-fed hamsters. A: The level of plasma LPS determined by ELISA; B: The level of mucin in colonic tissue determined by ELISA; C: Representative images of colonic goblet cells using alcian blue-periodic acid schiff (AB-PAS) staining. Scale bar: 200 μm; D: Representative images of immunofluorescent staining for OCLN (green) and ZO-1 (red) in colonic tissue of hamsters. Scale bar: 100 μm; E: The mRNA expression of the <i>Zo-1</i> and <i>Ocln</i> gene in colonic tissues; F: Correlation analysis between cecal or colonic SCFA levels and plasma LPS levels. <i>n</i> = 8-10, <span class="mag-xml-inline-formula">$ \overline{x} $</span> ± SEM. <sup>*</sup><i>P</i> < 0.05, <sup>**</sup><i>P</i> < 0.01, <sup>***</sup><i>P</i> < 0.001 , figureFileSmall=dwFep32TO0HTtGW7c+KApw==, figureFileBig=mP89lp4lcBbkKocu5mbuYw==, tableContent=null), ArticleFig(id=1210518250706834257, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1210518236060324143, language=EN, label=null, caption=null, figureFileSmall=G9F1vak56HfTipye7KFy/w==, figureFileBig=Afrfu0kJGD8+mivSryZxLA==, tableContent=null), ArticleFig(id=1210518250836857690, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1210518236060324143, language=CN, label=Figure 6, caption= DZSM attenuated inflammation in HFD-fed hamster livers <i>via</i> LPS-TLR4-NFKB pathway. A, B: The mRNA expression of pro-inflammatory genes (A: <i>Nfkb2</i>, <i>Nlrp3</i> and <i>Il1β</i>; B: <i>Tlr4</i> and <i>Ikkβ</i>) in colonic tissues of hamsters after DZSM treatment for 6 weeks (<i>n</i> = 8-10); C: The protein expression of pro-inflammatory factors in LPS or/and DZSM treated HepG2 cells; D: The mRNA expression of pro-inflammatory genes (<i>TLR4</i>, <i>IKKβ</i>, <i>NLRP3</i> and <i>NFKB2</i>) in HepG2 cells incubated with different concentrations of LPS (5, 2.5 and 1.25 μg·mL<sup>-1</sup>) for 24 h (<i>n</i> = 3); E: The mRNA expression of pro-inflammatory genes (<i>TLR4</i>, <i>IKKβ</i>, <i>NLRP3</i> and <i>NFKB2</i>) in LPS (5 μg·mL<sup>-1</sup>) treated HepG2 cells in the absence or presence of DZSM (125 and 500 μg·mL<sup>-1</sup>) (<i>n</i> = 3). <span class="mag-xml-inline-formula">$ \overline{x} $</span> ± SEM. <sup>*</sup><i>P</i> < 0.05, <sup>**</sup><i>P</i> < 0.01, <sup>***</sup><i>P</i> < 0.001 , figureFileSmall=G9F1vak56HfTipye7KFy/w==, figureFileBig=Afrfu0kJGD8+mivSryZxLA==, tableContent=null), ArticleFig(id=1210518250903966565, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1210518236060324143, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
SpeciesGeneForward primerReversed primer
HamsterGapdhTCGGAGTGAACGGATTTGGCAGCCTTGACTGTGCCTTTGA
Nlrp3CCTGACTCAAACCCACCAGTAAGGCTGCTCAGCAAAATGT
Mct1GTTCCTGGACCTGTCGTTGTCTAGCAAATGGCACACTCCA
Tlr4GACATGGCAGTTTCTGAGCATCTTCCGTCCAACAGAGCTT
IkkβTGCTGCAGAACGATGTTTTCAGGAGCCATCCTTACCCTGT
Nfkb2GCCAGACAAGGGTAGTGAGCCAGGCATGTGCAATATTTGG
Zo-1CCACGTTTTGAAGAGCCAGCCCCTTGTGACGGTACTTGCT
OclnGCGATCATACCCGGAGTCTGTTACCACTGCTGCTGTACCG
HumanGAPDHGGTGAAGGTCGGAGTCAACGTGGGTGGAATCATATTGGAACA
NFKB2TGTCAACCTCACCAACCACCGAGTCTCCATGCCGATCCAG
IKKβTTGTAGCAAGGTCCGTGGTCCACTCTTCTTGGCTGGCTCA
NLRP3AGGAGGACTTCGTGCAAAGGAGAACTGAAAAGAGGCCCCG
TLR4CATTGGTGTGTCGGTCCTCAAGGCAGAGCTGAAATGGAGG
), ArticleFig(id=1210518251013018474, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1210518236060324143, language=CN, label=Table 1, caption=

Primer sequences of genes in hamsters and human HepG2 cells. Gapdh: Glyceraldehyde-3-phosphate dehydrogenase; Nlrp3: Nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-3; Mct1: Monocarboxylate transporter 1; Tlr4: Toll like receptor 4; Ikkβ: Inhibitor of kappa B kinase β; Nfkb2: Nuclear factor kappa B 2; Zo-1: Zonula occludens-1; Ocln: Occludin

, figureFileSmall=null, figureFileBig=null, tableContent=
SpeciesGeneForward primerReversed primer
HamsterGapdhTCGGAGTGAACGGATTTGGCAGCCTTGACTGTGCCTTTGA
Nlrp3CCTGACTCAAACCCACCAGTAAGGCTGCTCAGCAAAATGT
Mct1GTTCCTGGACCTGTCGTTGTCTAGCAAATGGCACACTCCA
Tlr4GACATGGCAGTTTCTGAGCATCTTCCGTCCAACAGAGCTT
IkkβTGCTGCAGAACGATGTTTTCAGGAGCCATCCTTACCCTGT
Nfkb2GCCAGACAAGGGTAGTGAGCCAGGCATGTGCAATATTTGG
Zo-1CCACGTTTTGAAGAGCCAGCCCCTTGTGACGGTACTTGCT
OclnGCGATCATACCCGGAGTCTGTTACCACTGCTGCTGTACCG
HumanGAPDHGGTGAAGGTCGGAGTCAACGTGGGTGGAATCATATTGGAACA
NFKB2TGTCAACCTCACCAACCACCGAGTCTCCATGCCGATCCAG
IKKβTTGTAGCAAGGTCCGTGGTCCACTCTTCTTGGCTGGCTCA
NLRP3AGGAGGACTTCGTGCAAAGGAGAACTGAAAAGAGGCCCCG
TLR4CATTGGTGTGTCGGTCCTCAAGGCAGAGCTGAAATGGAGG
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灯盏生脉通过调节肠道微环境抑制非酒精性脂肪肝进程
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郭慧慧 1, # , 申浩然 1, # , 张红娟 1 , 王璐璐 2, * , 韩燕星 1, * , 蒋建东 1, 2
药学学报 | 专题报道：肠道黏膜免疫及菌群稳态与中医药调控 2022,57(12): 3524-3534
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药学学报 | 专题报道：肠道黏膜免疫及菌群稳态与中医药调控 2022, 57(12): 3524-3534
灯盏生脉通过调节肠道微环境抑制非酒精性脂肪肝进程
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郭慧慧1, #, 申浩然1, #, 张红娟1, 王璐璐2, * , 韩燕星1, * , 蒋建东1, 2
作者信息
  • 1.中国医学科学院、北京协和医学院药物研究所, 天然药物活性物质与功能国家重点实验室, 北京 100050
  • 2.中国医学科学院、北京协和医学院医药生物技术研究所, 北京 100050

通讯作者:

*王璐璐, Tel: 86-10-63017906, E-mail: ;
韩燕星, E-mail:
Dengzhan Shengmai inhibits nonalcoholic fatty liver disease via regulating intestinal microenvironment
Hui-hui GUO1, Hao-ran SHEN1, Hong-juan ZHANG1, Lu-lu WANG2, * , Yan-xing HAN1, * , Jian-dong JIANG1, 2
Affiliations
  • 1. State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
  • 2. Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
出版时间: 2022-12-12 doi: 10.16438/j.0513-4870.2022-0908
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摘要
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本研究旨在探讨灯盏生脉(Dengzhan Shengmai, DZSM) 对高脂饮食引起的非酒精性脂肪肝病(non-alcoholic fatty liver diseases, NAFLD) 的改善作用及机制。动物实验方案由中国医学科学院药物研究所伦理委员会审核并批准。高脂饮食建立叙利亚金黄地鼠的NAFLD模型, DZSM治疗6周后测定各组动物的血脂、肝脂、肝功能、炎症反应等指标; 采用16S rRNA基因测序技术和气相-质谱联用技术检测给药后对肠道菌群及短链脂肪酸(short-chain fatty acids, SCFAs) 的调节作用; 采用ELISA (enzyme linked immunosorbent assay)、RT-qPCR (reverse transcription-quantitative polymerase chain reaction)、Western blot及组织病理学方法检测肠屏障功能; 并在体外HepG2细胞中进行验证和机制研究。结果发现, DZSM改善NAFLD的作用在抗生素处理杀灭肠道菌群后明显减弱。进一步的机制研究表明, DZSM可明显调节肠道菌群结构和组成, 促进肠道内SCFAs产生和吸收进入肝脏, 从而减轻肝细胞内的脂质堆积; 而且DZSM通过改善肠屏障功能减少肠内毒素脂多糖(lipopolysaccharide, LPS) 进入机体, 抑制LPS激活的Toll样受体4 (Toll like receptor 4, TLR4)-核因子KB (nuclear factor kappa B, NFKB) 信号通路, 减轻肝脏炎症反应。以上结果表明, DZSM可通过调节肠道微环境改善NAFLD进程。

灯盏生脉  /  非酒精性脂肪肝病  /  肠道菌群  /  短链脂肪酸  /  脂多糖

The aim of this study was to investigate the efficacy and mechanism of Dengzhan Shengmai (DZSM) against nonalcoholic fatty liver diseases (NAFLD). The animal experiment program was reviewed and approved by the Ethics Committee of Institute of Materia Medica, Chinese Academy of Medical Sciences. The NAFLD model of Syrian golden hamsters was established by high fat diets. After 6 weeks of DZSM treatment, the serum lipid, hepatic lipid accumulation, liver function and inflammatory response were determined. The regulations of gut microbiota and short-chain fatty acids were detected by 16S rRNA gene sequencing and gas chromatography-mass spectrometry method, respectively. The gut barrier function was evaluated by enzyme linked immunosorbent assay (ELISA), reverse transcription-quantitative polymerase chain reaction (RT-qPCR), Western blot and histopathological methods and further verified in HepG2 cells. The results showed that the efficacy of DZSM against NAFLD was remarkably reduced after removal of the gut microbiota. The study of mechanism showed that DZSM significantly regulated the composition of gut microbiota, promoted the production and absorption of intestinal short-chain fatty acids, then leading to the reduction of hepatic lipid accumulation. Moreover, after DZSM treatment, the decreased lipopolysaccharide (LPS) level by improving the intestinal barrier function significantly inhibited the hepatic inflammation through down-regulating Toll like receptor 4 (TLR4)-nuclear factor kappa B (NFKB) signaling pathway. These results indicate that DZSM inhibits NAFLD via regulating intestinal microenvironment.

Dengzhan Shengmai  /  nonalcoholic fatty liver disease  /  gut microbiota  /  short-chain fatty acid  /  lipopolysaccharide
郭慧慧, 申浩然, 张红娟, 王璐璐, 韩燕星, 蒋建东. 灯盏生脉通过调节肠道微环境抑制非酒精性脂肪肝进程. 药学学报, 2022 , 57 (12) : 3524 -3534 . DOI: 10.16438/j.0513-4870.2022-0908
Hui-hui GUO, Hao-ran SHEN, Hong-juan ZHANG, Lu-lu WANG, Yan-xing HAN, Jian-dong JIANG. Dengzhan Shengmai inhibits nonalcoholic fatty liver disease via regulating intestinal microenvironment[J]. Acta Pharmaceutica Sinica, 2022 , 57 (12) : 3524 -3534 . DOI: 10.16438/j.0513-4870.2022-0908
正文
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目前, 非酒精性脂肪肝病(nonalcoholic fatty liver disease, NAFLD) 已是全球关注的健康问题, 影响全世界近30%的成年人口[1]。改变生活方式如健康饮食、加强运动等是当前缓解NAFLD最有效的方法, 但由于大多数人很难长期坚持, 而且临床也缺乏被批准用于治疗NAFLD的有效药物, 因此探寻新的、安全有效的治疗策略已成为公共卫生目标。近年来, 越来越多的研究发现肠道微生态紊乱与NAFLD的发展密切相关[2]。相比健康人群, NAFLD患者体内肠道菌群的结构和组成发生了较大变化, 这些变化会直接改变肠道微生物代谢产物如短链脂肪酸(short-chain fatty acids, SCFAs)、肠内毒素脂多糖(lipopolysaccharide, LPS) 的产生[3]; 而且长期高脂饮食对肠屏障功能的损伤会增加肠道通透性, 致使肠道致病菌及LPS经肝门静脉进入肝脏甚至全身各组织器官, 引发机体的炎症反应[4-6]。因此基于肠道微生态防治NAFLD将成为新的重要研究方向。
灯盏生脉(Dengzhan Shengmai, DZSM) 胶囊是一种中药制剂, 由灯盏细辛、人参、五味子和麦冬四味中药制成, 可益气养阴、活血健脑, 而且在高脂血症合并缺血性脑病、冠心病心绞痛方面有较好疗效[7, 8], 但目前尚无DZSM针对NAFLD的治疗作用的研究。而且, DZSM中的多个有效组分比如人参皂苷类、五味子素类及麦冬皂苷类等都较难吸收、口服生物利用度低, 药物口服后主要滞留于肠道, 可与肠道菌群和肠壁长时间接触并与之相互作用。本研究通过高脂饮食诱导的NAFLD金黄地鼠模型, 从血脂、肝脂、肝功能及炎症因子、肠道菌群及其代谢产物SCFAs、肠屏障功能等多角度出发, 探究DZSM治疗NAFLD的作用及对肠道微环境的调节作用。
材料与方法
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药品与试剂   DZSM喷干粉(批号20190023) 由云南生物谷药业股份有限公司提供; 挥发性游离脂肪酸标准品(10 mmol·L-1, 08168, 美国Sigma公司); 丁酸钠(A510838)、克拉霉素(A504058)、阿莫西林(A662203) 和氧氟沙星(A600673) [生工生物工程(上海) 股份有限公司]; MEM培养基、0.25%胰酶、青链霉素和胎牛血清(美国Gibco公司); RNA提取试剂盒(74106) 和粪便DNA提取试剂盒(51804) (美国Qiagen公司); LPS酶联免疫吸附检测(enzyme linked immunosorbent assay, ELISA) 试剂盒(YJ320197, 上海酶联生物科技有限公司); 油酸(SYSJ-KJ005, 西安鲲创科技有限公司); cDNA单链合成试剂盒(CW2569) 及SYBR Green实时定量PCR试剂盒(CW2601H) (江苏康为世纪生物科技股份有限公司); 抗体NFKB (nuclear factor kappa B, 10745-1-AP)、TLR4 (Toll like receptor 4, 19811-1-AP)、ZO-1 (zonula occludens-1, 21773-1-AP) 和OCLN (occludin, 66378-1-Ig) (美国Proteintech公司); 抗体IKKβ (inhibitor of kappa B kinase β, 8943)、NLRP3 (nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-3, 15101) (美国Cell Signaling Technology公司); Alexa Fluor 488-山羊抗小鼠二抗(A10680)、CY3-山羊抗兔二抗(A10520) 和BCA (bicinchoninic acid) 试剂盒(美国赛默飞世尔科技有限公司); 总胆固醇(cholesterol, CHO)、甘油三酯(triglyceride, TG)、低密度脂蛋白胆固醇(low-density lipoprotein cholesterol, LDL-c)、丙氨酸氨基转移酶(alanine aminotransferase, ALT) 和天门冬氨酸氨基转移酶(aspartate transaminase, AST) 检测试剂盒(中生北控生物科技股份有限公司)。
仪器   低温组织研磨仪(型号KZ-III-F, 武汉赛维尔生物科技有限公司); q-PCR仪(型号ABI 7500 Fast, 美国ABI公司); 全自动生化分析仪(型号7060, 日本Hitachi公司); 多功能酶标仪(型号ELx808, 美国BioTek公司); 三重四级杆气相色谱-质谱联用仪(型号GCMS-TQ8040NX, 日本岛津公司); 超微量紫外分光光度计(型号NanoDrop 2000)、高速冷冻离心机(型号ST 16R) (美国赛默飞世尔科技有限公司); 扫描仪(型号Pannoramic MIDI, 匈牙利3DHISTECH公司)。
细胞培养和处理   HepG2细胞购于美国ATCC细胞库, 采用含10%胎牛血清的MEM培养基进行培养。油酸(12 mmol·L-1) 储液用含血清的MEM培养基稀释成工作液(500 μmol·L-1)。细胞铺于12孔板, 待长至80%时, 用含油酸的培养基培养, 同时加入不同浓度的LPS (1.25、2.5、5 μg·mL-1)、DZSM (125、250、500 μg·mL-1) 和丁酸(50、100、200 μmol·L-1), 并设置空白溶剂孔作为对照。细胞加药处理24 h后, 一部分孔采用油红染色观察肝细胞的脂质堆积情况, 另一部分细胞提蛋白和RNA后检测炎症因子基因的表达。
细胞油红染色及定量   按照油红染液说明书配制油红工作液。给药结束的12孔板细胞弃去培养基, 磷酸盐缓冲液(PBS) 洗2次后使用4%多聚甲醛固定15 min, PBS再洗1次后加入油红工作液避光染色30 min, 异丙醇分化3 s后用纯水洗3次; 再加入苏木素染液对细胞核进行染色, 返蓝后水洗, 加入适量PBS覆盖细胞后用扫描显微镜扫描染色情况。未经苏木素染核的细胞各孔加入300 μL异丙醇, 振荡使油红染料溶解于异丙醇内, 经离心弃掉细胞沉淀后, 取上清液在490 nm波长下测定各孔吸光度(A) 值, 以异丙醇孔调零, 对油红染色结果进行定量分析。
动物实验   叙利亚金黄地鼠(雄性, 6周龄) 购自北京维通利华有限公司, 高脂饲料(1.0%胆固醇+ 0.2%胆酸钠+ 10.0%猪油+ 5.0%蛋黄粉+ 83.75%基础饲料) 购自北京科奥协力饲料有限公司。动物实验在中国医学科学院药物研究所动物实验中心完成, 许可证号SCXK (京) 2021-0011。动物实验方案由中国医学科学院药物研究所伦理委员会审核并批准(编号: 00009061), 并严格按照动物实验中心标准操作规程(SOP) 进行。将6周龄雄性金黄地鼠在动物房适应1周, 先分成2组: 正常组(normal chew diet, NCD: 食用正常维持饲料) 和高脂组(high fatty diet, HFD: 食用高脂饲料), 6周后, 再将高脂组随机分为: HFD组、DZSM组(720 mg·kg-1·d-1)、DZSM + 抗生素(antibiotics, AB) 组(DZSM + AB: 720 mg·kg-1·d-1 DZSM + 50 mg·kg-1·d-1阿莫西林+ 25 mg·kg-1·d-1克拉霉素+ 25 mg·kg-1·d-1氧氟沙星), 丁酸组(butyrate, 100 mg·kg-1·d-1), 每组10只。给药组通过灌胃给予不同药物(每只1 mL), NCD组和HFD组给予等量的溶剂(0.25%羧甲基纤维素钠溶液), 连续给药6周。给药结束, 取新鲜粪便液氮速冻后, 放于-80 ℃保存。动物禁食12 h后异戊巴比妥麻醉解剖, 心脏取血, 肝脏、结肠组织一部分用多聚甲醛固定, 另一部分冻存于-80 ℃进行后续分析。
肠道菌群16S rRNA基因测序分析   使用粪便DNA提取试剂盒提取粪便内的总DNA后, 选用靶向V3-V4区域的引物(338F: ACTCCTACGGGAGGCAGCAG, 806R: GGACTACHVGGGTWTCTAAT) 对粪便DNA进行扩增; 纯化后的扩增产物送至上海美吉生物医药科技有限公司进行测序分析, 测序分析平台为Illumina Miseq。测序后的原始序列数据经过滤, 区分样本后进行菌群的操作分类单元(operational taxonomic unit, OTU) 聚类分析和物种分类分析。基于OTU进行菌群多样性分析和物种组成分析。整个生物信息学数据分析依赖美吉生物的云平台(http://www.majorbio.com/)。
血浆LPS检测   加入抗凝剂的全血静置2 h后, 采用3 000 r·min-1的转速在4 ℃下离心10 min, 分离得到上层血浆, 用ELISA试剂盒检测血浆中的LPS水平。
血清生化指标检测   全血静置2 h后, 采用3 000 r·min-1的转速在4 ℃下离心10 min, 分离得到上层血清, 用试剂盒在全自动生化分析仪上同时检测CHO、TG、LDL-c、ALT和AST等指标。
SCFAs检测   分别称取盲肠内容物、结肠内容物和肝脏组织约50 mg, 加入9倍体积的H3PO4溶液(3%) 用研磨仪充分匀浆后, 采用10 000 r·min-1的转速在4 ℃下离心10 min, 取300 μL上清液加入300 μL正丁醇涡旋振荡10 min; 取血浆150 μL用同体积的H3PO4溶液(6%) 酸化后, 也加入300 μL正丁醇涡旋振荡10 min。振荡结束后, 采用10 000 r·min-1的转速在4 ℃下离心10 min, 取上层正丁醇层用三重四级杆气相色谱-质谱联用仪进行SCFAs含量分析。色谱柱为硝基对苯二甲酸修饰的聚乙二醇毛细管色谱柱毛细管柱(DB-FFAP122-3232, 0.25 mm × 0.25 μm × 30 m, Agilent); 升温程序: 90 ℃持续1 min, 然后10 ℃·min-1升温至200 ℃后再持续2 min; 进样口温度、离子源温度及接口温度分别为240、230和240 ℃; 载气(氦气) 采用恒线速度控制方式; 进样体积: 1 μL; 进样方式: 分流进样(分流比5∶1); 待检物质在选择离子模式(SIM) 下使用目标离子和参考离子进行检测, 并使用外标法(标准曲线) 进行定量。混合挥发性游离脂肪酸标准溶液(10 mmol·L-1) 用3% H3PO4溶液稀释成以下浓度: 1、2.5、5、10、25、50、100、250、500、1 000、2 000 μmol·L-1。
肝脏组织TG含量测定称取地鼠肝脏组织约50 mg, 加入9倍体积的无水乙醇, 用研磨仪充分匀浆后, 采用3 500 r·min-1的转速在4 ℃下离心10 min, 取上清用TG检测试剂盒测定肝脏中的TG含量。
组织病理学检测   取适量大小的肝脏组织于4%多聚甲醛溶液中固定24 h后, 进行石蜡组织包埋、切片、苏木精-伊红(hematoxylin eosin, H & E) 染色; 多聚甲醛固定过的肝脏组织进行包埋后放于冷冻切片机上切片进行油红染色; 染色后的切片用扫描显微镜进行扫描观察肝脏组织的损伤及脂质沉积情况, 并采用半定量分级评分方法来评估肝细胞脂肪变性及炎性坏死。评分标准: 0分, 没有脂肪变性、坏死; 1分, 轻度脂肪变性、坏死; 2分, 中度脂肪变性、坏死; 3分, 严重的脂肪变性、坏死。取适量大小的地鼠结肠组织于4%多聚甲醛溶液中固定24 h后, 进行石蜡组织包埋、切片(环切)、AB-PAS (alcian blue-periodic acid schiff) 染色, 用显微镜观察结肠组织中杯状细胞的数目。
免疫荧光检测   将石蜡包埋的结肠组织切片后经脱蜡、抗原修复、血清封闭后, 进行ZO-1和OCLN免疫荧光双标染色, 然后再用Alexa Fluor 488-山羊抗小鼠二抗和CY3-山羊抗兔二抗孵育, 最后用DAPI (4′, 6-diamidino-2-phenylindole) 复染细胞核。染色后的切片用荧光扫描显微镜下观察并采集图像。
RT-qPCR (reverse transcription-quantitative polymerase chain reaction) 检测   取肝脏、结肠组织或HepG2细胞, 加入适量裂解液, 用研磨仪使组织充分匀浆并裂解, 离心后用RNA提取试剂盒提取总RNA。取1 μg总RNA逆转录合成单链cDNA后再进行实时荧光定量PCR方法检测基因的表达, 以管家基因GAPDH (glyceraldehyde-3-phosphate dehydrogenase) 作为内参, 并用2-ΔΔCt计算基因的相对表达量。各基因的引物序列详见表 1。
Western blot检测   提取HepG2细胞内总蛋白, 用BCA法测蛋白浓度, 取适量变性的总蛋白进行SDS-PAGE (sodium dodecyl sulfate-polyacrylamide gel electrophoresis) 凝胶电泳、湿法转膜90 min、脱脂奶粉封闭后, 分别加入一抗(1∶1 000稀释) 于4 ℃孵育过夜, 洗膜后加入辣根过氧化物酶标记的二抗(1∶5 000稀释) 室温孵育1~2 h, 洗膜后用电化学发光法(ECL) 显色成像得到蛋白印记条带, 以GAPDH作为内参蛋白。
统计学分析   实验数据均以平均值±标准误[$ \overline{x} $ ± SEM (standard error of mean)] 表示, 采用GraphPad Prism 8.0软件进行数据处理和统计分析, 两组样本间比较采用unpaired t检验, 多组间比较采用单因素方差分析, 以P < 0.05为具有统计学差异。
结果
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1 DZSM通过肠道菌群抑制NAFLD进程
高脂饮食的金黄地鼠给予DZSM治疗6周后, 相对于HFD组, DZSM组地鼠血清中CHO、LDL-c和TG等血脂水平显著下降(图 1A), 肝脏组织中的TG含量也明显降低(图 1B), 而且DZSM能有效降低血清ALT水平(图 1C); 肝脏H & E染色结果显示, DZSM能显著抑制肝脏脂肪样变性(图 1D、E); 与H & E结果一致, 肝脏油红染色结果显示, 与HFD组相比, DZSM组地鼠的肝脏红色脂滴明显减少(图 1F)。而高脂饮食地鼠给予广谱抗生素处理杀灭肠道菌群后, DZSM改善血脂、肝脂及肝脏功能等抗NAFLD的作用明显减弱, 这说明肠道菌群可能参与了DZSM抗NAFLD的作用。
2 DZSM有效调节肠道菌群
采用16S rRNA基因测序分析DZSM对高脂饮食金黄地鼠的肠道菌群调节作用。主成分分析(principal component analysis, PCA) 和主坐标分析(principal coordinate analysis, PCoA) 结果显示, 相比于NCD组, HFD组明显向PC1方向偏移; 给予DZSM后, 可部分逆转HFD引起的PC1方向偏移, 其菌群更趋向于NCD组(图 2A)。各组动物的菌群物种组成分析结果(图 2B) 和菌群差异分析结果(图 2C) 显示, 在门水平上, DZSM明显逆转高脂饮食引起的厚壁菌门(Firmicutes) 丰度升高和拟杆菌门(Bacteroidota) 丰度降低, 而且明显增加放线菌门(Actinobacteriota) 丰度, 减少机会致病菌脱硫弧菌门(Desulfobacterota) 丰度; 在科水平上, 高脂饮食明显降低菌群丰度较高的Muribaculaceae、乳酸杆菌科(Lactobacillaceae)、双歧杆菌科(Bifidobacteriaceae) 多个产SCFAs菌群的含量, 升高毛螺菌科(Lachnospiraceae)、脱硫弧菌科(Desulfovibrionaceae) 和颤螺菌科(Oscillospiraceae) 菌群丰度, DZSM处理后能显著改善高脂饮食引起的以上菌群丰度的异常; 在属水平上, DZSM能明显升高乳酸杆菌属(Lactobacillus)、双歧杆菌属(Bifidobacterium)、Allobaculum等产SCFAs的益生菌群的丰度, 降低高脂饮食引起的毛螺菌科中多个属、脱硫弧菌属(Desulfovibrio)、Oscillibacter等菌群丰度的升高。而且发现DZSM给药后的肠道菌群结构变化和菌群丰度变化都与丁酸组相近。以上结果说明, DZSM有效调节肠道菌群结构和组成, 使其更趋向于正常饮食组菌群; 而且DZSM显著升高肠道菌群中多个重要的产SCFAs菌群的丰度。
3 DZSM促进肠道SCFAs产生和吸收
盲肠和结肠内容物的SCFAs含量测定结果显示, 与NCD组相比, 高脂饮食处理后, 肠道内的乙酸、丙酸、丁酸等主要SCFAs含量都有不同程度的降低; 而给予DZSM后, 能显著性增加这3个SCFAs的含量(图 3A), 然而给予抗生素处理后, 结肠和盲肠内容物中的SCFAs水平大幅度降低, 而且有部分样品甚至无法检测到乙酸、丙酸或丙酸。肠道内的SCFAs主要由肠道菌群产生, 以上结果说明DZSM可促进肠道菌群产生SCFAs。肠道内产生的SCFAs需经肠上皮细胞上的单羧酸转运体(monocarboxylate transporters, MCTs) 转运至肠细胞, 进而吸收至血液循环及各组织脏器。采用RT-qPCR方法检测结肠组织中Mct1基因的表达, 结果显示, 与HFD组相比, DZSM能显著上调Mct1基因的表达(图 3B); 而且血浆的SCFAs含量检测结果也发现DZSM能显著增加丁酸水平(图 3C)。MCT1也广泛表达于肝脏组织, 可将SCFAs经由血液转运至肝细胞, 通过检测发现DZSM处理也可显著上调肝脏组织Mct1基因的表达(图 3D), 并显著性增加肝脏中的丁酸含量(图 3E)。
4 DZSM通过SCFA改善肝细胞脂质堆积
为阐明DZSM减轻肝脏脂质堆积的内在机制, 在HepG2细胞中进行了研究。经油酸诱导的HepG2细胞内出现明显的脂肪堆积, 而给予不同剂量的DZSM处理后, HepG2细胞内的脂滴未见明显减轻, 说明在体外DZSM减轻肝细胞脂质堆积的作用较弱(图 4)。鉴于DZSM改善脂肪肝的作用与肠道菌群有关, 而且DZSM能明显增加肝脏中的丁酸含量, 推测DZSM可能通过肠道菌群产生的丁酸改善肝细胞脂质堆积。结果显示, 油酸诱导的HepG2细胞经丁酸处理后, 其肝细胞内的脂滴明显减轻, 而且呈现明显的剂量依赖性。以上结果说明DZSM通过促进肠道菌群产生的SCFAs有效改善肝细胞脂质堆积, 进一步证实了DZSM通过调节肠道菌群治疗NAFLD。
5 DZSM改善肠屏障功能
良好的肠屏障功能可有效抑制肠道病原菌及肠内毒素等物质渗漏至机体, 从而减轻机体全身各组织脏器的急慢性炎症反应[9]。采用ELISA试剂盒检测血浆LPS水平, 发现DZSM能显著减少高脂饮食所引起的血浆LPS水平升高, 而抗生素处理杀灭肠道菌群后DZSM抑制血浆LPS的作用消失(图 5A), 这说明肠道菌群在DZSM抑制肠内毒素LPS进入机体发挥了重要作用。肠道黏液屏障和紧密连接是构成肠壁屏障的重要因素, 因此检测了DZSM对这两个因素的影响。ELISA和AB-PAS染色结果显示, 与HFD组相比, DZSM能明显增加结肠组织中的黏蛋白含量和产黏液蛋白的杯状细胞数目(图 5B、C); 采用RT-qPCR方法和免疫荧光染色方法检测结肠组织中ZO-1和Ocln基因的表达, 发现DZSM能显著上调结肠紧密连接蛋白的表达(图 5D、E); 而给予抗生素处理杀灭肠道菌群后, 发现DZSM改善肠屏障功能的作用减弱。考虑到DZSM对肠道菌群及SCFAs的调节作用, 推测DZSM可能通过调节肠道菌群促进SCFAs产生, 进而改善肠屏障功能。随后, 对各组动物中的丁酸水平与血浆LPS水平进行了线性相关性分析, 结果显示, 结肠和盲肠内容物的丁酸含量都与血浆LPS水平之间呈现显著性的负相关(图 5F), 提示高脂饮食地鼠灌胃给予丁酸盐后确实能明显改善肠屏障功能。以上结果说明, DZSM通过调节肠道菌群和促进其代谢产物SCFAs的产生来改善高脂饮食的肠屏障功能, 从而抑制肠道致病菌产生的LPS进入机体。
6 DZSM通过抑制LPS-TLR4-NFKB通路降低肝脏的炎症反应
采用RT-qPCR对肝脏组织中的各炎症因子的表达进行检测, 结果显示(图 6), 与HFD组相比, DZSM能显著抑制多个促炎因子Nfkb2、Nlrp3和Il1β等基因的表达(图 6A)。LPS是激活TLR4-NFKB信号通路的关键因子[10], 前面已证实DZSM有效降低高脂饮食引起的血浆LPS水平升高, 因此认为DZSM通过降低机体LPS水平, 来抑制肝脏的TLR4-NFKB炎症信号通路, 通过检测发现DZSM可显著降低TLR4-NFKB信号通路中Tlr4和Ikkβ基因的表达(图 6B)。随后在体外HepG2细胞进一步进行验证。RT-qPCR和Western blot结果都显示, 相比空白对照组, HepG2细胞经油酸+LPS处理后, 能显著激活TLR4-NFKB信号通路中TLR4、IKKβ、NFKB2和NLRP3等基因的表达; 而随着LPS浓度的降低, 该通路上的各因子表达都有所降低(图 6C、D), 说明降低LPS浓度可有效抑制TLR4-NFKB通路, 减轻肝细胞炎症反应; 然而, 油酸+LPS处理的HepG2细胞在加入不同剂量的DZSM后并没有看到TLR4-NFKB信号通路的明显抑制作用(图 6C、E)。以上结果表明, 在体内观察到的DZSM对肝脏炎症反应的抑制作用是DZSM通过改善肠屏障功能、降低肠内毒素LPS进入机体, 从而抑制肝脏的TLR4-NFKB炎症信号通路来实现的, 而并非DZSM对TLR4-NFKB信号通路的直接作用。
讨论
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DZSM胶囊是由灯盏细辛与麦冬、人参、五味子制成的口服制剂, 2002年经国家药品监督管理局批准可用于脑卒中后遗症和缺血性心脑血管疾病, 以及高脂血症合并上述症候者[11]。而现代药理学研究显示, DZSM胶囊中的多个重要组分都有治疗NAFLD的作用。灯盏细辛中的灯盏乙素可通过增强自噬、PPARγ (peroxisome proliferator-activated receptor γ)-Nrf2 (nuclear factor erythroid 2 related factor 2) 等通路缓解NAFLD[12, 13]; 五味子作为保肝药物, 其保肝活性成分木质素、三萜、挥发油和多糖等对肝病变有显著效果[14], 比如五味子提取物对高脂饮食诱导的大鼠非酒精性脂肪性肝炎有明显缓解作用[6], 五味子醇甲通过调节肝脂代谢、氧化应激缓解NAFLD[15], 五味子油显著降低血脂、缓解胰岛素抵抗、改善胰岛β细胞功能[16]; 人参中的多种人参皂苷类成分如Rb2、Rg2、Rg1等也可通过多种机制治疗NAFLD[17]。这些均表明DZSM在治疗NAFLD上有良好的应用前景, 但目前尚无DZSM治疗NAFLD的针对性研究。在模型动物的选择上, 本课题组前期研究发现[18], 金黄地鼠发展为高血脂、肝脏脂质堆积、肝功能损伤的时间较短, 且非常显著, 可明显缩短实验周期, 因此本研究选择金黄地鼠作为NAFLD的模型动物。本研究结果显示, DZSM有效缓解高脂饮食所导致的金黄地鼠血脂紊乱和肝脏脂质沉积, 同时给药后的肝功能酶水平也明显下降, 说明DZSM有效抑制NAFLD进程。
DZSM胶囊组分复杂且大多数组分都不易吸收, 无法直接进入机体发挥生物学作用, 这些物质口服后在肠道长时间滞留, 可与肠道菌群相互作用, 改变肠道菌群的组成和代谢, 因此本研究着重从调节肠道菌群及代谢的角度研究了DZSM治疗NAFLD的内在机制。研究发现, 金黄地鼠在预先给予广谱抗生素处理杀灭大部分肠道菌群后, DZSM改善NAFLD的作用大大减弱, 说明肠道菌群参与了DZSM治疗NAFLD的疗效。
肠道菌群为定植于人体消化道内的微生物, 种类超过千种, 这些微生物在长期进化过程中相互生存与制约, 形成了相对稳定的肠道微生态, 并发挥着重要生理功能。高脂饮食可导致机体内肠道菌群的紊乱, 导致厚壁菌门的相对丰度增加, 拟杆菌门的相对丰度减少[18]。厚壁菌门与拟杆菌门比值的降低在改善NAFLD方面起着重要作用, 本研究结果进一步证实了这两种菌在NAFLD中的作用, DZSM可引起Muribaculaceae、乳酸杆菌、双歧杆菌等多个产SCFAs的菌群丰度的上调。
SCFAs是肠道内的特定结肠厌氧菌发酵膳食纤维和抗性淀粉后产生的一类重要代谢产物, 主要包括乙酸、丙酸和丁酸, 其作为重要能量来源和信号分子, 主要通过抑制组蛋白去乙酰化酶和G蛋白偶联受体传递信号[19]。SCFAs一方面通过肠上皮细胞上的MCTs吸收入血到达脂肪、肝脏等组织, 与靶组织上的受体结合, 促进组织内的脂肪分解[20]; 另一方面SCFAs还可刺激肠内分泌细胞分泌肠激素类胰高血糖素肽1和酪酪肽到达脑和胰腺等组织抑制食欲和能量摄入[20]; SCFAs还可通过调节免疫细胞趋化性、活性氧释放、肠道调节性T细胞(Treg) 细胞的数量和功能发挥抗炎作用[21]; 而且SCFAs作为肠上皮细胞的主要能量来源, 可促进上皮细胞增殖和分化, 减少细胞凋亡, 促进黏蛋白分泌, 增加肠道跨上皮电阻和紧密连接, 降低肠黏膜通透性, 从而增强肠上皮屏障功能, 抑制肠内致病菌和肠内毒素LPS进入机体, 减轻机体组织的炎症反应[22]。高脂饮食中的膳食纤维和抗性淀粉含量减少, 使之产生SCFAs的原料减少, 从而显著减少SCFAs的产生。高脂饮食的地鼠给予DZSM治疗后, 由于其较强的肠道菌群调节作用, 显著升高多个产SCFAs菌群的丰度, 因此升高了肠道内的SCFAs水平。肠内的SCFAs经肠上皮细胞上的MCTs迅速吸收进入肠细胞, 进而吸收入血, 随血液循环进入肝脏[23]。由于DZSM对MCT1蛋白表达的上调, 增加了血液和肝脏中的SCFAs水平, 推测SCFAs在DZSM减少肝脏脂质沉积的过程中发挥了重要作用。通过体外HepG2研究, 进一步证实了DZSM通过促进肠道菌群产生SCFAs和转运至肝脏来治疗高脂饮食引起的肝脏脂质沉积。本研究发现血浆LPS水平与肠道SCFAs含量显著性负相关, 说明DZSM也可能通过增加SCFAs改善肠壁屏障功能, 抑制肠道内毒素LPS进入机体, 从而抑制HFD组LPS增加引起的肝脏TLR4-NFKB炎症信号通路的激活。
作者贡献: 郭慧慧负责实验研究和文章初稿撰写; 申浩然负责动物实验、细胞实验和数据分析; 王璐璐负责文章初稿修改; 张红娟负责部分动物实验及数据分析; 韩燕星负责实验设计和论文修改; 蒋建东负责实验监督及论文终稿审查。
利益冲突: 所有作者均声明不存在利益冲突。
基金
收起
  • 国家重点研发计划项目(2019YFC1708900)
  • 国家自然科学基金资助项目(82104254)
  • 中央高校基本科研业务经费项目(3332021042)
  • 中国医学科学院创新工程重大项目(2022-I2M-JB-012)
  • 中国医学科学院创新工程重大项目(2021-I2M-1-007)
  • 北京市科技新星计划项目(Z201100006820052)
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参考文献 引证文献
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2022年第57卷第12期
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文章信息
doi: 10.16438/j.0513-4870.2022-0908
  • 接收时间：2022-07-25
  • 首发时间：2025-12-24
  • 出版时间：2022-12-12
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  • 收稿日期：2022-07-25
  • 修回日期：2022-08-26
基金
国家重点研发计划项目(2019YFC1708900)
国家自然科学基金资助项目(82104254)
中央高校基本科研业务经费项目(3332021042)
中国医学科学院创新工程重大项目(2022-I2M-JB-012)
中国医学科学院创新工程重大项目(2021-I2M-1-007)
北京市科技新星计划项目(Z201100006820052)
作者信息
    1.中国医学科学院、北京协和医学院药物研究所, 天然药物活性物质与功能国家重点实验室, 北京 100050
    2.中国医学科学院、北京协和医学院医药生物技术研究所, 北京 100050

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*王璐璐, Tel: 86-10-63017906, E-mail: ;
韩燕星, E-mail:
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2种不同金属材料的力学参数
科
Family		 属数
Number of
genus		 种数
Number of
species		 占总种数比例
Percentage of
total species (%)		 属
Genus		 种数
Number of
species		 占总种数比例
Percentage of total
species (%)
鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
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