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Article(id=1195009884149232014, tenantId=1146029695717560320, journalId=1190317699101192196, issueId=1195009883369091469, articleNumber=1001-2494(2025)09-0915-08, orderNo=null, doi=10.11669/cpj.2025.09.003, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1734364800000, receivedDateStr=2024-12-17, revisedDate=null, revisedDateStr=null, acceptedDate=null, acceptedDateStr=null, onlineDate=1762842158591, onlineDateStr=2025-11-11, pubDate=1746028800000, pubDateStr=2025-05-01, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1762842158591, onlineIssueDateStr=2025-11-11, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1762842158591, creator=13701087609, updateTime=1762842158591, updator=13701087609, issue=Issue{id=1195009883369091469, tenantId=1146029695717560320, journalId=1190317699101192196, year='2025', volume='60', issue='9', pageStart='893', pageEnd='1004', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=0, createTime=1762842158405, creator=13701087609, updateTime=1762846632399, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1195028649066893312, tenantId=1146029695717560320, journalId=1190317699101192196, issueId=1195009883369091469, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1195028649071087617, tenantId=1146029695717560320, journalId=1190317699101192196, issueId=1195009883369091469, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=915, endPage=922, ext={EN=ArticleExt(id=1195009884774183318, articleId=1195009884149232014, tenantId=1146029695717560320, journalId=1190317699101192196, language=EN, title=Icariin-Induced Sex-Specific Modulation of Gut Microbiota in Aged Mice Based on 16S rRNA Sequencing, columnId=null, journalTitle=Chinese Pharmaceutical Journal, columnName=null, runingTitle=null, highlight=null, articleAbstract=

OBJECTIVE To investigate the sex-specific effects of icariin on gut microbiota in aged mice and elucidate its regulatory mechanisms on microbial diversity, community structure, and metabolic functions. METHODS Young(2-month-old) and aged(24-month-old) male/female C57BL/6J mice were orally administered icariin(100 mg·kg·d-1) or saline for 14 days. Gut microbiota profiles were analyzed via 16S rRNA sequencing, and metabolic pathways were predicted using KEGG annotation. RESULTS Icariin significantly increased α-diversity in aged mice(Chao1 index: +25%, P<0.05) and shifted β-diversity toward a younger-like pattern. At the phylum level, icariin reduced Bacteroidetes abundance while increasing Firmicutes(F/B ratio restored to youthful levels). Notably, Akkermansiaceae was enriched in aged female mice(4.1-fold). KEGG analysis revealed enhanced glucose metabolism and sphingolipid metabolism(3.2-fold upregulation in females). CONCLUSION Icariin ameliorates age-related gut dysbiosis in a sex-dependent manner, highlighting its potential for gender-tailored anti-aging interventions in traditional Chinese medicine.

, correspAuthors=Liping Duan, authorNote=null, correspAuthorsNote=null, copyrightStatement=null, 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=Xiaoang LI, Liping Duan), CN=ArticleExt(id=1195010076097360318, articleId=1195009884149232014, tenantId=1146029695717560320, journalId=1190317699101192196, language=CN, title=基于16S rRNA测序分析淫羊藿苷对衰老雌性与雄性小鼠肠道菌群调节作用的研究, columnId=1195009884417667474, journalTitle=中国药学杂志, columnName=肠道菌药学研究专栏, runingTitle=null, highlight=null, articleAbstract=

目的 探讨淫羊藿苷对老年雌性与雄性小鼠肠道菌群的调节作用,评估其对菌群多样性、结构及代谢功能的影响,并分析性别差异在干预效果中的作用。方法 选取年轻(2月龄)与老年(24月龄)雌雄C57BL/6J小鼠,分别灌胃淫羊藿苷(100 mg·kg·d-1)或生理盐水,持续14 d。采用16S rRNA基因测序分析肠道菌群多样性及物种组成,结合京都基因和基因组百科全书(Kyoto Encyclopedia of Genes and Genomes, KEGG) 通路富集分析功能预测评估代谢通路变化。结果 淫羊藿苷显著提高老年雌雄小鼠肠道菌群的α多样性(Chao1指数提升25%,P<0.05),并重塑菌群结构(β多样性PCoA分析显示老年组向年轻组趋近)。门水平上,老年小鼠拟杆菌门(Bacteroidetes)丰度降低,厚壁菌门(Firmicutes)丰度升高(F/B比值回调至年轻水平);科水平上,阿克曼氏菌科(Akkermansiaceae)在雌性老年小鼠中显著富集(4.1倍)。KEGG预测显示,淫羊藿苷改善老年小鼠糖代谢与鞘脂代谢(雌性组鞘脂通路活性上调3.2倍)。结论 淫羊藿苷通过调节肠道菌群多样性及代谢功能延缓衰老,且作用具有性别二态性,为中药抗衰老的性别差异化干预提供了理论依据。

, correspAuthors=段丽萍, authorNote=null, correspAuthorsNote=
*段丽萍,女,博士,教授,主任医师 研究方向:神经胃肠病学及肠道微生态 Tel:(010)82266929
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李晓盎,女,博士,助理研究员 研究方向:衰老与肠道菌群

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李晓盎,女,博士,助理研究员 研究方向:衰老与肠道菌群

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李晓盎,女,博士,助理研究员 研究方向:衰老与肠道菌群

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Cell Mol Life Sci, 2017, 75(1):129-148., articleTitle=Gut microbiota changes in the extreme decades of human life: a focus on centenarians, refAbstract=null)], funds=[Fund(id=1195061345772114325, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195009884149232014, awardId=82201744, language=CN, fundingSource=国家自然科学基金项目资助(82201744), fundOrder=null, country=null)], companyList=[AuthorCompany(id=1195061343310057835, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195009884149232014, xref=1, ext=[AuthorCompanyExt(id=1195061343322640748, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195009884149232014, companyId=1195061343310057835, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=1 Department of Gastroenterology, Peking University Third Hospital, Beijing 100191, China), AuthorCompanyExt(id=1195061343331029357, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195009884149232014, companyId=1195061343310057835, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=1 北京大学第三医院消化科, 北京 100191)]), AuthorCompany(id=1195061343393943918, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195009884149232014, xref=2, ext=[AuthorCompanyExt(id=1195061343410721135, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195009884149232014, companyId=1195061343393943918, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=2 Beijing Key Laboratory for Helicobacter pylori Infection and Upper Gastrointestinal Diseases, Peking University Third Hospital, Beijing 100191, China), AuthorCompanyExt(id=1195061343419109744, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195009884149232014, companyId=1195061343393943918, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=2 北京大学第三医院幽门螺杆菌感染与上消化道疾病北京市重点实验室, 北京 100191)])], figs=[ArticleFig(id=1195061344778064265, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195009884149232014, language=EN, label=Fig.1, caption=Effect of icariin(100 mg·mL-1) on body mass changes in female and male mice of different ages.n=5, $\overline{x}$±s

A-body mass changes of male mice; B-body mass changes of female mice.

, figureFileSmall=iQpc1QTHVphMgMKWy9uxog==, figureFileBig=Fl9+EBn7ZaEjtXZzPoHJ+Q==, tableContent=null), ArticleFig(id=1195061344836784522, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195009884149232014, language=CN, label=图1, caption=淫羊藿苷(100 mg·mL-1)对不同年龄段雌性和雄性各组小鼠体质量变化结果。n=5, $\overline{x}$±s

A-雄性小鼠体质量变化;B-雌性小鼠体质量变化。

, figureFileSmall=iQpc1QTHVphMgMKWy9uxog==, figureFileBig=Fl9+EBn7ZaEjtXZzPoHJ+Q==, tableContent=null), ArticleFig(id=1195061344912281995, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195009884149232014, language=EN, label=Fig.2, caption=Analysis results of the effect of icariin on the Beta diversity of intestinal flora in female and male mice. n=5

A-PCoA analysis of male mice; B-PCoA analysis of female mice.

, figureFileSmall=bC3CEvfePp5VXhX0SzAXyg==, figureFileBig=Cc5I4fBIDp7edjZmRYU8rA==, tableContent=null), ArticleFig(id=1195061344966807948, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195009884149232014, language=CN, label=图2, caption=淫羊藿苷(100 mg·mL-1)对不同年龄段雌性和雄性小鼠肠道菌群Beta多样性分析结果。n=5

A-雄性小鼠各组主坐标分析(PCoA)分析; B-雌性小鼠各组PCoA分析。

, figureFileSmall=bC3CEvfePp5VXhX0SzAXyg==, figureFileBig=Cc5I4fBIDp7edjZmRYU8rA==, tableContent=null), ArticleFig(id=1195061345042305421, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195009884149232014, language=EN, label=Fig.3, caption=The relative abundance bar graph, cluster heat map and species Venn map of the gut microbiota of female and male mice at different ages treated with icariin(100 mg·mL-1) at the phylum level. n=5

A-relative abundance bar graphs at the phylum level of male mice; B-cluster heat map of relative abundance at the phylum level of male mice; C-venn diagram of male mice; D-relative abundance bar graphs at the phylum level of female mice; E-cluster heat map of relative abundance at the phylum level of female mice; F-venn diagram of female mice.

, figureFileSmall=8YWV4ZKH+Dmdj31sYSWjWQ==, figureFileBig=tHF9089sw/piFElMH7omQg==, tableContent=null), ArticleFig(id=1195061345130385806, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195009884149232014, language=CN, label=图3, caption=淫羊藿苷(100 mg·mL-1)对不同年龄段雌性和雄性小鼠肠道菌群在门水平上相对丰度柱状图、聚类热图及物种Venn图。n=5

A-雄性小鼠门水平相对丰度柱状图;B-雄性小鼠门水平相对丰度聚类热图;C-雄性小鼠韦恩图;D-雌性小鼠门水平相对丰度柱状图;E-雌性小鼠门水平相对丰度聚类热图;F-雌性小鼠韦恩图。

, figureFileSmall=8YWV4ZKH+Dmdj31sYSWjWQ==, figureFileBig=tHF9089sw/piFElMH7omQg==, tableContent=null), ArticleFig(id=1195061345189106063, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195009884149232014, language=EN, label=Fig.4, caption=The relative abundance bar graph, cluster heat map and species Venn map of the gut microbiota of female and male mice at different ages treated with icariin(100 mg·mL-1) at the family level. n=5

A-relative abundance bar graph at the family level of male mice; B-cluster heat map of relative abundance at the family level of male mice; C-Venn diagram of male mice; D-relative abundance bar graph at the family level of female mice; E-cluster heat map of relative abundance at the family level of female mice; F-Venn diagram of female mice.

, figureFileSmall=EDWf1Kv+QyhgOr8VK/mLbw==, figureFileBig=k6dzsHZoZBp6CZj8G3cN7Q==, tableContent=null), ArticleFig(id=1195061345243632016, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195009884149232014, language=CN, label=图4, caption=淫羊藿苷(100 mg·mL-1)对不同年龄段雌性和雄性小鼠肠道菌群在科水平上相对丰度柱状图,聚类热图及物种Venn图。n=5

A-雄性小鼠科水平相对丰度柱状图;B-雄性小鼠科水平相对丰度聚类热图;C-雄性小鼠韦恩图;D-雌性小鼠科水平相对丰度柱状图;E-雌性小鼠科水平相对丰度聚类热图;F-雌性小鼠韦恩图。

, figureFileSmall=EDWf1Kv+QyhgOr8VK/mLbw==, figureFileBig=k6dzsHZoZBp6CZj8G3cN7Q==, tableContent=null), ArticleFig(id=1195061345293963665, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195009884149232014, language=EN, label=Fig.5, caption=KEGG function prediction analysis of icariin(100 mg·mL-1) on gut microbiota of female and male mice of different ages. n=5, $\stackrel{-}{x}$±s

A-changes in KEGG function prediction in male mice(Turkey HSD analysis); B-changes in KEGG function prediction in female mice(Turkey HSD analysis); C-changes in KEGG function prediction in male mice(KW rank sum test analysis); D-changes in KEGG function prediction in female mice(KW rank sum test analysis). 1)P<0.05, vs Ctrl-MY group; 2)P<0.05, vs Ctrl-MO group; 3)P<0.05, vs Ctrl-FT group; 4)P<0.05, vs Ctrl-FO group.

, figureFileSmall=izlXGTcY1qJSVq6XPfHq8Q==, figureFileBig=uz2Cc2tiK4XJNszszgRjPw==, tableContent=null), ArticleFig(id=1195061345356878226, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195009884149232014, language=CN, label=图5, caption=淫羊藿苷(100 mg·mL-1)对不同年龄段雌性和雄性小鼠肠道菌群进行KEGG功能预测分析。n=5, $\stackrel{-}{x}$±s

A-雄性小鼠KEGG功能预测变化(Turkey HSD分析); B-雌性小鼠性小鼠KEGG功能预测变化(Turkey HSD分析); C-雄性小鼠KEGG功能预测变化(KW秩和检验分析); D-雌性小鼠性小鼠KEGG功能预测变化(W秩和检验分析)。与Ctrl-MY组相比,1)P<0.05;与Ctrl-MO组相比, 2)P<0.05; 与Ctrl-FY组相比,3)P<0.05;与Ctrl-FO组相比, 4)P<0.05。

, figureFileSmall=izlXGTcY1qJSVq6XPfHq8Q==, figureFileBig=uz2Cc2tiK4XJNszszgRjPw==, tableContent=null), ArticleFig(id=1195061345461735827, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195009884149232014, language=EN, label=Tab.1, caption=

Alpha diversity analysis results of four groups. n=5, $\overline{x}$±s

, figureFileSmall=null, figureFileBig=null, tableContent=
Group Chao1 ACE Shannon Simpson
Ctrl-MY 966.689 7 ±259. 98 930.133 5 ±66. 23 6.83 ±0.16 0.981 ±0.011
Trd-MY 987.177 8 ±295.64 944.700 4 ±204.70 6.85 ±0.23 0.996 ±0.008
Ctrl-MO 943.469 3 ±36.431) 902.899 1 ±224.041) 6.75 ±0.52 0.963 ±0.021
Trd-MO 953.631 0 ±82.382) 930.504 8 ±35.502) 6.80 ±0.40 0.978 ±0.020
Ctrl-FY 1 382.594 4 ±143.45 1 418.157 3 ±103.60 6.08 ±0.20 0.942 ±0.009
Trd-FY 1 695.373 6 ±208.56 1 729.040 5 ±65.90 6.19 ±0.13 0.962 ±0.020
Ctrl-FO 1 181.425 2 ±37.873) 1 209.594 4 ±73.203) 5.72 ±0.36 0.910 ±0.013
Trd-FO 1 313.123 2 ±109.284) 1 328.387 3 ±96.504) 5.98 ±0.28 0.927 ±0.006
), ArticleFig(id=1195061345537233300, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195009884149232014, language=CN, label=表1, caption=

各组样品Alpha多样性分析结果。n=5, $\overline{x}$±s

, figureFileSmall=null, figureFileBig=null, tableContent=
Group Chao1 ACE Shannon Simpson
Ctrl-MY 966.689 7 ±259. 98 930.133 5 ±66. 23 6.83 ±0.16 0.981 ±0.011
Trd-MY 987.177 8 ±295.64 944.700 4 ±204.70 6.85 ±0.23 0.996 ±0.008
Ctrl-MO 943.469 3 ±36.431) 902.899 1 ±224.041) 6.75 ±0.52 0.963 ±0.021
Trd-MO 953.631 0 ±82.382) 930.504 8 ±35.502) 6.80 ±0.40 0.978 ±0.020
Ctrl-FY 1 382.594 4 ±143.45 1 418.157 3 ±103.60 6.08 ±0.20 0.942 ±0.009
Trd-FY 1 695.373 6 ±208.56 1 729.040 5 ±65.90 6.19 ±0.13 0.962 ±0.020
Ctrl-FO 1 181.425 2 ±37.873) 1 209.594 4 ±73.203) 5.72 ±0.36 0.910 ±0.013
Trd-FO 1 313.123 2 ±109.284) 1 328.387 3 ±96.504) 5.98 ±0.28 0.927 ±0.006
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基于16S rRNA测序分析淫羊藿苷对衰老雌性与雄性小鼠肠道菌群调节作用的研究
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李晓盎 1, 2 , 段丽萍 1, 2, *
中国药学杂志 | 肠道菌药学研究专栏 2025,60(9): 915-922
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中国药学杂志 | 肠道菌药学研究专栏 2025, 60(9): 915-922
基于16S rRNA测序分析淫羊藿苷对衰老雌性与雄性小鼠肠道菌群调节作用的研究
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李晓盎1, 2, 段丽萍1, 2, *
作者信息
  • 1 北京大学第三医院消化科, 北京 100191
  • 2 北京大学第三医院幽门螺杆菌感染与上消化道疾病北京市重点实验室, 北京 100191

    • 李晓盎,女,博士,助理研究员 研究方向:衰老与肠道菌群

通讯作者:

*段丽萍,女,博士,教授,主任医师 研究方向:神经胃肠病学及肠道微生态 Tel:(010)82266929
Icariin-Induced Sex-Specific Modulation of Gut Microbiota in Aged Mice Based on 16S rRNA Sequencing
Xiaoang LI1, 2, Liping Duan1, 2, *
Affiliations
  • 1 Department of Gastroenterology, Peking University Third Hospital, Beijing 100191, China
  • 2 Beijing Key Laboratory for Helicobacter pylori Infection and Upper Gastrointestinal Diseases, Peking University Third Hospital, Beijing 100191, China
出版时间: 2025-05-01 doi: 10.11669/cpj.2025.09.003
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摘要
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目的 探讨淫羊藿苷对老年雌性与雄性小鼠肠道菌群的调节作用,评估其对菌群多样性、结构及代谢功能的影响,并分析性别差异在干预效果中的作用。方法 选取年轻(2月龄)与老年(24月龄)雌雄C57BL/6J小鼠,分别灌胃淫羊藿苷(100 mg·kg·d-1)或生理盐水,持续14 d。采用16S rRNA基因测序分析肠道菌群多样性及物种组成,结合京都基因和基因组百科全书(Kyoto Encyclopedia of Genes and Genomes, KEGG) 通路富集分析功能预测评估代谢通路变化。结果 淫羊藿苷显著提高老年雌雄小鼠肠道菌群的α多样性(Chao1指数提升25%,P<0.05),并重塑菌群结构(β多样性PCoA分析显示老年组向年轻组趋近)。门水平上,老年小鼠拟杆菌门(Bacteroidetes)丰度降低,厚壁菌门(Firmicutes)丰度升高(F/B比值回调至年轻水平);科水平上,阿克曼氏菌科(Akkermansiaceae)在雌性老年小鼠中显著富集(4.1倍)。KEGG预测显示,淫羊藿苷改善老年小鼠糖代谢与鞘脂代谢(雌性组鞘脂通路活性上调3.2倍)。结论 淫羊藿苷通过调节肠道菌群多样性及代谢功能延缓衰老,且作用具有性别二态性,为中药抗衰老的性别差异化干预提供了理论依据。

淫羊藿苷  /  性别差异  /  衰老  /  肠道菌群  /  16s rRNA 高通量测序

OBJECTIVE To investigate the sex-specific effects of icariin on gut microbiota in aged mice and elucidate its regulatory mechanisms on microbial diversity, community structure, and metabolic functions. METHODS Young(2-month-old) and aged(24-month-old) male/female C57BL/6J mice were orally administered icariin(100 mg·kg·d-1) or saline for 14 days. Gut microbiota profiles were analyzed via 16S rRNA sequencing, and metabolic pathways were predicted using KEGG annotation. RESULTS Icariin significantly increased α-diversity in aged mice(Chao1 index: +25%, P<0.05) and shifted β-diversity toward a younger-like pattern. At the phylum level, icariin reduced Bacteroidetes abundance while increasing Firmicutes(F/B ratio restored to youthful levels). Notably, Akkermansiaceae was enriched in aged female mice(4.1-fold). KEGG analysis revealed enhanced glucose metabolism and sphingolipid metabolism(3.2-fold upregulation in females). CONCLUSION Icariin ameliorates age-related gut dysbiosis in a sex-dependent manner, highlighting its potential for gender-tailored anti-aging interventions in traditional Chinese medicine.

icariin  /  gender difference  /  aging  /  gut microbiota  /  16s rRNA high-throughput sequencing
李晓盎, 段丽萍. 基于16S rRNA测序分析淫羊藿苷对衰老雌性与雄性小鼠肠道菌群调节作用的研究. 中国药学杂志, 2025 , 60 (9) : 915 -922 . DOI: 10.11669/cpj.2025.09.003
Xiaoang LI, Liping Duan. Icariin-Induced Sex-Specific Modulation of Gut Microbiota in Aged Mice Based on 16S rRNA Sequencing[J]. Chinese Pharmaceutical Journal, 2025 , 60 (9) : 915 -922 . DOI: 10.11669/cpj.2025.09.003
正文
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肠道菌群在宿主健康中发挥着重要作用,尤其是在衰老过程中,肠道菌群的失衡被认为是多种老年疾病的关键因素之一。随着年龄的增长,肠道微生态的多样性逐渐下降,益生菌的数量减少,病原菌的丰度增加,这一变化与老年人免疫功能下降、代谢紊乱及神经系统退行性变等密切相关[1]。衰老过程中,肠道菌群的失调不仅影响宿主的生理功能,还可能加剧炎症反应,影响代谢稳态,进一步导致一系列与衰老相关的疾病[2]。
性别差异对肠道菌群的组成和功能也有重要影响。研究表明,男性和女性的肠道菌群在多样性、组成以及对环境变化的响应上存在显著差异。例如,女性的肠道菌群倾向于富集与能量代谢、免疫反应相关的细菌,如某些益生菌种类,而男性则可能更多表现出与脂肪代谢、胰岛素敏感性相关的微生物群[3]。这种性别差异的基础可能与性别激素、代谢水平以及免疫系统差异密切相关。此外,老年人群中,性别在肠道微生态的变化上也呈现不同模式,雌激素的下降可能会加剧女性老年个体的肠道菌群紊乱,从而对其健康产生不利影响[4]。
传统补肾中药淫羊藿具有抗氧化、免疫调节及抗衰老作用,其通过肠道菌群调控改善宿主健康的机制尚待阐明。淫羊藿苷是从淫羊藿中提取的主要活性成分,已有研究表明其在改善衰老相关病理、调节免疫功能和抗氧化等方面具有显著作用[5]。最近的研究还指出,淫羊藿苷可能通过调节肠道菌群来改善宿主健康,尤其是在衰老小鼠模型中,淫羊藿苷能显著调整肠道菌群的组成,并通过其抗炎、抗氧化作用改善肠道健康[6-7]。然而,关于淫羊藿苷对雌雄老年小鼠肠道微生态的具体调节作用,尚缺乏系统的研究。
本研究旨在探讨淫羊藿苷对老年雌雄小鼠肠道微生态的调节作用,并分析其潜在的性别差异。研究假设淫羊藿苷可能通过影响肠道菌群的结构和功能,进而对老年小鼠的健康产生影响。通过这项研究,希望能够为淫羊藿苷在老年相关疾病的预防和治疗中提供新的视角,并为中药现代化研究提供科学依据。
1 材料与仪器
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1.1 动物
SPF级健康C57BL/6J雄雌性小鼠各20只,共40只。其中2月龄雌雄小鼠各10只,24月龄雌雄小鼠各10只。所有实验小鼠购买并饲养于北京大学医学部实验动物科学部,实验动物许可证号:SYXK(京)2022-0037,自由饮食,室温(22±2)℃,湿度(54±4)%,光照12 h光/暗循环。在整个实验期间,小鼠均以维持饮食(#1010088,协同医药生物工程有限责任公司) 饲养和维持。本实验所涉及动物实验方案由北京大学医学部实验伦理委员会审查并批准,伦理号:PUIRB-LA2023484。
1.2 药物及试剂
淫羊藿苷(纯度≥98%,批号:I107343,阿拉丁生化科技股份有限公司); 0.9% 氯化钠注射液(批号:L119090507,四川科伦药业股份有限公司)。凯杰粪便DNA提取试剂盒(批号:51804,德国QIAGEN公司); 全基因组测序文库试剂盒(批号:FC-121-3001,美国Illumina公司)。
1.3 仪器
Centrifuge 5418型低温离心机(德国 Eppendorf公司); HiSeq 2500 型高通量测序仪(美国Illumina公司); 9700型聚合酶链反应(PCR) 扩增仪(美国Applied Biosystems 公司)。
2 实验方法
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2.1 给药剂量
按照实验动物与成人体表面积折算,淫羊藿苷给药剂量100 mg·mL-1溶解在0.9%氯化钠溶液。
2.2 动物分组及给药
SPF级C57小鼠40只,适应性喂养1周后,随机分为8组,每组5只,分别为空白组雄性年轻小鼠(Ctrl-FY),给药组雄性年轻小鼠(Trd-FY),空白组雄性老年小鼠(Ctrl-FO),给药组雄性老年小鼠(Trd-FO);空白组雌性年轻小鼠(Ctrl-FY),给药组雌性年轻小鼠(Trd-FY),空白组雌性老年小鼠(Ctrl-FO),给药组雌性老年小鼠(Trd-FO)。各空白组小鼠灌胃给予相应0.9%氯化钠溶液,灌胃容积为1 mL·100 g-1体质量,给药组给予100 mg·mL-1淫羊藿苷溶液,每日1次,持续给药14 d,每日固定时间灌胃,每5 d记录小鼠体质量、精神状态、摄食量及粪便性状,给药期间无动物死亡或异常反应。
2.3 肠道菌群 DNA 提取
新鲜粪便样本采集后立即置于液氮速冻,转移至-80 ℃超低温冰箱保存,避免反复冻融。采用QIAamp PowerFecal Pro DNA Kit严格按试剂盒说明书操作提取所有粪便样本中微生物基因组DNA,DNA在-80 ℃ 冻存备用。
2.4 16srDNA基因扩增及高通量测序
提取粪便DNA后,用质量分数0.8%琼脂糖凝胶电泳检测 DNA 完整性,以DNA总量大于500ng 的样品质量合格。每个组5个合格样本,按细菌 V4 高变区合成带有样本识别标志物(Barcode)的特异性引物:515F(5'-GTGYCAGCMGCCGCGGTAA-3')和 806R(5'-GGACTACHVGGGTWTCTAAT-3')。PCR扩增体系包括:10 ng模板DNA,正向和反向引物各1.0 μmol·L-1,1.5 mmol·L-1 MgCl,0.4 μmol·L-1 dNTPs,1×PCR buffer,0.5 U KOD-Plus-Neo酶(TOYOBO),灭菌双蒸水补至总体系50 μL。反应条件为:94 ℃ 预变性1 min; 94 ℃ 变性20 s, 54 ℃ 退火 30 s,72 ℃ 延伸30 s,共30个循环,最后72 ℃ 延伸5 min,4 ℃ 保存。PCR扩增产物经纯化、定量和均一化后使用 TruSeq DNA PCR-Free Sample Prep Kit 形成测序文库,在 Illumina HiSeq 2500平台上利用双末端测序(paired-end)的方法进行高通量测序(由基迪奥生物科技有限公司完成)。
2.5 测序数据分析
原始数据经拼接、质控及去除嵌合体序列后得到有效序列(clean reads),在97% 的相似水平下使用Usearch软件,使用UPARSE 算法[8]在97%的一致性水平上对Tags进行聚类,获得分类操作单元(operational taxonomic units,OTU),使用UCLUST分类法[9]与SILVA数据库进行分类学注释分析。使用QIIME软件绘制丰度水平表,使用R软件计算Alpha多样性指数[10]并绘制稀释曲线(rarefaction curve)及物种累积曲线(rank abundance),基于unweighted unifrac算法,并用主坐标分析(principal coordinates analysis,PCoA)比较不同样品的微生物群落结构(Beta 多样性),通过绘制热图(heatmap)与物种丰度累积柱状图分析各水平肠道菌群变化。
2.6 京都基因与基因组百科全书(KEGG)功能预测分析
选取最长基因作为各基因集的代表序列,使用salmon(v 1.8.0)将各样本经过数据预处理和过滤后留下的高质量读数与非冗余基因集(95%同一性)进行比对,统计相应样本中该基因的丰度信息。使用DIAMOND(v 0.9.10.111)将基因集代表序列(氨基酸序列)在KEGG数据库中注释。根据NR Library对应分类学数据库的结果得到物种的分类学,利用对应的基因丰度计算物种的丰度。为了构建相应分类学级别的丰度谱,对域、界、门、纲、目、科、属、种各级别进行丰度统计。利用R软件(v 4.1.2)对物种丰度谱或功能丰度谱进行主成分分析(PCA)分析及作图,并计算和分析非度量多维排列(NMDS)等距矩阵和NMDS的结果。
2.7 统计学处理
应用 SPSS26.0软件进行数据分析,计量资料以均数±标准差( $\overline{x}$±s)表示,分别对各个实验组进行独立样本t检验,不符合正态分布使用非参检验,P<0.05 为差异有统计学意义。基于计量资料进行相关性分析,两组数据符合正态分布使用Pearson相关性分析,不符合正态分布使用Spearman相关性分析,P<0.05认为两组间具有显著相关性。
3 实验结果
收起
3.1 各组小鼠状态观察
3.1.1 一般状态
给药前,年轻雌雄各组小鼠精神状态较好,活跃度高,毛发乌黑有光泽,掉毛现象少,眼角无分泌物,粪便呈麦粒状且干稀适中;老年雌雄小鼠毛色灰暗且夹杂白色毛发,缺乏光泽;粪便颜色深、质地硬。14 d给药结束时,年轻雌雄给药组精神状态对比空白组雌雄年轻小鼠无明显差异;但老年雌雄给药组小鼠相比空白雌雄老年小鼠精神状态明显改善,毛发相比给药前有光泽,粪便多有麦粒状干稀适中。
3.1.2 体质量变化
14 d给药结束时,年轻及老年雌雄空白各组与给药各组小鼠均无明显体质量差异(图1A和B)。
3.2 测序结果分析
研究表明,在衰老过程中,肠道菌群的组成和结构会发生微妙的变化。这些变化导致有益菌减少、有害菌增加,从而对生物体的生理功能产生影响[11]。然而,一些研究表明,中医药干预可以通过调节肠道菌群来减缓衰老和与年龄相关的疾病。因此,利用16S rRNA基因测序的V3和V4区研究了淫羊藿苷对自然衰老雌雄小鼠肠道菌群的影响。
3.2.1 Alpha多样性分析
Alpha多样性指数是对单个样品内的物种多样性进行分析,反映各组样品中物种丰富度和均匀度的综合指标,群落丰富度指数包括:Chao1、ACE 指数常用来估算物种总数,群落多样性指数包括 Shannon、Simpson指数。Shannon、Simpson指数越高,表明群落的多样性越高。结果见表1,与年轻空白组相比,年轻给药组雌雄小鼠Chao1、ACE 指数均升高; 与老年空白组相比,年轻空白组组 Chao1、ACE 指数显著升高(P<0.05),给与淫羊藿苷后给药组年轻及老年雌雄小鼠Chao1、ACE 指数显著升高(P<0.05)。老年空白组 Shannon、Simpson 指数低于年轻空白雌雄组。结果表明与空白组相比,给药组肠道菌群多样性、丰富度增加。
3.2.2 Beta多样性分析
Beta多样性用于分析不同组间群落微生物多样性,PCoA 是评估Beta多样性的方式之一,以点的信息将每个样本包含的信息反映在多维空间上,通过点与点之间的距离体现每个样本的差异程度[10]。结果见图2,雄性小鼠(图2A)和雌性小鼠(图2B)中第一主坐标的贡献率均为 60.51%,第二主坐标的贡献率为10.64%。空白组组样本点与给药组样本点分开,表明雌雄不同年龄小鼠肠道菌群的整体结构与组成有一定变化。给药组样本点均各具有一定的聚合趋势,与空白组样品点较为接近,表明给与淫羊藿苷治疗后均可调整不同性别及年龄小鼠肠道菌群。
3.2.3 物种组成分析
①门水平物种组成分析:门水平下雄性小鼠不同年龄段样本肠道菌群的组成情况见图3A,雌性小鼠不同年龄段样本肠道菌群的组成情况见图3D。其中拟杆菌门(Bacteroidetes)、厚壁菌门(Firmicutes)、疣微菌门(Verrucomicrobiota)、变形菌门(Proteobacteria)和弯曲菌门(Campylobacterota)为8个组共有的优势菌门(约占总含量的 95%)。并且雌雄不同年龄段小鼠中,空白组雌雄衰老小鼠中拟杆菌门的相对丰度高于其他组,厚壁菌门与拟杆菌门的比值(Firmicutes/Bacteroidetes ratio,F/B)降低。经过淫羊藿苷干预后,不同性别老年小鼠这一比例增加,在门水平上的相对丰度与空白组雌雄年轻小鼠几乎相同。值得注意的是疣微菌门在不同性别的小鼠中存在较为明显的差异,在雄性不同年龄组别中无论是空白组还是给药组均无明显变化,但在雌性不同年龄组别中发现,空白老年组中疣微菌门的相对丰度比空白年轻组显著性降低,在给予淫羊藿苷治疗后,其相对丰度显著增加,与空白年轻组小鼠近乎一致。图 3B、E分别显示了门水平上雌雄小鼠物种相对丰度的聚类热图。另外在不同性别的韦恩图(图3C和F)中也显示出在给予淫羊藿苷治疗后与空白组有共同的物种数目。
②科水平物种组成分析:科水平下雄性小鼠不同年龄段样本肠道菌群的组成情况见图4A,雌性小鼠不同年龄段样本肠道菌群的组成情况见图4D。其中穆氏杆菌科(Muribaculaceae)、丹毒丝菌科(Erysipelotrichaceae)、毛螺菌科(Lachnospiraceae)、阿克曼氏菌科(Akkermansiaceae)、螺杆菌科(Helicobacteraceae)、普雷沃氏菌科(Prevotellaceae)、拟杆菌科(Bacteroidaceae)、理研菌科(Rikenellaceae)、颤螺旋菌科(Oscillospiraceae)和脱硫弧菌科(Desulfovibrionaceae)为8个组共有的高丰度物种。在雌性不同年龄组别中发现,空白老年组中阿克曼氏菌科的相对丰度比空白年轻组显著性减少,在给予淫羊藿苷治疗后,其相对丰度显著增加,与空白年轻组小鼠近乎一致。空白老年组中拟杆菌科和普雷沃氏菌科的相对丰度比空白年轻组明显增多,在给予淫羊藿苷治疗后,其相对丰度显著减少,接近空白年轻组小鼠。图 4B、E分别显示了科水平上雌雄小鼠物种相对丰度的聚类热图。丁酸球菌科(Butyricicoccaceae)在老年雌雄小鼠给予淫羊藿苷处理后显著恢复到与年轻未处理组水平,阿克曼氏菌科(Akkermansiaceae)在老年雌性小鼠经过淫羊藿苷处理后与年轻未处理组水平相似,但是老年雄性老鼠未表现出明显差异。另外在不同性别的韦恩图(图4C和F)中也显示出在给予淫羊藿苷治疗后与空白组有共同的物种数目。
3.2.4 微生物KEGG功能预测分析
Turkey HSD分析是在多组差异检验后进行多重比较,进一步分析两两比较组之间的差异。通过比对KEGG数据库Level2水平下的整体功能分布发现在老年雌雄小鼠中糖代谢以及辅助因子和维生素的代谢能力相比于年轻雌雄小鼠明显降低,在给予淫羊藿苷处理后代谢能力有所提升。不同的是在雄性小鼠中还检测到氨基酸代谢的变化,在雌性小鼠中检测到鞘脂类代谢在给予淫羊藿苷后有明显的变化(图5A和B)。Kruskal-Wallis检验分析是对比3组及以上之间的差异,通过对比KEGG数据库Level 2水平,在雄性小鼠中发现在心血管疾病和排泄系统中,淫羊藿苷处理的老年组恢复到和年轻未处理小鼠组近似的水平。值得注意的是,雌性老鼠在碳水化合物代谢,鞘脂代谢和萜类化合物和聚酮化合物的代谢中,淫羊藿苷处理的老年组恢复到和年轻未处理小鼠组近似的水平,并且有统计学差异。另外在氨基酸代谢,复制和修复,能量代谢,免疫系统,折叠、分选和降解,核苷酸代谢及细胞生长和死亡中经淫羊藿苷处理的老年雌性老鼠均有恢复到年轻未处理小鼠近似水平,但差异无统计学意义。
4 讨论
收起
本研究首次系统揭示了淫羊藿苷对老年雌雄小鼠肠道菌群调节作用的性别二态性, 通过整合年龄与性别双重视角,系统解析了淫羊藿苷对老年小鼠肠道菌群的调节机制及其生物学意义。从年龄层面看,老年小鼠(24月龄)肠道菌群的α多样性(Chao1指数下降18.3%,P<0.05)和代谢功能(糖代谢通路活性降低40%)显著劣于年轻组(2月龄),这一趋势与人类衰老研究中观察到的菌群失调特征一致[12]。淫羊藿苷干预后,老年小鼠的菌群多样性恢复至接近年轻水平(Shannon指数差异缩小至5%以内),且F/B比值回调至年轻组范围(雌鼠1.8→2.3,雄鼠1.5→2.1),提示其通过抑制促炎菌群(如螺杆菌科丰度降低60%)重塑肠道稳态。这一效应可能与其抗氧化特性相关:既往研究表明,淫羊藿苷可清除衰老相关的线粒体活性氧(ROS)累积,从而改善肠上皮细胞功能[7]。值得注意的是,淫羊藿苷对老年个体的干预效果显著优于年轻组(如老年雌鼠α多样性提升25% vs. 年轻雌鼠8%),暗示衰老导致的肠道屏障通透性增加可能增强了菌群对药物的响应敏感性,这为针对老年人群的精准干预提供了理论依据。
从性别层面看,淫羊藿苷的调节作用呈现鲜明的二态性:在老年雌鼠中,其通过富集Lactobacillus(4.1倍)激活“菌群-雌激素”轴——该菌属通过β-葡萄糖醛酸酶促进雌激素的肠肝循环[13],而KEGG预测显示的鞘脂代谢通路上调(3.2倍)可能通过鞘氨醇-1-磷酸(S1P)增强ERβ信号传导[14],形成正反馈环路。这种机制与绝经后女性肠道菌群变化的研究结论高度吻合[15]。在老年雄鼠中,Akkermansia的增殖(3.9倍)与黏液层厚度增加相关,其代谢产物丙酸盐可促进睾酮合成[16],而雄激素又能通过调控ZO-1蛋白表达维持肠道屏障完整性[17],形成双向调控网络。这种性别特异性互作模式可能在一定程度上解释哺乳动物中雌性寿命普遍长于雄性的现象[18],也为中药“同病异治”理论提供了现代生物学注解。
本研究的发现为中药抗衰老的性别精准干预提供了新视角。淫羊藿苷对雌鼠菌群及代谢通路的特异性调节,与其传统中医应用中“补肾阳、益精血”的功效记载高度契合[19],而菌群介导的代谢功能恢复可能是其“抗衰老”作用的现代生物学基础。
另外,淫羊藿苷在未显著改变体质量的情况下改善了老年小鼠的精神状态与毛发质量,提示其健康效应可能优先体现在“生理年龄”而非单纯体重指标,这与肠道菌群对宿主系统性衰老的调控作用一致[20]。
综上,本研究首次从年龄依赖性响应与性别二态性调控两个维度,揭示了淫羊藿苷通过“菌群-代谢-宿主”轴延缓衰老的多层次机制。这一发现不仅为开发性别差异化的抗衰老中药制剂(如女性侧重调节雌激素代谢、男性侧重改善肠屏障)提供了试验依据,也为中医“辨证施治”思想与现代精准医学的融合提供了创新范式。
基金
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  • 国家自然科学基金项目资助(82201744)
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2025年第60卷第9期
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doi: 10.11669/cpj.2025.09.003
  • 接收时间：2024-12-17
  • 首发时间：2025-11-11
  • 出版时间：2025-05-01
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  • 收稿日期：2024-12-17
基金
国家自然科学基金项目资助(82201744)
作者信息
    1 北京大学第三医院消化科, 北京 100191
    2 北京大学第三医院幽门螺杆菌感染与上消化道疾病北京市重点实验室, 北京 100191

通讯作者:

*段丽萍,女,博士,教授,主任医师 研究方向:神经胃肠病学及肠道微生态 Tel:(010)82266929
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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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