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Article(id=1308817702777618993, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1308817633789698171, articleNumber=null, orderNo=null, doi=10.16438/j.0513-4870.2025-0656, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=null, receivedDate=1749657600000, receivedDateStr=2025-06-12, revisedDate=1757952000000, revisedDateStr=2025-09-16, acceptedDate=null, acceptedDateStr=null, onlineDate=1789976056998, onlineDateStr=2026-09-21, pubDate=1770825600000, pubDateStr=2026-02-12, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1789976056998, onlineIssueDateStr=2026-09-21, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1789976056998, creator=13701087609, updateTime=1789976056998, updator=13701087609, issue=Issue{id=1308817633789698171, tenantId=1146029695717560320, journalId=1189982191388893191, year='2026', volume='61', issue='2', pageStart='321', pageEnd='676', issueExtLink='null', onlineDate='null', pubDate='1770825600000', pubDateStr='2026-02-12', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1789976040551, creator='13701087609', updateTime=1789984264575, updator='13701087609', preIssue=null, nextIssue=null, articleTotal=null, ext={EN=IssueExt(id=1308852127921963901, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1308817633789698171, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1308852127921963902, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1308817633789698171, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null, downloadFileDto=null}, startPage=465, endPage=475, ext={EN=ArticleExt(id=1308817704644084275, articleId=1308817702777618993, tenantId=1146029695717560320, journalId=1189982191388893191, language=EN, title=Role of gut microbiota in intestinal inflammation: a transcriptomic and 16S rRNA analysis study in Muc2‒/‒ mice, columnId=1190335348761793317, journalTitle=Acta Pharmaceutica Sinica, columnName=Original Articles, runingTitle=null, highlight=null, articleAbstract=

The intestinal mucus layer is mainly composed of mucin 2 (MUC2), a highly glycosylated protein secreted by goblet cells. The Muc2‒/‒ mice are a spontaneous colitis model, due to intestinal mucus barrier defects, gut microbes directly contact with intestinal epithelial cells and induce intestinal inflammation. Nevertheless, how gut microbes affect the intestinal epithelium and trigger inflammation in the absence of mucus remains unknown. This study analyzed histopathological changes, colonic transcriptome and gut microbiome of Muc2‒/‒ mice to elucidate the role of gut microbes in inducing intestinal inflammation. Animal experimentations were approved by the Institutional Animal Care and Use Committee of Nanjing University of Chinese Medicine, Ethical Review No. 202302A007. Pathological analysis showed that Muc2‒/‒ mice manifested considerable intestinal mucosal damage accompanied by inflammatory cell infiltration and goblet cell exhaustion. Transcriptomic analysis showed that mucus synthesis, endoplasmic reticulum stress, and autophagy-related gene expressions were altered in Muc2‒/‒ mice. Kyoto Encyclopedia of Genes and Gene Ontology pathway enrichment analyses showed considerable enrichment of inflammation and immune-related pathways, and pathways in response to bacteria derived molecules were upregulated. Microbial gene sequencing revealed dysbiosis of the gut microbiome in Muc2‒/‒ mice, with Akkermansia muciniphila expansion being the characteristic profile. The expansion of Akkermansia muciniphila was confirmed in Il10‒/‒ mice, which also displayed mucus barrier defects. Correlation analysis showed that the disturbed gut microbes of Muc2‒/‒ mice was positively correlated with intestinal inflammation and immune-related differentially expressed genes, which were enriched in pathways such as MAPK cascade and chemokine production. In conclusion, in the absence of intestinal mucus layer, gut microbes can induce immune response by affecting the colonic gene transcription, leading to sustained secretion of inflammatory cytokines and intestinal inflammation. This study investigated the mechanism by which gut microbiota induces colonic inflammation in the absence of the intestinal mucus layer through integrated analysis of colonic transcriptomic profiles and gut microbiota dynamics. The findings aim to identify therapeutic targets for colitis treatment and drug discovery.

, authors=Yu-meng WANG, Hua-shi LIANG, Qin-yu ZHANG, Cheng-xi LI, Jin-ao DUAN, Jian-ming GUO*, authorsList=Yu-meng WANG, Hua-shi LIANG, Qin-yu ZHANG, Cheng-xi LI, Jin-ao DUAN, Jian-ming GUO, authorCompany=null, correspAuthors=Jian-ming GUO, authorNote=null, correspAuthorsNote=null, copyrightStatement=Copyright ©2026 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, fund=null), CN=ArticleExt(id=1308817706091119168, articleId=1308817702777618993, tenantId=1146029695717560320, journalId=1189982191388893191, language=CN, title=Muc2‒/‒自发性结肠炎模型小鼠的肠道转录组学和肠道菌群关联分析研究, columnId=1190335348896011050, journalTitle=药学学报, columnName=研究论文, runingTitle=null, highlight=null, articleAbstract=

黏蛋白2 (mucin 2, MUC2) 是杯状细胞分泌的一种高度糖基化的蛋白质, 是肠黏液层的主要组成部分。Muc2‒/‒小鼠由于肠道黏液屏障功能缺失, 肠道菌群直接与肠道上皮细胞接触, 诱发肠道炎症, 而这一作用的具体机制尚不清楚。本研究分析了Muc2‒/‒小鼠结肠组织病理学、结肠转录组和肠道菌群变化, 以阐明肠道菌群在诱导肠道炎症中的作用。所有动物实验均严格按照南京中医药大学动物伦理委员会的规定进行, 伦理审核号: 202302A007。病理学分析显示, Muc2‒/‒小鼠表现出肠黏膜损伤, 并伴有炎症细胞浸润和杯状细胞耗竭。转录组学分析表明, Muc2‒/‒小鼠肠道黏液合成、内质网应激和自噬相关基因表达发生改变。富集分析显示, Muc2‒/‒小鼠结肠炎症和免疫相关通路显著富集, 对细菌来源分子的反应通路相关基因的表达增加。肠道菌群测序结果显示, Muc2‒/‒小鼠肠道菌群失调, 其中以Akkermansia muciniphila菌扩增为特征性表现, 此现象在另一种肠道黏液屏障缺陷小鼠(Il10‒/‒) 中也得以证实。相关性分析表明, Muc2‒/‒小鼠紊乱的肠道菌群与肠道炎症和免疫相关差异表达基因呈正相关, 这些基因在MAPK (mitogen-activated protein kinase) 级联反应和趋化因子产生等通路中富集。总而言之, 在缺乏肠道黏液的情况下, 肠道菌群可通过影响结肠基因转录水平诱发免疫反应, 导致炎症细胞因子的持续分泌, 最终诱导肠道炎症。本研究通过分析结肠转录组和肠道菌群的变化来深入探索缺失肠道黏液层时, 肠道菌群诱导结肠炎症的作用机制, 为结肠炎症的治疗和药物发现提供靶点。

, authors=王雨萌, 梁华诗, 张沁瑜, 李成曦, 段金廒, 郭建明*, authorsList=王雨萌, 梁华诗, 张沁瑜, 李成曦, 段金廒, 郭建明, authorCompany=null, correspAuthors=郭建明, authorNote=

作者贡献:

郭建明、王雨萌、段金廒负责课题总体设计及文章修改; 王雨萌、梁华诗负责实验操作、数据处理及论文撰写; 张沁瑜、李成曦协助实验完成。

, correspAuthorsNote=
郭建明, Tel: 86-25-85811917, E-mail:
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Nat Microbiol, 2025, 10: 654-666., articleTitle=null, refAbstract=null)], funds=null, companyList=[AuthorCompany(id=1308817978553107038, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308817702777618993, xref=null, ext=[AuthorCompanyExt(id=1308817978561495647, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308817702777618993, companyId=1308817978553107038, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources, Nanjing University of Chinese Medicine, Nanjing 210023, China), AuthorCompanyExt(id=1308817978574078560, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308817702777618993, companyId=1308817978553107038, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=南京中医药大学, 江苏省中药资源产业化过程协同创新中心, 江苏 南京 210023)])], figs=[ArticleFig(id=1308817981010969225, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308817702777618993, language=EN, label=null, caption=null, figureFileSmall=hSMvuBhvfr1+zLZfVwXqmw==, figureFileBig=LBqfezERUbg8sfnOTkLj2Q==, tableContent=null), ArticleFig(id=1308817981065495178, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308817702777618993, language=CN, label=Fig.1, caption=Muc2‒/‒ mice spontaneously develop intestinal inflammation. A: Body weight; B: Blood in diarrhea index; C: Fecal water content; D: Colon lengths; E: The representative mesenteric lymphadenitis nodes were photographed and weighed; F: Immunological organ index; G: Histopathological analysis of distal colonic tissue from mice and histological score (10×, 25×), scale bar, 100 μm, 50 μm; H: AB/PAS-stained sections of tissues and the number of goblet cells in each crypt (10×, 40×), scale bar, 100 μm, 20 μm; I: AB-stained sections of tissues and the thickness of mucin (10×, 40×), scale bar, 100 μm, 20 μm. n = 5 or 6, mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001. AB: Alcian blue; AB/PAS: Alcian blue/periodic acid-Schiff, figureFileSmall=hSMvuBhvfr1+zLZfVwXqmw==, figureFileBig=LBqfezERUbg8sfnOTkLj2Q==, tableContent=null), ArticleFig(id=1308817982755799691, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308817702777618993, language=EN, label=null, caption=null, figureFileSmall=p7PgG3GOzM9OoLeqoX60qg==, figureFileBig=zbarsl2THvwUiEBmXWcBBg==, tableContent=null), ArticleFig(id=1308817982843880076, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308817702777618993, language=CN, label=Fig.2, caption=The intestinal gene transcription profile was altered in Muc2‒/‒ mice. A: Scatter plot of PCA; B: Volcano plot of genes sequenced; C: Heatmap analysis of genes related to mucus synthesis; D: The expression of Gcnt4, Fut2, Galnt17, and Cldn1 was measured by real-time qPCR; E: GO pathway enrichment analysis of DEGs; F: KEGG pathway enrichment analysis of DEGs. n = 4-6, mean ± SEM. **P < 0.01, ****P < 0.000 1. WT: Wild-type; PCA: Principal component analysis; GO: Gene Ontology; KEGG: Kyoto Encyclopedia of Genes and Genomes; DEGs: Differentially expressed genes, figureFileSmall=p7PgG3GOzM9OoLeqoX60qg==, figureFileBig=zbarsl2THvwUiEBmXWcBBg==, tableContent=null), ArticleFig(id=1308817982915183245, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308817702777618993, language=EN, label=null, caption=null, figureFileSmall=OAKVjxVHe6X7I1W6+yq6Xg==, figureFileBig=3NYdTg4CkIaH7u2/wrRy/g==, tableContent=null), ArticleFig(id=1308817982999069326, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308817702777618993, language=CN, label=Fig.3, caption=The gut microbiota composition changed in Muc2‒/‒ mice. A: PCoA and NMDS analysis plot; B: Taxonomic distributions of gut microbiota composition at the family level; C: Differential microbiota of WT and Muc2‒/‒ mice at the genus level; D: Differences in microbial taxa at all taxonomic levels between WT and Muc2‒/‒ mice. The Mann-Whitney test was used, with P < 0.01 and LDA score > 2.00 considered statistically significant. n = 5, mean ± SEM. *P < 0.05, **P < 0.01, ****P < 0.000 1. PCoA: Principal coordinates analysis; NMDS: Non-metric multidimensional scaling, figureFileSmall=OAKVjxVHe6X7I1W6+yq6Xg==, figureFileBig=3NYdTg4CkIaH7u2/wrRy/g==, tableContent=null), ArticleFig(id=1308817983078761103, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308817702777618993, language=EN, label=null, caption=null, figureFileSmall=gtMSWo7srUa3/G71/OlBmg==, figureFileBig=cj7b8yjCZOHxWvChyu4m4A==, tableContent=null), ArticleFig(id=1308817983141675664, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308817702777618993, language=CN, label=Fig.4, caption=Intestinal inflammation in Muc2‒/‒ mice is associated with gut microbiota invasion. A: Representative images of fluorescence in situ hybridization staining (20×, 60×), scale bar, 100 μm, 20 μm; B: GSEA analysis of bacterial-associated responses in GO pathway analysis; C: Network diagram amongst DEGs in bacterial-associated responses pathway and differential microbiota; D: Correlation analysis amongst DEGs and differential microbiota. n = 3-5, mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001, figureFileSmall=gtMSWo7srUa3/G71/OlBmg==, figureFileBig=cj7b8yjCZOHxWvChyu4m4A==, tableContent=null), ArticleFig(id=1308817983221367441, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308817702777618993, language=EN, label=null, caption=null, figureFileSmall=EPrxNsUN2tef5tFA1KeWkQ==, figureFileBig=oY3lt7Iq+cvDmBqsScFaFg==, tableContent=null), ArticleFig(id=1308817983301059218, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308817702777618993, language=CN, label=Fig.5, caption=Il10‒/‒ mice spontaneously develop intestinal inflammation. A: Histopathological analysis of distal colonic tissue from mice and histological score (25×), scale bar, 50 μm; B: AB-stained sections of tissues and the thickness of mucin (40×), scale bar, 20 μm; C: AB/PAS-stained sections of tissues and the number of goblet cells in each crypt (40×), scale bar, 20 μm; D: Representative images of fluorescence in situ hybridization staining and the distance between luminal microbiota and the epithelial surface (60×), scale bar, 20 μm; E: PCoA and NMDS analysis; F: Taxonomic distributions of gut microbiota composition at the family level; G: Differences in microbial taxa at all taxonomic levels between WT and Il10‒/‒ mice. n = 5-7, mean ± SEM. ***P < 0.001. GSEA: Gene set enrichment analysis, figureFileSmall=EPrxNsUN2tef5tFA1KeWkQ==, figureFileBig=oY3lt7Iq+cvDmBqsScFaFg==, tableContent=null), ArticleFig(id=1308817983363973779, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308817702777618993, language=EN, label=null, caption=null, figureFileSmall=mFagKNa1TxN4VaNpEoJaPg==, figureFileBig=eao8f+OYyst3FaHBKEgbGg==, tableContent=null), ArticleFig(id=1308817983431082644, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308817702777618993, language=CN, label=Fig.6, caption=Changes of A. muciniphila abundance in Il10‒/‒ mice. A: The quantity of A. muciniphila in feces from Il10‒/‒ mice was assessed by real-time qPCR; B: DAI; C: Correlation of A. muciniphila abundance with DAI in Il10‒/‒ mice; D: AB-stained sections of tissues and the thickness of mucin (4×), scale bar, 100 μm; E: Il10‒/‒ mice were exposed to 10% fructose for 7 days; F: Changes of A. muciniphila after drinking 10% fructose for 7 days; G: Changes of A. muciniphila 10 days after cessation of fructose administration. n = 4-6, mean ± SEM. *P < 0.05, ***P < 0.001. DAI: Disease activity index, figureFileSmall=mFagKNa1TxN4VaNpEoJaPg==, figureFileBig=eao8f+OYyst3FaHBKEgbGg==, tableContent=null), ArticleFig(id=1308817983489802901, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308817702777618993, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
Lesion typeScoreStandard
Severity0No significant inflammatory cell infiltration
1Minor inflammatory cell infiltration
2Significant inflammatory cell infiltration
3Massive inflammatory cell infiltration
Extent0No lesions seen
1Lesions located only in the mucosal layer
2Lesions located in the mucosal and submucosal layers
3Transmural damage
Crypt damage0No crypt damage
11/3 crypt damage
22/3 crypt damage
3Only the surface epithelium is intact
4Both crypts and surface epithelium are missing
), ArticleFig(id=1308817983556911766, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308817702777618993, language=CN, label=Tab.1, caption=

Histological pathology scores

, figureFileSmall=null, figureFileBig=null, tableContent=
Lesion typeScoreStandard
Severity0No significant inflammatory cell infiltration
1Minor inflammatory cell infiltration
2Significant inflammatory cell infiltration
3Massive inflammatory cell infiltration
Extent0No lesions seen
1Lesions located only in the mucosal layer
2Lesions located in the mucosal and submucosal layers
3Transmural damage
Crypt damage0No crypt damage
11/3 crypt damage
22/3 crypt damage
3Only the surface epithelium is intact
4Both crypts and surface epithelium are missing
), ArticleFig(id=1308817983624020631, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308817702777618993, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
GeneForwardReverse
Gcnt4GCTGACGAGTGGTTGGTGAATGGATGAGGTGGCAGACAGGAGAC
Fut2TCCCAGGTTCTCTTCAAGGGATCCCAGGTTCTCTTCAAGGGA
Galnt17GCTACCAAACTGGATATAATCAGGACCAGGTAGCTATGGTACTCCAGAA
Cldn1ACTTCACTGTACAACCGCATCAGTCATATCCTCGAACAC
β-actinCTACAGCTTCACCACCACAGACCGCTCGTTGCCAATAGTG
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The primers in the experiment. Gcnt4: Glucosaminyl (N-acetyl) transferase 4, core 2 (beta-1,6-N-acetylglucosaminyltransferase); Fut2: Fucosyltransferase2; Galnt17: Polypeptide N-acetylgalactosaminyltransferase 17; Cldn1: Claudin-1

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GeneForwardReverse
Gcnt4GCTGACGAGTGGTTGGTGAATGGATGAGGTGGCAGACAGGAGAC
Fut2TCCCAGGTTCTCTTCAAGGGATCCCAGGTTCTCTTCAAGGGA
Galnt17GCTACCAAACTGGATATAATCAGGACCAGGTAGCTATGGTACTCCAGAA
Cldn1ACTTCACTGTACAACCGCATCAGTCATATCCTCGAACAC
β-actinCTACAGCTTCACCACCACAGACCGCTCGTTGCCAATAGTG
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Muc2‒/‒自发性结肠炎模型小鼠的肠道转录组学和肠道菌群关联分析研究
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王雨萌 , 梁华诗 , 张沁瑜 , 李成曦 , 段金廒 , 郭建明 *
药学学报 | 研究论文 2026,61(2): 465-475
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药学学报 |研究论文 2026 , 61 (2) : 465 -475
Muc2‒/‒自发性结肠炎模型小鼠的肠道转录组学和肠道菌群关联分析研究
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王雨萌, 梁华诗, 张沁瑜, 李成曦, 段金廒, 郭建明*
作者信息
  • 南京中医药大学, 江苏省中药资源产业化过程协同创新中心, 江苏 南京 210023
通讯作者:
郭建明, Tel: 86-25-85811917, E-mail:
作者简介:

作者贡献:

郭建明、王雨萌、段金廒负责课题总体设计及文章修改; 王雨萌、梁华诗负责实验操作、数据处理及论文撰写; 张沁瑜、李成曦协助实验完成。

Role of gut microbiota in intestinal inflammation: a transcriptomic and 16S rRNA analysis study in Muc2‒/‒ mice
Yu-meng WANG, Hua-shi LIANG, Qin-yu ZHANG, Cheng-xi LI, Jin-ao DUAN, Jian-ming GUO*
Affiliations
  • Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources, Nanjing University of Chinese Medicine, Nanjing 210023, China
出版时间: 2026-02-12 doi: 10.16438/j.0513-4870.2025-0656
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摘要
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黏蛋白2 (mucin 2, MUC2) 是杯状细胞分泌的一种高度糖基化的蛋白质, 是肠黏液层的主要组成部分。Muc2‒/‒小鼠由于肠道黏液屏障功能缺失, 肠道菌群直接与肠道上皮细胞接触, 诱发肠道炎症, 而这一作用的具体机制尚不清楚。本研究分析了Muc2‒/‒小鼠结肠组织病理学、结肠转录组和肠道菌群变化, 以阐明肠道菌群在诱导肠道炎症中的作用。所有动物实验均严格按照南京中医药大学动物伦理委员会的规定进行, 伦理审核号: 202302A007。病理学分析显示, Muc2‒/‒小鼠表现出肠黏膜损伤, 并伴有炎症细胞浸润和杯状细胞耗竭。转录组学分析表明, Muc2‒/‒小鼠肠道黏液合成、内质网应激和自噬相关基因表达发生改变。富集分析显示, Muc2‒/‒小鼠结肠炎症和免疫相关通路显著富集, 对细菌来源分子的反应通路相关基因的表达增加。肠道菌群测序结果显示, Muc2‒/‒小鼠肠道菌群失调, 其中以Akkermansia muciniphila菌扩增为特征性表现, 此现象在另一种肠道黏液屏障缺陷小鼠(Il10‒/‒) 中也得以证实。相关性分析表明, Muc2‒/‒小鼠紊乱的肠道菌群与肠道炎症和免疫相关差异表达基因呈正相关, 这些基因在MAPK (mitogen-activated protein kinase) 级联反应和趋化因子产生等通路中富集。总而言之, 在缺乏肠道黏液的情况下, 肠道菌群可通过影响结肠基因转录水平诱发免疫反应, 导致炎症细胞因子的持续分泌, 最终诱导肠道炎症。本研究通过分析结肠转录组和肠道菌群的变化来深入探索缺失肠道黏液层时, 肠道菌群诱导结肠炎症的作用机制, 为结肠炎症的治疗和药物发现提供靶点。

肠道炎症  /  黏液屏障  /  肠道菌群  /  黏蛋白2  /  Akkermansia muciniphila

The intestinal mucus layer is mainly composed of mucin 2 (MUC2), a highly glycosylated protein secreted by goblet cells. The Muc2‒/‒ mice are a spontaneous colitis model, due to intestinal mucus barrier defects, gut microbes directly contact with intestinal epithelial cells and induce intestinal inflammation. Nevertheless, how gut microbes affect the intestinal epithelium and trigger inflammation in the absence of mucus remains unknown. This study analyzed histopathological changes, colonic transcriptome and gut microbiome of Muc2‒/‒ mice to elucidate the role of gut microbes in inducing intestinal inflammation. Animal experimentations were approved by the Institutional Animal Care and Use Committee of Nanjing University of Chinese Medicine, Ethical Review No. 202302A007. Pathological analysis showed that Muc2‒/‒ mice manifested considerable intestinal mucosal damage accompanied by inflammatory cell infiltration and goblet cell exhaustion. Transcriptomic analysis showed that mucus synthesis, endoplasmic reticulum stress, and autophagy-related gene expressions were altered in Muc2‒/‒ mice. Kyoto Encyclopedia of Genes and Gene Ontology pathway enrichment analyses showed considerable enrichment of inflammation and immune-related pathways, and pathways in response to bacteria derived molecules were upregulated. Microbial gene sequencing revealed dysbiosis of the gut microbiome in Muc2‒/‒ mice, with Akkermansia muciniphila expansion being the characteristic profile. The expansion of Akkermansia muciniphila was confirmed in Il10‒/‒ mice, which also displayed mucus barrier defects. Correlation analysis showed that the disturbed gut microbes of Muc2‒/‒ mice was positively correlated with intestinal inflammation and immune-related differentially expressed genes, which were enriched in pathways such as MAPK cascade and chemokine production. In conclusion, in the absence of intestinal mucus layer, gut microbes can induce immune response by affecting the colonic gene transcription, leading to sustained secretion of inflammatory cytokines and intestinal inflammation. This study investigated the mechanism by which gut microbiota induces colonic inflammation in the absence of the intestinal mucus layer through integrated analysis of colonic transcriptomic profiles and gut microbiota dynamics. The findings aim to identify therapeutic targets for colitis treatment and drug discovery.

intestinal inflammation  /  mucus barrier  /  gut microbiota  /  mucin 2  /  Akkermansia muciniphila
王雨萌, 梁华诗, 张沁瑜, 李成曦, 段金廒, 郭建明. Muc2‒/‒自发性结肠炎模型小鼠的肠道转录组学和肠道菌群关联分析研究. 药学学报, 2026 , 61 (2) : 465 -475 . DOI: 10.16438/j.0513-4870.2025-0656
Yu-meng WANG, Hua-shi LIANG, Qin-yu ZHANG, Cheng-xi LI, Jin-ao DUAN, Jian-ming GUO. Role of gut microbiota in intestinal inflammation: a transcriptomic and 16S rRNA analysis study in Muc2‒/‒ mice[J]. Acta Pharmaceutica Sinica, 2026 , 61 (2) : 465 -475 . DOI: 10.16438/j.0513-4870.2025-0656
正文
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溃疡性结肠炎(ulcerative colitis, UC) 是一种病因复杂的慢性、复发性肠道炎症性疾病。UC患者的一个显著特征是肠道黏液屏障功能受损[1], 表现为杯状细胞萎缩和肠道黏液层耗竭。多项研究表明, 肠道黏液屏障功能障碍与UC早期炎症的发生发展密切相关, 其有望成为UC治疗的新靶点[2, 3]。
肠道黏液屏障是将肠道上皮与复杂肠腔环境分隔开的首要屏障, 在维持肠道稳态中发挥重要作用[4, 5]。由杯状细胞分泌的黏蛋白2 (mucin 2, MUC2) 是肠道黏液的关键组成成分, 其通过多聚化形成致密的聚合物网, 构成肠道黏液层的骨架, 以确保肠道黏液屏障的稳定性[6]。MUC2分泌减少会导致肠道上皮暴露于肠腔, 遭受外源性细菌的侵袭[7], 且这一过程先于并促进炎症的激活[8, 9]。
肠道菌群是UC的常见致病因素之一[10]。肠道菌群失调会导致致病菌在肠道中的定植和侵袭, 触发宿主免疫反应[11]。肠道黏液屏障在宿主与肠道菌群之间建立互利关系中发挥关键作用。有研究发现, 高果糖摄入显著促进Akkermansia muciniphila与Bacteroides fragilis等黏液降解菌增殖, 导致肠道黏液层变薄, 肠道黏膜屏障功能损伤, 最终加速小鼠结肠炎疾病进程[12]。
Muc2‒/‒小鼠是一种常见的用于UC和结直肠癌(colitis and colorectal cancer, CRC) 的实验模型小鼠[13], 其随年龄增长会出现自发性肠道炎症, 且通常在6月龄会发展为CRC[14]。Muc2‒/‒小鼠诱发的免疫反应不仅与活动期UC患者相似, 其肠道形态与炎症状态也与临床低度炎症UC患者相似[15]。尽管已有多项关于Muc2‒/‒小鼠肠道菌群的研究, 但这些研究并未探讨肠道菌群改变与Muc2‒/‒小鼠发病机制之间的关联[16]。
最近一项研究通过全基因表达微阵列芯片技术比较了2周和4周龄Muc2‒/‒小鼠和野生型小鼠的结肠组织基因表达谱[17]。本研究结合细菌16S rRNA基因测序和RNA-seq技术, 对Muc2‒/‒小鼠的结肠组织和肠道菌群进行了综合性分析。旨在通过分析结肠转录组和肠道菌群的变化来深入探索缺失肠道黏液层时, 肠道菌群诱导UC发病的作用机制, 为UC治疗提供依据。
材料与方法
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实验动物  C57BL/6J、Il10‒/‒和Muc2‒/‒小鼠购自南京集萃药康生物科技股份有限公司, 许可证号: SCXK (沪) 2017-0005。所有小鼠均在SPF级设施中饲养, 南京中医药大学动物实验伦理委员会批准了动物实验。所有动物实验均严格按照南京中医药大学动物伦理委员会的规定进行, 伦理审核号: 202302A007。同窝3月龄雌性小鼠按基因型分为WT组及Muc2‒/‒组, 每组6只。同窝6月龄雄性小鼠按基因型分为WT组及Il10‒/‒组, 每组8只。在果糖实验中, 采用同窝2月龄Il10‒/‒小鼠共6只, 通过在饮水中添加10%果糖溶液, 自由饮用7天后, 收集小鼠粪便用于后续分析。
药品与试剂  4%多聚甲醛固定液(批号: BL539A, Biosharp生物科技有限公司); FastPure cell/tissue total RNA isolation kit V2 (批号: ET113-01)、HiScript Ⅱ Q RT SuperMix kit (批号: P20329)、TransStart® Top Green qPCR SuperMix (批号: P20215) (南京诺唯赞生物科技股份有限公司); Carnoy's液(批号: G2312, 北京索莱宝科技有限公司); 柠檬酸钠(批号: AS2981)、胃蛋白酶(批号: G1146)、anti-MUC2 rabbit pAb (批号: L2331) (武汉赛维尔生物科技有限公司); Coralite488-conjugated goat anti-rabbit IgG (H+L) (批号: SA00402-3) (武汉三鹰生物技术有限公司)。
实验仪器  低温高速离心机(德国Beckman公司, 型号: Microfuge 22R); 微型旋涡混合仪(上海沪西分析仪器厂, 型号: XW-80A); 组织研磨仪(上海净业信发展有限公司); LABGIC CF2800M微孔板离心机(合肥兰杰柯科技有限公司); 涡旋振荡器(美国Scientific Industries公司); KQ-500B型超声波清洗器(昆山市超声仪器有限公司); 十万分之一电子天平(德国Saitorius公司); ABI 7500型实时荧光定量PCR仪(赛默飞世尔科技); STELLARIS 8 DIVE激光共聚焦显微镜+双光子激光器(德国Leica公司)。
组织病理学分析  收集远端结肠组织固定于4%多聚甲醛, 组织样本石蜡包埋并切片。切片经苏木精-伊红(hematoxylin-eosin, H&E) 染色。收集中段结肠包裹粪便及远端结肠组织于Carnoy's液固定, 组织样本石蜡包埋并切片。切片分别经阿尔新蓝(Alcian blue, AB) 和阿尔新蓝/过碘酸-希夫(Alcian blue/periodic acid-Schiff, AB/PAS) 染色进行肠道黏液层和杯状细胞的组织病理学染色。显微镜下拍摄并进行组织病理学评分、黏液层和杯状细胞计数。组织病理学评分细则如表1。
荧光原位杂交和MUC2染色  取中端结肠包裹粪便组织于Carnoy's液中固定, 常规石蜡包埋后切片, 切片经二甲苯脱蜡后复水。切片经柠檬酸钠进行抗原修复后, 37 ℃胃蛋白酶消化15 min, 随后用预杂交液预杂交1 h。在42 ℃与CY3-conjugated-eubacterial探针孵育过夜。FISH染色后进行MUC2染色, 切片用1∶500稀释的anti-MUC2 rabbit pAb在4 ℃下孵育过夜。PBS洗涤后, 用1∶1 000稀释的Coralite488-conjugated goat anti-rabbit IgG (H+L) 常温孵育1 h。PBS洗涤后, DAPI孵育10 min, 抗荧光淬灭剂封片。双光子激光共聚焦荧光显微镜镜检。
RNA提取和  RT-qPCR小鼠处死后, 结肠组织储存于RNA later保存液于-80 ℃冻存。称取结肠组织10 mg, 匀浆后使用FastPure cell/tissue total RNA isolation kit V2提取总mRNA, 使用HiScript Ⅱ Q RT SuperMix kit将mRNA逆转录为cDNA。使用TransStart® Top Green qPCR SuperMix检测目的基因的表达。β-Actin为内参, 用2-ΔΔCt法进行相对表达分析。分析使用的引物序列如表2。
16S rRNA分析  处死小鼠前收集新鲜粪便, 储存于-80 ℃, 样品委托上海派森诺科技股份有限公司进行文库制备、测序和分析。
RNA-Seq分析  结肠组织储存于-80 ℃, 样品委托上海派森诺科技股份有限公司进行文库制备、测序和分析。
统计学分析  使用GraphPad Prism 8.0进行统计学分析及作图。所有数据均以mean ± SEM表示。P < 0.05被认为具有统计学意义。
结果
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1　 Muc2‒/‒小鼠自发发展为结肠炎
Muc2‒/‒小鼠及其同窝野生型小鼠饲养于SPF环境中, 随着年龄增长, Muc2‒/‒小鼠逐渐出现腹泻和直肠脱垂等症状。与同窝野生型小鼠相比, 3月龄Muc2‒/‒小鼠表现出显著的体重减轻, 伴有严重腹泻和便血(图1A~C)。与野生型小鼠相比, Muc2‒/‒小鼠的结肠显著缩短, 且肠系膜淋巴结显著增大(图1D、E), 但脾脏和胸腺无明显变化(图1F)。对小鼠远端结肠组织进行H&E染色。组织病理学染色显示, Muc2‒/‒小鼠的结肠组织出现显著的炎症细胞浸润且入侵至黏膜下层, 并伴有肠上皮缺失和腺体结构消失等情况(图1G)。
杯状细胞通过持续分泌MUC2维持肠道黏液层的完整性, 基于MUC2在肠黏液稳态中的关键作用, 进一步对结肠组织进行AB和AB/PAS染色。结果表明, Muc2‒/‒小鼠的杯状细胞数量显著减少, 肠黏液层消失(图1H、I)。上述结果表明, Muc2缺失会导致肠道炎症、黏液屏障受损并促使小鼠发展为自发性UC。
2　 Muc2‒/‒小鼠结肠组织转录水平发生改变, 肠道免疫信号通路显著激活
为进一步探讨Muc2缺失对结肠基因组表达的影响, 对两组小鼠的结肠组织进行RNA测序。主成分分析(principal components analysis, PCA) 结果显示小鼠的基因表达模式存在显著差异(图2A), 其中共检测到535个差异表达基因(differentially expressed genes, DEGs), 通过火山图进行可视化分析, 其中170个基因在Muc2‒/‒小鼠中表达上调, 而365个基因表达下调(图2B)。转录组分析显示, Muc2‒/‒小鼠中参与黏液合成的基因表达发生显著变化(图2C)。
此外, Muc2‒/‒小鼠中自噬和内质网应激相关基因发生显著改变。内质网应激相关分子伴侣和转录因子的转录水平升高。内质网应激负调控基因和自噬调控基因的转录水平下降(图2C)。这与已有报道相符, 即MUC2分泌异常导致内质网应激和自噬水平降低。为验证测序结果的准确性, 对核心2分支酶, β-1,6-N-乙酰氨基葡萄糖转移酶4 (core 2 branching enzyme, beta-1,6-N-acetylglucosaminyltransferase 4, Gcnt4)、岩藻糖基转移酶2 (fucosyltransferase 2, Fut2)、紧密连接蛋白1 (claudin-1, Cldn1) 和多肽N-乙酰半乳糖胺转移酶17 (polypeptide N-acetylgalactosaminyltransferase 17, Galnt17) 的基因表达水平进行qPCR分析, qPCR与RNA测序结果高度一致, 证实RNA测序数据真实可靠(图2D)。
为了深入探究肠黏液屏障损伤对结肠组织的影响, 对DEGs进行了基因本体论(Gene Ontology, GO) 和京都基因与基因组百科全书(Kyoto Encyclopedia of Genes and Genomes, KEGG) 通路富集分析。GO富集分析显示, DEGs在多个免疫相关的GO术语中富集, 包括炎症反应的调节(GO: 0050727)、急性炎症反应(GO: 0002526)、趋化因子产生的调节(GO: 0032642)、白细胞介素-6 (interleukin-6, IL-6) 产生的正向调节(GO: 0032755) 以及p38丝裂原活化蛋白激酶(p38 mitogen-activated protein kinase, p38MAPK) 级联反应的正向调节(GO: 1900745) (图2E)。KEGG富集分析显示, DEGs显著富集于过氧化物酶体增殖物激活受体信号通路(mmu03320)、肿瘤坏死因子(tumor necrosis factor, TNF) 信号通路(mmu04668)、IL-17信号通路(mmu04657) 及MAPK信号通路(mmu04010) (图2F)。这些通路分析结果表明, 肠道黏液层破坏可诱导肠道免疫反应, 激活炎症信号通路, 并导致小鼠在幼年期出现代谢紊乱。
3　 Muc2‒/‒小鼠肠道菌群紊乱
肠道黏液层、肠道菌群与宿主免疫防御之间的稳态对于维持肠道环境稳态至关重要[18]。肠道黏液层的稳定有助于肠道益生菌的定植, 而肠道黏液完整性被破坏则会导致肠道菌群失调。对Muc2‒/‒小鼠的粪便样本进行16S rRNA测序, 以探讨其肠道菌群的变化。通过非度量多维标度(non-metric multidimensional scaling, NMDS) 和主坐标分析(principal coordinates analysis, PCoA) 分析菌群组成。结果显示, Muc2‒/‒小鼠的肠道菌群组成发生显著变化(图3A)。
对小鼠肠道菌群群落的科水平进行分析, Muc2‒/‒小鼠Turicibacteraceae、Rikenellaceae、Clostridiaceae、Odoribacteraceae、Comamonadaceae菌丰度降低, 而Verrucomicrobiaceae、Prevotellaceae、Porphyromonadaceae、Mogibacteriaceae、Christensenellaceae和Alcaligenaceae的丰度增加(图3B)。在属水平上, Muc2‒/‒小鼠Turicibacter、Odoribacter、Anaerotruncus和AF12的丰度降低, 而Prevotella、Akkermansia、Clostridium、Sutterella和Parabacteroides丰度增加(图3C)。
随后, 通过应用线性判别分析(linear discriminant analysis effect size, LEfSe) 表征Muc2‒/‒小鼠肠道菌群的特定变化。LEfSe显示, Muc2‒/‒小鼠与野生型小鼠之间的肠道菌群组成存在显著差异, 其中Akkermansia、Clostridia、Sutterella、Alcaligenaceae和Ruminococcaceae在Muc2‒/‒小鼠中显著富集。相比之下, Desulfovibrionaceae、Turicibacteraceae和Rikenellaceae在野生型小鼠中富集程度较高(图3D)。其中, Rikenellaceae与肠道免疫反应、短链脂肪酸的生成及肠道屏障的维持密切相关[19]。
4　肠道菌群激活Muc2‒/‒小鼠结肠组织炎症反应
Muc2‒/‒小鼠肠道菌群紊乱, 进一步研究发现肠道菌群与Muc2‒/‒小鼠的肠道上皮细胞直接接触(图4A)。在之前的分析结果中, 部分DEGs被注释为对细菌的反应(GO: 0009617), 且这些基因在GO通路中的富集程度非常高(图2E)。进一步采用了基因集富集分析结果显示, 与细菌响应相关的通路在Muc2‒/‒小鼠中总体上显著上调(图4B)。
为了深入挖掘在疾病进程中发挥作用的关键细菌, 结合16S rRNA测序所获得的属级数据与在相关通路中显著上调的16个DEGs, 开展了基于Spearman的相关性分析。结果显示, 16个DEGs均与肠道菌群密切相关, 其中Il1b是关键炎症因子(图4C)。Clostridium、Faecalibacterium、Sutterella和Christensenella与DEGs存在强正相关。这表明这些特定的细菌可能是驱动基因转录上调的关键因素, 在诱导Muc2‒/‒小鼠肠道炎症的发生和发展中扮演了至关重要的角色。
为进一步探讨肠道菌群与Muc2‒/‒小鼠肠道炎症之间的关系, 分析了参与炎症反应的细菌与DEGs之间的相关性。在与炎症反应紧密相关的40个DEGs中, 有38个基因的表达与肠道菌群存在着显著的相关性(图4D)。先前已经引起关注的Clostridium、Faecalibacterium、Sutterella和Christensenella与炎症相关DEGs的相关性较高。此外, Prevotella和Parabacteroides也与炎症相关DEGs高度相关。
5　 Il10‒/‒和Muc2‒/‒小鼠肠道Akkermansia muciniphila丰度增加
Akkermansia muciniphila (A. muciniphila) 通常被认为是依赖黏液的有益细菌[20]。有趣的是, 尽管Muc2‒/‒小鼠肠道黏液耗竭, 缺乏A. muciniphila繁殖所需的营养物质, 但A. muciniphila的丰度仍然增加(图3C、D)。为证实这一结果, 使用Il10‒/‒小鼠, 这是一种免疫缺陷小鼠, 可发展为慢性结肠炎。与野生型小鼠相比, Il10‒/‒小鼠的肠道组织表现出广泛的炎症损伤(图5A)。同时, Il10缺乏导致小鼠肠道黏液层变薄, 杯状细胞耗竭(图5B、C)。因此, Il10‒/‒小鼠表现出肠道菌群对肠道上皮细胞的侵袭增加(图5D)。
PCoA和NMDS分析显示, Il10‒/‒小鼠的粪便肠道菌群组成发生显著变化(图5E)。其中, Akkermansiaceae的丰度在Il10‒/‒小鼠中增加(图5F、G)。这些结果表明, 在Il10‒/‒和Muc2‒/‒小鼠中, A. muciniphila可能不是一种“益生菌”, 在缺乏黏液的情况下, 它可能与疾病过程密切相关, 并可能是一种促进疾病向更严重阶段发展的致病微生物。
6　 A. muciniphila异常扩增与Il10‒/‒小鼠肠道炎症呈正相关
为进一步确认上述发现, 根据疾病严重程度, 将Il10‒/‒小鼠分为UC发作组和未发作组(图6A、B)。研究结果发现, 与UC未发作组小鼠相比, UC发作组小鼠A. muciniphila丰度更高(图6C), 同时, 处于UC未发作阶段的Il10‒/‒小鼠肠道黏液层更厚(图6D)。这表明A. muciniphila的增殖可能导致肠道黏液层变薄, 增加肠道黏液层的通透性, 从而加速疾病进展。
高果糖摄入可引起肠道炎症反应和肠道组织黏液损伤[12]。为验证上述结果, 给Il10‒/‒小鼠自由饮用10%果糖7天(图6E)。给予10%果糖显著升高了Il10‒/‒小鼠中A. muciniphila的丰度, 且在停止给予果糖后, 仍有继续增殖的趋势(图6F、G)。
综上所述, A. muciniphila的丰度可能并非仅与其营养来源肠道黏液相关, 还可能存在与其他菌群的相互作用。A. muciniphila异常增殖可能加速疾病进展, 未来有望通过调节其丰度有效干预疾病进程, 使患者受益。
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肠道黏液屏障是肠道黏膜屏障的第一道防线, 对减少宿主肠道上皮细胞暴露于抗原和细菌至关重要[21]。肠道菌群失调在UC发生发展中起重要作用。本课题组先前的研究发现, 抗生素治疗显著减少了葡聚糖硫酸钠诱导的UC小鼠的肠道组织病理损伤和炎症[22]。而肠道黏液层作为分隔宿主与肠道菌群的主要界面, 可以通过清除黏液表层松散黏附的细菌, 限制致病微生物在肠道的黏附[23]。本课题组的研究表明, 肠道菌群紊乱是诱发Muc2‒/‒小鼠肠道炎症反应的首要因素。
Muc2‒/‒小鼠中与免疫调节和炎症反应相关的基因显著上调, 这些基因富集于趋化因子、IL-6、TNF信号通路和IL-17信号通路。其中, GO和KEGG通路分析均富集于p38MAPK通路。MAPK信号通路在肠道黏膜损伤[24]、凋亡、增殖和修复中发挥重要作用, 可导致肠道黏膜上皮细胞凋亡, 诱导多种炎症因子的分泌, 并通过磷酸化调节紧密连接。p38MAPK级联反应的激活表明上皮细胞处于显著的应激状态, 这可能是由于其持续暴露于致病微生物组[11]。此外, IL-17信号通路的上调表明其与肠道菌群失调密切相关[25]。在健康状态下, IL-17发挥抵御致病微生物感染的作用[26], Il17‒/‒小鼠对细菌感染的防御能力显著减弱。因此, 免疫系统可能通过激活IL-17信号通路以应对致病微生物的入侵。
在Muc2‒/‒小鼠中, 肠黏液层缺失导致肠道菌群结构发生显著改变[27]。一些已被报道过的肠道有益菌减少, 如Bifidobacterium可以通过调节肠道菌群结构、修复肠道屏障、改善宿主肠道免疫反应、抑制氧化应激等作用缓解肠道炎症[28]。同时, 多种潜在致病菌丰度增加, 如Prevotella可以通过减少IL-18的产生加剧肠道炎症, 并可能导致全身自身免疫[29]。Sutterella具有降解IgA的能力, 通过降低肠黏膜中IgA的浓度, 损害肠道抗菌免疫反应功能[30]。Alcaligenaceae与促进结肠炎向结直肠癌的转化有关[31]。LEfSe分析显示, Akkermansia、Clostridia、Sutterella、Alcaligenaceae和Ruminococcaceae是Muc2‒/‒小鼠的特征性细菌。其中, Akkermansia和Ruminococcaceae均已被报道与黏液降解相关。有趣的是, Akkermansia通常被报道为一种肠道益生菌, 其丰度在UC患者中减少[32], 恢复其丰度可有效改善UC小鼠肠道炎症[33]。目前普遍认为Akkermansia的丰度与肠道黏液层的厚度呈正相关, 肠道黏液层变薄会导致Akkermansia丰度降低[34]。
然而, 本研究发现, 在Muc2‒/‒及Il10‒/‒小鼠中, 肠道黏液层变薄甚至缺陷却导致了Akkermansia丰度增加。在临床CRC患者中也观察到这一现象[20], CRC患者肠道黏液层变薄, 而Akkermansia丰度增加。这提示Akkermansia的生长并不完全依赖于肠道黏液。研究表明, Akkermansia能利用肠道中的宿主源性寡糖, 如2'-岩藻糖基乳糖作为替代能源[35]。Shin等[36]在黏蛋白缺失的条件下对Akkermansia进行转录组学分析, 发现其参与糖酵解和能量代谢途径的相关基因表达上调。此外, 在黏蛋白缺乏环境下, Akkermansia可以利用Bacteroides thetaiotaomicron、Prevotella spp.等多糖降解菌的中间代谢物, 如低聚糖、乙酸和乳酸等, 以维持其增殖代谢[37, 38]。这些结果提示, 尽管Muc2‒/‒小鼠无法合成MUC2, 但参与合成MUC2的前体化合物, 如半乳糖、岩藻糖、N-乙酰葡糖胺等O-连接寡糖仍暴露于肠腔, 可能成为Akkermansia增殖所需的底物。
而Akkermansia过度增殖存在潜在的致病性, Seregin等[39]发现, 灌胃Akkermansia导致Il10‒/‒小鼠结肠炎严重程度增加。Akkermansia作为一种肠道共生菌, 本身无致病性, 但过度增殖的Akkermansia通过代谢会产生大量的琥珀酸, 进而增强致病菌毒力, 促使致病菌黏附肠道上皮, 加剧肠道感染[40]。
差异肠道菌群与DEGs之间的相关性分析表明, 肠道菌群在驱动炎症反应中起着关键作用。肠道菌群紊乱可通过直接或间接方式诱导炎症细胞因子的释放, 破坏肠道屏障功能, 诱导免疫反应。因此, 未来研究方向应聚焦于关键菌群与宿主免疫反应之间的相互作用, 以明确菌群通过何种代谢产物或信号途径驱动特定免疫通路活化。通过菌群重建、代谢物补充与通路抑制, 多层次联合调控。补充益生菌、益生元或粪菌移植, 恢复肠道菌群稳态与多样性; 补充具有免疫调节功能的代谢产物, 如短链脂肪酸; 通过小分子抑制剂, 精准阻断p38MAPK、IL-6及趋化因子产生等炎症信号通路激活, 为精准抗炎提供新策略。
然而, 本研究还存在一些局限性。尽管通过结肠转录组和肠道菌群测序证实了肠道黏液在抵御外来致病菌入侵中的关键作用, 但特定微生物与Muc2‒/‒小鼠免疫反应的关联尚不明确。未来研究可通过使用无菌小鼠或补充特定细菌的小鼠模型, 分析特定微生物在无肠道黏液情况下的作用机制。
总而言之, 本研究阐明了Muc2‒/‒小鼠中肠道菌群对结肠转录水平的影响, 强调了肠道黏液屏障在防止肠道菌群触发病理免疫反应方面的关键作用。Muc2‒/‒小鼠模型与UC患者的相似性表明, 恢复黏液屏障的治疗有助于减轻疾病严重程度。本研究对于理解UC的发病机制至关重要, 并提供了一种恢复UC患者肠道黏液屏障功能障碍的新见解。

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doi: 10.16438/j.0513-4870.2025-0656
  • 接收时间：2025-06-12
  • 首发时间：2026-09-21
  • 出版时间：2026-02-12
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  • 收稿日期：2025-06-12
  • 修回日期：2025-09-16
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    南京中医药大学, 江苏省中药资源产业化过程协同创新中心, 江苏 南京 210023

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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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