Article(id=1311350018787861414, tenantId=1146029695717560320, journalId=1227665162245664772, issueId=1311349919793905738, articleNumber=null, orderNo=null, doi=10.20043/j.cnki.MPM.202512353, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=null, receivedDate=1766332800000, receivedDateStr=2025-12-22, revisedDate=null, revisedDateStr=null, acceptedDate=null, acceptedDateStr=null, onlineDate=1790579808183, onlineDateStr=2026-09-28, pubDate=1782316800000, pubDateStr=2026-06-25, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1790579808183, onlineIssueDateStr=2026-09-28, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1790579808183, creator=13701087609, updateTime=1790579808183, updator=13701087609, issue=Issue{id=1311349919793905738, tenantId=1146029695717560320, journalId=1227665162245664772, year='2026', volume='53', issue='12', pageStart='2113', pageEnd='2304', issueExtLink='null', onlineDate='null', pubDate='1782316800000', pubDateStr='2026-06-25', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1790579784582, creator='13701087609', updateTime=1790588408144, updator='13701087609', preIssue=null, nextIssue=null, articleTotal=null, ext={EN=IssueExt(id=1311386089701597565, tenantId=1146029695717560320, journalId=1227665162245664772, issueId=1311349919793905738, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1311386089701597566, tenantId=1146029695717560320, journalId=1227665162245664772, issueId=1311349919793905738, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null, downloadFileDto=null}, startPage=2195, endPage=2202, ext={EN=ArticleExt(id=1311350019215680423, articleId=1311350018787861414, tenantId=1146029695717560320, journalId=1227665162245664772, language=EN, title=Correlation study on the effects of betaine on the composition of gut microbiota and the secretion of gut hormones in rats fed a high-fat diet, columnId=1228016572783063333, journalTitle=Modern Preventive Medicine, columnName=Nutrition and Food Hygiene, runingTitle=null, highlight=null, articleAbstract=
Objective

This study investigated the potential anti-obesity mechanisms of betaine by examining its effects on gut microbiota composition, intestinal hormone secretion, and visceral fat metabolism in rats fed a high-fat diet.

Methods

18 male SD rats were randomly divided into 3groups: the normal chow diet group (NCD), the high-fat diet group(HFD), and the high-fat diet + betaine group(HBE). Eight weeks later, the rats were sacrificed, and blood was collected to evaluate lipid metabolism and intestinal hormone secretion. 16SrRNA sequencing and reverse transcription quantitative PCR (RT-qPCR) were used to analyze the structure of the intestinal flora and the expression levels of adipocyte genes in rat feces.

Results

Compared with the high-fat diet group, betaine intervention significantly reduced the body weight (P=0.024) and epididymal white adipose tissue weight (P=0.001) of the rats, decreased the serum TG level (P=0.010), and increased the HDL-C (P=0.004) , PYY(P=0.001) and CCK (P=0.026) levels. In addition, linear regression analysis showed that the betaine-induced changes in the β-diversity of the intestinal flora could explain 22.43% of the changes in serum PYY levels (R2=0.224, P=0.047), and 25.09% of the changes in serum CCK levels (R2=0.251, P=0.034). Gene expression analysis showed that betaine intervention down-regulated the expression levels of Fabp3(P=0.019) and Akt1 (P<0.001) and up-regulated the expression of Abcd1 and Trem2 (P=0.010,0.035).

Conclusion

The changes in the intestinal microbiota induced by betaine intervention may improve obesity-related metabolic damage by regulating lipid metabolism and the secretion of intestinal hormones in the host.

, authors=Xian WANG, Xin SHANG, Gui-mei WEI, Pan-pan GUO, Yan PAN, Shu-xun YAN, authorsList=Xian WANG, Xin SHANG, Gui-mei WEI, Pan-pan GUO, Yan PAN, Shu-xun YAN, authorCompany=null, correspAuthors=Yan PAN, Shu-xun YAN, 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, fund=null), CN=ArticleExt(id=1311350023003136948, articleId=1311350018787861414, tenantId=1146029695717560320, journalId=1227665162245664772, language=CN, title=甜菜碱调控肠道菌群-肠道激素轴改善高脂饮食大鼠肥胖及脂代谢紊乱的机制研究, columnId=1228016573034721597, journalTitle=现代预防医学, columnName=营养与食品卫生, runingTitle=null, highlight=null, articleAbstract=
目的

通过分析甜菜碱干预对高脂饮食饲养大鼠肠道菌群组成、肠道激素分泌以及内脏脂肪代谢的影响,探讨甜菜碱可能的缓解肥胖的作用机制。

方法

将18只雄性SD大鼠随机分为标准饲料组、高脂饲料组和高脂饲料+甜菜碱组。实验结束后处死大鼠取血清评估血脂指标及肠道激素分泌情况,采用16SrRNA测序和逆转录实时定量聚合酶链式反应(RT-qPCR)分析大鼠肠道菌群结构及脂肪细胞基因表达水平。

结果

与高脂饲料组大鼠比较,8周的甜菜碱干预使得大鼠体质量(P=0.024)、附睾白色脂肪组织重量(P=0.001)明显降低,血清中甘油三酯(TG)的水平下降(P=0.010),高密度脂蛋白胆固醇(HDL-C)(P=0.004)、肽YY(PYY)(P=0.001)和胆囊收缩素(CCK)(P=0.026)的水平升高。此外,甜菜碱干预还使得高脂饲喂大鼠肠道菌群多样性指数上升,线性回归分析显示甜菜碱干预导致的肠道菌群β多样性变化能解释22.43%的血清PYY水平变化(R2=0.224,P=0.047)和25.09%的血清CCK水平变化(R2=0.251,P=0.034)。基因表达分析显示甜菜碱干预下调了脂肪酸结合蛋白3(Fatty acid binding protein 3,Fabp3)和AKT丝氨酸/苏氨酸激酶1(Akstrain transforming 1,Akt1)的表达水平(P<0.001),上调了ATP结合盒D亚家族成员1(ATP-binding cassette subfamily D member 1,Abcd1)和髓系细胞触发受体2(Triggering receptor expressed on myeloid cells 2,Trem2)的表达(P=0.010、0.035)。

结论

甜菜碱干预所改变的肠道菌群可能通过调节血脂和肠道激素的分泌影响宿主的脂肪代谢从而改善肥胖相关代谢损伤。

, authors=王娴, 尚鑫, 魏桂梅, 郭盼盼, 潘研, 燕树勋, authorsList=王娴, 尚鑫, 魏桂梅, 郭盼盼, 潘研, 燕树勋, authorCompany=null, correspAuthors=潘研, 燕树勋, authorNote=

王娴(1985—),女,硕士,副主任医师,研究方向:营养与慢性代谢性疾病

, correspAuthorsNote=
燕树勋和潘研为共同通信作者。
燕树勋,E-mail:
潘研,E-mail:
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Scientific Reports, 2023, 13(1): 482., articleTitle=TREM2 has a significant, gender-specific, effect on human obesity, refAbstract=null)], funds=[Fund(id=1311350028426372075, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1311350018787861414, awardId=2022JDZX021, language=CN, fundingSource=河南省中医药科学研究专项课题(2022JDZX021), fundOrder=null, country=null)], companyList=[AuthorCompany(id=1311350023409984437, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1311350018787861414, xref=null, ext=[AuthorCompanyExt(id=1311350023418373046, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1311350018787861414, companyId=1311350023409984437, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan 450001, China), AuthorCompanyExt(id=1311350023426761655, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1311350018787861414, companyId=1311350023409984437, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=河南中医药大学第一附属医院内分泌科,河南 郑州 450001)])], figs=[ArticleFig(id=1311350027411350497, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1311350018787861414, language=EN, label=Fig.1, caption=The effect of betaine on the intestinal microbiota structure in high-fat diet-fed rats, figureFileSmall=jZ6HeN6rLnoPSRdu4tTBAg==, figureFileBig=j7cAvmYAnhl7UBMM2g/4Aw==, tableContent=null), ArticleFig(id=1311350027499430882, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1311350018787861414, language=CN, label=图1, caption=甜菜碱对高脂饮食大鼠肠道菌群结构的影响

注:A:肠道菌群多样性指数(Sobs)组间差异分析;B:肠道菌群β多样性PCA分析;C:肠道健康指数(GMHI)组间差异分析;D-F:肠道菌群科、属水平物种差异分析;*:P<0.05。

, figureFileSmall=jZ6HeN6rLnoPSRdu4tTBAg==, figureFileBig=j7cAvmYAnhl7UBMM2g/4Aw==, tableContent=null), ArticleFig(id=1311350027738506211, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1311350018787861414, language=EN, label=Fig.2, caption=Linear regression analysis of the correlation between intestinal flora structure, lipid metabolism indicators and intestinal hormones in rats, figureFileSmall=8/3Q0f1/ODNPg1oVFC93tQ==, figureFileBig=iYkrJAtuyyyChKij7Udb4Q==, tableContent=null), ArticleFig(id=1311350027851752420, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1311350018787861414, language=CN, label=图2, caption=大鼠肠道菌群结构和脂代谢及肠道激素指标的线性回归分析, figureFileSmall=8/3Q0f1/ODNPg1oVFC93tQ==, figureFileBig=iYkrJAtuyyyChKij7Udb4Q==, tableContent=null), ArticleFig(id=1311350027956610021, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1311350018787861414, language=EN, label=Fig.3, caption=The effect of betaine on genes related to lipid metabolism in rats with a high-fat diet, figureFileSmall=SqiBcI26hTx2H5l88jtgOA==, figureFileBig=XktTLgHzIVPs+TMO3COi6Q==, tableContent=null), ArticleFig(id=1311350028036301798, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1311350018787861414, language=CN, label=图3, caption=甜菜碱对高脂饮食大鼠脂肪代谢相关基因的影响

注:*:P<0.05;**:P<0.01;***:P<0.001;****:P<0.0001。

, figureFileSmall=SqiBcI26hTx2H5l88jtgOA==, figureFileBig=XktTLgHzIVPs+TMO3COi6Q==, tableContent=null), ArticleFig(id=1311350028103410663, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1311350018787861414, language=EN, label=Fig.4, caption=Potential mechanism of betaine improving high-fat diet-induced obesity by regulating gut microbiota and gut hormones, figureFileSmall=bbIJNpavRwXH3AVmXLFArQ==, figureFileBig=a5odFIMPHe0mttNYZLYhQw==, tableContent=null), ArticleFig(id=1311350028183102440, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1311350018787861414, language=CN, label=图4, caption=甜菜碱通过调节肠道菌群与肠道激素改善高脂饮食诱导肥胖潜在机制图, figureFileSmall=bbIJNpavRwXH3AVmXLFArQ==, figureFileBig=a5odFIMPHe0mttNYZLYhQw==, tableContent=null), ArticleFig(id=1311350028246017001, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1311350018787861414, language=EN, label=Table 1, caption=

Comparison of body weight, adipose tissue mass, and serum biochemical parameters among the experimental groups()

, figureFileSmall=null, figureFileBig=null, tableContent=
标准饲料组高脂饲料组高脂饲料+甜菜碱组Pa AdjustedPc Adjusted
体质量(g)594.67±29.45693.50±16.72653.33±33.99<0.001b0.024b
附睾白色脂肪组织重量(g)14.15±3.0437.55±9.0622.69±5.66<0.001b0.001b
附睾白色脂肪组织
细胞面积(μm2)1 646.30±640.364 336.35 ±1 892.162 158.40 ±845.470.002b0.009b
甘油三酯(mmol/L)0.43±0.111.07±0.260.62±0360.001b0.010b
总胆固醇(mmol/L)1.41±0.371.94±0.172.06±0.320.008b0.494
高密度脂蛋白胆固(mmol/L)0.46±0.070.26±0.070.44±0.130.002b0.004b
低密度脂蛋白胆固(mmol/L)0.21±0.040.41±0.140.37±0.150.011b0.614
天冬氨酸转氨酶(mmol/L)128.77±38.85208.69±38.10175.09±105.800.0620.410
丙氨酸转氨酶(mmol/L)45.41±10.7168.19±17.8866.06±30.540.0840.865
空腹胰岛素(ng/ml)36.02±11.5729.14±4.6041.09±22.060.4280.178
瘦素(pg/ml)971.06±353.314 220.27±1 166.402 758.66±2 682.680.005b0.157
肠促胰素(pg/ml)258.27±82.73251.56±98.63311.80±84.190.8980.258
胆囊收缩素(pg/ml)33.16±17.7419.95±8.3130.86±6.050.0720.026b
肽YY(pg/ml)72.50±5.1560.33±11.7287.22±16.240.0980.001b
胃泌素(pg/ml)205.94±41.15201.01±29.82202.47±36.360.8160.945
胃动素(pg/ml)1 300.01±1 657.71556.16±324.13599.34±345.930.2150.941
), ArticleFig(id=1311350028329903082, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1311350018787861414, language=CN, label=表1, caption=

各组大鼠体质量、脂肪组织及血清生化指标比较()

, figureFileSmall=null, figureFileBig=null, tableContent=
标准饲料组高脂饲料组高脂饲料+甜菜碱组Pa AdjustedPc Adjusted
体质量(g)594.67±29.45693.50±16.72653.33±33.99<0.001b0.024b
附睾白色脂肪组织重量(g)14.15±3.0437.55±9.0622.69±5.66<0.001b0.001b
附睾白色脂肪组织
细胞面积(μm2)1 646.30±640.364 336.35 ±1 892.162 158.40 ±845.470.002b0.009b
甘油三酯(mmol/L)0.43±0.111.07±0.260.62±0360.001b0.010b
总胆固醇(mmol/L)1.41±0.371.94±0.172.06±0.320.008b0.494
高密度脂蛋白胆固(mmol/L)0.46±0.070.26±0.070.44±0.130.002b0.004b
低密度脂蛋白胆固(mmol/L)0.21±0.040.41±0.140.37±0.150.011b0.614
天冬氨酸转氨酶(mmol/L)128.77±38.85208.69±38.10175.09±105.800.0620.410
丙氨酸转氨酶(mmol/L)45.41±10.7168.19±17.8866.06±30.540.0840.865
空腹胰岛素(ng/ml)36.02±11.5729.14±4.6041.09±22.060.4280.178
瘦素(pg/ml)971.06±353.314 220.27±1 166.402 758.66±2 682.680.005b0.157
肠促胰素(pg/ml)258.27±82.73251.56±98.63311.80±84.190.8980.258
胆囊收缩素(pg/ml)33.16±17.7419.95±8.3130.86±6.050.0720.026b
肽YY(pg/ml)72.50±5.1560.33±11.7287.22±16.240.0980.001b
胃泌素(pg/ml)205.94±41.15201.01±29.82202.47±36.360.8160.945
胃动素(pg/ml)1 300.01±1 657.71556.16±324.13599.34±345.930.2150.941
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甜菜碱调控肠道菌群-肠道激素轴改善高脂饮食大鼠肥胖及脂代谢紊乱的机制研究
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王娴 , 尚鑫 , 魏桂梅 , 郭盼盼 , 潘研 , 燕树勋
现代预防医学 | 营养与食品卫生 2026,53(12): 2195-2202
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现代预防医学 |营养与食品卫生 2026 , 53 (12) : 2195 -2202
甜菜碱调控肠道菌群-肠道激素轴改善高脂饮食大鼠肥胖及脂代谢紊乱的机制研究
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王娴, 尚鑫, 魏桂梅, 郭盼盼, 潘研 , 燕树勋
作者信息
  • 河南中医药大学第一附属医院内分泌科,河南 郑州 450001
通讯作者:
燕树勋和潘研为共同通信作者。
燕树勋,E-mail:
潘研,E-mail:
作者简介:

王娴(1985—),女,硕士,副主任医师,研究方向:营养与慢性代谢性疾病

Correlation study on the effects of betaine on the composition of gut microbiota and the secretion of gut hormones in rats fed a high-fat diet
Xian WANG, Xin SHANG, Gui-mei WEI, Pan-pan GUO, Yan PAN , Shu-xun YAN
Affiliations
  • The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan 450001, China
出版时间: 2026-06-25 doi: 10.20043/j.cnki.MPM.202512353
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目的

通过分析甜菜碱干预对高脂饮食饲养大鼠肠道菌群组成、肠道激素分泌以及内脏脂肪代谢的影响,探讨甜菜碱可能的缓解肥胖的作用机制。

方法

将18只雄性SD大鼠随机分为标准饲料组、高脂饲料组和高脂饲料+甜菜碱组。实验结束后处死大鼠取血清评估血脂指标及肠道激素分泌情况,采用16SrRNA测序和逆转录实时定量聚合酶链式反应(RT-qPCR)分析大鼠肠道菌群结构及脂肪细胞基因表达水平。

结果

与高脂饲料组大鼠比较,8周的甜菜碱干预使得大鼠体质量(P=0.024)、附睾白色脂肪组织重量(P=0.001)明显降低,血清中甘油三酯(TG)的水平下降(P=0.010),高密度脂蛋白胆固醇(HDL-C)(P=0.004)、肽YY(PYY)(P=0.001)和胆囊收缩素(CCK)(P=0.026)的水平升高。此外,甜菜碱干预还使得高脂饲喂大鼠肠道菌群多样性指数上升,线性回归分析显示甜菜碱干预导致的肠道菌群β多样性变化能解释22.43%的血清PYY水平变化(R2=0.224,P=0.047)和25.09%的血清CCK水平变化(R2=0.251,P=0.034)。基因表达分析显示甜菜碱干预下调了脂肪酸结合蛋白3(Fatty acid binding protein 3,Fabp3)和AKT丝氨酸/苏氨酸激酶1(Akstrain transforming 1,Akt1)的表达水平(P<0.001),上调了ATP结合盒D亚家族成员1(ATP-binding cassette subfamily D member 1,Abcd1)和髓系细胞触发受体2(Triggering receptor expressed on myeloid cells 2,Trem2)的表达(P=0.010、0.035)。

结论

甜菜碱干预所改变的肠道菌群可能通过调节血脂和肠道激素的分泌影响宿主的脂肪代谢从而改善肥胖相关代谢损伤。

甜菜碱  /  肥胖  /  高脂饮食  /  肠道菌群  /  肠道激素
Objective

This study investigated the potential anti-obesity mechanisms of betaine by examining its effects on gut microbiota composition, intestinal hormone secretion, and visceral fat metabolism in rats fed a high-fat diet.

Methods

18 male SD rats were randomly divided into 3groups: the normal chow diet group (NCD), the high-fat diet group(HFD), and the high-fat diet + betaine group(HBE). Eight weeks later, the rats were sacrificed, and blood was collected to evaluate lipid metabolism and intestinal hormone secretion. 16SrRNA sequencing and reverse transcription quantitative PCR (RT-qPCR) were used to analyze the structure of the intestinal flora and the expression levels of adipocyte genes in rat feces.

Results

Compared with the high-fat diet group, betaine intervention significantly reduced the body weight (P=0.024) and epididymal white adipose tissue weight (P=0.001) of the rats, decreased the serum TG level (P=0.010), and increased the HDL-C (P=0.004) , PYY(P=0.001) and CCK (P=0.026) levels. In addition, linear regression analysis showed that the betaine-induced changes in the β-diversity of the intestinal flora could explain 22.43% of the changes in serum PYY levels (R2=0.224, P=0.047), and 25.09% of the changes in serum CCK levels (R2=0.251, P=0.034). Gene expression analysis showed that betaine intervention down-regulated the expression levels of Fabp3(P=0.019) and Akt1 (P<0.001) and up-regulated the expression of Abcd1 and Trem2 (P=0.010,0.035).

Conclusion

The changes in the intestinal microbiota induced by betaine intervention may improve obesity-related metabolic damage by regulating lipid metabolism and the secretion of intestinal hormones in the host.

Betaine  /  Obesity  /  High-fat diet  /  Intestinal flora  /  Intestinal hormones
王娴, 尚鑫, 魏桂梅, 郭盼盼, 潘研, 燕树勋. 甜菜碱调控肠道菌群-肠道激素轴改善高脂饮食大鼠肥胖及脂代谢紊乱的机制研究. 现代预防医学, 2026 , 53 (12) : 2195 -2202 . DOI: 10.20043/j.cnki.MPM.202512353
Xian WANG, Xin SHANG, Gui-mei WEI, Pan-pan GUO, Yan PAN, Shu-xun YAN. Correlation study on the effects of betaine on the composition of gut microbiota and the secretion of gut hormones in rats fed a high-fat diet[J]. Modern Preventive Medicine, 2026 , 53 (12) : 2195 -2202 . DOI: 10.20043/j.cnki.MPM.202512353
近年来,随着儿童肥胖症发病率的不断攀升,2型糖尿病、高血压、痛风等肥胖相关代谢性疾病的低龄化已成为我国重要的公共卫生问题[1]。儿童肥胖若未得到有效干预往往会持续到成年期,然而目前临床常用的肥胖治疗药物(如已得到减重适应症的司美格鲁肽、替尔泊肽、奥利司他胶囊等)在说明书中却大多声明不推荐应用于18岁以下未成年人,儿童减重用药风险问题依然突出[2]。甜菜碱作为一种天然营养素被认为可以改善人体成分和降低体脂率[3],且已被美国食品药品监督管理局(FDA)列为“公认安全”(Generally recognized as safe,GRAS)级别食品添加剂并在成人剂量高达4 g/日的临床试验中未发现严重不良反应,这为其研发成为可应用于未成年人群的药品转化提供了重要安全前提。
甜菜碱,也被称为N-三甲基甘氨酸,是一种天然食物成分,常见于贝类、小麦、甜菜和菠菜中。甜菜碱一方面来源于膳食摄入,另一方面来源于胆碱的氧化,是体内重要的甲基供体,在维持动物渗透压稳态和正常脂肪代谢中起着关键作用,其缺乏与脂质紊乱、糖尿病和血管疾病等多种代谢性疾病有关[4-5]。近年来大量研究证实作为人体重要的消化吸收器官,肠道菌群组成和激素分泌可对机体的能量代谢产生巨大影响[6-7]。与此同时,越来越多的研究表明甜菜碱具有靶向调控肠道菌群的潜力[8],但其具体作用机制、关键菌群靶点、代谢表型调控路径等仍不清晰。本课题组在既往研究中曾对甜菜碱干预高脂饮食大鼠的肠道菌群组成及附睾脂肪组织脂肪酸组成进行分析比较[9]。在上述基础上,本次研究利用课题组该项已发表工作中16S rRNA肠道菌群基因测序数据及动物实验原始实验数据,采用线性回归模型对菌群相对丰度变化与肠道激素水平之间的关联强度进行量化分析,此外还进一步对内脏脂肪组织进行RT-qPCR实验以验证甜菜碱对脂肪代谢基因的影响并对相关机制进行初步探讨,以期为营养性肥胖治疗相关的食源性药品开发提供理论依据。
SD大鼠(使用许可证号:SYXK豫2022-0007)购于北京维通利华实验动物技术有限公司;大鼠标准饲料和45%脂肪供能高脂饲料(MD12032)购于江苏美迪森生物医药有限责任公司。甜菜碱盐酸盐(纯度98%)购于上海泰坦科技股份有限公司。FastPure Stool DNA Isolation Kit购于上海美吉生物医药科技有限公司,FastPfu Polymerase购于北京全式金生物技术有限公司。CFX Connect PCR仪购于美国BIO-RAD公司;该项动物实验由河南中医药大学动物实验伦理审查委员会批准(IACUC-202307016)。
选取18只4周龄的雄性SD大鼠(100~150 g)随机分为3组,分别为饲喂标准饲料组(记为NCD组)、饲喂高脂饲料组(记为HFD组)、饲喂高脂饲料+甜菜碱组(记为HBE组)。喂养16周后,HBE组大鼠在饮水中添加1.5 %甜菜碱并继续高脂饲料喂养,其他组正常饮水,干预期为8周。
实验大鼠末次给予甜菜碱干预后禁食不禁水24 h,收集每只大鼠的新鲜粪便样本置于无菌EP管中,然后立即冷冻在-80℃冰箱。用戊巴比妥钠(40 mg/kg腹腔注射)进行深度麻醉,腹主动脉取血。血液标本4 ℃、3 000 r/min离心(离心半径10 cm)15分钟后取上清液,由武汉赛维尔生物科技公司使用ELISA试剂盒完成血清生化指标及肠道激素水平的测定。附睾白色脂肪组织(eWAT)及肝脏组织经10%中性福尔马林固定后包埋于石蜡中,切成5 μm厚的薄片。切片经苏木精染色和伊红染色(H&E)后,使用生物显微镜和Image J软件测量脂肪细胞面积。
从大鼠附睾白色脂肪组织样本中提取总RNA,使用逆转录试剂盒(武汉塞维尔生物,G3337)将RNA逆转录为cDNA。实验使用实时荧光定量PCR仪进行扩增反应,并通过配套软件分析荧光信号。以已知浓度的标准品构建标准曲线,通过Ct值计算样本中目标核酸的初始浓度,所有样本均进行三次重复实验,以确保结果的可靠性。
对3组大鼠的粪便样本进行微生物群落总基因组DNA抽提并对16S rRNA基因V3-V4可变区进行PCR扩增。肠道菌群数据分析采用mothur软件计算多样性指数,并采用Kruskal-Wallis秩和检验进行多样性的组间差异分析;使用基于欧式距离算法的PCA分析(主成分分析)检验样本间微生物群落结构的相似性;根据PCA分析结果进行线性回归分析用于评估微生物Beta多样性指数对临床指标的影响。
通过GraphPad Prism 9.0软件对数据进行处理,两组之间比较采用独立样本t检验,不符合正态分布使用Kruskal-Wallis秩和检验,P<0.05表示差异有统计学意义。
经过8周的甜菜碱干预,高脂饲料喂养大鼠的体质量、附睾白色脂肪组织重量、附睾白色脂肪组织细胞直径均明显下降(P=0.024、0.001、0.009),血清中TG的水平降低(P=0.010),HDL-C(P=0.004)、CKK(P=0.026)及PYY(P=0.001)的分泌得到恢复,结果见表1。
本研究对sobs指数(H=6.222,P=0.044)进行Kruskal-Wallis H检验以评估Alpha多样性的变化,从箱型图中可以观察到HFD组的中位数均低于HBE干预组(图1A),说明甜菜碱补充可以增加肠道菌群多样性。采用主成分分析(PCA)对三组研究对象肠道菌群的β多样性进行分析,结果显示3组样本分别产生了明显差异的聚集区域,且HBE组和NCD组间距离较近而距HFD组距离较远,说明高脂膳食显著改变了大鼠肠道菌群特征但甜菜碱补充则将这一改变重塑为更接近正常膳食的特征(图1B)。肠道菌群健康指数(GMHI)分析结果则表明甜菜碱干预可以使得高脂饮食大鼠的GMHI指数则回升(P=0.005;图1C)。
在科水平上对3组研究对象肠道粪便样本的菌群组成进行分析,结果显示高脂膳食使得毛螺菌科(Lachnospiraceae)丰度明显升高而乳杆菌科(Lactobacillaceae)丰度明显降低(图1D);在属水平上,高脂膳食降低了Clostridia_UCG-014丰度的同时增加了罗蒙布氏菌属(Romboutsia)、毛螺菌梭菌属(Lachnoclostridium)、布劳特氏菌属(Blautia)和异巴氏菌属(Allobaculum)的丰度,而甜菜碱干预则缓解了上述变化(图1E-F)。
为进一步探索肠道菌群结构对大鼠脂代谢指标及肠道激素分泌情况的影响,本研究基于肠道菌群PCA分析结果,以各组大鼠肠道菌群样本在PC1轴上的分值为X轴,以该样品对应的临床因子为Y轴做散点图进行了线性回归分析(图2)。结果显示反映宿主肠道菌群群落组成差异程度的标志物β多样性能解释22.43%的血清PYY水平变化(R2=0.224 3,P=0.047 1)和25.09%的血清CCK水平变化(R2=0.250 9,P=0.034 2)。
脂代谢相关基因表达水平测定结果(图3)发现高脂饮食大鼠的附睾脂肪组织中参与脂肪酸摄取的关键基因脂肪酸结合蛋白3(Fatty acid-binding protein 3,Fabp3)水平上调,而经过8周的添加甜菜碱干预Fabp3表达水平明显下调(P=0.019)。高脂膳食还使得附睾脂肪组织中参与胰岛素信号传导的基因AKT丝氨酸/苏氨酸激酶1(Akstrain transforming 1,Akt1)表达上调,而甜菜碱干预也使其表达水平发生下调(P<0.001)。此外,甜菜碱干预还显著上调了脂肪酸代谢基因ATP结合盒D亚家族成员1(ATP-binding cassette subfamily D member 1,Abcd1)和炎症抑制相关基因髓系细胞触发受体2(Triggering receptor expressed on myeloid cells 2,Trem2)的表达(P=0.010、0.035)。
甜菜碱是一种广泛存在于日常食物中的天然物质,其缺乏与许多肥胖相关的慢性代谢性疾病有关。多项研究表明甜菜碱可以通过增强脂蛋白酯酶活性和在代谢过程中充当甲基供体而发挥调节脂质代谢的作用[10-11]。但是,以上研究大多聚焦甜菜碱对肝脏细胞脂质代谢的影响,而甜菜碱在多大程度上可以通过调节内脏脂肪组织脂质代谢来有效缓解肥胖相关代谢紊乱仍存在争议。
在我们的研究中,8周的甜菜碱干预显著降低了高脂饮食大鼠的体重、附睾白色脂肪组织的重量和脂肪细胞大小,血脂分析结果也显示添加甜菜碱降低了HBE组血清中TG水平的同时升高了HDL-C水平,这与Szkudelska K等的研究结果一致[12]。此外,甜菜碱缓解了高脂膳食诱导的胆囊收缩素(CCK, Cholecystokinin)和肽YY(peptidetyrosinetyrosine, PYY)水平下降。CCK和PYY是2种重要的肠道激素,共同在胃肠道运动、食物消化吸收及能量代谢平衡方面发挥重要作用[13-14]。近年有研究发现,肥胖患者尤其是合并代谢综合征的个体其CCK水平更低[15],BMI大于30的肥胖人群血清PYY水平显著降低且与BMI呈现负相关[16]。因此本次结果提示甜菜碱可能不仅通过促进肝脏代谢缓解脂质紊乱,可能还通过影响肠道激素的调节影响能量代谢。
尽管肠道菌群与肥胖的密切关联已逐渐成为共识,但很多菌群的具体机制细节及属、种水平作用模式仍缺乏一致性证据。其中现有对于毛螺菌科与肥胖的关系报道存在矛盾现象,如有研究发现一些毛螺菌科菌属可将膳食纤维发酵为丁酸盐,具有改善胰岛素抵抗和肥胖的作用[17],而另一些研究报告部分毛螺菌科菌属能合成长链脂肪酸并扮演着促进脂肪组织脂质合成的角色[18],同时临床人群研究也显示毛螺菌科丰度与BMI呈显著正相关提示其可作为肥胖风险预警标志[19]。在本次结果中高脂膳食组肠道菌群多样性明显降低,合成丁酸相关的有益毛螺菌科菌属如Clostridia_UCG- 014[20]丰度下降,和肥胖相关有害毛螺菌科菌属罗蒙布氏菌属(Romboutsia)[21]、毛螺菌梭菌属(Lachnoclostridium)[22]、布劳特氏菌属(Blautia)[23-24]和异巴氏菌属(Allobaculum)[25]的丰度明显上升,而甜菜碱的补充缓解了上述菌属的变化。此外,在我们已发表的工作中还对菌群与肠道粪便中短链脂肪酸水平进行了相关分析,甜菜碱干预组和高脂膳食组相比丁酸的水平并没有下降反而上升[9],这提示甜菜碱干预可能通过抑制毛螺菌科中有害的亚群,使得在不牺牲产丁酸能力的情况下抑制了毛螺菌科的促肥胖作用。
由于肠道菌群与肠道激素在调节宿主的脂肪蓄积和能量代谢方面存在着密切而复杂的关系[26],本研究还对肠道菌群结构与脂代谢指标及肠道激素分泌水平之间的相关关系进行了探索。线性相关分析结果发现肠道菌群β多样性分别可以解释22.43%和25.09%的血清PYY和CCK水平变化。PYY和CCK作为肠道细胞分泌的核心激素,进入体循环后不仅可以直接结合脂肪细胞表面特异性受体调控脂肪分解与脂肪细胞炎症状态,还可以通过循环系统作用于中枢神经系统或激活交感神经通路,以抑制食欲减少能量摄入、促进棕色脂肪组织产热、加速脂肪分解等方式间接调控脂肪组织代谢。为进一步证实肠道激素对脂肪组织的影响,本研究还对甜菜碱干预大鼠内脏脂肪组织中脂肪酸代谢相关基因的表达水平进行了分析。其中Fabp3编码的脂肪酸结合蛋白3是一种细胞内脂肪酸转运蛋白,高脂膳食会显著增加其表达水平并导致脂肪酸代谢紊乱[27]。Akt1则是胰岛素信号通路中的关键分子,在高脂饮食诱导的肥胖小鼠模型中Akt1的敲除可显著减轻肥胖程度并改善相关代谢指标[28]。在本研究中,8周的甜菜碱干预使得高脂膳食大鼠附睾白色脂肪组织中Fabp3和Akt1表达水平明显下调。此外,Trem2基因负责编码一种免疫球蛋白超家族跨膜受体,可通过调节巨噬细胞的功能影响脂肪组织的炎症反应和代谢过程进而参与肥胖的发生发展。在脂肪组织中,Trem2的表达水平与BMI值呈正相关[29],而本研究表明甜菜碱干预可使得高脂饮食导致的Trem2高表达发生明显下调。
本研究尚存在以下局限性:本研究仅为甜菜碱对肠道菌群结构和肠道激素影响的相关性研究范畴,证据效能有限,未来还需进一步通过粪菌移植、菌群敲除或激素受体拮抗等实验直接验证甜菜碱干预对肠道激素分泌影响的因果关系。此外,本研究中甜菜碱的干预形式较单一,无法区分其对靶器官的影响是直接发挥或是通过影响食物代谢间接作用,且发现的差异菌种和相关基因之间的具体调控网络和信号通路还不明确。基于上述局限,后续工作中还需通过增加细胞体外试验和动物模型以明确甜菜碱发挥生物效应的作用路径,并聚焦本研究发现的关键菌种进一步验证其与肥胖代谢表型间的相互作用关系,以阐明甜菜碱对肠道菌群-激素-基因调控网络的具体信号通路。
综上所述,本研究首次通过线性回归量化菌群β多样性与肠道激素水平变化的关系,将甜菜碱的代谢获益聚焦在肠道菌群(如乳杆菌、毛螺菌科)和肠道内分泌激素(如CCK、PYY)代谢链上。我们应该认识到甜菜碱缓解肥胖相关代谢紊乱的机制是复杂的,它不仅在肝脏这一传统观念靶器官中发挥局部作用,还可以通过“菌群-肠道激素-脂肪代谢”轴对内脏脂肪组织产生远程影响(图4),这可以更好的解释甜菜碱对人体成分的改善现象。未来,甜菜碱有望作为食源性药物成分在儿童肥胖的精准营养干预中发挥作用。
  • 河南省中医药科学研究专项课题(2022JDZX021)
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2026年第53卷第12期
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doi: 10.20043/j.cnki.MPM.202512353
  • 接收时间:2025-12-22
  • 首发时间:2026-09-28
  • 出版时间:2026-06-25
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  • 收稿日期:2025-12-22
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河南省中医药科学研究专项课题(2022JDZX021)
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    河南中医药大学第一附属医院内分泌科,河南 郑州 450001

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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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