汉堡薯条加可乐,动脉粥样硬化不可避免?这项运动可预防!关键在于调节肠道微生物群!

2022-03-14 LILYMED MedSci原创

Sci Rep.:耐力运动通过调节微生物群及其代谢物来改善西方饮食引起的动脉粥样硬化。

世界卫生组织确定心血管疾病是全球死亡的主要原因;动脉粥样硬化是高发病率和死亡率的主要原因。定期的身体活动是维持内皮健康和功能以防止动脉粥样硬化发展的有效策略。肥胖也是动脉粥样硬化进展的关键危险因素,并伴有各种并发症和全身炎症。生理稳态由肠道微生物群调节,但运动通过微生物群减弱动脉粥样硬化的机制尚未阐明。

因此,本研究探讨了耐力运动对西方饮食(WD)和载脂蛋白E(ApoE)敲除在微生物群参数和代谢物方面引起的动脉粥样硬化的影响。

转基因ApoE敲除小鼠和野生型小鼠分为以下四组(n = 6),即喂养chow饮食(WT CD)的野生型小鼠,喂食chow饮食(ApoE CD)的ApoEKO小鼠, ApoEKO老鼠的WD (ApoE WD)和ApoEKO白鼠WD和执行耐力运动,干预为期12个月。

1.耐力运动对WD诱导的肥胖、高脂血症和炎症的影响

WT CD、ApoE CD、ApoE WD 和 ApoE WD EX 组的体重和血脂在 3 个月后表现出显著差异(表1);组间初始体重、胆固醇、甘油三酯水平也有显著差异(F(3,20)= 4.25,P = 0.018;F(3,20) = 29.1, P < 0.0001;F(3,20) = 10.1,P<分别为0.0001。干预前,ApoE CD组的体重显著高于WT CD和ApoE WD组,但WT CD组、ApoE WD组和ApoE WD EX组之间没有显著差异。由于ApoE敲除,ApoE CD,ApoE WD和ApoE WD EX组的脂质胆固醇和三酰基甘油水平显着高于干预前WT CD组的水平。经WD饮食和运动干预12周后,两组间体重、胆固醇和三酰基甘油水平差异有统计学意义(F(3,20) = 36.9,P <0.001;F(3,20) = 76.0, P < 0.0001;F(3,20) = 18.1,P 分别< 0.0001)。WD组(ApoE WD和ApoE WD EX)的体重显着高于正常饮食组(WT CD和ApoE CD),但运动显着改善了WD诱导的肥胖(与ApoE WD相比)。与饮食组相比,血脂异常WD组的胆固醇和甘油三酯水平显著升高(表1)。与动脉粥样硬化性疾病高度相关的血脂异常和炎症也被量化,以评估耐力运动的效果。干预后各组LDL胆固醇、HDL胆固醇和TNF-α水平显著差异(F(3,20) = 88.8,P <0.001;F(3,20) = 46.3, P < 0.0001;F(3,20) = 18.9,P <分别为 0.0001)。与WT CD小鼠和ApoE CD相比,由于ApoE敲除,LDL,胆固醇和甘油三酯显着增加,但HDL没有增加。在ApoE WD组,WD干预导致LDL胆固醇、HDL胆固醇和TNF-α水平显著升高,但运动(ApoE WD EX)改善HDL胆固醇和TNF-α水平。

2.耐力运动对动脉粥样硬化斑块发展的影响

以WT CD组、ApoE CD组、ApoE WD组和ApoE WD EX组主动脉窦切片H&E染色观察动脉粥样硬化病理综合征,作为代表性显微照片;研究人员量化这些图像以确定血管厚度和斑块面积(图1)。图1a所示的ApoE CD组、ApoE WD组和ApoE WD EX组图像中的箭头表示粥样斑块。在WD和正常chow饮食条件下,ApoE敲除小鼠均发现动脉粥样硬化斑块,WT CD组为阴性对照。

此外,WD诱导的主动脉根内皮增厚导致纤维斑块的形成,加速了动脉粥样硬化的发展,各组间主动脉厚度和斑块面积差异显著(F(3,20) = 32.1,P < 0.001和F(3,20) = 30.6,P < 0.0001)。ApoE敲除和WD(ApoE WD)组的主动脉厚度明显大于饮食组,但运动(ApoE WD EX)显着减轻由ApoE敲除和WD引起的血管增厚(图1b)。ApoE敲除组(ApoE CD,ApoE WD和ApoE WD EX)表现出轻度至重度的病理性斑块;与正常饮食(ApoE CD)相比,WD(ApoE WD)也加剧了这种病理综合征。运动干预导致ApoE WD EX组的斑块面积明显少于ApoE WD组。

因此,在动脉粥样硬化的发病过程中,耐力运动可以防止胆固醇驱动的斑块形成和主动脉根部血管增厚。

3.耐力运动缓解 WD 驱动的菌群失调

为了确定耐力运动对肠道微生物群组成的影响,研究人员对20个样品(每组n = 5个)进行了Illumina辅助的16S rRNA扩增子测序,以比较各组之间的微生物丰度,组成和种群(图2)。使用观察和Chao1指数评估组内和组间α多样性,并通过加权和未加权UniFrac主坐标分析(PcoA)测量β多样性。如图3所示,WD组(ApoE WD和ApoE WD EX)的α多样性明显低于正常饮食组(WT CD和ApoE CD);因此,饮食对群体内的微生物多样性影响至关重要。使用PcoA图的UniFrac分析,从构建的OTU中计算出微生物群落之间的距离(组间多样性),揭示微生物群组成组间存在显著差异(在Adonis试验中分别P = 0.001和P = 0.001),具有均匀的分散(P = 0.54和P = 0.41)。运动干预在高脂血症和高脂肪饮食条件下调节微生物群,起到生理调节作用。LEfSe和LDA测定用于表征微生物群落并鉴定丰度显着差异(图2);WT CD组包括大多数细菌群落。在ApoE WD EX组中,Rikenellaceae和Erysipelotrichaceae家族及其相关属Rikenella,Rikenellaceae RC9,DubosiellaFaecalibaculum数量显著增多。

4.运动和WD对肠道微生物群属的影响

微生物属主要属于拟杆菌门(Bacteroidetes)、厚壁菌门(Firmicutes)和变形菌门(Proteobacteria),类群间丰度差异显著。如图4所示,ApoE WD组的Desulfovibrio、Parabacteroides、Bacteroides、Ruminococcaceae spp.、Lactococcus、Peptococcaceae、Ruminiclostridium_5、Tyzzerella和Lachnospiraceae的丰度显著高于ApoE CD组。然而,耐力运动导致ApoE WD EX组中的脱硫弧菌副拟杆菌拟杆菌乳球菌,Peptococcaceae,Tyzzerella和Lachnospiraceae的相对丰度显着低于ApoE WD组,这一结果与运动诱导的动脉粥样硬化发病机制的抑制一致(图2)。

因此,耐力运动干预可有效预防高脂血症引起的肠道菌群失调,维持肠道菌群内环境稳定,预防疾病。

5.耐力运动促进粪便短链脂肪酸的产生

心血管疾病及其主要危险因素(如动脉粥样硬化和高血压)可能与与胆固醇代谢、肠道生态失调和微生物代谢物高度相关的炎症反应相关因此,本研究评估了粪便SCFAs的浓度,这是由膳食纤维和抗性淀粉产生的微生物群产生和发酵的主要代谢物(图5)。各组间SCFAs和丙酸盐和丁酸盐总水平差异显著(F(3,20) = 22.72,P <0.001;F(3,20) = 16.4, P < 0.0001;F(3,20) = 22.4,P <分别为 0.0001)。与WT CD组相比,ApoE CD,ApoE WD和ApoE WD EX组中由ApoE敲除引起的血脂异常显着降低了总SCFAs以及丙酸盐和丁酸盐水平。通过ApoE敲除,WD诱导的高脂血症(ApoE WD)导致总SCFAs以及丙酸盐和丁酸盐水平显着低于chow饮食。与ApoE WD组相比,运动干预(ApoE WD EX)导致微生物代谢产物水平显著升高。

6.耐力运动对动脉粥样硬化期间主动脉和炎性细胞因子表达的影响

趋化因子是最大的细胞因子家族,在动脉粥样硬化发展的所有阶段都发挥着关键作用,它们主要在内皮细胞、平滑肌细胞和白细胞等细胞中表达。分析主动脉组织中的趋化因子和细胞因子,以确定运动对动脉粥样硬化过程的影响。主动脉中的趋化因子(VCAM-1和MCP-1)和促炎细胞因子(IL-1β和TNF-α)表达在各组间差异显著(F(3,20)= 6.72,P = 0.003;F(3,20) = 6.26, P = 0.004;F(3,20) = 5.2, P = 0.008;F(3,20) = 6.9,P = 0.002)。WT CD和ApoE CD组在VCAM-1,MCP-1,IL-1β或TNF-α表达方面没有显着差异(图6)。

然而,ApoE WD组表现出比chow饮食组(WT CD和ApoE CD)显着更高的VCAM-1,MCP-1,IL-1β和TNF-α表达。在ApoE WD组中发现VCAM-1和MCP-1表达最高,介导白细胞粘附和募集到血管内皮以迁移到发炎部位;通过病理检查发现,主动脉促炎蛋白IL-1β和TNF-α水平升高,VCAM-1和MCP-1相互激活,导致动脉粥样硬化病变更加严重。ApoE WD EX组的运动干预显着降低了VCAM-1,MCP-1,IL-1β和TNF-α的表达,以减轻免疫细胞的化学牵引和主动脉中的局部炎症,改善动脉粥样硬化的发展;还观察到这是主动脉根部较轻的动脉粥样硬化病变(图2)。

综上,WD在ApoE WD组中显着诱发肥胖和动脉粥样硬化综合征。严重动脉粥样硬化病变和动脉厚度显著升高,并伴有ApoE WD组免疫细胞趋化性和炎症期间免疫细胞趋化性和炎症的VCAM-1,MCP-1,TNF-α和IL-1β增加。

此外,ApoE WD组的生态失调导致短链脂肪酸(SCFA)产生最低。耐力运动干预(ApoE WD EX)通过减少肥胖,显着抑制VCAM-1,MCP-1,TNF-α和IL-1β表达以及增加SCFAs的产生来显着缓解动脉粥样硬化综合征。在运动干预后,还观察到与炎症相关的微生物群的调节,例如脱硫弧菌泰泽氏菌,并增加了SCFA的产生。耐力运动可以通过改善肥胖,炎症和趋化性信号来缓解WD诱导的动脉粥样硬化,这些信号传导由微生物群和衍生的SCFAs调节。

总之,这项研究确定了微生物群落和微生物衍生的SCFAs施加的耐力运动的抗动脉粥样硬化作用的潜在机制。这是第一项证明耐力运动可以调节微生物种群的研究,用于抗炎活性和SCFA产生;运动后主动脉炎反应显著降低,动脉粥样硬化发病机制得到改善。

 

原文来源:

Huang WC, Tung CL, Yang YSH, Lin IH, Ng XE, Tung YT. Endurance exercise ameliorates Western diet-induced atherosclerosis through modulation of microbiota and its metabolites. Sci Rep. 2022 Mar 7;12(1):3612. doi: 10.1038/s41598-022-07317-x. PMID: 35256637; PMCID: PMC8901804.

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  5. [GetPortalCommentsPageByObjectIdResponse(id=1944740, encodeId=b70d1944e407d, content=<a href='/topic/show?id=411de6300ad' target=_blank style='color:#2F92EE;'>#粥样硬化#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=52, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=76300, encryptionId=411de6300ad, topicName=粥样硬化)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=b30d401, createdName=huangshifeng, createdTime=Wed Jun 01 12:06:07 CST 2022, time=2022-06-01, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1825374, encodeId=580f18253e4e1, content=<a href='/topic/show?id=702a5065860' target=_blank style='color:#2F92EE;'>#微生物#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=36, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=50658, encryptionId=702a5065860, topicName=微生物)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=0b7c20, createdName=wjcjjian, createdTime=Sun Jun 26 20:06:07 CST 2022, time=2022-06-26, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1298898, encodeId=efad129889830, content=<a href='/topic/show?id=2088816e487' target=_blank style='color:#2F92EE;'>#肠道微生物群#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=38, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=81674, encryptionId=2088816e487, topicName=肠道微生物群)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=6e43278, createdName=yangjxjc, createdTime=Tue Mar 15 06:06:07 CST 2022, time=2022-03-15, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1367880, encodeId=cb9c136e8808c, content=<a href='/topic/show?id=2cee50e22c6' target=_blank style='color:#2F92EE;'>#微生物群#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=40, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=50722, encryptionId=2cee50e22c6, topicName=微生物群)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=3609256, createdName=zhu_jun9837, createdTime=Tue Mar 15 06:06:07 CST 2022, time=2022-03-15, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1569598, encodeId=6cc81569598c6, content=<a href='/topic/show?id=436d3841186' target=_blank style='color:#2F92EE;'>#可乐#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=33, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=38411, encryptionId=436d3841186, topicName=可乐)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=eede15532060, createdName=by2014, createdTime=Tue Mar 15 06:06:07 CST 2022, time=2022-03-15, status=1, ipAttribution=)]
    2022-03-15 by2014

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