1、REVIEWOpen AccessGut microbiota and cardiovascular disease:opportunities and challengesNegin Kazemian1,Morteza Mahmoudi2*,Frank Halperin3,Joseph C.Wu4,5,6and Sepideh Pakpour1*AbstractCoronary artery disease(CAD)is the most common health problem worldwide and remains the leading cause ofmorbidity and
2、 mortality.Over the past decade,it has become clear that the inhabitants of our gut,the gutmicrobiota,play a vital role in human metabolism,immunity,and reactions to diseases,including CAD.Althoughcorrelations have been shown between CAD and the gut microbiota,demonstration of potential causalrelati
3、onships is much more complex and challenging.In this review,we will discuss the potential direct and indirectcausal roots between gut microbiota and CAD development via microbial metabolites and interaction with theimmune system.Uncovering the causal relationship of gut microbiota and CAD developmen
4、t can lead to novelmicrobiome-based preventative and therapeutic interventions.However,an interdisciplinary approach is required toshed light on gut bacterial-mediated mechanisms(e.g.,using advanced nanomedicine technologies andincorporation of demographic factors such as age,sex,and ethnicity)to en
5、able efficacious and high-precisionpreventative and therapeutic strategies for CAD.Key points?The causal relationship between gut microbiota andCAD development has yet to be confirmed.?It is imperative to understand the potential directand indirect causal roots between gut microbiotaand CAD developm
6、ent via microbial metabolitesand interaction with the immune system.?Dynamic elements including our diet anddemographic factors such as age,sex,and ethnicitycan also affect our gut microbiota and CADdevelopment and complicate this matter.?Interdisciplinary approaches are required to shedlight on the
7、 factors involved in the modulation ofgut microbiota and its association with CADdevelopment.?Elucidating the system-level multifaceted web of fac-tors involved in microbiome-mediated mechanismsand human health and disease can guide novel pre-ventative and therapeutic interventions for CAD.Introduct
8、ionHigh serum cholesterol(hypercholesterolemia)is a well-documented risk factor for the most prevalent form ofcardiovascular disease(CVD)known as coronary arterydisease(CAD)13,which is one of the leading causesof morbidity and mortality worldwide 4,5.Otherestablished risk factors for CVD include hyp
9、ertension,diabetes mellitus,obesity,and a sedentary lifestyle 6.The buildup of cholesterol-containing deposits(plaque)inside the artery walls can lead to atherosclerosis 7,which is expected to cause 12 million coronary deathsannually by 2030 8.Hypercholesterolemia can have agenetic origin 9,10 and a
10、ffect bodily functions that aremainly responsible for cholesterol homeostasis in thebody,including de novo synthesis,catabolism in the liverand secretion into bile,and intestinal absorption 11.The Author(s).2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 Internatio
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14、therwise stated in a credit line to the data.*Correspondence:mahmou22msu.edu;sepideh.pakpourubc.ca2Department of Radiology and Precision Health Program,Michigan StateUniversity,East Lansing,MI,USA1School of Engineering,University of British Columbia,Kelowna,Kelowna,BC,CanadaFull list of author infor
15、mation is available at the end of the articleKazemian et al.Microbiome (2020)8:36 https:/doi.org/10.1186/s40168-020-00821-0Cholesterol in the body originates from two sourcesand is synthesized de novo in the liver or can enter ourbody via our diet and cholesterol-rich foods.About onefourth of the ch
16、olesterol in the body comes from dietaryintake(exogenous)and the rest is synthesized de novo(endogenous)via the mevalonate pathway 12,13.Thecholesterol synthesized within the body is classified aseither high-density lipoproteins(HDL)cholesterol orlow-density lipoproteins(LDL)cholesterol,the latter o
17、fwhich can enter the circulatory system and becomes akey marker of CAD 14.By contrast,HDL cholesterol isinversely associated withCAD 15and hasanti-atherogenic functions by exerting anti-inflammatory andanti-oxidative effects and promoting reverse cholesteroltransport(RCT),which can eliminate LDL cho
18、lesterol16.However,HDL may lose its anti-atherogenic prop-ertiesandbecomespro-atherogenic(dysfunctional)under conditions such as inflammation,diabetes,andoxidative stress 16.Moreover,elevated LDL cholesterolis a risk factor for CAD 17,which may be due to theuptake of LDL cholesterol particles by mac
19、rophages thatleads to foam cells and atherosclerosis 18.The gut lumen plays an eminent role in controllingthe bodys cholesterol balance and is responsible for ex-ogenous intake via cholesterol absorption 19.Luminalcholesterol can come from different sources and ismainly derived from(i)our diet,(ii)b
20、ile via the hepato-biliary pathway 20,and(iii)de novo cholesterol via thetransintestinal cholesterol efflux(TICE)pathway 21,22(Fig.1a).In the liver,cholesterol is metabolized into bileacid and is secreted into bile via the hepatobiliary path-way where the ATP-binding cassette transporter,G5/ATP-bind
21、ing-cassettetransporterG8(ABCG5/G8),plays a key role in cholesterol efflux from hepatocytesinto bile 23.TICE is an alternative route to thehepatobiliary pathway,where cholesterol from the bloodcan directly enter enterocytes through LDL receptors(LDL-R)and is effluxed by ABCG5/G8 and the ATP-binding
22、cassette transporter B1(ABCB1a/b)into thelumen 22.The cholesterol content of the lumen is theneither absorbed into enterocytes via Niemann-Pick C1-like 1(NPC1L1)and incorporated into chylomicrons forentry into the circulatory system 19,or is reduced bygut microbiota to poorly absorbable coprostanol(
23、5B-Cholestan-3B-ol)2426,which is mostly excreted.Aside from the complex interplay of numerous choles-terol sources in the body,many other factors can affectcholesterol balance and CAD development including ourgut microbiota.To date,associations between an altered gutmicrobiome composition and metabo
24、lic disorders such asobesity,diabetes mellitus,and CVD(independent of age,sex,and host genetics)27,28,including atherosclerosis,dyslipidemia,hypertension,and heart failure have been sug-gested 2931.Such links can be through direct(via me-tabolites)and indirect pathways(via the immune system)27,32.Th
25、e adult human gastrointestinal tract harbors 100trillion bacteria belonging to at least several hundred species33.The gut microbiota plays multiple critical roles in themaintenance of their host health,including helping host nu-trition and energy harvest,intestinal epithelial homeostasis34,35,drug m
26、etabolism and toxicity 36,immune sys-tem response 37,and protection from pathogens 38.These microorganisms can also generate microbial productssuch as uremic toxins 39,bile acids 40,trimethylamine-N-oxide(TMAO)41,short chain fatty acids(SCFA)42,lipopolysaccharides(LPS)43,nitric oxide 44,vitamin K45,
27、vitamin B complex 46,gut hormones 47,and neu-rotransmitters 48,which can alter host metabolism andaffect bodily functions in health and disease states.Suscepti-bility to atherosclerosis,for example,has been demonstratedFig.1 Cholesterol,gut microbiota,and CAD.a Exogenous and endogenous sources of lu
28、minal cholesterol.b The multifaceted mechanismsinvolved in CAD development.The gut microbiota can directly(via metabolites)and indirectly(via the immune system)lead to CADKazemian et al.Microbiome (2020)8:36 Page 2 of 17to be transferable by microbiota transplantation in murinemodels 49.To date,many
29、 infectious agents have beenlinked to atherosclerosis including Helicobacter pylori,Cytomegalovirus,Hepatitis C virus,Chlamydia pneumoniae,and Porphyromonas gingivalis 50.Interestingly,a study byMitra et al.showed that microbiota displayed differencesbetween symptomatic and asymptomatic atherosclero
30、ticplaques,with asymptomatic plaques having an increasedabundance of host microbiome associated families includingPorphyromonadaceae,Bacteroidaceae,Micrococcacaea,andStreptococcacaea 51.In contrast,symptomatic atheroscler-otic plaques contained an increased abundance of patho-genic microbiome famili
31、es including Helicobacteracaea,Neisseriaceae,and Thiotrichacaea 51.Moreover,gutmicrobiota dysbiosis as a result of the disruption to theoverall state of gut microbiota has been associated with in-creased inflammation,which is linked with the developmentof atherosclerosis 52.Recently,alterations in t
32、he gutmicrobiota and its metabolites have also been associatedwith hypertension and vascular dysfunction 53,54.Heartfailure has also been associated with specific gut microbialspeciessuchasincreasedEscherichiacoli,Klebsiellapenumoniae,and Streptococcus viridans 55.One study hasshown that patients wi
33、th symptomatic stroke and transientischemic attack have an altered gut microbiota with in-creased opportunistic pathogens including Enterobacter,Megasphaera,Oscillibacter,and Desulfovibrio 56.Further-more,the gut microbiota have the capacity to contribute tosubstantial variation in blood lipid compo
34、sition 57,whichcan affect CAD development.For example,Firmicutes suchas Lactobacillus reuteri are associated with higher HDL58,whereas the genus Eggerthella is associated with de-creased HDL cholesterol 57.Currently,the causal relationship between the gutmicrobiome and CAD development remains unclea
35、rsince many other demographic factors such as age,sex,and ethnicity can not only affect gut microbiota andcholesterol levels but also our diet,which is anothercomponent affecting our gut microbiota and whole bodycholesterol levels.Thus,cholesterol regulation in thebody is a complex mechanism with fa
36、ctors that areintertwined in a multifaceted system(Fig.1b).Therefore,further studies are needed to understand the underlyingmechanisms and identify which microbial strains or theirmetabolites are responsible for CAD development.Thisreview will discuss the dynamic elements involved withthe gut microb
37、iota and their effects on hypercholesterol-emia and CAD development via direct and indirectpathways.In addition,we will address the current chal-lenges to prove causality,discuss the gaps in knowledge,and propose the potential role of nanotechnology inuncovering the underlying mechanisms involved in
38、 CADdevelopment and as well as a microbiome-targetedtherapeutic tool.Effects of gut microbiota on CADDirect effectGut microbiota can directly affect hypercholesterolemiaand CAD development via metabolite production suchas bile acids,coprostanol,short chain fatty acids,and tri-methylamine-N-oxide pro
39、duction.Bile acid modulationThe gut microbiota can affect the regulation of cholesterolmetabolism in the liver 40,59 and play a role in alteringbile acids that can influence systemic cholesterol levels 60(Fig.2).Bile acids,formed by the rate-limiting enzyme chol-esterol 7-alpha-hydroxylase(CYP7A1)61
40、,are the main me-tabolites of cholesterol in the liver that help in theabsorption of fats,nutrients,and lipophilic vitamins 62 andalso the regulation of lipids,glucose,and energy metabolism63,64.Primary bile acids are conjugated to amino acidstaurine or glycine to form bile salts that are secreted i
41、nto bileand stored in the gallbladder until they are released into thesmall intestine where they emulsify fats and forms micelleswhich are absorbed into enterocytes 62.In the gut,the pri-mary bile acids such as cholic acid(CA)and chenodeoxy-cholic acid(CDCA)become deconjugated by the gutmicrobiota a
42、nd bile salt hydrolase(BSH)to form secondarybile acids,including deoxycholic acid(DCA),lithocholic acid(LCA),and ursodeoxycholic acid(UDCA)62,65.All conju-gated and unconjugated bile acids in the lumen can be reab-sorbed(95%)and transported back to the liver,except forUDCA and LCA,which are mostly e
43、xcreted in feces 61.Signaling molecules such as bile acids in the gut can also ac-tivate nuclear receptor farnesoid X receptor(FXR)and themembrane G protein-coupled bile acid receptor Gpbar-1(aka TGR5)62.Through this mechanism,bile acids candownregulate bile acid synthesis 66,which can lead to in-cr
44、eased cholesterol levels.The order in which bile acids canactivate FXR are CDCADCALCACA 67.FXR can in-duce fibroblast growth factor 19(FGF19),which activatesfibroblast growth factor receptor 4(FGFR4)and suppressesCYP7A1 to downregulate bile acid synthesis 68.FXR canalso reduce bile acid uptake into
45、hepatocytes and increasebiliary secretion of bile acid by increasing the expression ofATP-binding cassette subfamily B member 11(ABCB11)66,69.Primary and secondary bile acid ratios may be im-plicated in hypercholesterolemia and CAD development.Forexample,in a study by Myerhofer et al.70,the plasma p
46、ri-mary bile acids were reduced,and the ratio of secondary toprimary bile acids was higher in heart failure patients 70.Bile acids can also play a role in cardiovascular function byreducing heart rate through regulating channel conductanceand calcium dynamics in sin-atrial and ventricular cardio-myo
47、cytes and regulating vascular tone 70.In addition,wepropose that the gut microbiota modulating bile acid ratios,if unbalanced and in an unhealthy state,could lead to re-duced secondary bile acids,which can increase primary bileKazemian et al.Microbiome (2020)8:36 Page 3 of 17acids such as CDCA,activ
48、ate FXR,downregulate bile acidproduction,and thus increase cholesterol and CAD develop-ment.Thus,the gut microbiota and the underlying mecha-nisms involved need to be further investigated.Coprostanol productionCertain gut microbiota have long been known to possess theability to convert absorbable ch
49、olesterol to coprostanol,a re-duced non-absorbable sterol,which is excreted in feces 7173.Coprostanol production in humans starts during the sec-ond half of the first year of life 26 and is sex-dependent,withyoung women being high converters compared to youngmales 74.Furthermore,currently,the rate o
50、f microbialcholesterol-to-coprostanol conversion in human populationsis believed to be bimodal,with high converters showing al-most complete cholesterol conversion and low converters withcoprostanol representing less than one third of the fecal neu-tral sterols content 75,76.To date,isolated cholest