{"paper_id":"2f4b21f2-dd2f-4cb2-8b7b-ac11cf6c7210","body_text":"Cardiovascular disease (CVD) remains the leading cause of mortality and \nmorbidity worldwide [ 1 ]. CVDs include atherosclerosis, myocardial infarction, \nstroke, heart failure, and hypertension, among others. Risk factors for CVD can \nbe categorized as either modifiable (habitual alcohol and tobacco use, high blood \nlipids, high blood pressure, excess adiposity/body fat, poor glucose \ncontrol/diabetes, physical inactivity, and high-fat “Western” diet) or \nnonmodifiable (age, biological sex, genetics). Physical inactivity is a known \ncontributor to the global rates of CVD [ 2 ]. The United States “Physical Activity \nGuidelines for Americans” recommend that adults engage in 150–300 minutes of \nmoderate or 75 minutes of vigorous physical activity each week [ 2 ].\nThis narrative review will build on our previous work by presenting novel data \nthat shows a clear relationship between CVD, exercise, sex, race and gut \nmicrobiota. Specifically, we highlight how biological sex and race impact gut \nmicrobiota and how exercise can be used to improve gut health while minimizing \ndisparities. These factors are all linked in a complicated system that ultimately \ncan strongly influence cardiovascular health. This review will provide a brief \noutline of each topic, take a deep dive into the impacts of exercise on CVD with \nconsiderations for sex, race and gut microbiota, truly getting to the heart of \nthe matter.\n\nIt is well known that exercise preserves health. Studies conducted as early as \nthe 1910’s highlight the protective effects of manual labor on degenerative \ndiseases [ 3 ]. Similar reports reinforced the notion that physical activity can \nhelp prevent disease [ 4 ]. More recently, studies have shown that aerobic capacity \ncorrelates with an increased lifespan and increased “healthspan” [ 5 ]. Exercise \nis known to decrease all-cause mortality, and we know that cardiorespiratory \nfitness correlates with longevity [ 6 ]. Over the past several decades researchers \nhave become interested in which potential mechanisms are responsible for these \nprotective effects. For the purposes of this paper, we will focus on the \nmechanisms involved with exercise-induced protection of the cardiovascular \nsystem.\nThe gut microbiota consists of trillions of microbial cells such as bacteria, \nfungi, viruses, and archaea [ 7 ]. Regarding gut bacteria, there are over 1100 \ngenera, and approximately 90% fall under the phylum Bacteroidota and Bacillota \n(formerly known as Bacteroidetes and Firmicutes [ 8 ], respectively) while, the \nminority of gut bacteria are Pseudomonadota, Actinomycetota, Fusobacteriota, and \nVerrucomicrobiota (formerly known as Proteobacteria, Actinobacteria, \nFusobacteria, Verrucomicrobia [ 8 ], respectively) phyla [ 9 ]. Commonly observed in \na healthy gut microbiota is a decreased Bacillota to Bacteroidota ratio, stable \ncommunity, and greater species diversity [ 10 ].\nThe gut microbiota is now recognized as being critical for the maintenance of \noptimal human health. When the gut microbiota is in symbiosis with the host, \nmicrobes can promote health. However, when in dysbiosis (unbalanced gut \nmicrobes) with the host, the bacteria can contribute to chronic disease. In a \nhealthy host, the gut microbiota favorably affects digestion, nutrient \nabsorption, and production of folate, vitamins, and short chain fatty acids \n(SCFAs).\nOur lab [ 10 ], and others [ 11 ,  12 ,  13 ] have examined the link between the gut \nmicrobiota and exercise in animal models. The gut microbiota of sedentary \nindividuals differs from active individuals [ 14 ,  15 ,  16 ,  17 ]. Results from humans and \nanimal studies clearly show that exercise is central to healthful aging, improves \nthe diversity of microbes within the Bacillota phylum [ 10 ,  13 ,  14 ], and increases \nthe abundance of beneficial bacteria such as  Roseburia intestinalis , \n Faecalibacterium prausnitzii , and  Akkermansia muciniphila  [ 15 ,  18 ].\nIn addition, the gut microbiota appears to adapt to the unique demands of \nexercise [ 19 ,  20 ,  21 ]. Changes in the gut microbiota that occur with exercise generate \nmetabolites that further provide the host with performance advantages [ 19 ,  20 ,  21 ,  22 ,  23 ,  24 ]. \nAthletes typically have improved carbohydrate metabolism, higher tolerance to \noxidative stress, greater insulin sensitivity, enhanced muscle tissue repair, and \ngreater energy harvesting [ 14 ,  25 ,  26 ,  27 ].\nMoreover, results from antibiotic and germ-free mouse models demonstrate a \nbidirectional relationship between gut microbiota and exercise. Results show that \ngut microbiota must be intact for exercise performance and various aspects of \nmaintenance of exercise training but perhaps not for adapting to exercise \ntraining [ 12 ,  19 ,  20 ,  21 ,  22 ,  23 ,  24 ,  28 ].\nIn summary, habitually exercise-trained individuals have a beneficial gut \nmicrobiota. Additionally, sedentary individuals who undertake exercise training \ncan improve the abundance of beneficial gut microbes. Importantly, \nexercise-induced microbial changes in human studies are observed across the \nlifespan and are seen in both men and women. It is important to underscore that \nthe favorable gut modifications that come with habitual exercise training are \nlost with cessation of exercise (“use it or lose it”). In conclusion, an \nintact gut microbiota must be present to fully adapt to exercise-induced training \nadaptations, including muscle hypertrophy.\nThere are established sex differences in heart size, stroke volume, and \nhemoglobin content contributing to exercise performance [ 29 ,  30 ,  31 ]. Among humans, \nsex differences in heart size do not manifest until puberty. By adulthood, hearts \nare approximately 30% larger in males compared to females, primarily due to \ngreater myocyte hypertrophy among males [ 32 ]. These observed sex-based \ndifferences in heart size are the primary factors contributing to larger stroke \nvolume among males compared to females [ 33 ,  34 ,  35 ]. However, there does not appear to \nbe a difference in maximum heart rate by sex [ 33 ]. Hemoglobin concentration in \nblood is higher for males compared to females, contributing to sex differences in \noxygen carrying capacity [ 36 ]. Although males have larger muscle fibers and more \ncapillaries per fiber, capillary density does not differ between sexes [ 37 ]. \nFurthermore, while skeletal muscles of men are usually stronger and more powerful \nthan women, men are often more fatigable than women for sustained or intermittent \nisometric contractions performed at a similar relative intensity [ 38 ]. \nImportantly, these fundamental differences between biologic males and females \nemerge at the onset of puberty, suggesting that sex hormones may be responsible \nfor conferring sex-based differences. This is relevant because exercise \nmotivation, particularly in females, has been shown to be regulated by \nestrogen. Krause  et al . [ 39 ] demonstrated that in estrogen deficiency \nthere was reduced melanocortin-4 signaling which lowered the drive to exercise, \nilluminating the power of estrogen during the reproductive cycle in motivating \nbehavior and maintaining an active lifestyle in women. Intriguingly, estrogen \ndeficiency (menopause) is also when CVD risk increases [ 40 ], meaning not only are \nwomen at high risk of CVD, but they may be less likely to want to engage in \nexercise which would help in the prevention of CVD and other metabolic risk \nfactors.\nStudies comparing compositional differences in the microbiota between males and \nfemales often find differences between each sex, but not always [ 41 ]. This may \nindicate that the sex differences are context-dependent. For example, in several \nstudies, compositional differences were described as females having higher levels \nof  Clostridium  from the Bacillota (formerly Firmicutes) phylum and males \nhaving higher levels of  Prevotella  from the Bacteroidota (formerly \nBacteroidetes) phylum and  Lactobacillus  from the Bacillota phylum \n[ 42 ,  43 ,  44 ]. Other observations include males having less microbial diversity \ncompared to females [ 42 ]. These compositional differences are not always \nconsistent between the sexes, particularly when a study alters an additional \nfactor like diet [ 42 ].\nA variety of factors impact microbiota in the early years of life including mode \nof birth, breastfeeding or formula feeding, antibiotic treatment, genetics, sex, \nand more [ 41 ]. Consequently, these microbes likely affect human development in a \nsex-dependent manner. Even from birth, some studies show different microbial \ncommunities between males and females [ 42 ]. For example, females delivered by \nasthmatic mothers are prone to  Bacteroidaceae  microbes compared to males \nthat tend to harbor  Lactobacilli  [ 45 ]. Another example of early sex \ndifferences observing 300 infants is the temperament of males appears to be more \npositive when  Bifidobacterium  of the Actinomycetota (formerly \nActinobacteria) phyla and  Clostridiaceae  of the Bacillota phyla are \npresent [ 46 ]. Female members that have gut communities with  Veillonella  \ntend to be more risk averse [ 46 ]. Using reverse-transcriptase qPCR a study showed \nthat boys had higher abundance of several  Bifidobacterium  spp. over \nthree years [ 47 ]. A study examined how normal weight pre-puberty girls have \nincreased Bacteroidota compared to obese girls [ 48 ]. Interestingly, these \ndifferences were not seen in boys of the same age [ 48 ]. Obesity in girls of this \ngroup had more developed adrenal glands and an underexpression of gonadal \nestradiol, the predominant estrogen [ 49 ]. Boys in this group had increased \ndehydroepiandrosterone (DHEA) [ 49 ]. Given that other studies have linked estrogen \nlevels with certain groups of microbes, it would suggest that these girls could \nhave gut microbes that play a role in estrogen-driven diseases.\nDuring puberty, the difference in levels of sex hormones between males and \nfemales increases, and the effects they have on the microbiome appear to be more \nprominent as well [ 50 ]. For example, in a human twin study of teenagers, there \nwas greater dissimilarity of the gut microbiota between opposite-sex twins than \nsame-sex twins during puberty [ 51 ]. In another study using mice, the \nalpha-diversity of females changed significantly compared to males after puberty \nand the sex-related compositional differences disappeared after these male mice \nwere castrated [ 52 ]. Interestingly, in a study by Yuan  et al . \n(2020) [ 53 ] there was no difference in alpha-and beta-diversity of girls \nand boys before puberty, but there was an association of certain microbes to \ntestosterone including  Adlercreutzia ,  Ruminococcus , \n Dorea ,  Clostridium , and  Parabacteroides . Similarly, \nmale mice undergoing a gonadectomy were administered testosterone and \nsubsequently, did not exhibit the microbiota changes [ 52 ]. Another group of mice \nthat had a gonadectomy that did not receive testosterone supplementation did \nexhibit microbial changes [ 52 ]. This highlights testosterone as a key factor in \nmicrobial change. Similar studies performing ovariectomies on mice showed changes \nin microbiota including a reduction of Pseudomonadota (formerly Proteobacteria), \nhigher  Akkermansia , and a decreased ratio of Bacillota to Bacteroidota \n[ 54 ].\nDuring adulthood, estrogen and testosterone are described as potent modifiers of \nthe human body and the microbiota [ 55 ]. And due to the different concentrations \nof sex hormones in males and females, the microbiota and its effects are \nmodulated in a sex-dependent manner [ 55 ]. The adult microbiota is also \ncharacterized as being more stable compared to other stages of life [ 42 ]. In a \nhuman study of 516 Japanese males and females,  Prevotellaceae  was more \nabundant in males and  Ruminococcaceae  was more abundant in females [ 44 ]. \nThe microbiota from 91 pregnant women were transplanted via fecal microbiota \ntransfer (FMT) into germ-free (GF) mice in the 1st and 3rd trimester [ 56 ]. Mice \nreceiving FMT from third trimester (T3) showed pregnancy-like effects like increased adiposity and \ninsulin sensitivity, but FMT from first trimester (T1) did not show these effects [ 56 ]. \nAdditionally, there was no correlation between the microbiota compared to \nestrogen levels throughout the menstrual cycle of 17 females [ 57 ]. Importantly, \nadulthood is when many diseases can progress, and this can have sex-dependent \neffects on the microbiota as well. In a study by Mahnic  et al . (2018) \n[ 58 ], they also found higher levels of  Bacteroides  and \n Prevotella  in males compared to females. To understand these \nrelationships fully, the mechanisms that influence them should be investigated.\nAs people age, the microbial changes between males and females become less \nprominent [ 42 ]. It is important to note that this is also when male and female \nhormone levels become more similar [ 41 ]. These events are likely not a \ncoincidence. In a study by Santos-Marcos  et al . (2018) [ 59 ], the \nmicrobiota of human males and post-menopausal females were compared to measure \nany differences between each sex. The Bacillota/Bacteroidota ratio was different \nbetween males and females as well as the amount of saccharolytic activity [ 59 ]. \nMore specifically, pre-menopausal women versus post-menopausal women and \npre-menopausal females versus males were most different [ 59 ]. Given that estrogen \nlevels are greatly reduced in post-menopausal women, the data suggests that the \nchanges in the microbiota are influenced by the changes in sex hormones [ 59 ]. \nInterestingly, Deltaproteobacteria in the cecum increased in abundance as mice \naged [ 60 ]. This raises the question of how age may impact the microbiota \ndifferently depending on where along the gastrointestinal tract the sample is \ntaken.\nAccording to the 2022 Centers for Disease Control, National Center of Health \nStatistics Data Brief on physical activity in the United States (US) the \npercentage of adults who met the guidelines for both aerobic and \nmuscle-strengthening activities varied by race and Hispanic origin [ 61 ]. In \ngeneral, in 2020, 24.2% of adults aged 18 and over met the 2018 Physical \nActivity Guidelines for Americans for both aerobic and muscle-strengthening \nactivities [ 61 ]. When accounting for race/ethnicity Hispanic men (23.5%) were \nless likely to meet both physical activity guidelines than non-Hispanic White \n(30.5%), non-Hispanic Asian (30.2%), and non-Hispanic Black (29.7%) men [ 61 ]. \nNon-Hispanic White women (24.3%) were more likely to meet both guidelines than \nHispanic (18.0%), non-Hispanic Asian (16.7%), and non-Hispanic Black (16.5%) \nwomen [ 61 ]. Across all race and Hispanic-origin groups, men were more likely than \nwomen to meet the guidelines for both aerobic and muscle-strengthening activities \n[ 61 ]. The percentage of men who met both physical activity guidelines increased \nas family income increased, from 16.2% of men with a family income of less than \n100% of the federal poverty level (FPL), to 20.0% of men with income at \n100%–199% of FPL, and 32.4% of those with income at 200% of FPL or more \n[ 61 ]. The percentage of women who met both physical activity guidelines increased \nas family income increased, from 9.9% of women with family income less than \n100% of FPL, to 13.6% of women with income at 100%–199% of FPL, and 25.9% \nof those with income at 200% of FPL or more [ 61 ]. Across all income groups, men \nwere more likely than women to meet the guidelines for both types of activity \n[ 61 ].\nCurrently, human gut microbiota studies have had a narrow focus or simply \ndescribe broad population-level changes to gut communities in response to \nenvironmental variation. As such, only a few studies have been designed to \naddress gut microbiota variation in relation to structural inequities, and even \nfewer have attempted to link host health to socially attributed variations in the \ngut microbiota [ 62 ,  63 ,  64 ,  65 ,  66 ]. Nevertheless, the small but existing literature does \nprovide accumulating evidence that the social and environmental factors that \ncontribute to health inequities may also predict gut microbiota characteristics. \nFor example, measures of socioeconomic status (SES) across globally diverse \npopulations, have been associated with a distinct gut microbiota in both adults \n[ 66 ,  67 ,  68 ] and children [ 69 ,  70 ,  71 ,  72 ,  73 ]. Similarly, the gut microbiota consistently varies \nwith race (e.g., Asian, Black, Hispanic, White) and/or ethnicity/ancestry \n(Arapaho, Cheyenne, Dutch, Ghanaian, Moroccan) in adults [ 62 ,  63 ,  65 ,  74 ] and \nchildren [ 70 ,  71 ,  75 ,  76 ].\nThere is strong evidence linking structural inequities to gut microbiota \nvariation in the context of SES. For example, neighborhood SES has been shown to \nexplain 12–25% of the variation in adult gut microbiota composition, after \nadjustment for demographic and lifestyle factors, and was positively correlated \nwith gut microbiota diversity [ 67 ]. Similar results noting an association between \nneighborhood SES and gut microbiota diversity were also obtained utilizing a \ndiscordant-twin analysis, which minimizes the possibility of confounding by \nshared genetic or family influences [ 68 ]. Finally, it has been shown that the \nrelative abundance of taxa, accounting for 38.8% of the gut microbiota, varies \nin relation to indices of wealth appraised as personal yearly income and spending \n[ 66 ].\nDespite the important contributions of these findings, most gut microbiota \nstudies in minoritized populations do not operationally define structural \ninequities. Furthermore, race and ethnicity/ancestry are often incorrectly \nconflated. Whether the gut microbiota is impacted more by the personal lived \nexperiences of perceived racism and discrimination (internalization) versus overt \nstructural/systemic oppressive policies remains largely unknown. It is likely a \ncombination of both. Similarly, the scale (i.e., household, neighborhood, and \nbeyond) at which structural inequities might affect the gut microbiota is \nunclear. Nonetheless, the existing literature demonstrates that the same social \ninequities that predict disease disparities also predict variation in the gut \nmicrobiota. These relationships underscore the likely role of the gut microbiota \nin mediating socially driven health disparities.\n\nExercise has many health benefits. These benefits apply to people of all ages, \nraces and ethnicities, and sexes. Exercise helps individuals maintain a healthy \nweight, reduces the risk of depression and a decline in cognitive function and \nlowers a person’s risk for many diseases, such as CVD and other chronic health \ndiseases [ 3 ,  4 ,  5 ,  6 ]. When done regularly, moderate- \nand vigorous-intensity physical activity strengthens the cardiac myocardium and \nimproves the heart’s ability to distribute blood to the body, thereby reducing \nCVD risk. Exercise can reduce this risk through a variety of mechanisms including \nlowering blood pressure, and triglycerides, raising HDL (high-density lipoproteins), \ndecreasing arterial stiffness, reducing the risk of being overweight or obese and maintaining \na healthy weight, maintenaining in-range blood glucose and insulin levels, and \nreducing inflammation [ 3 ,  4 ,  5 ,  6 ]. This section of the review will highlight the \nimpacts of exercise on the cardiovascular system and the mechanisms by which this \noccurs, providing a foundation for which we will later discuss the integrated \nroles of sex, race/ethnicity, CVD, and gut microbiota.\nBroadly, exercise decreases CVD [ 77 ] and increased aerobic fitness has been \nshown to reduce mortality rates of individuals following myocardial infarction \n[ 78 ]. These improvements have been shown in various animal models [ 79 ,  80 ,  81 ] and \nhuman studies [ 82 ,  83 ,  84 ]. Specifically, it is believed that chronic shear stresses \non the endothelial lining of the blood vessels and the endocardium, which are \nderived from exercise-induced increases in blood flow, increase nitric oxide (NO) \nbioavailability [ 85 ] (Fig.  1 ). NO is a vasoprotective molecule that prevents \nvascular dysfunction, platelet aggregation, leukocyte adhesion and vascular \nstiffening [ 86 ,  87 ]. Reductions in NO have been indicated in the development of \nhypertension and CVD [ 88 ,  89 ].\nA representation of nitric oxide signaling . Shear stress \nincreases intracellular calcium (Ca 2+ ) which enhances endothelial nitric \noxide synthase (eNOS) enzymatic action. eNOS catalyzes the synthesis of \nL-arginine to nitric oxide. Tetrahydrobiopterin (BH4) is a critical cofactor.\nFurthermore, exercise augments anti-oxidant defense and decreases reactive \noxygen species (ROS) production [ 90 ,  91 ,  92 ]. Production of ROS is known to increase \nthe potential for cellular damage [ 93 ,  94 ] and can augment the severity of \nmyocardial ischemia [ 95 ]. Previous work has shown that exercise-trained rodents \nhave increased cardiac output compared with sedentary littermates following \n in-vivo  myocardial ischemia [ 96 ]. Exercise has been long known to \nincrease cardiac output via myocardial hypertrophy and proliferation [ 97 ]. More \nrecently exercise has been shown to increase peroxisome proliferator-activated \nreceptor-gamma coactivator-1 α  [ 98 ,  99 ], which has the potential to \nincrease longevity and promote health [ 100 ]. Lastly, exercise has several \nindirect effects that improve cardiovascular health including weight reduction \n[ 101 ] and improved gut health [ 10 ]. In the following sections, we will review \neach of these mechanisms in detail.\nEndothelium-derived NO is essential for cardiovascular health [ 86 ,  87 ] and its \nproduction is augmented with acute [ 102 ] and chronic exercise [ 103 ]. \nEndothelial-derived NO is synthesized from L-arginine by endothelial nitric oxide \nsynthase (eNOS) and released by endothelial cells [ 104 ,  105 ]. Shear stresses \nplaced on the endothelial cells of blood vessels cause the release of NO, which \ntriggers vasodilation [ 104 ,  105 ]. The repeated shear stresses which are \nassociated with repeated bouts of exercise are thought to increase NO \nbioavailability by chronically stimulating its release [ 85 ].\nImprovements in rodent vascular NO bioavailability are often indicated \n in-vivo  by examining endothelial-dependent dilation (EDD) in the blood \nvessel of interest [ 90 ]. Because NO is a key regulator of vasodilation, \nreductions in EDD can be indicative of diminished NO bioavailability. Rodent \nexercise perturbations ranging from 2–13 weeks have been shown to improve EDD \n[ 90 ,  103 ,  106 ] and thus NO bioavailability. This was confirmed in an acute study \nconsisting of two to four weeks of treadmill training in healthy rats. \nDose-dependent EDD was improved in the skeletal muscle arterioles of the \nexercise-trained rats [ 107 ], while endothelial independent dilation was not \nchanged. In a 13-week exercise intervention, EDD and NO production in the \nfemoral artery were increased in Wistar-Kyoto rats following treadmill \ntraining [ 108 ]. Both eNOS expression and phosphorylated eNOS (Ser1177) expression \nwere increased in trained rats when compared to their sedentary littermates.\nExercise also has a vascular protective effect in several models of rodent \nvascular dysfunction. In a study by Guers  et al . [ 109 ], 6 weeks of \nvoluntary wheel running protected against salt-induced (4% NaCl chow) losses in \nEDD in rat femoral arteries. Western blot analysis demonstrated that this may \nhave been mediated through a decrease in protein concentration of the reactive \noxygen species: nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 4 (NOX4) and Gp91-phox, two subunits of NADPH \noxidase. Protein concentrations of both NOX4 and Gp91-phox were \ninitially increased following 6-weeks of a high salt diet in rodents. Exercise \nalso led to an upregulation of the antioxidant superoxide dismutase-2 (SOD2). \nCollectively, there was a reduction in overall oxidative stress and thus an \nincrease in vascular eNOS bioavailability. eNOS tends to become uncoupled with \nhigh levels of oxidative stress [ 110 ] and thus becomes unable to synthesize NO \n[ 111 ].\nExercise not only augments NO production in blood vessels but also in the heart \n[ 112 ]. In a study by Kuczmarski  et al . [ 113 ], 4 weeks of voluntary wheel \nrunning helped maintain left ventricular (LV) cardiac function following an \nischemia-perfusion injury in rats in a model of chronic kidney disease. \nKuczmarski found that wheel running protected against losses in LV NO levels and \nimproved overall cardiac redox status [ 113 ]. Specifically, this appeared to be \nmediated through an upregulation of the antioxidant SOD2 [ 113 ]. Furthermore, \nsimilar to blood vessels, eNOS is upregulated in the heart with chronic aerobic \nexercise [ 112 ]. Dogs who were treadmill trained for 10 days experienced increases \nin dose dependent EDD in both coronary arteries and the microvasculature of the \nheart [ 114 ]. The authors also found an increase in the constitutive nitric oxide \n( ECNOS ) gene. Together these data further support the notion of an \nincrease in NO bioavailability in the heart as a result of exercise.\nExercise also has the potential to increase NO bioavailability in humans [ 115 ,  116 ]. Performing moderate aerobic exercise for 1 hour a day for a month increased \nNO generation and reduced resting blood pressure. This effect was thought to be \nmediated through an increase in antioxidant enzymes in blood monocytes [ 115 ]. In \nanother study by Tanaka  et al . [ 117 ], the authors discovered that \nindividuals who have high levels of aerobic fitness do not experience the typical \nage-related decreases in vascular function as measured by EDD. Furthermore, 12 \nweeks of brisk walking restored losses in EDD in previously sedentary middle-aged \nand old individuals [ 117 ]. Lastly, four weeks of home-based exercise restored \nlosses in forearm EDD in individuals with hypercholesterolemia independent of \ndietary modifications [ 118 ].\nCollectively, patients with heart failure tend to have a significant reduction \nin aerobic capacity [ 119 ]. This appears to be at least partially mediated through \na reduction in NO [ 120 ]. Heart failure patients also consistently have a \nreduction in EDD [ 121 ] which can be partially restored with supplementation of \nL-Arginine, a precursor of NO [ 122 ]. A hallmark of heart failure tends to be the \nreduction in blood flow back towards the heart which diminishes pre-load. \nExercise training has been shown to improve outcomes in patients with heart \nfailure by increasing NO bioavailability and in turn blood flow and preload. \nFurther to this, 12 weeks of aerobic exercise training increases forearm EDD in \nhypertensive individuals [ 123 ].\nIn both the heart and blood vessels, as indicated in the aforementioned studies, \noxidative stress appears to be one of the principal mediators in reducing NO \nlevels consequently disrupting cardiovascular homeostasis. Oxidative stress is \ndefined as an imbalance of free radical production and the production of free \nradical scavenging antioxidants [ 124 ]. Oxidative stress has been indicated in a \nnumber of pathologies including CVD [ 95 ,  123 ,  125 ]. As an example of this: NADPH \noxidases were found to be significantly upregulated in aortic atherosclerotic \nlesions taken from human autopsies [ 126 ]. Furthermore, SOD2 knockout mice \nexperienced increased mitochondrial oxidative stress which led to the onset of \nhypertension [ 127 ] and elevations in oxidative stress levels were associated with \nthe severity of heart failure in both the left and right ventricles of mice \nfollowing myocardial ischemia [ 128 ]. Lastly, a clinical studyhas found \ncorrelations between markers of oxidative stress and instances of heart failure \n[ 129 ]. Interestingly, in many cases exogenous antioxidants have been shown to \nimprove outcomes in certain instances of CVD [ 130 ,  131 ].\nAs mentioned earlier exercise has the capacity to increase antioxidant defenses \nand decrease oxidative stress levels which protects against a reduction in NO \nbioavailability and maintains normal cardiovascular function. SOD is an antioxidant that can be upregulated through exercise [ 109 ,  113 ]. SOD is critical in the maintenance of cardiovascular homeostasis as it \nprevents the breakdown of NO by the reactive oxygen species superoxide \n(O 2 .- ) [ 132 ]. O 2 .-  has a high affinity for NO and \nrapidly converts it to peroxynitrite (ONOO-) which can damage lipoproteins. SOD \nreacts and dismutates O 2 .-  to H 2 O 2  before this reaction can \noccur. An increase in O 2 .-  disrupts vascular function [ 133 ] and \nelevations in ONOO- levels are associated with CVD [ 134 ] (Fig.  2 ).\nA representation of free radicals being scavenged by endogenous \nantioxidants . Superoxide (O 2 -) reacts with nitric oxide (NO) to form \nperoxynitrate (ONOO-). Superoxide dismutase (SOD) catalyzes the reaction of \nO 2 - to hydrogen peroxide (H 2 O 2 ), which participates in the \nformation of hydroxyl radicals ( ⋅ HO). Both catalase and glutathione \nperoxidase (GPx) reduce H 2 O 2  to water (H 2 O) and oxygen (O 2 ).\nTherefore, a deficiency in SOD will lead to a decrease in NO bioavailability and \ndiminishes vascular function. As an example, copper zinc SOD \n(CuZnSOD) deficient mice had a 2-fold increase in O 2 .-  relative to their control \nlittermates. Ultimately, this led to a decrease in dose-dependent EDD in the \ncarotid artery [ 135 ]. Reduced SOD has also been associated with a number of \npathologies including atherosclerosis, hypertension, and hypercholesterolemia \n[ 136 ]. Importantly, as mentioned previously aerobic exercise can increase SOD \nlevels. In a study by Durrant  et al . (2009) [ 103 ], old mice with access \nto a running wheel had greater levels of aortic SOD and lower levels of NADPH \noxidases relative to their untrained littermates. This coincided with better \ndose-dependent EDD and higher levels of aortic eNOS and phosphorylated eNOS \n(Ser1177) expression [ 103 ].\nH 2 O 2 , is the result of the dismutation of O 2 .-  by SOD \nand elevated levels of H 2 O 2  can also lead to oxidative stress [ 93 ] and \nvascular dysfunction [ 137 ]. The antioxidants, Glutathione peroxidase (GPx) and \ncatalase are both capable of reducing H 2 O 2  to oxygen and water. In \nhumans, low levels of GPx are associated with an increased risk of CVD [ 138 ]. \nFurthermore, in mice, GPx deficiency led to a reduction in NO and a decrease in \nvascular function [ 139 ]. Similar to GPx, low levels of catalase are also \nassociated with CVD [ 140 ]. Like SOD, several studies have shown that exercise \nincreases levels of both GPx and catalase [ 141 ].\nArterial stiffness is a consistent independent predictor of all-cause mortality \nin individuals with hypertension [ 142 ]. Arterial stiffening is often associated \nwith atherosclerosis, aging, smoking, obesity, and hyperlipidemia amongst other \nfactors [ 143 ]. Over time, the structural properties of the vasculature can \nchange. Collagen deposition in the tunica media and the degradation of elastin \ndecreases the ability of arteries to dampen pulse waves and increases blood \npressure [ 144 ]. Furthermore, chronic elevations in blood pressure increase LV \noverload which leads to the eventual development of LVventricular hypertrophy. \nSpecifically, the loss of the ability to “dampen” a pulse wave in the aorta \nleaves organs with low vascular resistance vulnerable to injury [ 144 ]. One \nparticular example is the kidneys where the exacerbation of damage is associated \nwith the stiffening of both resistance arteries as well larger elastic arteries \n[ 145 ].\nIt has been established that exercise has the ability to slow down and help \nprevent vascular stiffening as well as decrease collagen levels in rodents [ 90 ,  91 ,  146 ] and humans [ 147 ,  148 ]. Further, arterial stiffness tends to be \ncorrelated with maximal aerobic capacity [ 130 ]. Fleenor  et al . \n2010 [ 146 ], found that 10–14 weeks of voluntary exercise was associated with decreased \nage-related vascular stiffness. Specifically, collagen I and III fibers were \nreduced. Another study examining a model of heart failure in mice discovered that \n6 weeks of treadmill exercise was able to prevent the onset of aortic stiffening \nrelative to sedentary mice [ 149 ]. Wheel running also protected young and old mice \nfrom arterial stiffness after consuming a Western-style diet (40% fat and 19% \nsucrose) for 10–14 weeks. Sedentary mice placed on a Western-style diet also had \ndiminished EDD and NO bioavailability, exercise protected from losses in both. \nLastly, rats placed on a high salt diet for 6 weeks experienced increased \nvascular stiffness and aortic collagen I protein expression [ 90 ]. All of these \nvariables were attenuated when rats were given access to a running wheel during \nthe same 6 weeks. Exercise-trained mice also had higher levels of aortic SOD2 \nprotein expression when compared to sedentary rats who were placed on the same \ndiet.\nArterial stiffening and oxidative stress tend to go hand in hand. Oxidative \nstress is a known initiator of vascular inflammation [ 150 ]. Studies have shown \nthat antioxidant therapy is successful at decreasing oxidative stress and \narterial stiffness. While this appears evident in animal models [ 131 ,  151 ] the \nresults tend to be mixed in human trials [ 150 ,  152 ]. When TEMPOL \n(4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl), a superoxide dismutase mimetic \nwas given to aging mice, not only was EDD improved there was lower levels of \noxidative stress and large artery stiffness decreased [ 131 ]. Mitoquinone (MitoQ), \nan antioxidant which targets mitochondrial specific reactive oxygen species, not \nonly reduced oxidative stress in aging mice but decreased aortic stiffness [ 153 ]. \nMitoQ was also shown to be effective in healthy older adults. Following chronic \nsupplementation brachial flow-mediated dilation and aortic stiffness were lower \n[ 151 ].\nTherefore, reduction and protection from arterial stiffness may be related to \nthe ability of exercise to reduce oxidative stress. Spontaneous hypertensive rats \nhad reduced vascular stiffness in the mesenteric and coronary arteries following \n12 weeks of treadmill training. Authors found that these mice also had high NO \nbioavailability and less evidence of oxidative stress when compared to the \nspontaneous hypertensive rats who did not exercise [ 92 ]. Finally, voluntary wheel \nrunning reversed aortic stiffening in old mice. There was also a subsequent \nreduction in aortic O 2  bioavailability [ 154 ].\n\nWe have previously reviewed the strong connection between the gut microbiome and \ncardiovascular disease, showing how dysbiosis and specific gut-derived \nmetabolites can cause endothelial dysfunction, large artery stiffening, \nhypertension, and ultimately CVD [ 155 ]. Since our review on this topic, the \nliterature has continued to evolve and continues to support a strong association \nbetween the gut microbiome and CVD. Here, we will summarize seminal new findings \non the gut-heart axis since the publication of our previous review.\nStudies since our last review have focused on understanding the role of gut \nmicrobial derived metabolites in CVD [ 156 ,  157 ,  158 ]. These studies have produced \nequivocal results with some metabolites like Indole-3-Propionic acid protecting \nagainst heart failure in patients with preserved ejection fraction [ 159 ], but \nothers like butyrate showing no signs of altering, perhaps increasing CVD related \ndiseases like hypertension [ 160 ] while gut microbial metabolite imidazole \npropionate (ImP) is increased in individuals with heart failure and is a \npredictor of overall survival [ 161 ].\nWith regards to studies associating specific gut microbiota to CVD, there have \nbeen some recent advances. Okami  et al . [ 162 ], showed that as coronary \nartery calcification (CAC) scores rose in Japanese men, so did the Bacillota to \nBacteroidota ratio, suggesting a relationship between higher gram-positive \nmicrobes and artery calcification. Given this is at such a high level of \ntaxonomic resolution, the authors further reported that  Lactobacillales  \nwere associated with a 1.3- to 1.4-fold higher risk of CVD and a higher CAC \nscore. In addition, presence of  Streptococcaceae  and \n Streptococcus  were linked to a higher risk of CVD while \n Enterobacteriaceae  correlated with CAC scores. \nSayols-Baixeras  et al . [ 163 ], showed that  Streptococcus anginosus  and \n Streptococcus oralis  had the strongest associations to CAC. Keeping in \nmind findings at the level of species and strain could be beneficial for the \ngeneration of -biotics, using bugs and drugs. Salvado  et al . [ 164 ], showed that early vascular aging was associated with  Bilophila , \n Faecalibacterium sp.UBA1819  and  Phocea . Furthermore, when \nlogistic regression analysis was completed,  Bilophila  remained \nsignificant. This is important because animal work has shown that \n Bilophila. wadsworthia  caused systemic inflammation, suggesting the \npathogenicity of this bacterium [ 165 ]. Guo  et al . [ 166 ], showed that the \ngenera  Escherichia-Shigella ,  Lactobacillus , \n Enterococcus  were more abundant in patients with resistant hypertension \ncompared to normotensive adults.\nWhile trimethylamine N-oxide (TMAO) continues to be a major gut \nmicrobial-derived metabolite of focus for CVD [ 167 ], an emerging metabolite \nphenylacetylgutamine (PAGln) has received a lot of attention recently [ 168 ]. In \n2020, PAGln was discovered and is both associated with atherothrombotic heart \ndisease in humans [ 169 ,  170 ,  171 ], and mechanistically linked to cardiovascular disease \npathogenesis in animal models via modulation of adrenergic receptor signaling \n[ 172 ,  173 ]. Since then, Romano  et al . [ 174 ] demonstrated that \ncirculating PAGln levels were dose-dependently associated with heart failure \npresence and indices of severity (reduced ventricular ejection fraction, elevated \nN-terminal pro-B-type natriuretic peptide) independent of traditional risk \nfactors and renal function, with associations between TMAO and incident heart \nfailure being stronger among Black and Hispanic/Latino adults compared to White \nadults. Similar findings were shown by Tang  et al . [ 175 ], which extended \nthe work to show that PAGIn levels, independent of TMAO, may be used as a \npredictor of future CV events.\nDespite these recent advances, mechanistic studies are still either in their \ninfancy or lacking in the field and even more importantly studies which compare \nsex and race/ethnicity need urgent attention. Knowledge of which gut microbes \nmay be involved is a good start, but understanding their function and role in the \ndevelopment of CVD is still lacking. Finally, there has been a lot of attention \non ways to manipulate the gut microbiota via fecal transplants, symbiotics, \nprobiotics, high-fiber diets and prebiotics, while this is outside the scope of \nthis review, it has recently been reviewed elsewhere and the authors call your \nattention to Theofilis  et al . [ 176 ].\nDespite trends for reductions in mortality rates from CVD in the US between 1980 \nand 2010, deaths attributable to CVD are once again on the rise. One pattern that \nhas remained constant during this time is that racial and ethnic minority groups \nin the US (and globally) experience a disproportionate burden of CVD compared to \ntheir White counterparts [ 177 ,  178 ,  179 ,  180 ]. Overall, CVD prevalence remains highest among \nnon-Hispanic Black women (59%) and non-Hispanic Black men (58.9%) [ 179 ,  181 ]. \nBlack women and Black men are more than twice as likely to die of CVD, relative \nto White women and White men [ 179 ,  181 ] and among young and middle-aged adult \nsurvivors of a myocardial infarction, Black patients have a 2-fold higher risk of \nadverse outcomes [ 182 ].\nIt has been suggested that hypertensive target organ damage is widespread in \nBlack and African American adults [ 183 ]. Young Black patients have an increasing \nburden of CVD risk factors [ 177 ]. Individuals of Black and African American \nancestry experience hypertensive target organ damage earlier in life compared \nwith White Americans [ 184 ]. Black/African American adults may also be more \nsusceptible to the damaging effects of high blood pressure [ 185 ,  186 ]. Numerous \nstudies note large disparities in measures of vascular health, with Black/African \nAmerican adults displaying lower NO-mediated EDD and higher large artery \nstiffness and pressure from wave reflections compared with White Americans \n[ 187 ,  188 ,  189 ]. We and others have shown that disparities in these vascular health \nmeasures can be seen in childhood and correlate with proxies of target organ \ndamage such as carotid intima-media thickness, LV mass, myocardial work, and \ncoronary perfusion [ 190 ,  191 ,  192 ,  193 ]. Such “early vascular aging” in Black/African \nAmerican adults likely serves as the catalyst for detrimental LV remodeling, \nheart failure, and future CVD [ 194 ]. For the past several decades, racial \ndifferences in CVD were ascribed to biological (“genetic”) differences (e.g., \nbiological differences in inflammation, oxidative stress, NO metabolism, \nrenin-angiotensin-aldosterone system, and autonomic nervous system function), \nneglecting the crucial role of the environment on risk [ 195 ,  196 ,  197 ]. It is now \ncommonly recognized that cardiovascular health disparities are driven largely by \ndeep-rooted structural racism and not race per se [ 178 ,  198 ,  199 ,  200 ].\nIndividuals who self-identify as members of a racial or ethnic minority group \nexperience greater obstacles to health due to social, economic, and/or \nenvironmental disadvantages [ 199 ]. Systemic oppressive structures, policies, and \npractices in the US (i.e., social injustice) have created inequity in access to \nresources, services, and opportunities in minoritized (and marginalized) groups, \ndriving disparities in SES and cardiovascular health [ 201 ]. Minority-related \npsychosocial stressors experienced by marginalized groups such as prejudice, \ndiscrimination, pressure to conform to a group stereotype by members of the same \nmarginalized group, and pressure to acculturate/acculturation, are emerging as \npowerful risk factors for CVD and cardiovascular mortality [ 202 ]. Indeed, \nperceived discrimination is associated with increased risk for hypertension, \nsystemic inflammation and oxidative stress, subclinical atherosclerosis, and \ndetrimental vascular remodeling (increased carotid intima-media thickness, \ncoronary artery calcification, and large artery stiffness), target organ damage, \nmyocardial infarction, heart failure, and stroke [ 203 ,  204 ,  205 ,  206 ,  207 ]. Other factors related \nto structural racism such as lower SES, educational attainment, place of birth, \nneighborhood safety and food insecurity from residential segregation, and built \nenvironment (i.e., access to blue and green space, also shaped by \nneighborhood-level racial residential segregation) are barriers to ideal \ncardiovascular health [ 208 ,  209 ,  210 ,  211 ,  212 ,  213 ]. Moreover, each of these social determinants of \nhealth (SDoH) along with others such as stress from the incarceration of family \nor friends, job insecurity, violence in the home setting, and healthcare access \nare also associated with hypertension, inflammation, and oxidative stress, \nsubclinical atherosclerosis, detrimental vascular remodeling, target organ \ndamage, and ultimately CVD [ 214 ,  215 ,  216 ,  217 ,  218 ,  219 ,  220 ,  221 ]. We have recently shown that environmental \ntoxicants found in higher concentrations in areas of lower SES are \n“cardiovascular disruptors” in children, contributing to altered vascular \nreactivity (greater blood pressure and vascular resistance in response to \npsychological stress) and subclinical CVD measured as carotid intima-media \nthickness at a young age [ 222 ,  223 ,  224 ,  225 ]. Additionally, we have shown that relative to \nWhite children, Black children have significantly greater hair cortisol levels \nand flatter diurnal slopes, which were in turn associated with subclinical CVD \n(measured as carotid intima-media thickness and aortic stiffness) [ 222 ]. Black \nchildren experienced significantly more environmental stress than White children \nwith income inequality partially explaining the higher subclinical CVD risk in \nBlack children [ 222 ]. Taken together, psychosocial determinants are the likely \ndrivers of early (premature) vascular aging in Black and African American people \nin the US, some of which may be transmitted intergenerationally via biological \n(i.e., prenatal fetal programming) and social (i.e., early life adversity) \nmechanisms. This hypothesis is in keeping with minority stress theory and the \nweathering hypothesis whereby chronic exposure to social and economic \ndisadvantage leads to increased allostatic load and accelerated biological (and \nphysiological) “wear and tear” on end organs causing inflammation and oxidative \nstress, hastening aging [ 226 ].\nThis section will examine racial variation in the gut microbiome with \nconsideration for how the systemic environment (i.e., structural racism) impacts \nthe microbial environment to perpetuate cardiovascular health disparities. As \nintroduced above, there is growing evidence that the social and environmental \ngradients which contribute to health inequities also predict gut microbiota \ntraits [ 227 ]. Evidence shows that the human microbiome variation is linked to the \nincidence, prevalence, and mortality of many diseases and is associated with race \nand ethnicity in the US. To date, there have been several studies (discussed next) that have \nexamined this outcome and have identified gut microbiota profiles shaped by host \nenvironments which affect host metabolic, immune, and neuroendocrine functions, \nmaking it an important pathway by which differences in experiences caused by \nsocial, political, and economic forces could contribute to health inequities.\nIt is thought that the gut microbiota is well established by the time a child is \n4 years old, and there is strong evidence that maternal, and family socioeconomic \nstatus can influence gut microbiota. Several investigators have analyzed data \nfrom the Food and Microbiome Longitudinal Investigation (FAMiLI) study to obtain \nanswers on how maternal family and SES influences the gut. FAMiLI is an ongoing \nmulti-ethnic prospective study in the US that began in 2016 where participants \ncomplete demographic questionnaires and (optional) food frequency questionnaires \nand provide oral and stool samples. In 2020, Peters  et al . [ 228 ], \nanalyzed samples from 863 US residents, including US-born (315 White, 93 Black, \n40 Hispanic) and foreign-born (105 Hispanic, 264 Korean). The authors determined \ndietary acculturation from dissimilarities based on food frequency questionnaires \nand used 16S rRNA gene sequencing to characterize the microbiome [ 228 ]. Their \nresults showed a clear difference in gut microbiome composition across study \ngroups. They found the largest differences in gut microbiota between foreign-born \nKoreans and US-born Whites, and significant differences were also observed \nbetween foreign-born and US-born Hispanics. Specifically, differences in \nsub-operational taxonomic unit (s-OTU) abundance between foreign-born and US-born \ngroups tended to be distinct from differences between US-born groups. \n Bacteroides plebeius , a seaweed-degrading bacterium, was strongly \nenriched in foreign-born Koreans, while  Prevotella copri  and \n Bifidobacterium adolescentis  were strongly enriched in foreign-born \nKoreans and Hispanics, compared with US-born Whites. Dietary acculturation in \nforeign-born participants was associated with specific s-OTUs, resembling \nabundance in US-born Whites; e.g., a  Bacteroides plebeius  s-OTU was \ndepleted in highly diet-acculturated Koreans. The authors concluded that US \nnativity is a determinant of the gut microbiome in a US resident population.\nThe “sociobiome” was coined by Nobre and Alpuim Costa [ 229 ] to describe the \nmicrobiota composition occurring in residents of a neighborhood or geographic \nregion due to similar socioeconomic exposures; socioeconomic status. Recently, \nKwak  et al . [ 230 ], using the FAMiLI cohort, investigated the sociobiome \nin a large, multi-ethnic sample. The cohort consisted of 825 adults (36.7% \nmale), with a mean age of 59.6 years and racial and ethnic group composition \nconsisting of 311 (37.7%) non-Hispanic White, 287 (34.8%) non-Hispanic Asian, \n89 (10.8%) non-Hispanic Black, and 138 (16.7%) Hispanic participants and \ncompared alpha-diversity, beta-diversity, and taxonomic and functional pathway \nabundance by SES. They showed that lower SES was significantly associated with \ngreater  α -diversity and compositional differences among groups, as \nmeasured by  β -diversity. Several taxa related to low SES were identified, \nespecially an increasing abundance of  Prevotella copri  and \n Catenibacterium sp000437715 , and decreasing abundance of \n Dysosmobacter welbionis  in terms of their high log-fold change \ndifferences. This is significant as  Dysosmobacter welbionis  was isolated \nfrom human commensal bacterium from samples provided by the Human Microbiome \nProject, American Gut Project, Flemish Gut Flora Project and Microbes4U projects. \nThis bacterium was detected in 62.7%–69.8% of the healthy population and \ncorrelates negatively with body mass index, fasting glucose and glycated \nhemoglobin. In addition, Cani’s group using the humanized mouse model, taking \nhuman fecal samples/strains and putting them into a mouse, showed that \n Dysosmobacter welbionis  prevented diet-induced obesity and metabolic \ndisorders in mice by reducing fat mass gain, insulin resistance and white adipose \ntissue hypertrophy and inflammation [ 231 ]. In addition, live \n Dysosmobacter welbionis  administration protected the mice from brown \nadipose tissue inflammation in association with increased mitochondria number and \nnon-shivering thermogenesis. While this has yet to be translated to humans, the \nreduction of this bacteria in the human study coupled with its actions seen in \nanimal studies suggest that the lack of this bacteria may place individuals at \nincreased risk for metabolic disorders and adipose tissue dysfunction which could \nlead to adverse CVD outcomes.\nMost recently, Mallott  et al . [ 232 ], set out to determine the age at \nwhich microbiome variability emerges between race and ethnic groups. They used 8 \ndatasets with 16S ribosomal RNA (rRNA) sequencing data and available race and ethnicity metadata \nfor this study. Individuals between birth and 12 years of age, living in the US, \nwith a caregiver-reported race of Black, White, or Asian/Pacific Islander, and \nwith a caregiver-reported ethnicity of Hispanic or non-Hispanic were included in \nthe analysis. They found that race and ethnicity did not significantly vary with \ngut microbiome alpha-diversity or beta-diversity in the early weeks and months of \nlife, including the first week, 1 to 5.9 weeks, and 6 weeks to 2.9 months, \nhowever, at 3 to 11.9 and 12 to 35.9 months, gut microbiome composition varied \nslightly but significantly by both race and ethnicity. The group concluded that \nrace and ethnicity are associated with gut microbiome composition and diversity \nbeginning at 3 months of age, indicative of a narrow window of time when this \nvariation emerges [ 232 ].\nFinally, discrimination and stress have been found to contribute to changes in \ngut microbiota among racial and ethnic groups [ 233 ,  234 ]. A study by Dong \n et al . [ 235 ], examined 154 adults from the Los Angeles community and \nclinics. Participants self-reported race and ethnicity (Asian American, Black, \nHispanic, or White) and discrimination was measured using the Everyday \nDiscrimination Scale. Hispanic individuals self-reported the highest levels of \nearly-life adversity, while Black individuals reported the highest levels of \nresilience. Microbiome and metabolite differences related to discrimination were \nonly apparent when stratified by race/ethnicity. Results showed that \n Prevotella copri  was the highest in Black and Hispanic individuals, who \nexperienced high levels of discrimination, whereas White individuals reported low \nlevels of discrimination. Isovalerate and valerate were significantly lower in \nHispanic than in White individuals and fucosterol was significantly higher in \nAsian rather than White individuals. In a related study, Zhang  et al . \n[ 236 ], investigated the impact of discrimination exposure on brain reactivity to \nfood images and associated dysregulations in the brain–gut–microbiome axis. By \nemploying multi-omics analyses of neuroimaging and fecal metabolite, they showed \nthat discrimination is associated with increased food-cue reactivity in regions \nof the brain important for reward, motivation and executive control; altered \nglutamate-pathway metabolites involved in oxidative stress and inflammation as \nwell as a preference for unhealthy foods. In addition, the relationship between \ndiscrimination-related brain and gut signatures was shifted towards unhealthy \nsweet foods after adjusting for age, diet, body mass index, race and SES. Given \nthe extensive literature on diet, obesity and the gut microbiota, these results \nare significant in suggesting that individuals facing discrimination may prefer \nunhealthy foods (and/or may not have access to healthy foods) contributing to a \nmore dysbiotic gut and thus adverse cardiometabolic health outcomes.\nIn conclusion, there are distinct gut microbiota profiles between racial and \nethnic groups, which appear to be influenced by acculturation [ 237 ,  238 ,  239 ], \ndiscrimination and stress [ 233 ,  234 ], and diet [ 240 ], which may occur as early as \n3 months of age. Where a person lives and the related neighborhood and \nenvironmental constraints, what stresses they are exposed to, and what a person \neats (both what they choose to eat and what they have access to eat) may shape \nthe gut microbiome more than race or ethnicity per se. Finally, these distinct \ngut microbial community structures can exacerbate CVD risk among minority racial \nand ethnic groups [ 241 ] (Fig.  3 ).\nWorking conceptual model . Race, ethnicity, gender, and sex \ninteract (i.e., intersectionality) and are shaped by social determinants of \nhealth (SDoH) to moderate gut effects (dysbiosis, diversity, specific \nmetabolites, gut “age”) on subclinical cardiovascular disease (CVD) \n(endothelial dysfunction, large artery stiffness) - driving CV health disparities \nand overt CVD (hypertension, coronary ischemia and vasospasm, myocardial \ninfarction, heart failure). CV, cardiovascular.\nAnother prejudice that has a profound impact on health and CVD risk is sexism \n[ 242 ]. Women, in general, have also been historically marginalized due to \ninstitutionalized patriarchy and a male-dominated social system. When considering \nthe impact of sexism on CVD, we must first operationalize and contextualize \ndifferences (and overlap) between biological sex and gender. Sex, when considered \nbiologically, comprises genetic differences related to chromosomes, gonadal \nstructure and function, and hormonal sequela. We will conceptualize sex as \nreferring to male, female, and intersex. Gender is a social construct based on \nsociocultural predetermined roles, relationships, and stereotypes (e.g., \nmasculine versus feminine). Gender can be shaped by different power dynamics and \nhow we interact with others around us based on ascribed gender and can vary based \non regionality, nationality, and temporality (i.e., ideals can change over time). \nGender also encompasses gender identity referring to a person’s inner sense of \nself as a man, woman, nonbinary person, or agender person among other identities. \nSex and gender can be considered together to inform on both biological sex and \nself-identified gender. For example, a person who identifies as a cis-gender \nwoman is a woman whose self-identified gender aligns with the biological sex \nassigned at birth.\nIn the context of CVD, biological sex and gender may converge to affect risk \n[ 243 ,  244 ]. Women are typically believed to be at lower risk for CVD owing to the \nbiological effects of the gonadal hormone estrogen. Note here that we do not \nconsider estrogen a sex hormone per se as both men and women produce estrogen \n(and testosterone), just in varying amounts. Just as low estrogen is associated \nwith increased risk for coronary heart disease and CVD mortality in older men \n[ 245 ], low testosterone is associated with a greater risk of ischemic CVD and \nmajor adverse cardiovascular events in older women [ 246 ,  247 ]. Subsequently, CVD \nrisk increases in women with advancing age, particularly post-menopause. With \nthat said, it should be highlighted that CVD remains the leading cause of \nmortality in women of all ages, and hospitalizations and deaths attributed to CVD \nhave witnessed an increase for younger and middle-aged women [ 248 ]. The reasons \nfor these observations are likely multifactorial and may partly be related to \nsocietal sex- and gender-based discriminatory attitudes [ 249 ]. Not until the \nAmerican Heart Association’s “Go Red” campaign has there been equitable \neducation and promotion of CVD risk for women. As such, educational efforts on \nsigns, symptoms, risk factors, and consequences of CVD in women were sparse. This \nmay have contributed to increased CVD risk factor burden in women and women being \nless likely to seek timely medical care for signs and symptoms related to CVD. As \ncardiology is still a predominantly male workforce drawing from scientific \nliterature where women are underrepresented, implicit bias may affect clinical \ndecision-making. For example, signs of myocardial infarction are often \ncategorized as “atypical” in women not because they are abnormal but because \nthey are different from men, with male symptomology being construed as the norm. \nSome male physicians may also incorrectly assume that a younger/middle-aged woman \npresenting with chest pain cannot be having a myocardial infarction because that \nwould go against the entrenched dogma that estrogen is cardioprotective. As a \nresult, when seeking care, women have longer wait times when presenting with \nchest pain, are more likely to be misdiagnosed, more likely to have symptomology \ndismissed, and are less likely to be prescribed medications or treatments known \nto mitigate risk [ 250 ]. Women are also less likely to be referred to cardiac \nrehabilitation after a cardiac event [ 251 ,  252 ]. Together, all of these factors \ncontribute to women having poorer outcomes after a cardiovascular event compared \nto men.\nWomen are more likely to develop concentric LV remodeling and heart failure with \npreserved ejection fraction than men [ 253 ]. The pathophysiology of coronary \nartery disease also differs by sex with women possibly having coronary \nendothelial dysfunction and microvascular defects compared to men, contributing \nto sexual dimorphism in acute coronary syndromes [ 254 ]. While premenopausal women \nmay have better endothelial function than men [ 255 ], we and others have shown \nthat women may have greater pressure from wave reflections increasing central \nhemodynamic load [ 256 ,  257 ,  258 ]. Sex differences in central hemodynamic burden may \ncontribute to greater LV diastolic dysfunction and associations between arterial \nstiffness and LV mass/LV diastolic dysfunction may be greater in women compared \nto men [ 259 ,  260 ,  261 ]. Large artery stiffness increases disproportionately in \npostmenopausal women and the association between large artery stiffness and CVD \nmortality is almost twofold higher in women versus men [ 262 ]. As noted above, it \nis difficult to parse out how much CVD risk is attributable to sex and how much \nto gender. Some CVD risk in this setting has been suggested to be related to \nstature (e.g., smaller coronary arteries experiencing more shear stress, shorter \naortic length contributing to greater pressure from wave reflections) [ 263 ,  264 ], \nwhich may be theorized to be biologically driven. Some CVD risk may be related to \nthe physiological response to mental stress [ 265 ,  266 ,  267 ], which may be influenced by \npsychosocial determinants of health. Myocardial ischemia and peripheral \nmicrovascular endothelial dysfunction in response to mental stress are greater in \nwomen compared to men and associated with major adverse cardiovascular events in \nwomen only [ 268 ]. Taken together, CVD risk in women likely captures the \ninteraction of both sex and gender on cardiovascular structure and function.\nWhile traditional risk factors (age, lipids, glucose, smoking, blood pressure) \naffect CVD risk in women and men similarly, there are also sex-specific risk \nfactors that are critically important to consider for women [ 269 ]. Sex-specific \nrisk factors relate to biological variation in reproductive health factors and \nare uniquely ascribed to female biological sex [ 270 ]. Such risk factors may \ninclude adverse pregnancy outcomes (e.g., hypertensive disorders of pregnancy, \ngestational diabetes, fetal growth restriction, preterm delivery, and placental \nabruption), premature menarche, premature menopause and vasomotor symptoms, \nendometriosis and polycystic ovarian syndrome [ 270 ]. Additionally, there are \nother emerging CVD risk factors caused by other comorbidities and social factors \nthat are more prevalent in women and may be influenced by both sex and gender. \nThese factors include autoimmune disorders, migraine, fibromyalgia, postural \northostatic tachycardia syndrome, osteoporosis, breast cancer, irritable bowel \nsyndrome, abuse, intimate partner violence, post-traumatic stress disorder, \nanxiety, and depression [ 270 ]. Each of the aforementioned female sex-specific and \nfemale sex-prevalent risk factors is associated with increased risk for \nhypertension, systemic inflammation and oxidative stress, subclinical \natherosclerosis, and detrimental vascular remodeling (increased carotid \nintima-media thickness, coronary artery calcification, and large artery \nstiffness), target organ damage, myocardial infarction, heart failure, and stroke \n[ 271 ].\nWhen considering intersectionality, Black and Hispanic women may encounter \n“double jeopardy” due to the combination of race and ethnicity bias, coupled \nwith sex and gender bias [ 272 ]. Minority women experience additional ethnic, \nracial and gender constraints and risks including reduced health care access, \npossible language barriers, lower health literacy, racial discrimination, \npressure to acculturate or conform to both a racial and culturally gendered \nidentity, higher reports of depression and higher incidence of pregnancy \ncomplications (e.g., hypertensive disorders of pregnancy) [ 273 ,  274 ]. As stated \nabove, these SDoH are also CVD risk factors and are as important and sometimes \nmore important correlates of subclinical CVD in women [ 275 ,  276 ,  277 ,  278 ,  279 ,  280 ,  281 ]. As such, the \nprevalence of sex-specific CVD risk factors, coronary artery disease, heart \nfailure, and stroke is highest among non-Hispanic Black women [ 282 ]. As stated by \nthe American Heart Association, to understand and address the root causes of the \nprominent disparities in CVD outcomes between Black and White women and men in \nthe United States, the intersectional aspects between race, sex, and gender must \nbe considered [ 283 ]. Nearly 60% of Black women have CVD, contributing to a \npersistent life expectancy gap in the US [ 181 ]. Current life expectancy for \nNon-Hispanic Black women is 75 years on average compared with 80 years for \nnon-Hispanic White women [ 269 ]. CVD is also the most prominent cause of mortality \namongst Hispanic women, with approximately 42% of Hispanic women having CVD \n[ 181 ]. Paradoxically, despite a higher prevalence of such traditional CVD risk \nfactors such as diabetes, obesity, and metabolic syndrome, CVD death rates in \nHispanic women have remained 15% to 20% lower than in non-Hispanic White women \n- an observation commonly referred to as the Hispanic Paradox [ 284 ]. \nInterestingly, we have seen that young Hispanic women have better endothelial \nfunction and lower large artery stiffness compared to White women [ 285 ], \nsuggesting that traditional CVD risk factors may not capture actual CVD risk in \nthis population. It should be noted that this paradox is disappearing as Hispanic \nAmerican individuals acculturate and adopt the high-fat, sedentary lifestyle of \nthose with US nativity [ 286 ]. As noted above, sex differences in the vascular \nresponse to mental stress are a predictor of major adverse cardiovascular events \nin women. Endothelial dysfunction in response to mental stress is also a \npredictor of adverse CV outcomes in Black adults, explaining 69% of their excess \nrisk [ 287 ]. Notable predictors of the development of transient endothelial \ndysfunction with mental stress beyond Black race include female gender, \nemployment status, income, and a composite distress score derived from \npost-traumatic stress disorder, depression, anxiety, anger, perceived stress and \nracial discrimination [ 288 ,  289 ,  290 ,  291 ]. These findings highlight the importance of \nintersectionality and psychosocial determinants of vascular health impacting CVD \nrisk in women, particularly Black women.\nThere is also emerging evidence that lesbian, gay, bisexual, transgender, and \nqueer or questioning (LGBTQ+) adults, as a stigmatized and marginalized group, \nexperience notable cardiovascular health disparities [ 292 ,  293 ]. According to the \nAmerican Heart Association, people who are transgender and gender diverse may be \nat greater risk for CVD [ 294 ]. There is growing evidence that LGBTQ+ adults \nexperience worse cardiovascular health relative to their cisgender heterosexual \npeers [ 292 ,  295 ]. For example, men who are transgender have a  > 2-fold and \n4-fold increase in the prevalence of myocardial infarction compared with men who \nare cisgender and women who are cisgender, respectively. Conversely, women who \nare transgender have  > 2-fold increase in the prevalence of myocardial \ninfarction compared with women who are cisgender. Moreover, compared to \nheterosexuals, sexual minorities are at a higher risk of hypertension and CVD and \nmore likely to develop CVD at an earlier age [ 296 ,  297 ]. It should be underscored \nthat the LGBTQ+ (intersexual, asexual, pansexual, two spirit) community is not a \nmonolithic group [ 298 ]. Each has unique lived experiences that may subsequently \nshape CVD risk. Differences in CVD risk are partially, but not completely, \nexplained by traditional CVD risk factors suggesting that SDoH plays a \nsignificant role. LGBTQ+ adults not only experience significantly higher \ndiscrimination from the broader community, but also specifically from healthcare \nprofessionals [ 299 ]. Additional psychosocial risk factors including self-stigma \nand internalized phobia, gender-related victimization, expectations of rejection, \nand concealment, all detrimentally impact mental health (anxiety, depression) and \nbehavioral health (diet, sleep, physical activity, alcohol and tobacco/nicotine \nuse) [ 300 ,  301 ]. Together, these factors may contribute to inflammation and \noxidative stress, hastened vascular aging, subclinical atherosclerosis, target \norgan damage and overt CVD [ 302 ,  303 ].\nBiological effects of gender-affirming hormone therapy (GAHT) may also have an \nimpact on CVD risk [ 304 ,  305 ]. Use of GAHT in transgender and nonbinary \nindividuals is perceived to improve cardiovascular health [ 306 ]. The association \nbetween GAHT and CVD risk is complex [ 307 ]. A higher blood concentration of \ntestosterone among women who are transgender is associated with higher odds of \nhaving hypertension. Cross-sectional comparisons between men who are transgender \nreceiving testosterone cypionate compared with age-matched women who are \ncisgender have found reduced endothelial function measured via brachial artery \nflow-mediated dilation [ 308 ]. In cross-sectional studies, carotid intima-media \nthickness, arterial stiffness and measured via brachial-ankle pulse wave \nvelocity, and carotid augmentation index are higher in men transitioning (female \nto male) receiving testosterone than in men who are transgender not receiving \nhormone therapy [ 309 ,  310 ,  311 ]. Similarly, transgender men on long-term treatment with \ntestosterone have higher aging-related aortic stiffening [ 312 ], suggesting \naccelerated vascular aging in transgender men receiving gender-affirming hormone \ntreatment. This is supported by animal studies noting that female mice receiving \ndihydrotestosterone experience hastened rates of arterial stiffening and \ncardiovascular damage, mediated by decreased estrogen receptor expression [ 313 ]. \nBrachial artery flow-mediated dilation is higher in women who are transgender \ntreated with estrogen than in age-matched men who are cisgender but is similar to \nwomen who are cisgender [ 314 ,  315 ]. Women who are transgender receiving estrogen \nalso have a greater forearm blood flow response to acetylcholine, an \nendothelial-dependent vasodilator, than age-matched men who are cisgender [ 314 ]. \nIn summary, GAHT is associated with an increased risk of subclinical \natherosclerosis in transgender men but may have either neutral or beneficial \neffects in transgender women [ 316 ].\nThis section will consider the mediating and moderating effects of sex, \nsex-specific CVD risk factors, and gender (operationalized as sexual orientation \nand gender identity) on the gut microbiome as an effector of CVD risk (Fig.  3 ). \nAs stated above, there are notable sex differences in gut microbiota across a \nlifespan, and these differences may serve, in part, as the substrate for sex \ndifferences in CVD risk across a lifespan. The distribution of gut microbiota \nvaries according to age (childhood, puberty, pregnancy, menopause, and old age) \nand sex. Also, as already established, this gut microbiota can contribute and is \nlinked to CVD. It is critical to understand which gut microbiota and/or microbial \nderived metabolites may be linked to CVD in the sexes. To that end, \nGarcia-Fernandez  et al . [ 317 ], analyzed gut microbiota data from the \nCORDIOPREV study, a clinical trial which involved 837 men and 165 women with CVD \ncompared to their reference group of 375 individuals (270 men, 105 women) without \nCVD. They clearly demonstrated a sex-specific difference in beta diversity. \nAdditional analysis showed there were sex-specific alterations in the gut \nmicrobiota linked to CVD. Women who have CVD show increased  UBA1819  \n( Ruminococcaceae ),  Bilophila ,  Phascolarctobacterium , \nand  Ruminococcaceae incertae sedis  while men with CVD had a higher \nabundance of  Subdoligranulum , and  Barnesiellaceae . The authors \nconcluded that the dysbiosis of the gut microbiota associated with coronary heart disease (CHD) seems to \nbe partially sex-specific, which may influence the sexual dimorphism in its \nincidence particularly since the bacteria identified to be higher in CVD patients \nare linked to inflammation, intestinal barrier dysfunction, and CVD directly \n[ 317 ,  318 ].\nThe dysbiotic gut microbiome is associated with increased blood pressure and \nrisk of hypertension [ 319 ]. Virwani  et al . [ 320 ], specifically examined \nsex differences, gut microbiota and hypertension. Interestingly they reported \nthat significant differences in beta-diversity and gut microbiota composition in \nhypertensive versus normotensive groups were only observed in women and not in \nmen. Specifically,  Ruminococcus gnavus ,  Clostridium bolteae , \nand  Bacteroides ovatus  were significantly more abundant in hypertensive \nwomen, whereas  Dorea formicigenerans  was more abundant in normotensive \nwomen. Furthermore, total plasma short-chain fatty acids and propionic acid were \nindependent predictors of systolic and diastolic blood pressure in women but not \nmen.  Ruminococcus gnavus  and  Clostridium bolteae  have been \nreported to induce inflammation and are pathogenic in humans. Gut \nmicrobial-derived metabolites are likely critical to affect the way gut \nmicrobiota influences systemic disease states. As noted above, butyrate may \nexacerbate hypertension, as propionate has also been demonstrated in this study \n[ 160 ]. However, the mechanisms by which this occurs are not elucidated, but need \nto be to fully understand the interactions of these SCFA and hypertension \noutcomes in women.\nIn addition to sex differences in gut microbiota and CVD, there are also sex \ndifferences in many of the risk factors associated with CVD of which most have \nassociations with the gut microbiota including diabetes, hypertension and \ndyslipidemia, and obesity (see review by Ahmed and Spence [ 321 ]), which may \nbe further exacerbated by race and ethnicity [ 322 ]. In addition, sex-specific CVD \nrisk factors related to maternal health during pregnancy may also influence and \nbe influenced by the gut microbiome. In 2023, Colonetti  et al . [ 323 ], \nconducted a meta-analysis which included 6 studies, with 479 pregnant women. They \nreported a significantly lower gut microbiota alpha diversity in pregnant women \nwith pre-eclampsia in comparison with healthy controls, while no significant \ndifferences were found in the relative abundance of Bacteroidota, Bacillota, \nActinomycetota, and Pseudomonadota, despite significant differences being \nreported in the individual studies [ 323 ]. However, this could be due to a number \nof factors, most significantly the analytical techniques used to identify lower \nlevels of taxonomic resolution that vary greatly between gut microbiota studies. \nA rodent study by Jama  et al . [ 324 ], examined female C57BL/6J dams fed \nnutrient-matched high- or low-fiber diets during pregnancy and lactation, to \nunderstand how maternal fiber influences the gut microbiota. In addition, to \nevaluate long-term effects and predisposition to CVD, the authors exposed \n6-week-old male offspring to saline or angiotensin II for 4 weeks to induce \nhypertension and organ damage. Results showed that male offspring from \nlow-fiber-fed dams had significantly larger hearts relative to body weight, and \nechocardiography studies in the offspring demonstrated low-fiber offspring had \nincreased LV posterior wall thickness, confirming hypertrophy, and reduced \nejection fraction, showing reduced LV contraction [ 324 ]. Regarding the gut \nmicrobiota, offspring born to dams who received a low-fiber diet showed distinct \ngut microbial colonization that persisted into adulthood, with higher levels of \nseveral taxa, including  Akkermansia  species. Furthermore, the authors \nreported that they identified 174 microbial enzymatic pathway signatures enriched \nin low-fiber offspring with 154 of the identified enzyme signatures in low-fiber \nbelonged to  Akkermansia muciniphila .  Akkermansia \nmuciniphila -upregulated genes encoded for mucolytic enzymes that degrade the \nintestinal mucus, putting the colon at risk for inflammation [ 324 ]. In contrast, \nhigh-fiber offspring had only 5 grouped enzyme signatures, which belonged to \n Bacteroides ovatus ,  Escherichia coli , and  Lactobacillus \nmurinus ; the latter of which has been known to reduce inflammatory pathways and \nblood pressure. The gut microbiota of women with hypertensive disorders of \npregnancy is different from that of women with normotensive pregnancy [ 325 ]. \nPregnant women with hypertensive disorders of pregnancy had a higher abundance of \n Rothia ,  Actinomyces , and  Enterococcus  and a lower \nabundance of  Coprococcus  than pregnant women with normotension [ 325 ]. \nIndeed, results from Mendelian randomization support a causal relationship \nbetween gut microbiota and hypertensive disorders of pregnancy [ 326 ]. Wu \n et al . [ 326 ] found causal associations  of \nLachnospiraceaeUCG010 ,  Olsenella ,  RuminococcaceaeUCG009 , \n Ruminococcus2 ,  Anaerotruncus ,  Bifidobacterium , and \n Intestinibacter  with gestational hypertension, of  Eubacterium  \n( ruminantium group ),  Eubacterium  ( ventriosum group ), \n Methanobrevibacter ,  RuminococcaceaeUCG002 , and \n Tyzzerella3  with preeclampsia, and of  Dorea  and \n RuminococcaceaeUCG010  with eclampsia, respectively. These findings are \nsupported by experimental studies whereby fecal microbiota transplantation from \npreeclamptic women into preeclamptic rats significantly exacerbated the phenotype \nwhereas the gut microbiota of healthy pregnant women had significant protective \neffects [ 327 ].  Akkermansia muciniphila , propionate, or butyrate \nsignificantly alleviated the symptoms of preeclamptic rats whereas \n Akkermansia ,  Oscillibacter , and SCFAs could be used to \naccurately diagnose preeclampsia [ 327 ]. Taken together, recent findings support \nthat gut dysbiosis is important in the etiology of preeclampsia, a significant \nsex-specific risk factor for CVD in women.\nTo date there are very few studies examining gut microbiota and gender \n(operationalized as sexual orientation and gender identity) hence research in \nthis area is greatly needed. Rosendale  et al . [ 328 ], recently published \na cross-sectional study of 12,180 adults using 2007–2016 National Health and \nNutrition Examination Survey data, Black, Hispanic, and White sexual minority \nfemale individuals with the primary outcome of overall cardiovascular health \nscore. Results showed that Black, Hispanic, and White sexual minority female \nadults had lower overall cardiovascular health scores compared with their \nheterosexual counterparts. Furthermore, there were no differences in overall \ncardiovascular health scores for sexual minority male individuals of any race or \nethnicity compared with White heterosexual male individuals [ 328 ]. It is \nimportant to mention that there are even fewer studies on GAHT and gut microbiota \n[ 329 ], and none to our knowledge which include CVD which is an area of research \nimportance.\n\nThe mantra “exercise is medicine” is often touted as a solution to restore \ncardiovascular health and prevent disease. Indeed, as discussed above, exercise \nhas a powerful effect on improving gut health, attenuating vascular aging, \nimproving large artery compliance and systemic vascular endothelial function \nthrough its antioxidant effects, and preserving nitric oxide bioavailability - \nall reducing the risk for CVD. However, exercise (like medicine) is not \naccessible to all and exercise is not medicine for all. Black adults, Hispanic \nadults, and women in general are not meeting physical activity recommendations. \nUnique social barriers such as neighborhood dynamics (safety and cohesion) may \ncontribute to disparities in physical activity engagement across different races \nand ethnicities [ 330 ,  331 ]. There is also considerable heterogeneity in the \nresponse to exercise across race and sex [ 332 ]. For example, while women may have \na blunted cardiovascular physiological response to exercise training compared to \nmen [ 333 ], women derive greater protection against CVD mortality from that same \namount of exercise [ 334 ]. Indeed, the female athlete’s heart has a lower risk of \nexperiencing exercise-induced coronary calcification, LV fibrosis, atrial \nfibrillation, lethal ventricular arrhythmias and sudden cardiac death. There is \nalso racial variation in the cardiovascular response to acute exercise and \nexercise training [ 335 ,  336 ]. Some of the differences in cardiovascular responses \nto exercise may be related to the physiological impact of various psychosocial \nfactors [ 337 ,  338 ]. For example, racial discrimination is associated with \noxidative stress and endothelial damage [ 339 ,  340 ]. Future research is needed to \nexplore racial variation and sex differences in the gut microbiome’s response to \nexercise. Can targeting the gut with diet (e.g., prebiotics), probiotics and/or \nexercise confer cardiovascular resilience? Additional research is also needed to \nexamine the effect of the gut microbiome on cardiovascular responses to exercise \ntraining. Does underlying dysbiosis mediate or moderate heterogeneity in \nphysiological adaptations to exercise training? Additional research will also be \nneeded to understand the importance of intersectionality on the gut microbiome, \nconsidering race, ethnicity, sex and gender.\n\nStudies continue to support that gut dysbiosis is a CVD risk factor, with \nnumerous microbes impacting unique aspects of cardiovascular structure and \nfunction. The gut microbiome is shaped by biological sex, gender, race and \nethnicity, potentially contributing to cardiovascular health disparities and sex \ndifferences in CVD. Psychosocial factors related to systemic racism, sexism, and \ndiscrimination impact the microbiome via effects on diet and food access. These \nsame factors may also activate physiological stress systems, contributing to \ninflammation, oxidative stress, subclinical changes in vascular structure and \nfunction (i.e., EDD and arterial stiffening) and ultimately CVD.\nTo conclude, sociology impacts physiology and contributes to pathophysiology. \nOppressive social factors experienced by minorities and women may shape the gut, \nin turn contributing to cardiovascular health disparities. Exercise remains a \ncritical lifestyle and biobehavioral factor to promote gut resilience and foster \ncardioprotection.","source_license":"CC-BY-4.0","license_restricted":false}