Sex differences in gut microbiota, hypertension, and cardiovascular risk.

Age and sex play major roles in the diversity seen in the gut microbiota. Women, particularly in the young-aged adult’s range, display greater gut microbial diversity than males( de la Cuesta-Zuluaga et al., 2019 ). While most of the diversity differences between sexes is observed in pediatric and young adult patients, the gut microbiome composition continues to change even after the seventh decade of life. Specifically, males have significantly increased levels of bacteria such as Prevotella, Megamonas, and Fusobacterium while females have increased levels of Bifidobacterium, Ruminococcus, and Akkermansia( Takagi et al., 2019 ). One possible explanation for these findings is the increase in sex hormones during puberty seen earlier in women, a point which supports young adults having the most gut diversity differences between males and females( de la Cuesta-Zuluaga et al., 2019 ). Studies in four core phenotypes reported that sex hormones override sex chromosome in shaping the gut microbiota( Sakamuri et al., 2023 ). This is reinforced by studies in women with Polycystic Ovarian Syndrome (PCOS), who have hyperandrogenic hormonal states that may result in significantly increased Proteobacteria and Actinobacteria flora( Santos-Marcos et al., 2023 ). Clearly, sex hormones and their fluctuations throughout life influence the gut microbiome composition changes. Variations in the immune system between males and females also influence the gut microbiome( Rio et al., 2024 ). Males have a lower amount of T cells with a higher amount of CD80 + dendritic cells and natural killer cells in their Peyer patches that correlates with a stronger innate immune response but a weaker adaptive response( Rio et al., 2024 ). This immune difference can result in different gut microbiome compositions as gender-specific immune systems select for certain gut flora compositions. Applying this further, the X-chromosome in females harbors the largest number of genes involved in immunity so variations in alleles for genes could explain the differences in gut microbiomes within a female population( Fransen et al., 2017 ). Just as a patient’s sex can influence the gut microbiome, the gut flora also plays a role in the metabolism of sex-specific hormones and pathways. Estrobolome is genes present and expressed by the gut microbiome that metabolizes estrogens into several metabolites of importance that trigger intracellular signaling cascades( Baker et al., 2017 ). In particular, microbial bacteria can secrete β-glucuronidase that converts estrogen from its conjugate to an unconjugated form that can bind to estrogen receptors. Elevated levels of this estrogen-specific metabolism have been implicated in multiple conditions, including endometriosis, PCOS, and breast cancer. In males, the gut microbiome may perform deglucuronidation of dihydrotestosterone (DHT) and testosterone which increases the active forms of these androgens( Santos-Marcos et al., 2023 ). Males have larger pools of bile acids, which can be converted to secondary bile acids and eventually testosterone; this point highlights yet another sex-specific difference in the functional capacity of the gut microbiome. Interestingly, the gut microbiome drives a sex bias in glucose metabolism and glutamine/glutamate ratios( Gao et al., 2021 ). In male adult mice, there is a different gut microbiome than in females that is strongly associated with poor glucose tolerance and decreased insulin sensitivity. This association was assisted by antibiotic depletion of male microbiota that negated the sex difference in glucose metabolism. Elsewhere, specific flora such as Ruminococcus has the ability to convert pregnenolone and hydroxypregnenolone into androgens, increasing the base serum testosterone levels and accelerating prostate cancer tumor growth( Del Castillo-Izquierdo et al., 2022 ). The gut microbiome plays a pivotal role in hypertension and cardiovascular diseases. SCFAs produced by bacteria stimulated by high-fiber diets can reduce blood pressure( Razavi et al., 2019 ). Differences in fiber intake between men and women may result in sex-specific signatures of gut microbial activity that affects CVD risk. Additionally, women have more Akkermansia ( Sinha et al., 2019 ), which may be beneficial to the host( Cani et al., 2022 ; Kim et al., 2024 ). Men, on the other hand, are lacking an abundance of certain intestinal microbiota like Barnesciellaceae that have cardioprotective associations such as decreased arterial stiffness and carotid-femoral pulse wave velocity( Garcia-Fernandez et al., 2024 ). It is important to acknowledge that evidence mentioned in this section is mostly preliminary and pre-clinical. Future investigation into which specific flora is elevated or absent from certain sexes and how it plays a role in cardiovascular diseases can provide a database of microbes to look for when considering contributing factors.

The idea of the gut microbiome influencing cardiovascular health has been explored in many ways. A vast number of microorganisms, such as Bacteroides , Enterobacteriaceae , and Streptococcus , have been associated with cardiovascular disease and could be considered as diagnostic markers in patients suffering from coronary artery disease( Novakovic et al., 2020 ). Direct infection from gut microbes of the Proteobacteria and Firmicutes phylum have been identified as contributing parts of atherosclerotic plaques. One paradigm proposes that microorganisms trigger the production of inflammatory cytokines and acute-phase reactants that promote inflammation in chronic atherosclerotic plaques( Rosenfeld and Campbell, 2011 ). Another paradigm argues that the gut microbiome manipulates the host intestinal mucosal surface, which compromises the epithelial barrier and allows translocation of unwanted products into the systemic circulation to influence CVD progression( Kim et al., 2018 ). Regardless, microbial compositional changes have been reported in patients with CVD risk factors such as hypertension, dyslipidemia, and insulin resistance( Witkowski et al., 2020 ). The gut microbiota is influenced by diet components such as macronutrients, fiber prebiotics, and probiotics, which determine the production and release of major metabolites such as SCFAs( Kaye et al., 2020 ). The gut microbiome may influence cardiovascular health through various mechanisms. Fermentation of dietary fibers by the gut microbiome produces SCFAs such as acetate, propionate, and butyrate which regulate energy and lipid metabolism as well as insulin sensitivity( Nogal et al., 2021 ). SFCAs may also influence regulation of blood pressure by adjusting the release of hormones such as peptide YY (PYY) and glucagon-like peptide (GLP-1) which affect vascular function and satiety. Additionally, the gut epithelium serves as a barrier preventing harmful substances passing from the gut lumen into the bloodstream. Various mechanisms such as mucus production and antimicrobial peptides maintain the barrier, and disruption of this may increase gut permeability, resulting in translocation of bacteria( Carabotti et al., 2015 ). With an increased number of bacteria, systemic inflammation may occur, a driving factor of CVD. Stress is a significant risk factor for CVD. The gut-brain axis allows the gastrointestinal tract and the central nervous system to bidirectionally communicate, which means the gut microbiome can influence stress hormone levels as well as neurotransmitter production( Carabotti et al., 2015 ). Signals from the gut can influence activity in the brain and vice versa. The hypothalamic-pituitary-adrenal (HPA) axis activates in stress response, which releases stress hormones such as cortisol( Appleton, 2018 ). Gut microbiomes can also module this axis. For example, the gut primarily produces the hormone serotonin, a mood regulator. Gut microbiome imbalances can affect neurotransmitter levels (such as serotonin), which may result in changes in stress levels (such as cortisol) and cardiovascular function. Maintaining a healthy gut microbiome through the first-line treatment of diet and lifestyle modifications may reduce cardiovascular risk by lowering blood pressure. However, although diet is mentioned as an integral modification to lower blood pressure in the hypertension guidelines, the specific benefits of dietary fiber are not discussed( Jama et al., 2024 ). Diversifying fiber intake from fruits, vegetables, and whole grains promotes a healthy gut microbiome that may reduce systolic blood pressure by 2.8 mm Hg diastolic blood pressure by 2.1 mm Hg( Jama et al., 2024 ). Prebiotics, probiotics, and synbiotics serve as potential modulators of promoting a healthy gut microbiome( Olas, 2020 ). Evidence from a phase II randomized trial of prebiotic intervention with HAMSAB in patients with essential hypertension showed reduced ambulatory systolic blood pressure without any adverse side effects and independent of factors such as age, sex, and body mass index. HAMSAB increased levels of acetate and butyrate which increased the prevalence of SCFA metabolites( Jama et al., 2023 ). The healthier gut microbiome supported by the increased production of SCFA contributed to lower blood pressure in essential hypertensive patients. In contrast, highly processed foods may alter the gut microbial composition and cause adverse disruptions to the gut microbiome and lead to gut inflammation( Shi, 2019 ). Additionally, increased antibiotic use may also disrupt the gut microbiome, as microbial diversity may be reduced as a result of negative changes to host health.

Sex hormones influence the composition of the gut microbiome, which can directly increase or decrease hypertension risk. Estrogen in women can promote the growth of specific taxa such as Proteobacteria, Veillonella, Lactobacilli , Blautia , and Akkermansia muciniphila ( Capozza, et al., 2022 ). Additionally, the sex hormones are partially responsible for development of the mucosal immune system and gut epithelial barrier, which also influence the ratios of microbes in the gut. The gut microbiome differences between sexes could explain the differences in hypertension risk and prevalence in males and females. Angiotensin II is a potent vasoconstrictor that demonstrates stronger potency in males than females ( Capozza, et al., 2022 ). The increased Lactobacilli in women gut microbiomes offers an explanation for lower blood pressure levels seen in same-aged fertile women as men ( Capozza, et al., 2022 ). Proinflammatory T helper 17 (TH17) cells are also elevated in hypertensive animal models, which may trigger arterial hypertension and are more prevalent in men. Once again, Lactobacillus plays a pivotal role in decreasing blood pressure via decreasing TH17 cells in women. The gut microbiome produces multiple metabolites whose levels are sex-specific and influence blood pressure. Examples of such metabolites include bile acids, SCFAs, and tryptophan derivatives. SCFAs in particular are produced by the gut microbiome when digesting fiber and are cardioprotective via antihypertensive effects( Bardhan and Yang, 2023 ). Butyrate is a type of SCFA; butyrate-producing bacteria and butyrate-creating enzymes were found to be decreased in hypertensive animal models, demonstrating the potential antihypertensive effects of butyrate metabolites. These metabolites have sex-specific implications due to the different levels of their production in females or males. Akkermansia muciniphila is a bacterium that has been shown to be more abundant in female gut microbiomes( Sakamuri et al., 2023 ; Sinha et al., 2019 ) and increases secretion of SCFAs, maintains the blood-brain barrier, and may decrease the activity of the renin-angiotensin system( Bardhan and Yang, 2023 ; Cani et al., 2022 ; Lakshmanan et al., 2022 ). Other studies have shown that Coprococcus comes is higher in male feces, which can metabolize ACE inhibitors used for hypertension treatment and decrease their therapeutic effect( Ma et al., 2021 ; Yang et al., 2022 ). One last metabolite that is repeatedly linked to hypertension and CVD is trimethylamine N-oxide (TMAO), which is normally formed by gut bacteria that digest carnitine and choline( Poll et al., 2020 ). TMAO has a role in atherosclerosis development via alteration of bile acid levels that activates farnesoid X receptors and eventually inhibition of bile acid synthesis. Elevated TMAO levels are seen in women because of increased expression of hepatic flavin monooxygenase 3 (FMO3), increasing their risk of atherosclerosis more than men( Razavi et al., 2019 ). A recent study reported that female gut microbiota harbors a greater buffering capacity against environmental stimuli (i.e. salt, tryptophan), which may in turn protect the females from developing salt-induced blood pressure increase( Bardhan et al., 2024 ). It is important to acknowledge that evidence mentioned in this section is mostly preliminary and pre-clinical.

The gut microbiome is defined as the entire microbial community that populates the human gastrointestinal tract, with the heaviest concentration of microbes being housed in the colon( Zhang, 2022 ). There are five major phyla that the gut microbiome consists of: Firmicutes , Bacteroidetes , Actinobacteria , Proteobacteria , and Verrucomicrobia . Of these, Firmicutes and Bacteroidetes constitute 90% of the gut microbiota( Zhang, 2022 ). With this microbiome comes the additional expression of their respective genes. While the human genome can express approximately 23,000 genes, the colonized gut microbes can encode greater than three million genes that produce metabolites responsible for host functions( Valdes et al., 2018 ). After consumption of fiber and protein, large bowel bacteria are responsible for their fermentation into secondary metabolites such as short chain fatty acids (SCFA), ammonia, and vitamins( Conlon and Bird, 2014 ). Certain microbes also influence digestion via enzyme production that may increase carbohydrate breakdown or promote phytic acid degradation to release minerals like calcium, magnesium, and phosphate. Interestingly, long-term diets also influence the composition of the gut microbiome, with high protein and animal fat diets favoring Bacteroides proliferation while plant-based foods correlate with increased Prevotella growth( Makki et al., 2018 ). The existence of the gut microbiome and its role in processing metabolites while extracting essential parts of our diet provides a starting point for understanding how it may affect human health. Historically, the gut microbiome was considered a simple environment consisting of two polar groups: benign nonpathogenic organisms and toxic, pathogenic microbes. As a result, much of the research on microbes till the 1990s explored unknown microorganisms that were assumed to be pathogenic, with little emphasis on the benign microbes. Culture-based methods were first introduced by Robert Koch in 1881, which brought limitations as the swabbed plates isolated microbes for selective properties such as gram stains and aerobic conditions( Hiergeist et al., 2015 ). Culture-based methods persisted till 1990 when researchers used 16S rRNA sequencing methods to uncover GI bacteria that were unculturable but detectable via genomic techniques( Ward et al., 1990 ). Competition of growth with fast-growing species and inappropriate conditions such as pH, temperature, and nutrient availability continue to make culturing of gut microbes a challenge( Hiergeist et al., 2015 ). It is thought that less than 20% of all gut microbiota can be grown in media. NGS has emerged as a new lab technology that allows for massive sequencing of whole genomes, which can then be cross-referenced with a human genome or bacterial genome database to analyze variants and mutations( Qin, 2019 ). Additionally, metabolomics can provide deeper insight into microbial interactions and metabolism changes within the gut ecosystem. The gut microbes play a crucial role in maintaining immune homeostasis via the development of the immune system and a protective layer of defense( Schlechte et al., 2023 ). Consequently, the imbalance of the GI tract microbes or the addition of external flora to the gut may cause dysbiosis, which can precipitate acute infections in nosocomial settings or chronic immune diseases( Schlechte et al., 2023 ). Specifically, gut microbes like Enterobacteriaceae can proliferate and suppress the innate immune system by impairing neutrophil maturation( Schlechte et al., 2023 ). Interestingly, animal models devoid of gut microbiota demonstrate constitutively lower amounts of circulating myeloid cells( Balmer et al., 2014 ). Transfer of filtered serum from animal models with gut microbiomes to the germ-free mice increased myeloid counts but required a functional MyD88/TICAM1 signaling pathway for granulopoiesis( Balmer et al., 2014 ). This evidence suggests two key points: factors produced by the gut microbiome can also influence the immune system, and these activated pathways work at a non-specific low level as opposed to a stronger adaptive immune response( Balmer et al., 2014 ). Studies in infants and children show that the composition of the gut microbiome and the specific metabolites can contribute to allergies susceptibility. The hygiene hypothesis proposes that a lack of exposure to microbes in early childhood, especially in western countries where ultra-processed food and overused antibiotics are common, explains the higher levels of allergies in developed countries( Riiser, 2015 ). These suggested the important and persistent role of gut microbiota in the early development of the immune system. Gut dysbiosis has also been identified in other chronic diseases such as type 2 diabetes( Qin et al., 2012 ), Crohn’s Disease or Ulcerative Colitis( Frank et al., 2007 ), and colorectal cancer( Yang et al., 2013 ). While the pathophysiology explaining the correlations is complex, the uniqueness of metabolites produced exclusive to the gut microbiome has been identified. Trimethylamine (TMA) is one such metabolite that is synthesized by the gut microbiome after consumption of carnitine and choline, which is then converted to the toxic trimethylamine- N -oxide (TMAO) by monooxygenases in the liver( Wang et al., 2011 ). Elevated serum levels of TMAO have been seen in patients with type 2 diabetes, chronic kidney disease (CKD), and cardiovascular diseases (CVD)( Winter and Bäumler, 2023 ). Microbial communities in the gut that elevate TMA and the identification of TMAO have provided one way of understanding how microbial metabolites contribute to disease development and progression. The flora of the gut and the brain also communicate and influence each other in an axis coined the “microbiota-gut-brain axis”; glial cells of the CNS can be regulated or impacted by this axis, which can accelerate neurodegenerative disease onset( Loh et al., 2024 ). Chronic inflammation from gut microbes at a low grade can damage neurons. Compromisation of GI barriers can permit infiltration of toxins into the bloodstream that travel to the blood-brain-barrier, and production of microbial metabolites like short-chain fatty acids (SCFAs) can affect glial cells( Loh et al., 2024 ). To summarize, there is a body of work that demonstrates that dysbiosis alters the composition and function of the gut microbiome. These alterations can increase the risk for inflammatory diseases such as type 2 diabetes and neurodegeneration. Microbiome-based treatment describes the novel therapeutic approach that utilizes prebiotics, probiotics, fecal microbiota transplantation (FMT), and postbiotics to restore healthy gut flora in patients with dysbiosis( Alam et al., 2022 ). Prebiotics are non-digestible, non-living molecules like lactulose that are indigestible by the host but promote the growth of certain bacteria in the gut( Alam et al., 2022 ; Sanders et al., 2019 ). Probiotics, on the other hand, are live microorganisms like Lactobacillus and Bifidobacterium species that are ingested to colonize non-native host guts( Alam et al., 2022 ; Riiser, 2015 ). Synbiotics are a combination of prebiotics and probiotics that can be synergistically used to reduce systemic inflammation by increasing the density of bacteria that produce SCFAs( Hui et al., 2019 ). Prebiotics, probiotics, and synbiotics have been used to decrease metabolic syndrome prevalence, decrease cardiovascular risk factors such as triglyceride counts, and dampen the Th17 pathway that is involved in many chronic diseases such as atherosclerosis and hypertension( Bardhan and Yang, 2023 ; Gao et al., 2024 ; Hui et al., 2019 ; Riiser, 2015 ; Weingarden et al., 2014 ). FMT is emerging as a promising microbiome-based therapy for treating gut disorders( Alam et al., 2022 ). It has become one of the most effective ways of treating Clostridium difficile infections that demonstrate growing antibiotic resistance and are notorious for causing recurrent diarrhea in hospitalized patients( Hui et al., 2019 ). In C.diff infections, there is a decrease in secondary bile acids, litholic and ursodeoxycholic acids that normally inhibit the proliferation of Clostridium . FMT treatment increases the levels of secondary bile acids and SCFAs to decrease inflammation in the colon in addition to directly inhibiting C. diff growth( Alam et al., 2022 ; Weingarden et al., 2014 ). Microbiome-based therapies also carry the risk of side effects and ethical implications that need to be considered. For example, FMT has been reported to have minimal side effects such as bloating and abdominal discomfort, but certain patients with IBD flare-ups required hospitalization when FMT was used to treat C.diff ( Weingarden et al., 2014 ). While the transfer of fecal microbiota to a donor is relatively easier than other organ transfers, the human gut microbiome should be thought of as an “extrinsic organ” and hence screened and treated as seriously as other organ transplantations. The gut microbiome is also unique to each individual and as such, could be usable as an identifier in the future that needs to be protected by patient privacy laws. Furthermore, the utilization of FMT and other microbiome-therapies as a last resort option as opposed to a first-line treatment means patients may provide consent to treatment without being fully informed as they are medically vulnerable. Informed consent encompasses the patient understanding the risks and benefits of a procedure and weighing all factors before approving a treatment option; scientists and clinicians alike must uncover more algorithms and patterns of gut microbiota before offering microbiome-based therapies so that we can better warn patients about detrimental side effects. The FDA is treating FMT as a biological drug but needs to be more stringent about regulations surrounding FMT, like donor screening, fecal processing, and personalized treatment protocols( Sachs and Edelstein, 2015 ). The human gut microbiota is filled with diversity, and with that comes a great deal of unknown information about the flora and implications of transferring or utilizing them to strengthen human health. The accepted dogma is that bacteria such as Firmicutes, Bacteroidetes, Actinobacteria, and Verrucomicrobia dominate the healthy adult microbiome; however, there are large differences inter-individually and intra-individually that need to be unraveled before large-scale application of microbiota manipulation as treatment( McBurney et al., 2019 ). Most of the current knowledge on the gut microbiome revolves around bacteria and not viruses, yeast, fungi, and protozoa that may be present but not discovered yet. Expanding past unknown organisms, it is vital to study the strain-specific characteristics as the same bacterial species may demonstrate both benign and pathogenic potential. The most well-documented example of this is Eschirichia coli , that has been found as a benign strains in most human guts but also is pathogenic as the enterohemorrhagic O157:H7 strain or carcinogenic in colibactin-producing pks gene + E.coli ( Yan et al., 2020 ). Appreciating the factors that can influence diversity in the gut microbiome is also key. Diet plays a major role in the development and turnover of gut microbes( Yan et al., 2020 ). A patient on a Mediterranean-style diet of olive oil, fish, and fruits can have a greater abundance of Prevotella corpi than counterparts on other diets, but this observation can still vary due to fat level consumption and strain types. The future of microbiome is very exciting and multiple ideas are being offered to revolutionize microbiome-based medicine. A future consideration of microbiome-based therapy is to utilize the diversity of the gut microbiota specific to a single patient, which discredits the idea of a one-size-fits-all when considering what flora to prescribe for treatment. Personalized nutrition analyzes an individual’s specific factors to develop nutrition recommendations that protect or bolster health; with the variation of gut microbiome composition that exists, the analysis of the microbiomes may be a significant factor in personalized nutrition( Hitch et al., 2022 ). The application of this idea was implemented in a study performed on 48 patients whose gut composition was analyzed via 16S rRNA NGS, which guided the specific probiotic mixture that each volunteer received ( Ryšávka et al., 2022 ). After 3 months, each patient demonstrated statistically significant increases in beneficial gut bacteria such as Lactobacilli, Bifidobacteria , and Actinobacteria that improved stool frequency, showing that a personalized approach can be more effective than a standardized probiotic use. Future steps to make personalized microbiome interventions a reality should involve metagenomic and meta-metabolic analyses of populations’ gut microbiomes in order to create a database that can increase scientific knowledge of predictive modeling systems( Hitch et al., 2022 ). The use of personalized modulation of gut microbiome along with auto-transplantation of ex-vivo human gut microbiota is on the horizon and can address the unique microbial imbalances on the level of individual patients. In immunology, researchers are studying the correlation between pediatric bacterial gut composition and increased immune response to vaccines that could bolster public health measured in third-world countries( Gulliver et al., 2022 ). Elsewhere in animal models, reduced microbiota from ingesting antibiotics before chemotherapy with cisplatin resulted in decreased response to the alkylating agent and other immune checkpoint inhibitors like anti-programmed cell death protein 1 (anti-PD-1). Additionally, the insertion of beneficial bacteria via biotics can benefit the immune system by decreasing inflammation and hypersensitivities present from infections, allergic responses, and IBD. Therapeutically, the gut microbiome affects drug metabolism and efficacy so maintaining healthy bacterial ratios can be used to increase drug responses in hard-to-treat conditions such as IBD, IBS, and certain neurodegenerative diseases( Sharma et al., 2020 ). New studies are being conducted to test the potential of FMT in the treatment of cancer, diabetes, atherosclerosis, hepatic encephalopathy, and NAFLD. Slight genetic engineering of probiotics has been used to produce Lactococcus lactis which is usable for the treatment of oral mucositis in the form of mouthwash as it expresses a cytopeptide that promotes epithelial healing( Hou et al., 2022 ). All of these examples represent a small pool of ideas that will progress the use of microbiome-based treatment for a multitude of human diseases. A multitude of biological and social factors contribute to sex disparities in CVD such as hormonal influences, genetics, and physiological effects of stress. CVD remains the leading cause of death globally. Understanding how the gut microbiome contributes to cardiovascular risk may provide further reasoning towards preventative measures. Specifically in the United States, heart disease has been the leading cause of death since 1950( Heron and Anderson, 2016 ). However, beneath this overarching statistic lies distinct sex disparities within CVD, which affect prevalence, mortality, and morbidity rates between men and women. Although the lifetime risk for both sexes is surprisingly similar, CVD manifests differently in men and women. Compared to women, men have a higher incidence of CVD at younger ages. However, women tend to surpass men in regards to morbidity and mortality rates as age increases. Particular to hormonal influences in maintaining cardiovascular health, estrogen in premenopausal women plays a protective role by promoting vasodilation, decreasing inflammation, and regulating lipid metabolism ( Ryan et al., 2024 ). However, the decline in estrogen seen in postmenopausal women, risk of vascular stiffness, adverse endothelial function, and harmful increases in lipid profiles predisposes aging women to a higher risk of CVD. Sex-specific genetic predispositions may also contribute to CVD susceptibility. Pathways involved in lipid metabolism, inflammation, and coagulation may have varying degrees of susceptibility to CVD in men and women( Hartiala et al., 2021 ). Additionally, considering social determinants alongside biological factors is integral in thoroughly determining CVD risk. Disparities in access to healthcare, preventative knowledge, education, monetary resources, lifestyle, and cultural norms can exacerbate CVD susceptibility in certain socioeconomic populations. Gender roles and societal norms may lead to differences in initial outreach to medical care, eventual diagnosis, and treatment outcomes between men and women. Addressing sex disparities in CVD would not be possible without a comprehensive understanding of gender biases, equitable healthcare access, and preventative care efforts that strategically account for sex-specific risk factors. Lifestyle choices are significant in shaping and determining CVD risk, and health behavior differences between men and women may impact the outcome. Traditional gender role patterns may influence behaviors and tendencies in smoking, unhealthy diet, and physical inactivity. For example, although men have historically had higher smoking rates than women, more recent societal norms indicate significant increases in smoking prevalence among women( Willemars et al., 2022 ). Additionally, it is important to consider how social and economic factors may cause disparities in the health behaviors of women. A history of traditional and societal expectations towards caregiving and household responsibilities may have disproportionately burdened women, resulting in decreased prioritization of health. Lack of childcare support due to financial constraints may also affect time or energy given towards personal healthcare or preventative care. Cultural norms are also vital in understanding how men and women prioritize their health differently. For example, men may place more importance on self-reliance and be hesitant in seeking medical care. Women may face pressure to look after others’ well-being resulting in a lack of personal care. A multifaceted approach in understanding social determinants of health is required to address gender disparities in CVD risk. Initiatives that aim to challenge norms and promote equity to make healthier lifestyle choices may reduce overall CVD risk in men and women. Hypertension, often known as high blood pressure, is a major modifiable risk factor for cardiovascular disease. Elevated blood pressure levels increase stress on the heart and blood vessels, which ultimately causes damage over time. Notable sex-specific differences exist in the prevalence, risk factors, and clinical presentation of hypertension( Cross et al., 2018 ). In men, hypertension is more common at ages below 65, whereas in women, hypertension is more common in older ages above 65 presumably due to hormonal changes from the aftermath of menopause( Everett and Zajacova, 2015 ; Nwankwo et al., 2013 ). Additional risk factors like inadequate exercise, unhealthy diet, and predisposition to obesity may have different impacts on men and women. The clinical presentation of hypertension can also differ specifically in pregnant women. Preeclampsia is a pregnancy-specific condition characterized by hypertension which causes complications and remains one of the major causes of maternal deaths in the United States( Garovic and August, 2013 ). Differences in healthcare-seeking behavior may also cause differences in the prevalence of hypertension between men and women and may contribute to the reason women often have lower levels of blood pressure than men. Additionally, several biological mechanisms may contribute to sex differences in hypertension. Estrogen levels in women may influence vascular reactivity and regulation of blood pressure. Postmenopausal changes may contribute to decreased estrogen levels, which may lead to increased hypertension risk for women( Ryan et al., 2024 ). Also, sex hormones affect Renin-Angiotensin-Aldosterone System (RAAS) activity, a key contributor to blood pressure regulation. Premenopausal women may have lower blood pressure due to the protective effects of estrogen on the RAAS system by favoring vasodilation when altering the balance between vasoconstriction and vasodilation( Ryan et al., 2024 ).

The contributions of gut microbiota to cardiovascular diseases, such as hypertension and atherosclerosis, have been extensively presented elsewhere. This paper initially defined the gut microbiota and its general interaction with the host in chronic diseases. We reviewed the current knowledge on sex differences in gut microbiota and offered explanations on how the differences may contribute to the sex dimorphic traits in cardiovascular diseases. Sex hormones strongly influence gut microbiota, thereby upregulating or downregulating production of secondary metabolites that influence health. Our conclusions advocate for future research on the idea of sex-specific care of cardiovascular diseases. One potential topic of research is understanding how hormonal fluctuations during the estrous cycle and menopause may affect the composition and functioning of the gut microbiota. Additionally, it is still unclear if modifying the gut microbiota could be used therapeutically given how most data is currently preliminary and pre-clinical. Further research is needed to fully elucidate the role of sex differences on cardiovascular disease risk.

The human body is colonized by trillions of microbes. Close associations are being uncovered between the microbes housed in the gastrointestinal (GI) tract and the human body’s health. The GI tract is classically thought of for its pivotal role in the digestion and absorption of nutrients. Still, its constant flow of ingested food and saliva provides niche microbial communities with opportunities to grow( Schmidt et al., 2019 ). The gut microbiome contains trillions of bacteria, archaea, viruses, and fungi, all harboring complicated genomes that give them commensal, symbiotic, and pathogenic properties( Yang et al., 2018 ). It is thought that at birth, newborns are exposed to a diverse group of microbes that seed the infant’s gut and develop the naive immune system( Sbihi et al., 2019 ). Till the age of 3, the state of the microbiome is dynamic; however, detrimental alterations, termed dysbiosis, may contribute to allergy and asthma development in susceptible infants( Sbihi et al., 2019 ). Additionally, the composition of the gut microbiome is greatly influenced by malnutrition during early life stages, and can potentially lead to reduced beneficial bacteria like Bifidobacterium resulting in digestion inefficiencies. This altered gut environment from effects of gut metabolites and dysbiosis may increase inflammation or impact cholesterol metabolism, potentially contributing to atherosclerotic cardiovascular diseases (ASCVD). ASCVD, known as a chronic inflammatory condition where lipids accumulate in arteries, begins early in life with the formation of fatty streaks. Evidence of direct involvement are findings of gut bacteria in atherosclerotic plaques which may be linked to the initiation of atherogenesis( Sarkar et al., 2021 ). Not only is the microbiome’s size massive, but its implications on adult human health carry an equally high weight. Major inflammation-related diseases such as atherosclerosis, diabetes, inflammatory bowel disease (IBD), and allergies are all contributed to by the diversity of microorganisms in the GI tract( Lkhagva et al., 2021 ). For instance, obese mice have elevated ratios of Firmicutes to Bacteroidetes, which dropped as they lost weight or started a low-calorie diet( Turnbaugh et al., 2006 ). Impaired gut permeability can increase bacterial translocation to other regions in the gut, initiating metabolic inflammation that can cause endotoxemia or hepatic insulin resistance( Burcelin, 2016 ). All of these points serve to highlight the major role the gut microbiome plays on maintaining good health while considering the potential for future therapeutics via alterations and specific measurements of these microbes.