Sex differences in the intestinal microbiome: interactions with risk factors for atherosclerosis and cardiovascular disease

Shamon Ahmed, J David Spence, Shamon Ahmed, J David Spence

Abstract

Background: There are clearly sex differences in cardiovascular disease. On average, women experience cardiovascular events at an older age, and at any age, women, on average, have less atherosclerotic plaque than men. The role of the human intestinal microbiome in health and disease has garnered significant interest in recent years, and there have been indications of sex differences in the intestinal microbiome. The purpose of this narrative review was to evaluate evidence of sex differences in the interaction between the intestinal microbiome and risk factors for cardiovascular disease. Several studies have demonstrated changes in microbiota composition and metabolic profile as a function of diet, sex hormones, and host metabolism, among other factors. This dysbiosis has consequently been associated with several disease states, including atherosclerosis and cardiovascular disease. In this respect, there is a growing appreciation for the microbiota and its secreted metabolites, including trimethylamine N-oxide (TMAO), derived from intestinal bacterial metabolic pathways involving dietary choline and L-carnitine, as novel risk factors for atherosclerosis and cardiovascular outcomes. Although traditional risk factors for vascular disease have been studied broadly over the years, there exists little research to evaluate interactions of cardiovascular risk factors with a potentially sexually dimorphic intestinal microbiome. This review evaluates the role of sex differences in the composition of the intestinal microbiome, including effects of sex hormones on the microbiome, and the effects of these sex differences on cardiovascular risk factors. Diabetes and obesity exhibit sexual dimorphism, while the data concerning hypertension and dyslipidemia remain inconclusive based on the available literature. In addition, an increased proportion of gram-negative species capable of driving metabolic endotoxemia and a low-grade inflammatory response, as well as decreased numbers of butyrate-producing species, have been observed in relation to traditional vascular risk factors. In this context, circulating SCFAs and TMAO are recognized as key metabolites of the intestinal microbiome that can be readily measured in the blood for the evaluation of metabolic profile.

Conclusion: Novel strategies focused on resolving intestinal dysbiosis as a means to slow progression of atherosclerosis and reduce the risk of cardiovascular disease should be evaluated through a lens of sex differences.

Keywords: Atherosclerosis; Cardiovascular risk; Diabetes; Hypertension; Intestinal microbiome; Obesity; Sex differences.

Conflict of interest statement

Neither author had a competing interest relating to this topic.

Figures

Fig. 1
Fig. 1
Sex differences in burden of atherosclerosis by age groups. Carotid total plaque area was measured by ultrasound in patients attending vascular prevention clinics at the Stroke Prevention and Atherosclerosis Research Centre (SPARC), Robarts Research Institute, Western University, London, Ontario, Canada. At any age, women on average had less carotid plaque burden than men
Fig. 2
Fig. 2
Sex differences in the interaction between the microbiome and risk factors for atherosclerosis and cardiovascular disease. Sex-specific microbiome dysbiosis affects the secretion of metabolites produced by the intestinal microbiome, such as trimethylamine N-oxide (TMAO) derived from dietary intake of phosphatidylcholine and l-carnitine. Such metabolites affect atherosclerosis and cardiovascular risk, through complex interactions with traditional risk factors for atherosclerosis and cardiovascular disease, including diabetes, hypertension, dyslipidemia, and obesity. Flavin mono-oxidase (FMO); hypertension (HTN); type 2 diabetes mellitus (T2DM); trimethylamine N-oxide (TMAO); trimethylamine (TMA)

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