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Gut microbiome composition, a third player in the inflammation–arterial stiffness relationship

The growing interest in the clinical measurement of arterial stiffness comes from the repeated demonstration that arterial stiffness has predictive value for cardiovascular (CV) events. The measurement or arterial stiffness through carotid–femoral pulse wave velocity (PWV) is generally considered as an index of early vascular ageing, i.e. integrating all damage done to the arterial wall until the time of measurement, in response either to well-known CV risk factors or to other CV risk factors, such as inflammation and oxidative stress. The measurement of PWV has been recommended by the 2013 European Society of Hypertension–European Society of Cardiology Guidelines for the Management of Hypertension and the Sixth Joint Task Force of the European Society of Cardiology on Cardiovascular Disease Prevention in order to detect arterial stiffening and reclassify patients at intermediate risk into a higher or lower CV risk. Although a large body of evidence has been published during the last decade concerning the epidemiology, pathophysiology, and pharmacology of arterial stiffness, several issues are still pending, including the therapeutic possibility to reduce arterial stiffness beyond blood pressure reduction, for instance through lifestyle changes. Indeed, the relationship between arterial stiffness and chronic low-grade inflammation, that has been well established, may be explained by the role of the gut microbiome, known to play a major role in inflammatory and autoimmune disease. The article by Menni et al., published in the present issue of the European Heart Journal, provides an original and important contribution with regard to the relationship between gut microbiome composition and arterial stiffness. The authors studied 617 middle-aged women enrolled in the TwinsUK registry, a national register of adult twins recruited as volunteers without selecting for any particular disease or traits. They determined aortic stiffness according to gold standard measurement of carotid–femoral PWV. Microbiota analysis included microbiome composition and diversity. They additionally determined circulating serum levels of specific metabolites known to be generated by the gut microbiome and to influence CV risk: phenylacetylglutamine, trimethylamine oxide (TMAO), and indole proprionate (IPA). The major finding is that arterial stiffness is inversely correlated with gut microbiome diversity, as well as with the abundance of specific microbial taxa. The mediation analysis allowed the conclusion to be reached that the effect of gut microbiome composition on PWV is only marginally mediated by C-reactive protein (CRP), the HOMA index, visceral fat, and traditional risk factors. Indeed, a major strength of this study is that all analyses were adjusted for a large number of variables, including not only the three major determinants of PWV in that population [age, mean blood pressure (MBP), and body mass index (BMI)], but also other parameters known to influence PWV and seldom available in cross-sectional studies, such as dietary components and social deprivation. In particular, the relationship between PWV and the gut microbiome composition remained significant after adjustment to four categories of confounding factors: (i) lifestyle risk factors such as smoking/alcohol drinking habits, physical activity, adherence to Mediterranean diet, socio-economic status, and proton pump inhibitor (PPI) and antibiotic use; (ii) traditional cardiovascular risk factors such as the 10-year ASCVD (atherosclerotic cardiovascular disease) risk score; (iii) inflammatory markers, such as CRP; and (iv) metabolic factors, such as visceral fat mass and insulin resistance. The findings of Menni et al. are also stimulating because the authors state in their Introduction that arterial stiffness ‘is weakly or unrelated to conventional risk factors’. Although the reader understands that this is a way to suggest that further studies should be done to detect non-CV determinants, still the major influence of age and MBP has been overlooked in this statement, since age and MBP can explain up to 50% of PWV variance in the general population according to the Reference Value Collaboration study. The authors observed that microbiome factors explained 4.1–8.4% of the variance of PWV, whereas ASCVD score, HOMA index, and visceral fat taken together explained 5.51–11.24% of PWV variance. These numbers