Association of equol producing status with aortic calcification in middle-aged Japanese men: The ERA JUMP study

Highlights

• Equol-producers had a lower burden of aortic atherosclerosis than non-producers.

• There was no association between serum soy isoflavones and aortic atherosclerosis.

• Equol may be the key anti-atherogenic factor of soy isoflavones.

Abstract

Background

Equol, an isoflavone (ISF)-derived metabolite by the gut microbiome in certain individuals termed as equol-producers, might be the key anti-atherogenic component of ISFs. Our objective was to determine the association between equol-producing status and aortic atherosclerosis assessed as aortic calcification (AC).

Methods

This population-based study of 302 Japanese men aged 40–49, free of cardiovascular disease, examined serum levels of equol and ISFs, AC in the entire aorta by electron-beam computed tomography with Agatston method, and cardiovascular risk factors. We defined equol-producers as individuals with serum levels of equol ≥20 nM and prevalent AC as an AC score ≥ 10. We analyzed the association between equol-producing status and AC using Tobit and logistic regressions. We performed age-stratified analyses since age was a significant effect-modifier.

Results

The 70th to 90th percentile AC scores were 4 to 243 in equol-producers and 15 to 444 in non-producers, respectively. Overall, equol-producers (41% of the sample) had lower AC scores (−209, [95% confidence interval (CI): −455, 36]) and odds of AC (odds ratio (OR): 0.7 [95% CI: 0.4, 1.3]), although not statistically significant, compared to non-producers after controlling for cardiovascular risk factors. Among men aged 46–49, equol-producers had significantly lower AC scores (−428 [95% CI: −827, −29]). Furthermore, there were null associations between serum levels of ISFs and both AC score and the odds of AC.

Conclusion

In middle-aged Japanese men, equol-producers had a non-significantly lower burden of aortic atherosclerosis than non-producers whereas ISFs had a null association. Studies with larger sample sizes in both sexes are warranted.

Introduction

Soy isoflavones (ISFs) are non-steroidal phytoestrogens regularly consumed in East Asian countries whereas their intake in the US is very limited (an average of 25–50 mg/day in East Asia vs. <2 mg/day in the US [[1], [2], [3]]). As compared to estrogen which preferably binds to estrogen receptor α that are abundant in reproductive tissues, ISFs show a greater affinity toward estrogen receptors β (ER β) which are expressed in many systems including the vascular system [4,5]. Several studies in East Asian countries reported that dietary intake of ISFs is significantly and inversely associated with incident coronary heart disease (CHD) [[6], [7], [8]]. However, a randomized clinical trial in the US among 350 postmenopausal women showed that ISFs intervention for 2.7 years had a null treatment effect on atherosclerosis, overall [9]. This discrepancy may be due to the higher capacity of producing equol after consuming ISFs among people living in the East Asian countries than in the US; such individuals are referred to as “equol-producers”. Equol is a metabolite of an ISF daidzein by the gut bacteria [10,11]. Compared to ISFs, equol is more biologically active, a more potent antioxidant, and has a similar or greater affinity to ERβ and thus may have a higher anti-atherogenic effect [10,12,13]. In fact, a nested case-control study within a prospective cohort study in China demonstrated that urinary equol but not ISFs or their other metabolites is significantly associated with incident CHD [7]. Interestingly, 50 to 70% of the population residing in East Asian countries are equol-producers in contrast to 20 to 30% in Western countries. This is due to the differences in microbiome but not genetics [10,11] and suggests that equol may be the key anti-atherogenic component of ISFs. High microbial diversity caused by a healthy eating pattern may enhance the quality of equol-producing bacteria and thus boost the production of equol [14].

Aortic calcification (AC) and coronary artery calcification (CAC) are biomarkers of atherosclerosis. While CAC is a powerful predictor of future cardiovascular events and significantly improves the classification of cardiovascular risk status [15], several studies have suggested that both presence and progression of AC significantly predict future cardiovascular events independent of CAC [[16], [17], [18]]. To date, no study has examined the association between equol producing status and AC.

This study aimed to assess the association between equol producing status and AC in a sample of middle-aged Japanese men from the ERA JUMP (Electron-Beam Tomography, Risk Factor Assessment Among Japanese and U.S. Men in the Post-World War II Birth Cohort) study. The ERA JUMP Study reported that Japanese men in Japan had a significantly lower odds of AC presence compared to White and Japanese Americans (32%, 49%, and 43%, respectively) despite similar or greater exposure to traditional cardiovascular risk factors in Japanese in Japan, including hypertension, diabetes, hypercholesterolemia and especially smoking [19,20]. The Pathobiological Determinants of Atherosclerosis in Youth study has reported that smoking is a stronger determinant of atherosclerosis in the aorta than in the coronary artery [21]. Therefore, significantly lower AC in Japanese in Japan may suggest some protective factors in this population. In this study, we hypothesize that equol-producers had a significantly lower degree of AC than non-producers in middle-aged men in Japan.