Potential Protective Mechanisms of S-equol, a Metabolite of Soy Isoflavone by the Gut Microbiome, on Cognitive Decline and Dementia

Abstract

S-equol, a metabolite of soy isoflavone daidzein transformed by the gut microbiome, is the most biologically potent among all soy isoflavones and their metabolites. Soy isoflavones are phytoestrogens and exert their actions through estrogen receptor-β. Epidemiological studies in East Asia, where soy isoflavones are regularly consumed, show that dietary isoflavone intake is inversely associated with cognitive decline and dementia; however, randomized controlled trials of soy isoflavones in Western countries did not generally show their cognitive benefit. The discrepant results may be attributed to S-equol production capability; after consuming soy isoflavones, 40-70% of East Asians produce S-equol, whereas 20-30% of Westerners do. Recent observational and clinical studies in Japan show that S-equol but not soy isoflavones is inversely associated with multiple vascular pathologies, contributing to cognitive impairment and dementia, including arterial stiffness and white matter lesion volume. S-equol has better permeability to the blood-brain barrier than soy isoflavones, although their affinity to estrogen receptor-β is similar. S-equol is also the most potent antioxidant among all known soy isoflavones. Although S-equol is available as a dietary supplement, no long-term trials in humans have examined the effect of S-equol supplementation on arterial stiffness, cerebrovascular disease, cognitive decline, or dementia.

Keywords: Alzheimer’s disease and related dementias; S-equol; arterial stiffness; estrogen receptor-β agonist; vascular contributions to cognitive impairment and dementia; white matter lesions.

Figure 1

Chemical structures of daidzein, genistein (two major soy isoflavones), equol, and estradiol. Daidzein and genistein are two major soy isoflavones and comprise >95% of their dietary source. Soy isoflavones and S-equol are structurally similar to estradiol. S-equol is a metabolite of daidzein, transformed by the gut microbiome. Daidzein is reduced to S-equol through the intermediate dihydrodaidzein and then converted by deoxygenation to yield S-equol. [27] Daidzein, genistein and equol are structurally similar to estradiol (images of chemical structures are from Wikimedia Commons and Pixabay).