To say that studying the microbiota, which refers to the population of microorganisms residing in the gut, is a hot area of research is a bit of an understatement. Last year, there were more than 14,000 papers indexed in PubMed involving the microbiota; in 2010, there were little more than 1,000. Recent research supports a long-held belief the microbiota may play a key role in determining the health benefits of soyfoods. If you have the right microbiota, one of those benefits may be protection against Alzheimer’s disease.1
The microbiota play an important role in the absorption and reabsorption of isoflavones and, as a result, contribute to the significant variation among individuals in circulating isoflavone and isoflavone metabolite levels in response to the intake of similar amounts of isoflavones.2,3 The isoflavone metabolite that has attracted the most attention is equol. It is produced by the microbiota in some people. Scientists have known about equol for decades. It was first isolated from equine urine in 19324 and 50 years later it was identified in human urine.5 Twenty years after that, it was proposed that those individuals whose large intestine host the microbiota capable of converting the isoflavone daidzein into equol are more likely to benefit from soyfood consumption than those whose do not.6 Approximately 50% of Japanese fall into the equol-producing category, whereas only about 25-30% of Westerners do.7,8
So where does the equol hypothesis stand today, twenty years after it was first proposed? While it still remains to be proven, the hypothesis received a big boost from a just-published Japanese study.1 This study examined the relationship between isoflavone intake and the volume of white matter lesions among 91 cognitively normal elderly Japanese. Blood isoflavone and equol levels were analyzed approximately 6 to 9 years prior to the determination of white matter lesions. White matter is found in the deeper tissues of the brain and contains nerve fibers that affect brain function and learning. White matter lesions disrupt brain function and are associated with an increased risk for cognitive impairment and Alzheimer’s disease.
The Japanese results showed that circulating isoflavone levels were unrelated to the volume of white matter lesions. However, among the 23 study participants with the highest circulating equol levels, lesion volume was reduced by approximately 50%. The results of this study are biologically plausible because equol has been shown to reduce arterial stiffness, a significant determinant of white matter lesion volume in the elderly.9 The stiffer and harder the blood vessel walls, the more the heart must work to pump blood into the arteries. However, the impact on arterial stiffness cannot be the entire explanation, because clinical studies indicate that isoflavones (not just equol) also reduce arterial stiffness.10
Most of the evidence in support of the equol hypothesis is based on observational studies, such as the one described above, in which the health status of equol producers is compared to equol non-producers. Consequently, the question that arises is whether or not equol is simply reflective of some unidentified phenotype or characteristic that leads to a different response to soy than the response of non-producers. While that is a distinct possibility, equol is biologically active in humans. In fact, clinical trials have shown equol alleviates hot flashes in menopausal women.11 But, the same can also be said for genistein, a soybean isoflavone which is not converted into equol.12
Nothing about the equol hypothesis suggests that isoflavones do not exert beneficial effects in equol producers and in non-producers alike. Both equol and isoflavones can have benefits. If equol does have benefits independent of isoflavones, a reasonable question is whether anything can be done to make equol producers out of non-producers. Since one study found vegetarians are more likely to be equol producers than non-vegetarians, it may be that diet affects the intestinal bacteria in a way that can lead to equol production.13
To conclude, soyfoods may offer multiple nutritional and health benefits. If you happen to have the right microbiota – and are an equol producer– one of those benefits may be protection against Alzheimer’s disease.
References
- Sekikawa A, Higashiyama A, Lopresti BJ, et al. Associations of equol-producing status with white matter lesion and amyloid-β deposition in cognitively normal elderly Japanese. Alzheimer’s & Dementia: Translational Research & Clinical Interventions. 2020.
- Lampe JW, Gustafson DR, Hutchins AM, et al. Urinary isoflavonoid and lignan excretion on a Western diet: relation to soy, vegetable, and fruit intake. Cancer Epidemiol Biomarkers Prev. 1999;8(8):699-707.
- Rowland IR, Wiseman H, Sanders TA, et al. Interindividual variation in metabolism of soy isoflavones and lignans: influence of habitual diet on equol production by the gut microflora. Nutr Cancer. 2000;36(1):27-32.
- Marrian GF, Haselwood GAD, C.X.L.V. Equol, a new active phenol isolated from ketohydroxyestrin fraction of mares urine. Biochem J. 1932;261226-32.
- Axelson M, Sjovall J, Gustafsson BE, et al. Origin of lignans in mammals and identification of a precursor from plants. Nature. 1982;298(5875):659-60.
- Setchell KD, Brown NM, Lydeking-Olsen E. The clinical importance of the metabolite equol-a clue to the effectiveness of soy and its isoflavones. J Nutr. 2002;132(12):3577-84.
- Setchell KD, Clerici C. Equol: history, chemistry, and formation. J Nutr. 2010;140(7):1355S-62S.
- Setchell KD, Clerici C. Equol: pharmacokinetics and biological actions. J Nutr. 2010;140(7):1363S-8S.
- Usui T, Tochiya M, Sasaki Y, et al. Effects of natural S-equol supplements on overweight or obesity and metabolic syndrome in the Japanese, based on sex and equol status. Clin Endocrinol (Oxf). 2013;78(3):365-72.
- Man B, Cui C, Zhang X, et al. The effect of soy isoflavones on arterial stiffness: a systematic review and meta-analysis of randomized controlled trials. Eur J Nutr. 2020.
- Daily JW, Ko BS, Ryuk J, et al. Equol decreases hot flashes in postmenopausal women: A systematic review and meta-analysis of randomized clinical trials. J Med Food. 2019;22(2):127-39.
- Taku K, Melby MK, Kronenberg F, et al. Extracted or synthesized soybean isoflavones reduce menopausal hot flash frequency and severity: systematic review and meta-analysis of randomized controlled trials. Menopause. 2012;19(7):776-90.
- Setchell KD, Cole SJ. Method of defining equol-producer status and its frequency among vegetarians. J Nutr. 2006;136(8):2188-93.