Dietary Soy Metabolite Produced by Gut Bacteria Linked with Reduced Levels of Dementia Risk Factor

A metabolite produced following consumption of dietary soy may decrease a key risk factor for dementia—but perhaps only with the help of the right gut bacteria—according to the results of a human study led by scientists at the University of Pittsburgh Graduate School of Public Health. The research, reported in Alzheimer’s & Dementia: Translational Research & Clinical Interventions, found that elderly Japanese men and women who produce equol— a metabolite of dietary soy that is generated by certain types of gut bacteria—displayed lower levels of white matter lesions (WML) in the brain.

“White matter lesions are significant risk factors for cognitive decline, dementia and all-cause mortality,” said lead author Akira Sekikawa, MD, PhD, associate professor of epidemiology at Pitt Public Health. “We found 50% more white matter lesions in people who cannot produce equol compared to people who can produce it, which is a surprisingly huge effect.” Equol, which is available as a nutritional supplement, has previously been reported to improve arterial stiffness, and the team are now advocating that a randomized controlled trial is carried out evaluate the metabolite for its effects on WML volume, arterial stiffness, and cognition.

Sekikawa and colleagues at the University of Pittsburgh, and the National Cerebral and Cardiovascular Center in Osaka, describe their findings in a paper titled, “Associations of equol-producing status with white matter lesion and amyloid-β deposition in cognitively normal elderly Japanese.”

Akira Sekikawa, MD, PhD, Associate professor of epidemiology, University of Pittsburgh Graduate School of Public Health. [Tim Betler/UPMC]

Epidemiological studies in Japan, where soy is regularly consumed, have found that a diet high in soy and soy isoflavones (ISFs) is linked with a lower risk of heart disease and dementia. In contrast, most clinical trials in America have failed to show the same benefit, the researchers suggested. The scientists reasoned that this discrepancy in results between studies in Japan and the U.S. might be at least in part due to differences in peoples’ ability to produce the soy ISF metabolite equol, dependent on their gut microbiome composition. “Equol, a metabolite of the ISF daidzein bio-transformed by the microbiome, is most bioactive among all ISFs and 40% to 70% of Japanese can convert daidzein to equol in contrast to 20% to 30% of Americans,” they noted. “The difference in the prevalence is speculated to be due to differences in bacteria species and complexities of the microbiome in the gut, forms of ISF (aglycon form in Asian countries vs glycoside in Western countries) and to a lesser degree, genetic factors.”

Foods such as tofu and soy are rich in isoflavones, and the diets of Japanese people may include 25–50 mg of isoflavone per day, whereas Americans typically may only consume less than 2 mg of soy isoflavones per day, Sekikawa noted at a recent press briefing. “Unless one consumes soy isoflavone, equol cannot be produced. That is a major point.”

To investigate the effects of equol on the development of WML in the brain, the team carried out a study involving 91 elderly Japanese individuals (aged 79–85 years) who had normal cognition. The researchers measured blood equol levels in each participant, and then sorted the individuals according to equol production status. Their initial analyses showed that equol was produced by 51% of participants in the study.

Then, six to nine years later, the participants underwent brain imaging to detect levels of white matter lesions, and also assess deposits of amyloid-beta, the suspected molecular cause of Alzheimer’s disease. The researchers found that while equol production did not appear to impact on levels of amyloid-beta deposited in the brain, it was associated with reduced white matter lesion volumes (measured as WML%), even after adjusting for potential confounding factors. “These results indicate that long-term exposure to equol is associated with lower WML% independent of amyloidogenic processes,” they wrote. Sekikawa’s team also discovered that high levels of ISFs had no effect on levels of white matter lesions or amyloid-beta, when equol wasn’t produced.

“The major finding of the current study was that among cognitively normal elderly Japanese, equol-producing status determined 6 to 9 years before the imaging study was significantly inversely associated with WML%,” the team noted. “High equol producers had >50% lower WML% than non-producers.”

According to Sekikawa, the ability to produce equol from soy isoflavones may be the key to unlocking protective health benefits from a soy-rich diet. His team had also demonstrated an association between equol production and reduced risk of heart disease. As heart disease is strongly associated with cognitive decline and dementia, equol production could help protect the aging brain as well as the heart.

Equol is just one of a number of soy isoflavone metabolites produced by the actions of liver enzymes and the gut microbiome, but it does appear to be the most bioactive, Sekikawa noted. This may be in part because it has the most potent antioxidant effects, and it has the longest half life of all the metabolites.

While noting limitations of the reported study, Sekikawa said that equol supplements could one day be combined with existing diet-based prevention strategies that appear to lower the risk of dementia, particularly the Dietary Approaches to Stop Hypertension (DASH) and Mediterranean diets. He hopes to evaluate the neuroprotective effects of equol supplements in a future randomized clinical trial (RCT), the primary outcome of which would be WML%, with secondary outcomes of arterial stiffness and cognitive decline. “Our observation that more than 50% lower WML% in high equol producers as compared to non-producers has important implications for future RCTs,” the investigators wrote. “Equol has been tested in RCTs on post-menopausal symptoms, skin aging, and arterial stiffness, but has never been tested on WML%.”

Sekikawa further commented, “Our study is just observational, so whether equol works or not needs to be confirmed in a randomized clinical trial setting … but the interesting thing here is that equol is currently available as a dietary supplement, so that our first step is scientifically speaking, is we need to confirm if equol supplementation has actually beneficial effects on cognition, or WML …”

And with respect to carrying out such an RCT, Sekikawa said, “We are preparing … I can’t say any more.”

In the meantime he also urges caution to anyone who might be tempted to purchase equol supplements to stave off dementia. “This type of study always catches people’s attention, but we cannot prove that equol protects against dementia until we get a randomized clinical trial with sufficient evidence,” he said.

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