The human gut microbiota has a wide-reaching impact on health. One of the ways this complex community of micro-organisms benefits us is by enhancing the bioavailability of food components, such as polyphenols, which are metabolized into simpler, more easily absorbed products(1).
Polyphenols can act as prebiotics, modifying the composition of microbial colonies, which also has benefits for human health.
Although phenolic metabolites can affect the brain indirectly—for example, by increasing levels of neurotransmitters such as dopamine—this article is focused on those that are able to cross the blood–brain barrier and exert direct neurocognitive effects. The function of this important physiological barrier is to prevent harmful substances from reaching the brain, but it can also keep out xenobiotics, including polyphenols.
Therefore, the ability to penetrate the blood–brain barrier largely conditions the effects of phenolic compounds on
the central nervous system. Whereas the generation of phenolic metabolites by microbiota has been extensively studied, research on their blood–brain barrier permeability has only recently gained attention.
The first function described for the blood–brain barrier was the protection of the brain from uncontrolled diffusion of substances from the blood. It is now understood to be a complex and dynamic interface that regulates the exchange of substances between the blood and the central nervous system(2).
Specifically, the functions of the blood–brain barrier are to:
Brain microvascular endothelial cells control the movement of nutrients, energy metabolites, and other vital molecules from the blood to the brain and removal of metabolic waste products from the brain’s interstitial fluid into the blood. Nonessential molecules like phenolic compounds, that prevent oxidative stress, can also cross the barrier and
exert beneficial effects on the brain(2).
The figure below illustrates that phenolic bioavailability in the brain is affected by physicochemical traits, including molecular weight, hydrophobicity, and lipophilicity, as well as physiological factors.
Figure: Summary of blood–brain barrier permeability of microbial phenolic metabolites(3)
A recent review explored the potential of dietary polyphenols, once ingested, making their way from
the gut to the brain and the potentially exerting direct neuroprotective effects.
This research highlights potential polyphenolic compounds
(or their metabolites produced through bacterial metabolism in the intestines) that may impact brain function and cognition(3).
Dietary flavonoids are mostly metabolized into phenolic acids by the gut microbiota. Isoflavonoids such as genistin and daidzin, as well as their aglycones genistein and daidzein, are almost exclusively found in soybeans and soy-derived products (eg, tofu, soymilk, miso soup), which typically contain 0.01%–0.3% isoflavonoids(4).
Equol is regarded as a phytoestrogen due to its structural similarity to 17β-estradiol and is thought to exert its effects through the estrogen signal transduction pathway(5). Equol demonstrates the potential to modulate glial cell migration and enhance hippocampal synaptic plasticity.
Several mechanisms of action have been described by which equol improves brain health. Studies demonstrate that equol enhances glial cell migration, an essential process for brain development, and possesses neuroprotective properties that counteract the cytotoxicity of β-amyloid plaques generated in a cellular model of Alzheimer’s disease(6).
It has also been reported that equol enhances hippocampus and synaptic plasticity. Other evidence indicates that equol reduces oxidative stress and protects against cerebral ischemia and neuronal apoptosis (i.e., programmed cell death).
Ellagitannins and ellagic acid are found in nuts and some fruits, such as pomegranates and berries, and are generally poorly absorbed. In the intestinal tract, ellagitannins are metabolized by
the gut microbiota to ellagic acid, and ellagic acid is hydrolyzed into urolithins, which, in addition to health benefits, have potential application as dietary biomarkers(7).
Promising effects on neurocognitive health have been reported for urolithin A and B. According to numerous in vivo and preclinical studies, urolithin A is involved in several molecular mechanisms that prevent cognitive deterioration. It reduces the formation of ß-amyloid plaques, decreases apoptosis, and enhances neurogenesis.
The mammalian lignans enterodiol and enterolactone are generated in the colon by
bacteria acting on lignan plant precursors, such as secoisolariciresinol diglycoside, which are abundant in fiber-rich foods such as cereals, with lower amounts found in vegetables and fruits.
Flaxseed is one of the best sources of dietary lignans. In a clinical study, blood enterolactone concentration was doubled by adding ground flaxseed and flaxseed oil to 1 or 2 daily meals. The availability of lignans in flaxseed is enhanced by crushing or grinding the whole seeds, likely due to improved accessibility for the microbiota to interact with the lignans.
Sesame seeds and rye grain also have a high concentration of lignans and are therefore an alternative to flaxseed as rich sources of enterodiol and enterolactone precursors. Regular consumption of rye bread increases serum concentrations and urinary excretion of enterolactone much more than eating refined-wheat cereal.
While dietary lignans have been associated with neurological benefits, the role of the metabolite enterolactone has been less studied. This enterolignan has shown neuroprotective properties, as it suppresses nitric oxide production and proinflammatory cytokines. It can also inhibit enzymes involved in the development of Alzheimer’s disease(8).
Coffee, fruits, whole grains, and nuts are the most abundant dietary sources of phenolic acids. The cognitive effects of caffeic acid have been widely investigated. Notable for its role in decreasing tau hyperphosphorylation and β-amyloid accumulation, it also supports neurogenesis in the hippocampus. Although the benefits of coffee on cognitive health have been reported, they cannot be attributed solely to caffeic acid due to the presence of other known neuroprotective substances such as caffeine.
Cocoa and tea are the main dietary sources of flavan-3-ols, an important group of flavonoids that are extensively metabolized in the colon to phenyl-γ-valerolactones. Green tea is another good source of flavan-3-ols. The beneficial effects of phenyl-γ-valerolactone metabolites in relation to ß-amyloid plaques is that they reduce neuroinflammation and prevent the formation of ß-amyloid oligomers(9).
Cumulative evidence highlights that the gut microbiota plays a key role in the relationship between polyphenols and cognition through the gut–brain axis, since it transforms dietary polyphenols into biologically active metabolites able to cross the blood-brain barrier and exert benefits for cognitive health.
Figure: Summary of the molecular mechanisms of phenolic compounds in the brain. Abbreviations: AChE, acetylcholinesterase; BChE, butylcholinesterase; CA, carbonic anhydrase; MAO, monoamine oxidase(3).
Promising results have been obtained for these microbial phenolic metabolites, many of which can regulate mechanisms involved in neurodegenerative disease pathogenesis—for example, by reducing oxidative stress, apoptosis, or neuroinflammation.
The gut microbiome plays a critical role in your health and and immune system via the gut-brain axis, but it takes more than eating a diet rich in polyphenols to feel the full benefits.
It involves a total lifestyle commitment that can pay huge dividends in improved health no matter how old you are.
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References:
1. Cardona F, Andrés-Lacueva C, Tulipani S, et al: Benefits of polyphenols on gut microbiota and implications in human health. J Nutr Biochem 24:1415-22, 2013
2. Velásquez-Jiménez D, Corella-Salazar DA, Zuñiga-Martínez BS, et al: Phenolic compounds that cross the blood-brain barrier exert positive health effects as central nervous system antioxidants. Food Funct 12:10356-10369, 2021
3. Domínguez-López I, López-Yerena A, Vallverdú-Queralt A, et al: From the gut to the brain: the long journey of phenolic compounds with neurocognitive effects. Nutrition Reviews, 2024
4. Franke AA, Hebshi SM, Pagano I, et al: Urine accurately reflects circulating isoflavonoids and ascertains compliance during soy intervention. Cancer Epidemiol Biomarkers Prev 19:1775-83, 2010
5. Sekikawa A, Ihara M, Lopez O, et al: Effect of S-equol and Soy Isoflavones on Heart and Brain. Curr Cardiol Rev 15:114-135, 2019
6. Tsai MC, Lin SH, Hidayah K, et al: Equol Pretreatment Protection of SH-SY5Y Cells against Aβ (25-35)-Induced Cytotoxicity and Cell-Cycle Reentry via Sustaining Estrogen Receptor Alpha Expression. Nutrients 11, 2019
7. Cerdá B, Tomás-Barberán FA, Espín JC: Metabolism of antioxidant and chemopreventive ellagitannins from strawberries, raspberries, walnuts, and oak-aged wine in humans: identification of biomarkers and individual variability. J Agric Food Chem 53:227-35, 2005
8. Köse LP GI: Inhibition effects of some lignans on carbonic anhydrase, acetylcholinesterase and butyrylcholinesterase enzymes. Rec Nat Prod. 11:558–561, 2017
9. Ruotolo R, Minato I, La Vitola P, et al: Flavonoid-Derived Human Phenyl-γ-Valerolactone Metabolites Selectively Detoxify Amyloid-β Oligomers and Prevent Memory Impairment in a Mouse Model of Alzheimer's Disease. Mol Nutr Food Res 64:e1900890, 2020
