To date, the population of dementia is approximately 45 million worldwide (this number will double if mild cognitive impairment (MCI) is included), and this population is expected to triple (approximately 130 million) by 2050 [1]. As the population of older adults is increasing, interest in the aging brain and the quest for “healthy brain aging” is growing. Modern medicine and nutrition evidence has confirmed that polyphenol consumption is an effective strategy in delaying brain aging [2]. However, the poor bioavailability of dietary polyphenols in vivo is contradictory to their health benefits ^[3][4][3,4]. Recently, there has been increasing evidence suggesting that the health benefits of polyphenols are mainly based on: (1) Polyphenols being either directly absorbed or in most cases converted into bioactive metabolites by gut microbiota and then get to the target tissues; (2) Polyphenols reshaping the gut microbiome during their bidirectional interaction. In addition, microbial-derived metabolites of polyphenols can be used as biomarkers to predict individual health status or even the efficacy of some drugs in vivo [5]. Over the past decade, research on gut microbiota and the gut–brain axis has brought increasingly new insights into humans [6]. Several pathways have been confirmed in the communication of the gut microbiota and the brain: (1) neuroendocrinology: the gut cells secrete a large amount of the signaling molecules in neuroendocrinology which can be influenced by gut microbiota; (2) neuroimmunity: the GI tract itself is the largest immune organ to stress response and the gut microbiota can promote immune cells to produce cytokines that can affect the brain; (3) neurotransmitters: the gut microbiota can affect the neurotransmitter secretion directly (several neurotransmitters, including acetylcholine, dopamine, noradrenaline, and serotonin can be synthesized by gut bacteria) and indirectly; and (4) microbial-derived metabolites: neuroactive metabolites mediate bidirectional interactions between the gut, gut microbiome, and the brain to modulate host neurophysiology and behavior ^[7][8][9][7,8,9].

As many of the host–microorganism interactions pertaining to human health are mediated by metabolites, interest in the microbial-derived metabolites has been increasing ^[10][11][12][10,11,12]. Among these active metabolites, urolithins (Uros), the gut bacterial metabolites of ellagitannins (ETs) and ellagic acid (EA), have shown to be beneficial in delaying many age-related diseases such as cancer (especially prostate, breast, and colorectal cancers), cardiovascular diseases, and chronic metabolic disorders (diabetes and hyperuricemia) ^{[13][14][15][16][17][18]}[13,14,15,16,17,18]. Recently, growing evidence has supported the multiple health benefits of Uros against brain aging and the therapeutic potential for neurodegenerative diseases ^{[17][19][20][21][22]}[17,19,20,21,22]. Moreover, Uros have been proposed as biomarkers of gut dysbiosis and disease stage in Parkinson’s patients [23].

2. Overview and Advantage of Uros

Uros are gut metabolites derived from ETs and EA, which are richly available in many fruits (pomegranates, berries), nuts (walnuts), wood-aged wine, and some medicinal plants (galla chinensis, chebulae fructus, and seabuckthorn leaf) [12]. ETs and EA have very poor bioavailability in vivo and are converted into Uros by intestinal microbes in the colon, which are believed to be responsible for their biological activities ^[24][25][24,25]. ETs are a group of important dietary polyphenols and hydrolysable tannins that share a common core, hexahydroxydiphenoyl (HHDP), and differ in the number of monomer residues. ETs are mainly hydrolyzed to EA in the upper GI tract (stomach and small intestine), and most of the EA is converted to Uros in the lower GI tract (mainly in the colon) ^[25][26][27][25,26,27]. Uros are 6H-dibenzo [b, d] pyran-6-one derivatives which differ in their hydroxyl groups. The family includes the main end metabolites, dihydroxy derivatives UroA, Iso-UroA and monohydroxy derivative UroB, and other intermediates UroC, UroD, UroE, UroM-5, UroM-6, and UroM-7. Overall, UroA is the main metabolite produced in humans, which demonstrates the highest concentrations in plasma and urine, and remains high for days after the consumption of ET-rich food ^[28][29][30][28,29,30]. The bioconversion of Uros from ETs and EA varies considerably between individuals. Some individuals can produce high plasma concentrations of Uros (high Uro producers), while others cannot produce significant levels of Uros (low Uro producers). Additionally, Uro producers can also be classified into “metabotype A” (only high concentration of UroA is produced), and “metabotype B” (more Iso-UroA and/or UroB in comparison to UroA is produced) [31]. Therefore, the consumption of dietary ETs will produce different health benefits in high or low Uro producers, and those with different metabolic phenotypes. The different capacities for excreting Uros are mainly attributed to the variability of gut microbiota ecology, and vary with age, health status, dietary intake, obesity, and digestive organ surgery ^[32][33][32,33]. Notably, age is a key factor that affects the bioconversion of Uros. The bioconversion of Uros significantly decreases with aging. According to clinical observations, approximately 10% of individuals (aged 5–90) are non-Uro producers, and only 40% of elderly people (>60) can produce meaningful levels of Uros from dietary precursors [34]. Therefore, Uro supplementation may be a good alternative for certain individuals (e.g., elderly people) to meet the required healthy Uro level [35]. In comparison to precursors and live bacteria, Uros possess clear chemical structure, good bioavailability, and high safety in animals and humans ^[36][37][36,37]. Recently, two multi-center clinical trials showed that long-term (4-month) oral administration of UroA is safe and well tolerated ^[38][39][38,39]. Moreover, UroA is considered as GRAS (generally recognized as safe) for its use in food products by the Food and Drug Administration (FDA) [40]. Notably, Uros can also pass through the blood–brain barrier (BBB) and distribute in a brain-targeted manner after absorption ^[17][41][42][17,41,42], which may greatly facilitate their activities in the central nervous system (CNS), while other ET derivatives cannot cross the BBB. Additionally, as increasing evidence supporting the involvement of the gut metabolites in human health and diseases, metabolite-based treatment has been considered as a novel and promising therapeutic approach. It can overcome limitations and deficiencies of microbiome-based treatment (probiotics and prebiotics supplementation or fecal microbiome transplantation), such as colonization resistance and inter-individual variation in microbial composition [43]. Microbial-derived metabolites may be able to provide an improved efficacy (safety, stability, and individual variation) by exerting a beneficial host effect downstream of the microbiome. Collectively, these findings highlight the advantages of Uros in developing into functional food or drugs. Many studies have investigated the biotransformations of ETs and EA to Uros. ETs are first converted into EA, facilitated by physiological pH and/or microbial enzymes such as tannin–hydrolase and lactonase. EA is then catalyzed by several microbial enzymes, including lactonase, decarboxylase, dehydroxylases, methyl esterases, and hydrolases, to produce Uros in the colon [25]. The metabolic pathways associated with these enzymes have been elucidated. Recently, several Uro-producing gut bacteria have been identified that can facilitate the conversion of EA to Uros in vitro ^[44][45][46][44,45,46]. Therefore, in addition to the chemical synthesis of Uros, the biotransformation of Uros with bacteria or enzymes in vitro in the near future can be expected ^[28][47][28,47]. As previously described, the consumption of dietary polyphenols is highly correlated with human health and the risk of neurodegenerative diseases [12]. Dynamic two-way communications between the gut, gut microbiome, and the CNS have been considered an increasingly vital factor for cognitive health and disease. Novel perspectives suggest that microbial-derived metabolites of polyphenols can be used as biomarkers to predict the risk of neurodegenerative diseases [48]. Therefore, in addition to the potential as functional food or drugs, Uros may be potential biomarkers of age-related cognitive decline and related disorders, which is mainly based on the following: (1) As bioactive metabolites, they exert multiple health benefits against brain aging and related diseases (which we will discuss below in detail); (2) the level of Uros in baseline is an indicator of personalized nutrition status (the consumption of dietary polyphenols in individuals, particularly for ETs and EA consumption), which is highly correlated with the risk of neurodegenerative diseases; (3) the level of Uros after consuming ET- or EA-rich food is an indicator of individual metabotypes associated with specific gut microbial ecologies (gut microbiota composition and functionality), which is tightly involved in neurodegenerative diseases. A recent study based on 52 patients and 117 healthy individuals showed that gut dysbiosis occurred during the onset and progression of Parkinson’s disease (PD) and the concentration of Uros in urine was highly associated with the severity of gut dysbiosis and PD in elderly people [23].