Natural Dibenzo-α-Pyrones: Friends or Foes?

Natural dibenzo-α-pyrones (DAPs) can be viewed from two opposite angles. From one angle, the gastrointestinal metabolites urolithins are regarded as beneficial, while from the other, the emerging mycotoxin alternariol and related fungal metabolites are evaluated critically with regards to potential hazardous effects. Thus, the important question is: can the structural characteristics of DAP subgroups be held responsible for distinct bioactivity patterns? If not, certain toxicological and/or pharmacological aspects of natural DAPs might yet await elucidation. Thus, this review focuses on comparing published data on the two groups of natural DAPs regarding both adverse and beneficial effects on human health. Literature on genotoxic, estrogenic, endocrine-disruptive effects, as well as on the induction of the cellular anti-oxidative defense system, anti-inflammatory properties, the inhibition of kinases, the activation of mitophagy and the induction of autophagy, is gathered and critically reviewed. Indeed, comparing published data suggests similar bioactivity profiles of alternariol and urolithin A. Thus, the current stratification into hazardous Alternaria toxins and healthy urolithins seems debatable. An extrapolation of bioactivities to the other DAP sub-class could serve as a promising base for further research. Conclusively, urolithins should be further evaluated toward high-dose toxicity, while alternariol derivatives could be promising chemicals for the development of therapeutics.

Urolithin A enhances muscle performance in elderly and positively impacts biomarkers linked to cellular health

Background Aging is associated with decline in mitochondrial function and reduced exercise capacity. Urolithin A (UA) is a natural gut metabolite shown to stimulate mitophagy and improve muscle function in aged animals, and induce mitochondrial gene expression in elderly. Purpose Investigate if oral administration of UA improved walking distance (6MWT), muscle fatigue resistance in hand (FDI) and leg (TA) muscles, and had an impact on plasma biomarkers. Method: We conducted a randomized, double-blind, placebo-controlled study (NCT03283462) in elderly subjects (65-90 yrs.) supplemented daily with 1000mg UA or placebo for 4 months. 128 subjects were screened and 66 randomized. 6MWT and ATPmax via MRS were assessed at baseline and at 4 months. Muscle fatigue tests and plasma analysis of biomarkers were assessed at baseline, 2 and 4 months. Results UA significantly improved muscle endurance (i.e., change in number of muscle contractions from baseline) in two different muscles (hand: PL 11.6 ±147.5, UA 95.3 ± 115.5; and leg: PL 5.7± 127.1, UA 41.4 ±65.5) compared with placebo at 2-months. Plasma levels of several acylcarnitines, ceramides and C-reactive-protein were decreased by UA at the end-of study. 6MWT distance (PL 42.5 ± 73.3 m, UA 60.8± 67.2 m) and ATPmax increased in both groups from baseline (PL 13.7±31.4%, UA19.4± 56.8%) with UA supplemented group exhibiting greater improvements, although these were not statistically different between groups. Conclusion UA supplementation improved muscle endurance, metabolic and inflammatory plasma biomarkers after 2-months, suggesting that UA can have a positive impact on muscle and cellular health in the elderly.

Urolithins: Diet-Derived Bioavailable Metabolites to Tackle Diabetes

Diabetes remains one of the leading causes of deaths and co-morbidities in the world, with tremendous human, social and economic costs. Therefore, despite therapeutics and technological advancements, improved strategies to tackle diabetes management are still needed. One of the suggested strategies is the consumption of (poly)phenols. Positive outcomes of dietary (poly)phenols have been pointed out towards different features in diabetes. This is the case of ellagitannins, which are present in numerous foodstuffs such as pomegranate, berries, and nuts. Ellagitannins have been reported to have a multitude of effects on metabolic diseases. However, these compounds have high molecular weight and do not reach circulation at effective concentrations, being metabolized in smaller compounds. After being metabolized into ellagic acid in the small intestine, the colonic microbiota hydrolyzes and metabolizes ellagic acid into dibenzopyran-6-one derivatives, known as urolithins. These low molecular weight compounds reach circulation in considerable concentrations ranging until micromolar levels, capable of reaching target tissues. Different urolithins are formed throughout the metabolization process, but urolithin A, isourolithin A, and urolithin B, and their phase-II metabolites are the most frequent ones. In recent years, urolithins have been the focus of attention in regard to their effects on a multiplicity of chronic diseases, including cancer and diabetes. In this review, we will discuss the latest advances about the protective effects of urolithins on diabetes.

Comparative Analysis of the Impact of Urolithins on the Composition of the Gut Microbiota in Normal-Diet Fed Rats

The gut microbiota consists of a community of microorganisms that inhabit the large intestine. These microbes play important roles in maintaining gut barrier integrity, inflammation, lipid and carbohydrate metabolism, immunity, and protection against pathogens. However, recent studies have shown that dysfunction in the gut microbiota composition can lead to the development of several diseases. Urolithin A has recently been approved as a functional food ingredient. In this study, we examined the potentials of urolithin A (Uro-A) and B (Uro-B) in improving metabolic functions and their impact on gut microbiota composition under a metabolically unchallenged state in normal rats. Male Wistar rats (n = 18) were randomly segregated into three groups, with Group 1 serving as the control group. Groups 2 and 3 were administered with 2.5 mg/kg Uro-A and Uro-B, respectively, for four weeks. Our results showed that both Uro-A and B improved liver and kidney functions without affecting body weight. Metagenomic analysis revealed that both Uro-A and B induced the growth of Akkermansia. However, Uro-A decreased species diversity and microbial richness and negatively impacted the composition of pathogenic microbes in normal rats. Taken together, this study showed the differential impacts of Uro-A and B on the gut microbiota composition in normal rats and would thus serve as a guide in the choice of these metabolites as a functional food ingredient or prebiotic.

Urolithin A Inhibits Enterovirus 71 Replication and Promotes Autophagy and Apoptosis of Infected Cells in Vitro

Hand, foot and mouth disease (HFMD) is a serious threat to the health of infants, which can be caused by enterovirus 71 (EV71). The clinical symptoms are mostly self-limited, but some of them develop into aseptic meningitis with poor prognosis and even death. In this study, we screened Urolithin A (UroA), an intestinal metabolite of ellagic acid, significantly inhibited the replication of EV71 in cells. Further evaluation showed that UroA was better than ribavirin in CC50, IC50 and selection index (SI). Moreover, we found that UroA inhibits the proliferation of EV71 by promoting autophagy and apoptosis of infected cells. Therefore, UroA is a candidate drug for the treatment of EV71 infection.

Therapeutic Potential of Mitophagy-Inducing Microflora Metabolite, Urolithin A for Alzheimer’s Disease

Mitochondrial dysfunction including deficits of mitophagy is seen in aging and neurodegenerative disorders including Alzheimer’s disease (AD). Apart from traditionally targeting amyloid beta (Aβ), the main culprit in AD brains, other approaches include investigating impaired mitochondrial pathways for potential therapeutic benefits against AD. Thus, a future therapy for AD may focus on novel candidates that enhance optimal mitochondrial integrity and turnover. Bioactive food components, known as nutraceuticals, may serve as such agents to combat AD. Urolithin A is an intestinal microbe-derived metabolite of a class of polyphenols, ellagitannins (ETs). Urolithin A is known to exert many health benefits. Its antioxidant, anti-inflammatory, anti-atherogenic, anti-Aβ, and pro-mitophagy properties are increasingly recognized. However, the underlying mechanisms of urolithin A in inducing mitophagy is poorly understood. This review discusses the mitophagy deficits in AD and examines potential molecular mechanisms of its activation. Moreover, the current knowledge of urolithin A is discussed, focusing on its neuroprotective properties and its potential to induce mitophagy. Specifically, this review proposes potential mechanisms by which urolithin A may activate and promote mitophagy.