Pomegranate’s Neuroprotective Effects against Alzheimer’s Disease Are Mediated by Urolithins, Its Ellagitannin-Gut Microbial Derived Metabolites

Abstract

Pomegranate shows neuroprotective effects against Alzheimer's disease (AD) in several reported animal studies. However, whether its constituent ellagitannins and/or their physiologically relevant gut microbiota-derived metabolites, namely, urolithins (6H-dibenzo[b,d]pyran-6-one derivatives), are the responsible bioactive constituents is unknown. Therefore, from a pomegranate extract (PE), previously reported by our group to have anti-AD effects in vivo, 21 constituents, which were primarily ellagitannins, were isolated and identified (by HPLC, NMR, and HRESIMS). In silico computational studies, used to predict blood-brain barrier permeability, revealed that none of the PE constituents, but the urolithins, fulfilled criteria required for penetration. Urolithins prevented β-amyloid fibrillation in vitro and methyl-urolithin B (3-methoxy-6H-dibenzo[b,d]pyran-6-one), but not PE or its predominant ellagitannins, had a protective effect in Caenorhabditis elegans post induction of amyloid β(1-42) induced neurotoxicity and paralysis. Therefore, urolithins are the possible brain absorbable compounds which contribute to pomegranate's anti-AD effects warranting further in vivo studies on these compounds.

Gut microbiota, cognitive frailty and dementia in older individuals: a systematic review

“…The results of these studies are summarized in Table 4. The presence of a gut–brain axis modulating dementia physiopathology was first demonstrated with the circumstance that urolithins, gut microbiota-derived metabolites from grape seed ellagitannins, can improve β-amyloid aggregation and signs of cognitive impairment in animal models 80,81. Then, the administration of other prebiotics, including teasaponin, fructo-oligosaccharides, baicalein and xylo-oligosaccharides, proved effective in preventing the advancement of cognitive symptoms in mouse models of AD or vascular dementia 79,82–84…”

“…Polyphenols represent a prototype of this possible mechanism 118. In fact, red raspberry-derived anthocyanins and ellagitannins need specific gut microbiota metabolism to be transformed into urolithins,119 which may exert important neuroprotective effects 80,81. Similarly, curcumin has recently emerged as a promising modulator of the gut microbiota, showing neuroprotective effects 120.…”

Effects of a Standardized Phenolic-Enriched Maple Syrup Extract on β-Amyloid Aggregation, Neuroinflammation in Microglial and Neuronal Cells, and β-Amyloid Induced Neurotoxicity in Caenorhabditis elegans

“…Aβ 1–42 solutions were prepared following previously reported methods with minor modifications [24]. In brief, fibril formation was induced by incubating 50 μM Aβ 1–42 solutions at 37 °C for 5 d. Treatment included MSX at varying concentrations (50, 100, 200 and 500 μg/mL) and the widely studied neuroprotective polyphenolic compound, resveratrol (RESV), used as the positive control (at 50 μg/mL).…”

Influence of Commensal Microbiota on the Enteric Nervous System and Its Role in Neurodegenerative Diseases

“…The ellagitannins contained in these plant products are rapidly converted by gut microbiota and do not reach the circulation in an intact chemical structure. Yuan et al [69] reported that urolithins derived by microbial conversion of ellagitannins might be a bioactive compound that is capable of preventing A-β olicomerization in vitro and of protecting Caenorhabditis elegans from amyloid-β-induced toxicity. More of such relations will be surely found in future studies and microbial organisms contributing to such conversion then might offer assistance in therapeutic approaches.…”