Ellagitannins, urolithins, and neuroprotection: Human evidence and the possible link to the gut microbiota

Ellagitannins (ETs) and ellagic acid (EA) are dietary polyphenols poorly absorbed but extensively metabolized by the human gut microbiota to produce different urolithins (Uros). Depending on the individuals' microbial sig-natures, ETs metabolism can yield the Uro metabotypes A, B, or 0, potentially impacting human health after consuming ETs. Human evidence points to improved brain health after consuming ET-rich foods, mainly pomegranate juices and extracts containing punicalagin, punicalin, and different EA-derivatives. Although ETs and (or) EA are necessary to exert the effects, the precise mechanism, actual metabolites, or final drivers responsible for the observed effects have not been unraveled. The cause-and-effect evidence on Uro-A admin-istration and the improvement of animal brain health is consistent but not addressed in humans. The Uro-A's in vivo anti-inflammatory, mitophagy, autophagy, and mitochondrial biogenesis activities suggest it as a possible final driver in neuroprotection. However, the precise Uro metabolic forms reaching the brain are unknown. In addition to the possible participation of direct effectors in brain tissues, the current evidence points out that improving blood flow, gut microbiota ecology, and gut barrier by ET-rich foods and (or) Uro-A could contribute to the neuroprotective effects. We show here the current human evidence on ETs and brain health, the possible link between the gut microbiota metabolism of ETs and their effects, including the preservation of the gut barrier integrity, and the possible role of Uros. Finally, we propose a roadmap to address what is missing on ETs, Uros, and neuroprotection.

Automated summary

Ellagitannins (ETs) and ellagic acid (EA) are dietary polyphenols metabolized by gut microbiota to produce urolithins (Uros), which have potential health benefits. Consuming ET-rich foods, such as pomegranate, may improve brain health. However, the specific mechanism and metabolites responsible for these effects are still unknown. Uro-A, a metabolite of ETs, shows potential in neuroprotection through anti-inflammatory, mitophagy, autophagy, and mitochondrial biogenesis activities. Improving blood flow, gut microbiota ecology, and gut barrier integrity may also contribute to the neuroprotective effects. This article reviews the current evidence and proposes a roadmap for further research in this area.