Urolithin A alleviates blood-brain barrier disruption and attenuates neuronal apoptosis following traumatic brain injury in mice

Gong, Qiuyuan; Cai, Lin; Yao, Jing; Wang, Wei; Yang, Danni; Chen, Shiwen; Huang, Tian

doi:10.4103/1673-5374.335163

Cited by 33 publications

(24 citation statements)

References 64 publications

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“…The gut microbiome converts ETs to ellagic acid (EA). EA has a variety of health benefits related to the protection it provides from oxidative stress [ 20 , 188 , 190 , 191 , 192 ]. EA is reported to have a low water solubility and bioavailability, however, when it is converted to urolithin A (UA) by the gut microbiome, UA retains the biological activities of EA and has high solubility and bioavailability ( Figure 8 ).…”

Section: Complex Heterocyclic Polyphenolic Precursor Compounds That A...mentioning

confidence: 99%

“…Punicalagin, chebulinic acid, and chebulagic acid are complex polyphenolic ellagitannins that occur in pomegranate and are degraded to form EA by the gut microbiome ( Figure 8 ). EA is further degraded to the urolithins; these are not synthesised or generated by mammalian cells and have antioxidant and anti-inflammatory properties [ 20 , 100 , 190 , 191 , 192 , 193 , 194 , 195 , 196 , 197 , 198 ]. Panduratin A is an antioxidant polycyclic chalcone phenolic that has also been identified in pomegranate and in the Thai medicinal plant Boesenbergia rotunda that has reported antiviral properties against SARS-CoV-2 [ 199 ].…”

Section: Complex Heterocyclic Polyphenolic Precursor Compounds That A...mentioning

confidence: 99%

“…Flavonoid metabolites that retain or exceed the antioxidant and anti-inflammatory capacity of the intact flavonoid indicate these have potent therapeutic potential. Furthermore, some flavonoid metabolites display biological activities not evident in the native flavonoid, which can be of therapeutic utility in the treatment of pathological neurodegenerative features in AD, PD, and HD by inhibiting the assembly and promoting the disassembly of protein aggregates in these disorders, reducing apoptosis of neurons and improving memory reducing cognitive decline in these neurodegenerative diseases [ 20 , 36 , 37 , 38 , 190 , 194 , 197 , 207 , 355 , 356 , 357 ].…”

Section: Catechin Metabolitesmentioning

confidence: 99%

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The Potential of Flavonoids and Flavonoid Metabolites in the Treatment of Neurodegenerative Pathology in Disorders of Cognitive Decline

Melrose

2023

Antioxidants

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Flavonoids are a biodiverse family of dietary compounds that have antioxidant, anti-inflammatory, antiviral, and antibacterial cell protective profiles. They have received considerable attention as potential therapeutic agents in biomedicine and have been widely used in traditional complimentary medicine for generations. Such complimentary medical herbal formulations are extremely complex mixtures of many pharmacologically active compounds that provide a therapeutic outcome through a network pharmacological effects of considerable complexity. Methods are emerging to determine the active components used in complimentary medicine and their therapeutic targets and to decipher the complexities of how network pharmacology provides such therapeutic effects. The gut microbiome has important roles to play in the generation of bioactive flavonoid metabolites retaining or exceeding the antioxidative and anti-inflammatory properties of the intact flavonoid and, in some cases, new antitumor and antineurodegenerative bioactivities. Certain food items have been identified with high prebiotic profiles suggesting that neutraceutical supplementation may be beneficially employed to preserve a healthy population of bacterial symbiont species and minimize the establishment of harmful pathogenic organisms. Gut health is an important consideration effecting the overall health and wellbeing of linked organ systems. Bioconversion of dietary flavonoid components in the gut generates therapeutic metabolites that can also be transported by the vagus nerve and systemic circulation to brain cell populations to exert a beneficial effect. This is particularly important in a number of neurological disorders (autism, bipolar disorder, AD, PD) characterized by effects on moods, resulting in depression and anxiety, impaired motor function, and long-term cognitive decline. Native flavonoids have many beneficial properties in the alleviation of inflammation in tissues, however, concerns have been raised that therapeutic levels of flavonoids may not be achieved, thus allowing them to display optimal therapeutic effects. Dietary manipulation and vagal stimulation have both yielded beneficial responses in the treatment of autism spectrum disorders, depression, and anxiety, establishing the vagal nerve as a route of communication in the gut-brain axis with established roles in disease intervention. While a number of native flavonoids are beneficial in the treatment of neurological disorders and are known to penetrate the blood–brain barrier, microbiome-generated flavonoid metabolites (e.g., protocatechuic acid, urolithins, γ-valerolactones), which retain the antioxidant and anti-inflammatory potency of the native flavonoid in addition to bioactive properties that promote mitochondrial health and cerebrovascular microcapillary function, should also be considered as potential biotherapeutic agents. Studies are warranted to experimentally examine the efficacy of flavonoid metabolites directly, as they emerge as novel therapeutic options.

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Section: Complex Heterocyclic Polyphenolic Precursor Compounds That A...mentioning

confidence: 99%

Section: Complex Heterocyclic Polyphenolic Precursor Compounds That A...mentioning

confidence: 99%

Section: Catechin Metabolitesmentioning

confidence: 99%

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The Potential of Flavonoids and Flavonoid Metabolites in the Treatment of Neurodegenerative Pathology in Disorders of Cognitive Decline

Melrose

2023

Antioxidants

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“…B. wexlerae was previously shown to be depleted in children with diabetes (Benítez-Páez et al, 2020), and that oral administration of B. wexlerae partially ameliorated weight gain and inflammation from a high-fat diet in a mouse model of T2D (Hosomi et al, 2022; Liu et al, 2021). In children over 18 months of age, several microbial species were significantly enriched (q-value < 0.20) in children with higher cognitive function scores, including Gordonibacter pamelaeae , which produces the neuroprotective metabolite urolithin (Gong et al, 2022; Selma et al, 2014), Asaccharobacter celatus and Adelcreutzia equolifaciens , which produce phytoestrogen-derived equol (Maruo et al, 2008; Thawornkuno et al, 2009), and the SCFA-producing probiotic species such as Eubacterium eligens and Faecalibacterium prausnitzii (Ghosh et al, 2020; Lopez-Siles et al, 2017; Mukherjee et al, 2020) (Figure 2B).…”

Section: Resultsmentioning

confidence: 99%

“…Many members of this family are known in part due to unique metabolic activities. For example, A. equolofaciens produces the nonsteroidal estrogen equol from isoflaven found in soybeans (Wang et al, 2005), and G. pamelaeae can metabolize the polyphenol ellagic acid (found in pomegranates and some berries) into urolithin, which has been shown in some studies to have a neuroprotective effect (Gong et al, 2022; Selma et al, 2014). E. lenta has been extensively studied for its ability to metabolize drug compounds such as the plant-derived heart medication digoxin (Haiser et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

Gut-resident microorganisms and their genes are associated with cognition and neuroanatomy in children

Bonham

Bruchhage

Rowland

et al. 2020

Preprint

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Both the brain and microbiome of humans develop rapidly in the first years of life, enabling extensive signaling between the gut and central nervous system (dubbed the “microbiome-gut-brain axis”). Emerging evidence implicates gut microorganisms and microbiota composition in cognitive outcomes and neurodevelopmental disorders (e.g., autism), but the influence of gut microbial metabolism on typical neurodevelopment has not been explored in detail. We investigated the relationship of the microbiome with the neuroanatomy and cognitive function of 281 healthy children in a cross-sectional analysis and demonstrated that differences in gut microbial taxa and gene functions are associated with the size of brain regions and with overall cognitive function. Many species, including Eubacterium eligens and Roseburia hominis, were associated with higher cognitive function, while some species such as Ruminococcus gnavus was more commonly found in children with low cognitive scores. Microbial enzymes involved in the metabolism of neuroactive compounds such as glutamate and GABA, were also associated with structure of the brain, including the first brain regions to develop such as the cerebellum, and with overall cognitive function.

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Urolithin A improves Alzheimer's disease cognition and restores mitophagy and lysosomal functions

Hou,

Chu,

Park

et al. 2024

Alzheimer's & Dementia

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BACKGROUNDCompromised autophagy, including impaired mitophagy and lysosomal function, plays pivotal roles in Alzheimer's disease (AD). Urolithin A (UA) is a gut microbial metabolite of ellagic acid that stimulates mitophagy. The effects of UA's long‐term treatment of AD and mechanisms of action are unknown.METHODSWe addressed these questions in three mouse models of AD with behavioral, electrophysiological, biochemical, and bioinformatic approaches.RESULTSLong‐term UA treatment significantly improved learning, memory, and olfactory function in different AD transgenic mice. UA also reduced amyloid beta (Aβ) and tau pathologies and enhanced long‐term potentiation. UA induced mitophagy via increasing lysosomal functions. UA improved cellular lysosomal function and normalized lysosomal cathepsins, primarily cathepsin Z, to restore lysosomal function in AD, indicating the critical role of cathepsins in UA‐induced therapeutic effects on AD.CONCLUSIONSOur study highlights the importance of lysosomal dysfunction in AD etiology and points to the high translational potential of UA.Highlights Long‐term urolithin A (UA) treatment improved learning, memory, and olfactory function in Alzheimer's disease (AD) mice. UA restored lysosomal functions in part by regulating cathepsin Z (Ctsz) protein. UA modulates immune responses and AD‐specific pathophysiological pathways.

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Urolithin A alleviates blood-brain barrier disruption and attenuates neuronal apoptosis following traumatic brain injury in mice

Cited by 33 publications

References 64 publications

The Potential of Flavonoids and Flavonoid Metabolites in the Treatment of Neurodegenerative Pathology in Disorders of Cognitive Decline

The Potential of Flavonoids and Flavonoid Metabolites in the Treatment of Neurodegenerative Pathology in Disorders of Cognitive Decline

Gut-resident microorganisms and their genes are associated with cognition and neuroanatomy in children

Urolithin A improves Alzheimer's disease cognition and restores mitophagy and lysosomal functions

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