Heterogeneity in gut microbiota drive polyphenol metabolism that influences α-synuclein misfolding and toxicity

Ho, Lap; Zhao, Danyue; Ono, Kenjiro; Ruan, Kai; Mogno, Ilaria; Tsuji, Mayumi; Carry, Eileen; Brathwaite, Justin; Sims, Steven; Frolinger, Tal; Westfall, Susan; Mazzola, Paolo; Wu, Qingli; Hao, Ke; Lloyd, Thomas E.; Simon, James E.; Faith, Jeremiah J.; Pasinetti, Giulio Maria

doi:10.1016/j.jnutbio.2018.10.019

“…The Thy1-α-Syn [ASO] transgenic PD mouse model study also suggested that PD patient-derived microbiota have adverse effect on the Parkinson's pathogenesis in this mouse model including the accumulation of α-Syn and change in the motor phenotype 32 . Several other mouse studies also suggested the gut dysbiosis in chemically induced toxins and other PD models [32][33][34][35][36][37][38] . Human studies from fecal metabolites suggested that PD patients have reduced short chain fatty acids (SCFAs), which are the metabolic products of certain gut bacteria 31 .…”

mentioning

confidence: 87%

DJ-1 (Park7) affects the gut microbiome, metabolites and the development of innate lymphoid cells (ILCs)

Singh

¹

,

Trautwein

²

,

Dhariwal

³

et al. 2020

Sci Rep

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The proper communication between gut and brain is pivotal for the maintenance of health and, dysregulation of the gut-brain axis can lead to several clinical disorders. In Parkinson’s disease (PD) 85% of all patients experienced constipation many years before showing any signs of motor phenotypes. For differential diagnosis and preventive treatment, there is an urgent need for the identification of biomarkers indicating early disease stages long before the disease phenotype manifests. DJ-1 is a chaperone protein involved in the protection against PD and genetic mutations in this protein have been shown to cause familial PD. However, how the deficiency of DJ-1 influences the risk of PD remains incompletely understood. In the present study, we provide evidence that DJ-1 is implicated in shaping the gut microbiome including; their metabolite production, inflammation and innate immune cells (ILCs) development. We revealed that deficiency of DJ-1 leads to a significant increase in two specific genera/species, namely Alistipes and Rikenella. In DJ-1 knock-out (DJ-1-/-) mice the production of fecal calprotectin and MCP-1 inflammatory proteins were elevated. Fecal and serum metabolic profile showed that malonate which influences the immune system was significantly more abundant in DJ-1−/− mice. DJ-1 appeared also to be involved in ILCs development. Further, inflammatory genes related to PD were augmented in the midbrain of DJ-1−/− mice. Our data suggest that metabolites and inflammation produced in the gut could be used as biomarkers for PD detection. Perhaps, these metabolites and inflammatory mediators could be involved in triggering inflammation resulting in PD pathology.

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“…141 Effects on the host may, in turn, modulate microbial ecology and metabolism, while changes in microbial populations or gene expression may modulate host physiology, including ADME, collectively resulting in dynamic host-microbiota interactions that modulate or even generate the observed responses to ingested interventions. 3,147 Speakers stressed the importance of a strong, though not necessarily complete, understanding of the pharmacokinetics and metabolism of a NP intervention for optimizing the design of large-scale CT, although opinions differed on whether such knowledge was necessary before pursuing early-phase trials. For example, gut microbiota can convert grape constituents to phenolic acids such as 3-hydroxy benzoic acid and dihydrocaffeic acid, which have been reported to inhibit β-amyloid and α-synuclein oligomerization, respectively, and epigenetically modulate gene expression.…”

Section: Np Specifications and Integritymentioning

confidence: 99%

Improving natural product research translation: From source to clinical trial

Sorkin

¹

,

Kuszak

²

,

Bloss

³

et al. 2019

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While great interest in health effects of natural product (NP) including dietary supplements and foods persists, promising preclinical NP research is not consistently translating into actionable clinical trial (CT) outcomes. Generally considered the gold standard for assessing safety and efficacy, CTs, especially phase III CTs, are costly and require rigorous planning to optimize the value of the information obtained. More effective bridging from NP research to CT was the goal of a Septe mber, 2018 trans disci plina ry workshop. Participants emphasized that replicability and likelihood of successful translation depend on rigor in experimental design, interpretation, and reporting across the continuum of NP research. Discussions spanned good practices for NP characterization and quality control; use and interpretation of models (computational through in vivo) with strong clinical predictive validity; controls for experimental artefacts, especially for in vitro interrogation of bioactivity and mechanisms of action; rigorous assessment and interpretation of prior research; transparency in all reporting; and prioritization of research questions. Natural product clinical trials prioritized based on rigorous, convergent supporting data and current public health needs are most likely to be informative and ultimately affect public health. Thoughtful, coordinated implementation of these practices should enhance the knowledge gained from future NP research. K E Y W O R D S clinical predictive validity, dietary supplements, model systems, rigor and replicability, value of information | 43 SORKIN et al.still provide invaluable guidance, the results of such trials are often met with concerns that different design choiceswhether of product, dose, timing, participant eligibility criteria, outcomes, etc.-might have yielded a substantially different result. Each interventional trial represents a substantial investment, with well-powered Phase III CTs typically consuming more than $10 million and many person-years. 9,10 Additionally, as time and funds are limited, and participant pools may also be constrained, a decision to invest in a CT often precludes pursuing other research questions, 11 which may provide more useful public health-relevant knowledge than an RCT with an insufficient evidence base.

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“…Gastrointestinal microbiota have been shown in many cases to be required for the generation of bioactive metabolites of NPs. For example, gut microbiota can convert grape constituents to phenolic acids such as 3-hydroxy benzoic acid and dihydrocaffeic acid, which have been reported to inhibit -amyloid and -synuclein oligomerization, respectively, and epigenetically modulate gene expression (2,148). Speakers stressed the importance of a strong, though not necessarily complete, understanding of the pharmacokinetics and metabolism of a NP intervention for optimizing the design of large-scale CT, although opinions differed on whether such knowledge was necessary before pursuing early-phase trials.…”

Section: Chemical and Metabolic Factorsmentioning

confidence: 99%

Improving Natural Product Research Translation: from Source to Clinical Trial

Sorkin¹,

Kuszak²,

Fukagawa³

et al. 2019

Preprint

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While great interest in health effects of natural product (NP) including dietary supplements and foods persists, promising preclinical NP research is not consistently translating into actionable clinical trial (CT) outcomes. Generally considered the gold standard for assessing safety and efficacy, CTs, especially phase III CTs, are costly and require rigorous planning to optimize the value of the information obtained. More effective bridging from NP research to CT was the goal of a https://events-support.com/events/Natural_Product_Clinical_Trials. Participants emphasized that replicability and likelihood of successful translation depend on rigor in experimental design, interpretation, and reporting across the continuum of NP research. Discussions spanned good practices for NP characterization and quality control; use and interpretation of models (computational through in vivo) with strong clinical predictive validity; controls for experimental artefacts, especially for in vitro interrogation of bioactivity and mechanisms of action; rigorous assessment and interpretation of prior research; transparency in all reporting; and prioritization of research questions. Natural product clinical trials prioritized based on rigorous, convergent supporting data and current public health needs are most likely to be informative and ultimately affect public health. Thoughtful, coordinated implementation of these practices should enhance the knowledge gained from future NP research.

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Heterogeneity in gut microbiota drive polyphenol metabolism that influences α-synuclein misfolding and toxicity

Cited by 55 publications

References 33 publications

DJ-1 (Park7) affects the gut microbiome, metabolites and the development of innate lymphoid cells (ILCs)

DJ-1 (Park7) affects the gut microbiome, metabolites and the development of innate lymphoid cells (ILCs)

Improving natural product research translation: From source to clinical trial

Improving Natural Product Research Translation: from Source to Clinical Trial

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