Gut microbiome: An intermediary to neurotoxicity

Dempsey, Joseph L.; Little, Mallory; Cui, Julia Yue

doi:10.1016/j.neuro.2019.08.005

Cited by 44 publications

(21 citation statements)

References 404 publications

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“…A53T α-Syn (B6C3F1/J-Tg-Prnp/SNCA*A53T/83Vle/J) heterozygous breeders (Jackson Laboratories, Bar Harbor, ME, USA) were used to produce A53T homozygous (SNCA) and Non-Tg littermates (WT). All mice were genotyped by SeqWright-DNA-Technology (Houston,TX, USA), and defined as WT (< 0), heterozygous (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20) and homozygous (> 20) of α-synuclein mutant. Animals were mix-housed in their home cages in the same shelf of the AAALAC accredited animal facilities at the National Institute of Environmental Health Sciences/NIH, with standard temperature (70 ± 2 °F), 12 h light:dark cycle (8:00 -8:00) and fed on standard rodent chow and tap water ad libitum.…”

Section: Animals and Exposuresmentioning

confidence: 99%

Norepinephrine depleting toxin DSP-4 and LPS alter gut microbiota and induce neurotoxicity in α-synuclein mutant mice

Song

Liu

Zhang

et al. 2020

Sci Rep

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This study examined the genetic mutation and toxicant exposure in producing gut microbiota alteration and neurotoxicity. Homozygous α-synuclein mutant (SNCA) mice that overexpress human A53T protein and littermate wild-type mice received a single injection of LPS (2 mg/kg) or a selective norepinephrine depleting toxin DSP-4 (50 mg/kg), then the motor activity, dopaminergic neuron loss, colon gene expression and gut microbiome were examined 13 months later. LPS and DSP-4 decreased rotarod and wirehang activity, reduced dopaminergic neurons in substantia nigra pars compacta (SNpc), and SNCA mice were more vulnerable. SNCA mice had 1,000-fold higher human SNCA mRNA expression in the gut, and twofold higher gut expression of NADPH oxidase (NOX2) and translocator protein (TSPO). LPS further increased expression of TSPO and IL-6 in SNCA mice. Both LPS and DSP-4 caused microbiome alterations, and SNCA mice were more susceptible. The altered colon microbiome approximated clinical findings in PD patients, characterized by increased abundance of Verrucomicrobiaceae, and decreased abundance of Prevotellaceae, as evidenced by qPCR with 16S rRNA primers. The Firmicutes/Bacteroidetes ratio was increased by LPS in SNCA mice. This study demonstrated a critical role of α-synuclein and toxins interactions in producing gut microbiota disruption, aberrant gut pro-inflammatory gene expression, and dopaminergic neuron loss.

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Section: Animals and Exposuresmentioning

confidence: 99%

Norepinephrine depleting toxin DSP-4 and LPS alter gut microbiota and induce neurotoxicity in α-synuclein mutant mice

Song

Liu

Zhang

et al. 2020

Sci Rep

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“…Toxicants may factor into the aforementioned mechanisms by targeting specific subpopulations of microbes to alter bacterial community diversity, creating or enhancing a leaky gut or neuroimmune state, or by undergoing biotransformation by bacteria to neurotoxic metabolites. The potential role of the gut-brain axis in chemical-induced neurotoxicity has been broadly reviewed previously [164,165]. Despite the large body of literature pointing to interconnectivity of the microbiome, chemical exposure, and the brain, few studies have successfully linked all three factors in a manner that confers causality.…”

Section: Environmental Exposures and The Microbiome-gut-brain Axismentioning

confidence: 99%

Beyond the looking glass: recent advances in understanding the impact of environmental exposures on neuropsychiatric disease

Hollander

Cory‐Slechta

Jacka

et al. 2020

Neuropsychopharmacol.

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The etiologic pathways leading to neuropsychiatric diseases remain poorly defined. As genomic technologies have advanced over the past several decades, considerable progress has been made linking neuropsychiatric disorders to genetic underpinnings. Interest and consideration of nongenetic risk factors (e.g., lead exposure and schizophrenia) have, in contrast, lagged behind heritable frameworks of explanation. Thus, the association of neuropsychiatric illness to environmental chemical exposure, and their potential interactions with genetic susceptibility, are largely unexplored. In this review, we describe emerging approaches for considering the impact of chemical risk factors acting alone and in concert with genetic risk, and point to the potential role of epigenetics in mediating exposure effects on transcription of genes implicated in mental disorders. We highlight recent examples of research in nongenetic risk factors in psychiatric disorders that point to potential shared biological mechanisms-synaptic dysfunction, immune alterations, and gut-brain interactions. We outline new tools and resources that can be harnessed for the study of environmental factors in psychiatric disorders. These tools, combined with emerging experimental evidence, suggest that there is a need to broadly incorporate environmental exposures in psychiatric research, with the ultimate goal of identifying modifiable risk factors and informing new treatment strategies for neuropsychiatric disease.

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“…Ammonia is a key factor contributing to hepatic encephalopathy which is accumulated in the brain when the liver undergoes dysfunction (Wijdicks, 2016), and modulation of gut microbiota has been demonstrated effective in decreasing ammonia production and subsequently alleviating encephalopathy (Shen et al, 2015). Moreover, the intestinal microbiota is also indirectly engaged in neurotoxicity of xenobiotics including environmental neurotoxicants, metals, drugs, and pesticides (Dempsey et al, 2019) of which neurotoxicity is the most frequently encountered adverse effect in antibiotic exposure representing in multiple ways including headache, delirium, psychosis, and seizure (Bangert and Hasbun, 2019;Champagne-Jorgensen et al, 2019) (Fig.5). While some absorbable antibiotics enter the brain through blood brain barrier (BBB) and cause direct damage, most non-absorbable antibiotics such as neomycin and vancomycin also induce impairments in nervous system and behavior, suggesting a pivotal of the gut-brain axis plays therein (Fröhlich et al, 2016).…”

Section: Gut Microbiota-mediated Drug Neurotoxicitymentioning

confidence: 99%

Connecting the dots: targeting gut microbiota in drug toxicity

Luo¹,

Zhou²

2020

Preprint

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Gut microbiota has been demonstrated to have a vast influence on human health in recent decades and its role in initiating, aggravating, or ameliorating diseases is emerging. Therapeutic strategies have therefore increasingly developed by targeting gut microbial modulation. Recently, its contribution to heterogeneous toxicological responses is also gaining attention, especially in drug-induced toxicity. Oral drugs interact directly with gut microbiota within the gastrointestinal tract and a number of them elicit toxicity mediated by intestinal microbiota. Present studies focus more on the unidirectional influence of how xenobiotics disturb intestinal microbial composition and function and consequently induce altered homeostasis. However, interactions between gut microbiota and xenobiotics are bidirectional and the impact of gut microbiota on xenobiotics especially on drugs should not be neglected. Thus, in this review, we intend to focus on how gut microbiota modulates drug toxicity by highlighting gut microbiota, microbial enzyme, and metabolites to proffer references for seeking common countermeasures in coping with drug toxicity by targeting gut microbiota. Moreover, we give a hypothesis that drugs capable of inducing gut dysbiosis tend to more or less impact the gut-connected organs as evidenced by the drug-induced hepatic encephalopathy, indicating an underlying link among the gut, liver, brain, and other possible organs in drug-induced toxicity.

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Gut microbiome: An intermediary to neurotoxicity

Cited by 44 publications

References 404 publications

Norepinephrine depleting toxin DSP-4 and LPS alter gut microbiota and induce neurotoxicity in α-synuclein mutant mice

Norepinephrine depleting toxin DSP-4 and LPS alter gut microbiota and induce neurotoxicity in α-synuclein mutant mice

Beyond the looking glass: recent advances in understanding the impact of environmental exposures on neuropsychiatric disease

Connecting the dots: targeting gut microbiota in drug toxicity

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