Gut Microbiota to Microglia: Microbiome Influences Neurodevelopment in the CNS

Bettag, Jeffery; Goldenberg, Daniel; Carter, Jasmine; Morfin, Sylvia; Borsotti, Alison; Fox, James; ReVeal, Matthew; Natrop, Dylan; Gosser, David; Kolli, Sree; Jain, Ajay K.

doi:10.3390/children10111767

Cited by 3 publications

(2 citation statements)

References 67 publications

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“…This occurs in zebrafish [122][123][124], crayfish [125], and mice [126][127][128], and exposure to polyethylene microplastics also affects the immature human and non-human gut microbiome [129,130]. The gut microbiome influences neurodevelopment and when impaired can cause neurodevelopmental disorders [131,132].…”

Section: The Gut-brain Axis and Mnplsmentioning

confidence: 99%

Nanoplastics and Neurodegeneration in ALS

Eisen,

Pioro,

Goutman

et al. 2024

Brain Sciences

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Plastic production, which exceeds one million tons per year, is of global concern. The constituent low-density polymers enable spread over large distances and micro/nano particles (MNPLs) induce organ toxicity via digestion, inhalation, and skin contact. Particles have been documented in all human tissues including breast milk. MNPLs, especially weathered particles, can breach the blood–brain barrier, inducing neurotoxicity. This has been documented in non-human species, and in human-induced pluripotent stem cell lines. Within the brain, MNPLs initiate an inflammatory response with pro-inflammatory cytokine production, oxidative stress with generation of reactive oxygen species, and mitochondrial dysfunction. Glutamate and GABA neurotransmitter dysfunction also ensues with alteration of excitatory/inhibitory balance in favor of reduced inhibition and resultant neuro-excitation. Inflammation and cortical hyperexcitability are key abnormalities involved in the pathogenic cascade of amyotrophic lateral sclerosis (ALS) and are intricately related to the mislocalization and aggregation of TDP-43, a hallmark of ALS. Water and many foods contain MNPLs and in humans, ingestion is the main form of exposure. Digestion of plastics within the gut can alter their properties, rendering them more toxic, and they cause gut microbiome dysbiosis and a dysfunctional gut–brain axis. This is recognized as a trigger and/or aggravating factor for ALS. ALS is associated with a long (years or decades) preclinical period and neonates and infants are exposed to MNPLs through breast milk, milk substitutes, and toys. This endangers a time of intense neurogenesis and establishment of neuronal circuitry, setting the stage for development of neurodegeneration in later life. MNPL neurotoxicity should be considered as a yet unrecognized risk factor for ALS and related diseases.

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Section: The Gut-brain Axis and Mnplsmentioning

confidence: 99%

Nanoplastics and Neurodegeneration in ALS

Eisen,

Pioro,

Goutman

et al. 2024

Brain Sciences

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“…The gut microbiota has a major role in the complex bidirectional interaction between the gut and the brain. Indeed, gut dysbiosis can affect neuropeptides and neurotransmitters 20,21 . Indeed, several neuropeptides, such as neuropeptide Y (NPY), are secreted from enteroendocrine cells in the gastrointestinal tract allowing bidirectional communication between the gut-brain, and can also affect behaviors related to psychological disorders, such as anxiety and depression 22 .…”

Section: Introductionmentioning

confidence: 99%

Neuropeptide Y causes sex dependent changes in microbiota-intestinal-brain communication in a mouse model of autism spectrum disorder

Gonçalves,

Martins,

Martins

et al. 2024

Preprint

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The microbiome-gut-brain axis plays a role in anxiety and social development and is of growing interest in neuropsychiatic conditions, including autism spectrum disorder (ASD). The present study investigated the behavioral phenotype and the molecular profile of neuropeptide Y (NPY), an anxiolytic peptide, in microbiome-gut-brain communication of Nf1+/− mice, a well-established animal model of ASD. Sex differences, up to date poorly investigated in animal models, were specifically addressed. Our data revealed that females Nf1+/− exhibited more prominent anxious-like behavior. In addition, molecular analyses indicated sex-related differences in expression of NPY and NPY receptors’ transcripts in transgenic animals, with a more prominent effect in females. In addition, the analysis of microbiota revealed sex-specific changes in the Lactobacillus content which correlated with NPY and Y2 receptor changes in transgenic females. Remarkably, the Y2 receptor exhibited sex-dependent expression in both gut and brain of Nf1+/− mice, suggesting its potential as a molecular biomarker for ASD symptoms, namely social anxiety and gastrointestinal issues. For the first time, our findings suggest NPY-mediated regulation of gut-brain communication to be altered in autism and hold potential for the development of new interventions addressing sex-specific aspects of ASD.

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Intraduodenal fecal microbiota transplantation ameliorates gut atrophy and cholestasis in a novel parenteral nutrition piglet model

Manithody,

Denton,

Mehta

et al. 2024

American Journal of Physiology-Gastrointestinal and Liver Physi

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Background: Total parenteral nutrition (TPN) provides lifesaving nutritional support intravenously; however it is associated with significant side effects. Given gut microbial alterations noted with TPN, we hypothesized that transferring fecal microbiota from healthy controls would restore gut-systemic signaling in TPN and mitigate injury. Methods: Using our novel ambulatory model (US Patent: US 63/136,165), 31 piglets were randomly allocated to enteral nutrition (EN), TPN only, TPN + antibiotics (TPN-A) or TPN + intraduodenal fecal microbiota transplant (TPN-FMT) for 14 days. Gut, liver, and serum were assessed through histology, biochemistry, and qPCR. Stool samples underwent 16s rRNA sequencing. PERMANOVA, Jaccard and Bray-Curtis metrics were performed. Results: Significant bilirubin elevation in TPN and TPN-A vs EN (p<0.0001) was prevented with FMT. IFN-G, TNF-alpha, IL-beta, IL-8 and LPS were significantly higher in TPN (p=0.009/0.001/0.043/0.011/<0.0001), with preservation upon FMT. Significant gut-atrophy by villous/crypt ratio in TPN (p<0.0001) and TPN-A (p=0.0001) vs EN was prevented by FMT (p=0.426 vs EN). Microbiota profiles using Principal Coordinate Analysis demonstrated significant FMT and EN overlap, with the largest separation in TPN-A followed by TPN, driven primarily by Firmicutes and Fusobacteria. TPN altered gut barrier was preserved upon FMT. Upregulated CYP7A1 and BSEP in TPN and TPN-A, and downregulatedFGFR4, EGF, FXR and TGR5 vs EN was prevented by FMT. Conclusion: This study provides novel evidence of prevention of gut atrophy, liver injury and microbial dysbiosis with intraduodenal FMT, challenging current paradigms into TPN injury mechanisms and underscores importance of gut microbes as prime targets for therapeutics and drug discovery.

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Gut Microbiota to Microglia: Microbiome Influences Neurodevelopment in the CNS

Cited by 3 publications

References 67 publications

Nanoplastics and Neurodegeneration in ALS

Nanoplastics and Neurodegeneration in ALS

Neuropeptide Y causes sex dependent changes in microbiota-intestinal-brain communication in a mouse model of autism spectrum disorder

Intraduodenal fecal microbiota transplantation ameliorates gut atrophy and cholestasis in a novel parenteral nutrition piglet model

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