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Review

Gut Microbiota Defined Epigenomes of Alzheimer’s and Parkinson’s Diseases Reveal Novel Targets for Therapy

ORCID Icon, ORCID Icon, ORCID Icon &
Pages 57-77 | Received 29 Sep 2023, Accepted 20 Nov 2023, Published online: 13 Dec 2023

References

  • Bianchi VE , Herrera PF , Laura R . Effect of nutrition on neurodegenerative diseases. A systematic review. Nutr. Neurosci. 24(10), 810–834 (2021).
  • Vaquer-Alicea J , Diamond MI . Propagation of protein aggregation in neurodegenerative diseases. Annu. Rev. Biochem. 88, 785–810 (2019).
  • Vallerga CL , Zhang F , Fowdar J et al. Analysis of DNA methylation associates the cystine–glutamate antiporter SLC7A11 with risk of Parkinson’s disease. Nat. Commun. 11(1), 1238 (2020).
  • Xu Y , Xu L , Han M et al. Altered mitochondrial DNA methylation and mitochondrial DNA copy number in an APP/PS1 transgenic mouse model of Alzheimer disease. Biochem. Biophys. Res. Commun. 520(1), 41–46 (2019).
  • Andrade-Guerrero J , Santiago-Balmaseda A , Jeronimo-Aguilar P et al. Alzheimer’s disease: an updated overview of its genetics. Int. J. Mol. Sci. 24(4), 3754 (2023).
  • Nalls MA , Blauwendraat C , Vallerga CL et al. Identification of novel risk loci, causal insights, and heritable risk for Parkinson’s disease: a meta-analysis of genome-wide association studies. Lancet Neurol. 18(12), 1091–1102 (2019).
  • Zhou L-T , Liu D , Kang H-C et al. Tau pathology epigenetically remodels the neuron-glial cross-talk in Alzheimer’s disease. Sci. Adv. 9(16), eabq7105 (2023).
  • Zhang D , Zhang J , Wang Y et al. Targeting epigenetic modifications in Parkinson’s disease therapy. Med. Res. Rev. 43, 1748–1777 (2023).
  • Shen L , Wang C , Chen L , Wong G . Dysregulation of MicroRNAs and PIWI-Interacting RNAs in a Caenorhabditis elegans Parkinson’s disease model overexpressing human α-synuclein and influence of tdp-1 . Front. Neurosci. 15, 600462 (2021).
  • Cammann D , Lu Y , Cummings MJ et al. Genetic correlations between Alzheimer’s disease and gut microbiome genera. Sci. Rep. 13(1), 5258 (2023).
  • Morais LH , Schreiber Iv HL , Mazmanian SK . The gut microbiota–brain axis in behaviour and brain disorders. Nat. Rev. Microbiol. 19(4), 241–255 (2021).
  • Zhu B , Wang X , Li L . Human gut microbiome: the second genome of human body. Protein Cell. 1(8), 718–725 (2010).
  • Zhao Y , Jaber V , Lukiw WJ . Gastrointestinal tract microbiome-derived pro-inflammatory neurotoxins in Alzheimer’s disease. J. Aging Sci. 9(Suppl. 5), 2 (2021).
  • Zmora N , Suez J , Elinav E . You are what you eat: diet, health and the gut microbiota. Nat. Rev. Gastroenterol. Hepatol. 16(1), 35–56 (2019).
  • Ghosh TS , Shanahan F , O’toole PW . The gut microbiome as a modulator of healthy ageing. Nat. Rev. Gastroenterol. Hepatol. 19(9), 565–584 (2022).
  • Stan TL , Soylu-Kucharz R , Burleigh S et al. Increased intestinal permeability and gut dysbiosis in the R6/2 mouse model of Huntington’s disease. Sci. Rep. 10(1), 18270 (2020).
  • Sochocka M , Donskow-Łysoniewska K , Diniz BS , Kurpas D , Brzozowska E , Leszek J . The gut microbiome alterations and inflammation-driven pathogenesis of Alzheimer’s disease – a critical review. Mol. Neurobiol. 56, 1841–1851 (2019).
  • Kowalski K , Mulak A . Brain–gut–microbiota axis in Alzheimer’s disease. J. Neurogastroenterol. Motil. 25(1), 48 (2019).
  • Shandilya S , Kumar S , Jha NK , Kesari KK , Ruokolainen J . Interplay of gut microbiota and oxidative stress: perspective on neurodegeneration and neuroprotection. J. Adv. Res. 38, 223–244 (2022).
  • Tarawneh R , Holtzman DM . The clinical problem of symptomatic Alzheimer disease and mild cognitive impairment. Cold Spring Harb. Perspect. Med. 2(5), a006148 (2012).
  • Scheiblich H , Trombly M , Ramirez A , Heneka MT . Neuroimmune connections in aging and neurodegenerative diseases. Trends Immunol. 41(4), 300–312 (2020).
  • Power R , Prado-Cabrero A , Mulcahy R , Howard A , Nolan JM . The role of nutrition for the aging population: implications for cognition and Alzheimer’s disease. Annu. Rev. Food Sci. Technol. 10, 619–639 (2019).
  • Long JM , Holtzman DM . Alzheimer disease: an update on pathobiology and treatment strategies. Cell 179(2), 312–339 (2019).
  • Risacher SL , Anderson WH , Charil A et al. Alzheimer disease brain atrophy subtypes are associated with cognition and rate of decline. Neurology 89(21), 2176–2186 (2017).
  • Haass C , Kaether C , Thinakaran G , Sisodia S . Trafficking and proteolytic processing of APP. Cold Spring Harb. Perspect. Med. 2(5), a006270 2012).
  • Naj A , Schellenberg G , Alzheimer’s Disease Genetics Consortium (ADGC) . Genomic variants, genes, and pathways of Alzheimer’s disease: an overview. Am. J. Med. Genet. B. Neuropsychiatr. Genet. 174, 5–26 (2017).
  • Wang Z , Zhao Y , Xu N et al. NEAT1 regulates neuroglial cell mediating Aβ clearance via the epigenetic regulation of endocytosis-related genes expression. Cell. Mol. Life Sci. 76, 3005–3018 (2019).
  • Smith AR , Smith RG , Condliffe D et al. Increased DNA methylation near TREM2 is consistently seen in the superior temporal gyrus in Alzheimer’s disease brain. Neurobiol. Aging 47, 35–40 (2016).
  • Lardenoije R , Roubroeks JA , Pishva E et al. Alzheimer’s disease-associated (hydroxy) methylomic changes in the brain and blood. Clin. Epigenetics 11(1), 1–15 (2019).
  • Song H , Yang J , Yu W . Promoter hypomethylation of TGFBR3 as a risk factor of alzheimer’s disease: an integrated epigenomic-transcriptomic analysis. Front. cell dev. biol. 9, 825729 (2022).
  • Lang A-L , Eulalio T , Fox E et al. Methylation differences in Alzheimer’s disease neuropathologic change in the aged human brain. Acta Neuropathol. Commun. 10(1), 1–17 (2022).
  • Sommerer Y , Dobricic V , Schilling M et al. Entorhinal cortex epigenome-wide association study highlights four novel loci showing differential methylation in Alzheimer’s disease. Alzheimer’s Res. Ther. 15(1), 92 (2023).
  • Park H , Shin J , Kim Y , Saito T , Saido TC , Kim J . CRISPR/dCas9-Dnmt3a-mediated targeted DNA methylation of APP rescues brain pathology in a mouse model of Alzheimer’s disease. Transl. Neurodegener. 11(1), 1–12 (2022).
  • Santana DA , Smith MDaC , Chen ES . Histone modifications in alzheimer’s disease. Genes 14(2), 347 (2023).
  • Zotarelli-Filho IJ , Mogharbel BF , Irioda AC et al. State of the art of microRNAs signatures as biomarkers and therapeutic targets in Parkinson’s and Alzheimer’s diseases: a systematic review and meta-analysis. Biomedicines 11(4), 1113 (2023).
  • De Bastiani MA , Bellaver B , Brum WS et al. Hippocampal GFAP-positive astrocyte responses to amyloid and tau pathologies. Brain Behav. Immun. 110, 175–184 (2023).
  • Shireby G , Dempster EL , Policicchio S et al. DNA methylation signatures of Alzheimer’s disease neuropathology in the cortex are primarily driven by variation in non-neuronal cell-types. Nat. Commun. 13(1), 5620 (2022).
  • Kim E , Kim H , Jedrychowski MP et al. Irisin reduces amyloid-β by inducing the release of neprilysin from astrocytes following downregulation of ERK-STAT3 signaling. Neuron 111(22), 3619–3633.e8 (2023).
  • Nalivaeva NN , Belyaev ND , Turner AJ . New insights into epigenetic and pharmacological regulation of amyloid-degrading enzymes. Neurochem. Res. 41, 620–630 (2016).
  • Chen Y-A , Lu C-H , Ke C-C et al. Evaluation of class IIA histone deacetylases expression and in vivo epigenetic imaging in a transgenic mouse model of Alzheimer’s disease. Int. J. Mol. Sci. 22(16), 8633 (2021).
  • Hugais MM , Cobos SN , Bennett SA , Paredes J , Foran G , Torrente MP . Changes in histone H3 acetylation on lysine 9 accompany Aβ 1-40 overexpression in an Alzheimer’s disease yeast model. MicroPubl. Biol. 2021, doi: 10.17912/micropub.biology.000492 (2021).
  • Blanco-Luquin I , Acha B , Urdánoz-Casado A et al. NXN gene epigenetic changes in an adult neurogenesis model of Alzheimer’s disease. Cells 11(7), 1069 (2022).
  • Zhang W , Young JI , Gomez L et al. Distinct CSF biomarker-associated DNA methylation in Alzheimer’s disease and cognitively normal subjects. Alzheimer’s Res. Ther. 15(1), 78 (2023).
  • Shao Y , Shaw M , Todd K et al. DNA methylation of TOMM40-APOE-APOC2 in Alzheimer’s disease. J. Hum. Genet. 63(4), 459–471 (2018).
  • Fertan E , Gendron WH , Wong AA , Hanson GM , Brown RE , Weaver IC . Noncanonical regulation of imprinted gene Igf2 by amyloid-beta 1–42 in Alzheimer’s disease. Sci. Rep. 13(1), 2043 (2023).
  • Klein H-U , Mccabe C , Gjoneska E et al. Epigenome-wide study uncovers large-scale changes in histone acetylation driven by tau pathology in aging and Alzheimer’s human brains. Nat. Neurosci. 22(1), 37–46 (2019).
  • Kakoty V , Kc S , Dubey SK , Yang C-H , Marathe SA , Taliyan R . Epigenetic regulation and autophagy modulation debilitates insulin resistance associated Alzheimer’s disease condition in rats. Metab. Brain Dis. 37(4), 927–944 (2022).
  • Maggiore A , Casale AM , Toscanelli W et al. Neuroprotective effects of PARP inhibitors in drosophila models of Alzheimer’s disease. Cells 11(8), 1284 (2022).
  • Bellver-Sanchis A , Singh Choudhary B , Companys-Alemany J et al. Structure-based virtual screening and in vitro and in vivo analyses revealed potent methyltransferase G9a inhibitors as prospective anti-Alzheimer’s agents. ChemMedChem 17(13), e202200002 (2022).
  • Liu H , Chu W , Gong L , Gao X , Wang W . MicroRNA-26b is upregulated in a double transgenic mouse model of Alzheimer’s disease and promotes the expression of amyloid-β by targeting insulin-like growth factor 1. Mol. Med. Rep. 13(3), 2809–2814 (2016).
  • Xing H , Guo S , Zhang Y , Zheng Z , Wang H . Upregulation of microRNA-206 enhances lipopolysaccharide-induced inflammation and release of amyloid-β by targeting insulin-like growth factor 1 in microglia. Mol. Med. Rep. 14(2), 1357–1364 (2016).
  • Geekiyanage H , Chan C . MicroRNA-137/181c regulates serine palmitoyltransferase and in turn amyloid β, novel targets in sporadic Alzheimer’s disease. J. Neurosci. 31(41), 14820–14830 (2011).
  • Fu L , Jiang G , Weng H , Dick GM , Chang Y , Kassab GS . Cerebrovascular miRNAs correlate with the clearance of Aβ through perivascular route in younger 3xTg-AD mice. Brain Pathol. 30(1), 92–105 (2020).
  • Bloem BR , Okun MS , Klein C . Parkinson’s disease. Lancet 397(10291), 2284–2303 (2021).
  • Lashuel HA , Overk CR , Oueslati A , Masliah E . The many faces of α-synuclein: from structure and toxicity to therapeutic target. Nat. Rev. Neurosci. 14(1), 38–48 (2013).
  • Nicoletti A , Luca A , Baschi R et al. Incidence of mild cognitive impairment and dementia in Parkinson’s disease: the Parkinson’s disease cognitive impairment study. Front. Aging Neurosci. 11, 21 (2019).
  • Dehay B , Bourdenx M , Gorry P et al. Targeting α-synuclein for treatment of Parkinson’s disease: mechanistic and therapeutic considerations. Lancet Neurol. 14(8), 855–866 (2015).
  • Li J , Jin M , Wang L , Qin B , Wang K . MDS clinical diagnostic criteria for Parkinson’s disease in China. J. Neurol. 264, 476–481 (2017).
  • Pajares M , Rojo AI , Manda G , Boscá L , Cuadrado A . Inflammation in Parkinson’s disease: mechanisms and therapeutic implications. Cells 9(7), 1687 (2020).
  • Li X , Li Q , Zhang Y et al. Nickel oxide nanoparticles increase α-synuclein amyloid formation and relevant overexpression of inflammatory mediators in microglia as a marker of Parkinson’s disease. Arab. J. Chem. 14(10), 103380 (2021).
  • Caputi V , Giron MC . Microbiome–gut–brain axis and toll-like receptors in Parkinson’s disease. Int. J. Mol. Sci. 19(6), 1689 (2018).
  • Perez-Pardo P , Dodiya HB , Engen PA et al. Role of TLR4 in the gut-brain axis in Parkinson’s disease: a translational study from men to mice. Gut 68(5), 829–843 (2019).
  • Kontopoulos E , Parvin JD , Feany MB . α-synuclein acts in the nucleus to inhibit histone acetylation and promote neurotoxicity. Hum. Mol. Genet. 15(20), 3012–3023 (2006).
  • Outeiro TF , Kontopoulos E , Altmann SM et al. Sirtuin 2 inhibitors rescue α-synuclein-mediated toxicity in models of Parkinson’s disease. Science 317(5837), 516–519 (2007).
  • Dai L , Wang J , He M et al. Lovastatin alleviates α-synuclein aggregation and phosphorylation in cellular models of synucleinopathy. Front. Mol. Neurosci. 14, 682320 (2021).
  • Mittal S , Bjørnevik K , Im DS et al. β2-Adrenoreceptor is a regulator of the α-synuclein gene driving risk of Parkinson’s disease. Science 357(6354), 891–898 (2017).
  • Harrison IF , Smith AD , Dexter DT . Pathological histone acetylation in Parkinson’s disease: neuroprotection and inhibition of microglial activation through SIRT 2 inhibition. Neurosci. Lett. 666, 48–57 (2018).
  • Musacchio T , Yin J , Kremer F et al. Temporal, spatial and molecular pattern of dopaminergic neurodegeneration in the AAV-A53T α-synuclein rat model of Parkinson’s disease. Behav. Brain Res. 432, 113968 (2022).
  • Toker L , Tran GT , Sundaresan J et al. Genome-wide histone acetylation analysis reveals altered transcriptional regulation in the Parkinson’s disease brain. Mol. Neurodegener. 16(1), 1–20 (2021).
  • Fedotova EY , Iakovenko EV , Abramycheva NY , Illarioshkin SN . SNCA gene methylation in Parkinson’s disease and multiple system atrophy. Epigenomes 7(1), 5 (2023).
  • Smith AR , Richards DM , Lunnon K , Schapira AH , Migdalska-Richards A . DNA methylation of α-synuclein intron 1 is significantly decreased in the frontal cortex of Parkinson’s individuals with GBA1 mutations. Int. J. Mol. Sci. 24(3), 2687 (2023).
  • Bakhit Y , Schmitt I , Hamed A et al. Methylation of alpha-synuclein in a Sudanese cohort. Parkinsonism Relat. Disord. 101, 6–8 (2022).
  • Henderson AR , Wang Q , Meechoovet B et al. DNA methylation and expression profiles of whole blood in Parkinson’s disease. Front. Genet. 12, 640266 (2021).
  • Wang R , Tong S , Wang M et al. CREB5 hypermethylation involved in the ganglioside GM1 therapy of Parkinson’s disease. Front. Aging Neurosci. 15, 1122647 (2023).
  • Magalingam KB , Somanath SD , Radhakrishnan AK . A glimpse into the genome-wide DNA methylation changes in 6-hydroxydopamine-induced in vitro model of Parkinson’s disease. Exp. Neurobiol. 32(3), 119 (2023).
  • Fu KA , Paul KC , Lu AT et al. DNA methylation-based surrogates of plasma proteins are associated with Parkinson’s disease risk. J. Neurol. Sci. 431, 120046 (2021).
  • Fisher DW , Tulloch J , Yu C-E , Tsuang D . A preliminary comparison of the methylome and transcriptome from the prefrontal cortex across Alzheimer’s disease and Lewy body dementia. J. Alzheimers Dis. Rep. 7(1), 279–297 (2023).
  • Gordevicius J , Li P , Marshall LL et al. Epigenetic inactivation of the autophagy–lysosomal system in appendix in Parkinson’s disease. Nat. Commun. 12(1), 5134 (2021).
  • Caldi Gomes L , Roser AE , Jain G et al. MicroRNAs from extracellular vesicles as a signature for Parkinson’s disease. Clin. Transl. Med. 11(4), e357 (2021).
  • Cappelletti C , Henriksen SP , Geut H et al. Transcriptomic profiling of Parkinson’s disease brains reveals disease stage specific expression changes. Acta Neuropathol. 146, 227–244 (2023).
  • Duan Y , Wang Y , Liu Y et al. Circular RNAs in Parkinson’s disease: reliable biological markers and targets for rehabilitation. Mol. Neurobiol. 60(6), 3261–3276 (2023).
  • Meng J , Wang F , Ji L et al. Comprehensive methylation profile of CSF cfDNA revealed pathogenesis and diagnostic markers for early-onset Parkinson’s disease. Epigenomics 13(20), 1637–1651 (2021).
  • Guhathakurta S , Kim J , Adams L et al. Targeted attenuation of elevated histone marks at SNCA alleviates α-synuclein in Parkinson’s disease. EMBO Mol. Med. 13(2), e12188 (2021).
  • Sardoiwala MN , Srivastava AK , Kaundal B , Karmakar S , Choudhury SR . Recuperative effect of metformin loaded polydopamine nanoformulation promoting EZH2 mediated proteasomal degradation of phospho-α-synuclein in Parkinson’s disease model. Nanomedicine 24, 102088 (2020).
  • Jowaed A , Schmitt I , Kaut O , Wüllner U . Methylation regulates alpha-synuclein expression and is decreased in Parkinson’s disease patients’ brains. J. Neurosci. 30(18), 6355–6359 (2010).
  • Srivastava AK , Choudhury SR , Karmakar S . Neuronal BMI-1 is critical for melatonin induced ubiquitination and proteasomal degradation of α-synuclein in experimental Parkinson’s disease models. Neuropharmacology 194, 108372 (2021).
  • Liu P , Sun L , Zhao X-L , Zhang P , Zhao X-M , Zhang J . PAR2-mediated epigenetic upregulation of α-synuclein contributes to the pathogenesis of Parkinson’s disease. Brain Res. 1565, 82–89 (2014).
  • Li B , Jiang Y , Xu Y , Li Y , Li B . Identification of miRNA-7 as a regulator of brain-derived neurotrophic factor/α-synuclein axis in atrazine-induced Parkinson’s disease by peripheral blood and brain microRNA profiling. Chemosphere 233, 542–548 (2019).
  • Xylaki M , Paiva I , Al-Azzani M et al. miR-101a-3p impairs synaptic plasticity and contributes to synucleinopathy. J. Parkinsons Dis. 13, 179–196 (2023).
  • Lin D , Zhang H , Zhang J et al. α-Synuclein induces neuroinflammation injury through the IL6ST-AS/STAT3/HIF-1α axis. Int. J. Mol. Sci. 24(2), 1436 (2023).
  • Schaffner SL , Wassouf Z , Hentrich T , Nuesch-Germano M , Kobor MS , Schulze-Hentrich JM . Distinct impacts of alpha-synuclein overexpression on the hippocampal epigenome of mice in standard and enriched environments. Neurobiol. Dis. 186, 106274 (2023).
  • Zhao A , Li Y , Niu M et al. SNCA hypomethylation in rapid eye movement sleep behavior disorder is a potential biomarker for Parkinson’s disease. J. Parkinsons Dis. 10(3), 1023–1031 (2020).
  • Kaut O , Kuchelmeister K , Moehl C , Wüllner U . 5-methylcytosine and 5-hydroxymethylcytosine in brains of patients with multiple system atrophy and patients with Parkinson’s disease. J. Chem. Neuroanat. 96, 41–48 (2019).
  • Zhou T , Lin D , Chen Y et al. α-synuclein accumulation in SH-SY5Y cell impairs autophagy in microglia by exosomes overloading miR-19a-3p. Epigenomics 11(15), 1661–1677 (2019).
  • Tao H , Liu Y , Hou Y . miRNA-384-5p regulates the progression of Parkinson’s disease by targeting SIRT1 in mice and SH-SY5Y cell. Int. J. Mol. Med. 45(2), 441–450 (2020).
  • Obrenovich ME . Leaky gut, leaky brain? Microorganisms 6(4), 107 (2018).
  • Hollander D , Kaunitz JD . The “leaky gut”: tight junctions but loose associations? Dig. Dis. Sci. 65(5), 1277–1287 (2020).
  • Nagpal R , Mainali R , Ahmadi S et al. Gut microbiome and aging: physiological and mechanistic insights. Nutr. Healthy Aging 4(4), 267–285 (2018).
  • Qian Y , Yang X , Xu S et al. Detection of microbial 16S rRNA gene in the blood of patients with Parkinson’s disease. Front. Aging Neurosci. 10, 156 (2018).
  • Forsyth CB , Shannon KM , Kordower JH et al. Increased intestinal permeability correlates with sigmoid mucosa alpha-synuclein staining and endotoxin exposure markers in early Parkinson’s disease. PLOS ONE 6(12), e28032 (2011).
  • Park A-M , Tsunoda I . Helicobacter pylori infection in the stomach induces neuroinflammation: the potential roles of bacterial outer membrane vesicles in an animal model of Alzheimer’s disease. Inflamm. Regen. 42(1), 39 (2022).
  • Wang S , Prajapati SK , Mishra SP , Jain S , Yadav H . Protection of cognitive decline and Alzheimer’s disease progression by a human origin-probiotic biotherapy. Alzheimers Dement. 18, e066137 (2022).
  • Li H , Liu C-C , Zheng H , Huang TY . Amyloid, tau, pathogen infection and antimicrobial protection in Alzheimer’s disease–conformist, nonconformist, and realistic prospects for AD pathogenesis. Transl. Neurodegener. 7, 1–16 (2018).
  • Shukla PK , Delotterie DF , Xiao J et al. Alterations in the gut–microbial–inflammasome–brain axis in a mouse model of Alzheimer’s disease. Cells 10(4), 779 (2021).
  • Kaya-Tilki E , Dikmen M . Neuroprotective effects of some epigenetic modifying drugs’ on Chlamydia pneumoniae-induced neuroinflammation: a novel model. PLOS ONE 16(11), e0260633 (2021).
  • Ahmadi S , Wang S , Nagpal R et al. A human-origin probiotic cocktail ameliorates aging-related leaky gut and inflammation via modulating the microbiota/taurine/tight junction axis. JCI Insight 5(9), e132055 (2020).
  • Ren M , Li H , Fu Z , Li Q . Centenarian-sourced lactobacillus casei combined with dietary fiber complex ameliorates brain and gut function in aged mice. Nutrients 14(2), 324 (2022).
  • Zhao X , Kong M , Wang Y et al. Nicotinamide mononucleotide improves the Alzheimer’s disease by regulating intestinal microbiota. Biochem. Biophys. Res. Commun. 670, 27–35 (2023).
  • Unger MM , Spiegel J , Dillmann K-U et al. Short chain fatty acids and gut microbiota differ between patients with Parkinson’s disease and age-matched controls. Parkinsonism Relat. Disord. 32, 66–72 (2016).
  • Vogt NM , Romano KA , Darst BF et al. The gut microbiota-derived metabolite trimethylamine N-oxide is elevated in Alzheimer’s disease. Alzheimer’s Res. Ther. 10, 1–8 (2018).
  • Choudhury SP , Bano S , Sen S et al. Altered neural cell junctions and ion-channels leading to disrupted neuron communication in Parkinson’s disease. NPJ Parkinson’s Dis. 8(1), 66 (2022).
  • Sampson TR , Debelius JW , Thron T et al. Gut microbiota regulate motor deficits and neuroinflammation in a model of Parkinson’s disease. Cell 167(6), 1469–1480. e1412 (2016).
  • Guo X , Tang P , Hou C et al. Integrated microbiome and host transcriptome profiles link Parkinson’s disease to Blautia genus: evidence from feces, blood, and brain. Front. Microbiol. 13, 875101 (2022).
  • Ferreiro AL , Choi J , Ryou J et al. Gut microbiome composition may be an indicator of preclinical Alzheimer’s disease. Sci. Transl. Med. 15(700), eabo2984 (2023).
  • Kundu P , Torres ERS , Stagaman K et al. Integrated analysis of behavioral, epigenetic, and gut microbiome analyses in App NL-GF, App NL-F, and wild type mice. Sci. Rep. 11(1), 4678 (2021).
  • Blacher E , Levy M , Tatirovsky E , Elinav E . Microbiome-modulated metabolites at the interface of host immunity. J. Immunol. 198(2), 572–580 (2017).
  • Chen S-J , Chen C-C , Liao H-Y et al. Association of fecal and plasma levels of short-chain fatty acids with gut microbiota and clinical severity in patients with Parkinson disease. Neurology 98(8), e848–e858 (2022).
  • Dalile B , Van Oudenhove L , Vervliet B , Verbeke K . The role of short-chain fatty acids in microbiota–gut–brain communication. Nat. Rev. Gastroenterol. Hepatol. 16(8), 461–478 (2019).
  • Zhang L , Wang Y , Xiayu X et al. Altered gut microbiota in a mouse model of Alzheimer’s disease. J. Alzheimer’s Dis. 60(4), 1241–1257 (2017).
  • Marizzoni M , Cattaneo A , Mirabelli P et al. Short-chain fatty acids and lipopolysaccharide as mediators between gut dysbiosis and amyloid pathology in Alzheimer’s disease. J. Alzheimer’s Dis. 78(2), 683–697 (2020).
  • Xu Y , Wei S , Zhu L et al. Low expression of the intestinal metabolite butyric acid and the corresponding memory pattern regulate HDAC4 to promote apoptosis in rat hippocampal neurons. Ecotoxicol. Environ. Saf. 253, 114660 (2023).
  • Sarkar S , Abujamra AL , Loew JE , Forman LW , Perrine SP , Faller DV . Histone deacetylase inhibitors reverse CpG methylation by regulating DNMT1 through ERK signaling. Anticancer Res. 31(9), 2723–2732 (2011).
  • Xie A , Ensink E , Li P et al. Bacterial butyrate in Parkinson’s disease is linked to epigenetic changes and depressive symptoms. Mov. Disord. 37(8), 1644–1653 (2022).
  • Sun Y , Zhang H , Zhang X et al. Promotion of astrocyte–neuron glutamate–glutamine shuttle by SCFA contributes to the alleviation of Alzheimer’s disease. Redox. Biol. 62, 102690 (2023).
  • Avagliano C , Coretti L , Lama A et al. Dual-hit model of Parkinson’s disease: impact of dysbiosis on 6-Hydroxydopamine-insulted mice – neuroprotective and anti-inflammatory effects of butyrate. Int. J. Mol. Sci. 23(12), 6367 (2022).
  • Chen G , Ran X , Li B et al. Sodium butyrate inhibits inflammation and maintains epithelium barrier integrity in a TNBS-induced inflammatory bowel disease mice model. EBioMedicine 30, 317–325 (2018).
  • Getachew B , Csoka AB , Bhatti A , Copeland RL , Tizabi Y . Butyrate protects against salsolinol-induced toxicity in SH-SY5Y cells: implication for Parkinson’s disease. Neurotox. Res. 38, 596–602 (2020).
  • Fernando W , Martins IJ , Morici M et al. Sodium butyrate reduces brain amyloid-β levels and improves cognitive memory performance in an Alzheimer’s disease transgenic mouse model at an early disease stage. J. Alzheimer’s Dis. 74(1), 91–99 (2020).
  • Bayazid AB , Jeong YH , Jeong SA , Lim BO . Sodium butyrate alleviates potential Alzheimer’s disease in vitro by suppressing Aβ and tau activation and ameliorates Aβ-induced toxicity. Food Agric. Immunol. 34(1), 2234100 (2023).
  • Jiang Y , Li K , Li X , Xu L , Yang Z . Sodium butyrate ameliorates the impairment of synaptic plasticity by inhibiting the neuroinflammation in 5XFAD mice. Chem. Biol. Interact. 341, 109452 (2021).
  • Govindarajan N , Agis-Balboa RC , Walter J , Sananbenesi F , Fischer A . Sodium butyrate improves memory function in an Alzheimer’s disease mouse model when administered at an advanced stage of disease progression. J. Alzheimer’s Dis. 26(1), 187–197 (2011).
  • Wang C , Zheng D , Weng F , Jin Y , He L . Sodium butyrate ameliorates the cognitive impairment of Alzheimer’s disease by regulating the metabolism of astrocytes. Psychopharmacology (Berl.) 239,215–227 (2022).
  • Kilgore M , Miller CA , Fass DM et al. Inhibitors of class 1 histone deacetylases reverse contextual memory deficits in a mouse model of Alzheimer’s disease. Neuropsychopharmacology 35(4), 870–880 (2010).
  • Nuutinen T , Suuronen T , Kauppinen A , Salminen A . Valproic acid stimulates clusterin expression in human astrocytes: Implications for Alzheimer’s disease. Neurosci. Lett. 475(2), 64–68 (2010).
  • Yuan B , Liu M , Gong Y et al. Sodium butyrate exerts antioxidant stress effects and attenuates Aβ25-35-induced cytotoxicity in PC12 cells. Arch. Biochem. Biophys. 731, 109448 (2022).
  • Sun J , Yuan B , Wu Y et al. Sodium butyrate protects N2a cells against Aβ toxicity in vitro . Mediators Inflamm. 2020, 7605160 (2020).
  • Ho L , Ono K , Tsuji M , Mazzola P , Singh R , Pasinetti GM . Protective roles of intestinal microbiota derived short chain fatty acids in Alzheimer’s disease-type beta-amyloid neuropathological mechanisms. Expert Rev. Neurother. 18(1), 83–90 (2018).
  • Long ZM , Zhao L , Jiang R et al. Valproic acid modifies synaptic structure and accelerates neurite outgrowth via the glycogen synthase kinase-3β signaling pathway in an Alzheimer’s disease model. CNS Neurosci. Ther. 21(11), 887–897 (2015).
  • Noh H , Seo H . Age-dependent effects of valproic acid in Alzheimer’s disease (AD) mice are associated with nerve growth factor (NGF) regulation. Neuroscience 266, 255–265 (2014).
  • Sorial ME , El Sayed NSED . Protective effect of valproic acid in streptozotocin-induced sporadic Alzheimer’s disease mouse model: possible involvement of the cholinergic system. Naunyn. Schmiedebergs Arch. Pharmacol. 390, 581–593 (2017).
  • Xuan A-G , Pan X-B , Wei P et al. Valproic acid alleviates memory deficits and attenuates amyloid-β deposition in transgenic mouse model of Alzheimer’s disease. Mol. Neurobiol. 51, 300–312 (2015).
  • Lang W , Li X , Wang Y et al. Sodium propionate improves cognitive and memory function in mouse models of Alzheimer’s disease. Neurosci. Lett. 791, 136887 (2022).
  • Sharma S , Taliyan R , Singh S . Beneficial effects of sodium butyrate in 6-OHDA induced neurotoxicity and behavioral abnormalities: modulation of histone deacetylase activity. Behav. Brain Res. 291, 306–314 (2015).
  • Guo T-T , Zhang Z , Sun Y et al. Neuroprotective effects of sodium butyrate by restoring gut microbiota and inhibiting TLR4 signaling in mice with MPTP-induced Parkinson’s disease. Nutrients 15(4), 930 (2023).
  • Zhang Y , Xu S , Qian Y et al. Sodium butyrate attenuates rotenone-induced toxicity by activation of autophagy through epigenetically regulating PGC-1α expression in PC12 cells. Brain Res. 1776, 147749 (2022).
  • Kakoty V , Kc S , Dubey SK , Yang C-H , Taliyan R . Neuroprotective effects of trehalose and sodium butyrate on preformed fibrillar form of α-synuclein-induced rat model of Parkinson’s disease. ACS Chem. Neurosci. 12(14), 2643–2660 (2021).
  • Rane P , Shields J , Heffernan M , Guo Y , Akbarian S , King JA . The histone deacetylase inhibitor, sodium butyrate, alleviates cognitive deficits in pre-motor stage PD. Neuropharmacology 62(7), 2409–2412 (2012).
  • Laurent RS , O’brien LM , Ahmad S . Sodium butyrate improves locomotor impairment and early mortality in a rotenone-induced Drosophila model of Parkinson’s disease. Neuroscience 246, 382–390 (2013).
  • Paiva I , Pinho R , Pavlou MA et al. Sodium butyrate rescues dopaminergic cells from alpha-synuclein-induced transcriptional deregulation and DNA damage. Hum. Mol. Genet. 26(12), 2231–2246 (2017).
  • Liu J , Wang F , Liu S et al. Sodium butyrate exerts protective effect against Parkinson’s disease in mice via stimulation of glucagon like peptide-1. J. Neurol. Sci. 381, 176–181 (2017).
  • Kakoty V , Kc S , Yang C-H , Dubey SK , Taliyan R . Exploring the epigenetic regulated modulation of fibroblast growth factor 21 involvement in high-fat diet associated parkinson’s disease in rats. ACS Chem. Neurosci. 14(4), 725–740 (2023).
  • Zhang Y , Xu S , Qian Y et al. Sodium butyrate ameliorates gut dysfunction and motor deficits in a mouse model of Parkinson’s disease by regulating gut microbiota. Front. Aging Neurosci. 15, 1099018 (2023).
  • Hou Y , Li X , Liu C et al. Neuroprotective effects of short-chain fatty acids in MPTP induced mice model of Parkinson’s disease. Exp. Gerontol. 150, 111376 (2021).
  • Dilmore AH , Martino C , Neth BJ et al. Effects of a ketogenic and low-fat diet on the human metabolome, microbiome, and foodome in adults at risk for Alzheimer’s disease. Alzheimers. Dement. 19(11), 4805–4816 (2023).
  • Ma D , Wang AC , Parikh I et al. Ketogenic diet enhances neurovascular function with altered gut microbiome in young healthy mice. Sci. Rep. 8(1), 6670 (2018).
  • Nagpal R , Neth BJ , Wang S , Craft S , Yadav H . Modified Mediterranean–ketogenic diet modulates gut microbiome and short-chain fatty acids in association with Alzheimer’s disease markers in subjects with mild cognitive impairment. EBioMedicine 47, 529–542 (2019).
  • Zhu Y , Tang X , Cheng Z , Dong Q , Ruan G . The anti-inflammatory effect of preventive intervention with ketogenic diet mediated by the histone acetylation of mGluR5 promotor region in rat Parkinson’s disease model: a dual-tracer PET study. Parkinsons Dis. 2022, 3506213 (2022).
  • Cheng B , Yang X , An L , Gao B , Liu X , Liu S . Ketogenic diet protects dopaminergic neurons against 6-OHDA neurotoxicity via up-regulating glutathione in a rat model of Parkinson’s disease. Brain Res. 1286, 25–31 (2009).
  • Hernandez AR , Kemp KM , Burke SN , Buford TW , Carter CS . Influence of aging, macronutrient composition and time-restricted feeding on the Fischer344 x brown norway rat gut microbiota. Nutrients 14(9), 1758 (2022).
  • Whittaker DS , Akhmetova L , Carlin D et al. Circadian modulation by time-restricted feeding rescues brain pathology and improves memory in mouse models of Alzheimer’s disease. Cell Metab. 35(10), 1704–1721.e6 (2023).
  • Zhou Z-L , Jia X-B , Sun M-F et al. Neuroprotection of fasting mimicking diet on MPTP-induced Parkinson’s disease mice via gut microbiota and metabolites. Neurotherapeutics 16, 741–760 (2019).
  • Hsieh T-H , Kuo C-W , Hsieh K-H et al. Probiotics alleviate the progressive deterioration of motor functions in a mouse model of Parkinson’s disease. Brain Sci. 10(4), 206 (2020).
  • Asl ZR , Sepehri G , Salami M . Probiotic treatment improves the impaired spatial cognitive performance and restores synaptic plasticity in an animal model of Alzheimer’s disease. Behav. Brain Res. 376, 112183 (2019).
  • Srivastav S , Neupane S , Bhurtel S et al. Probiotics mixture increases butyrate, and subsequently rescues the nigral dopaminergic neurons from MPTP and rotenone-induced neurotoxicity. J. Nutr. Biochem. 69, 73–86 (2019).
  • Zhang Y , Shen Y , Liufu N et al. Transmission of Alzheimer’s disease-associated microbiota dysbiosis and its impact on cognitive function: evidence from mouse models and human patients. Mol. Psychiatry DOI doi: 10.1038/s41380-023-02216-7 (2023).
  • Li T , Chu C , Yu L et al. Neuroprotective effects of Bifidobacterium breve CCFM1067 in MPTP-induced mouse models of Parkinson’s disease. Nutrients 14(21), 4678 (2022).
  • Ghyselinck J , Verstrepen L , Moens F et al. Influence of probiotic bacteria on gut microbiota composition and gut wall function in an in-vitro model in patients with Parkinson’s disease. Int. J. Pharm: X 3, 100087 (2021).
  • Tsao S-P , Nurrahma BA , Kumar R et al. Probiotic enhancement of antioxidant capacity and alterations of gut microbiota composition in 6-hydroxydopamin-induced parkinson’s disease rats. Antioxidants 10(11), 1823 (2021).
  • Sancandi M , De Caro C , Cypaite N et al. Effects of a probiotic suspension Symprove™ on a rat early-stage Parkinson’s disease model. Front. Aging Neurosci. 14, 1525 (2023).
  • Kaur H , Golovko S , Golovko MY , Singh S , Darland DC , Combs CK . Effects of probiotic supplementation on short chain fatty acids in the App NL-GF mouse model of Alzheimer’s disease. J. Alzheimer’s Dis. 76(3), 1083–1102 (2020).
  • Sun J , Xu J , Yang B et al. Effect of Clostridium butyricum against microglia-mediated neuroinflammation in Alzheimer’s disease via regulating gut microbiota and metabolites butyrate. Mol. Nutr. Food Res. 64(2), 1900636 (2020).
  • Yen C-H , Wang C-H , Wu W-T , Chen H-L . Fructo-oligosaccharide improved brain β-amyloid, β-secretase, cognitive function, and plasma antioxidant levels in D-galactose-treated Balb/cJ mice. Nutr. Neurosci. 20(4), 228–237 (2017).
  • Sun J , Liu S , Ling Z et al. Fructooligosaccharides ameliorating cognitive deficits and neurodegeneration in APP/PS1 transgenic mice through modulating gut microbiota. J. Agric. Food Chem. 67(10), 3006–3017 (2019).
  • Wu S , Zhang J , Jiang C , Wang S , Que R , An L . Up-regulation of neprilysin mediates the protection of fructo-oligosaccharides against Alzheimer’s disease. Food Funct. 11(7), 6565–6572 (2020).
  • Wang N , Feng B-N , Hu B , Cheng Y-L , Guo Y-H , Qian H . Neuroprotection of chicoric acid in a mouse model of Parkinson’s disease involves gut microbiota and TLR4 signaling pathway. Food Funct. 13(4), 2019–2032 (2022).
  • Zhang S , Wei D , Lv S et al. Scutellarin modulates the microbiota–gut–brain axis and improves cognitive impairment in APP/PS1 mice. J. Alzheimer’s Dis. 89(3), 955–975 (2022).
  • Pyo IS , Yun S , Yoon YE , Choi J-W , Lee S-J . Mechanisms of aging and the preventive effects of resveratrol on age-related diseases. Molecules 25(20), 4649 (2020).
  • Grinan-Ferre C , Bellver-Sanchis A , Izquierdo V et al. The pleiotropic neuroprotective effects of resveratrol in cognitive decline and Alzheimer’s disease pathology: from antioxidant to epigenetic therapy. Ageing Res. Rev. 67, 101271 (2021).
  • Tao J , An Y , Xu L et al. The protective role of microbiota in the prevention of MPTP/P-induced Parkinson’s disease by resveratrol. Food Funct. 14(10), 4647–4661 (2023).
  • Zhang W , Guo Y , Cheng Y , Yao W , Qian H . Neuroprotective effects of polysaccharide from Sparassis crispa on Alzheimer’s disease-like mice: involvement of microbiota–gut–brain axis. Int. J. Biol. Macromol. 225, 974–986 (2023).
  • Behera J , Kelly KE , Tyagi N . Altered non-coding RNA-histone acetylation regulatory circuit is associated with cognitive impairment via gut dysbiosis in aging mice. FASEB J. 33(S1), 714.713 (2019).
  • Abdolmaleky HM , Zhou J-R . Underlying mechanisms of brain aging and neurodegenerative diseases as potential targets for preventive or therapeutic strategies using phytochemicals. Nutrients 15(15), 3456 (2023).
  • Bordoni L , Gabbianelli R , Fedeli D et al. Positive effect of an electrolyzed reduced water on gut permeability, fecal microbiota and liver in an animal model of Parkinson’s disease. PLOS ONE 14(10), e0223238 (2019).
  • Cuervo-Zanatta D , Syeda T , Sánchez-Valle V et al. Dietary fiber modulates the release of gut bacterial products preventing cognitive decline in an Alzheimer’s mouse model. Cell. Mol. Neurobiol. 43(4), 1595–1618 (2023).
  • Koutzoumis DN , Vergara M , Pino J et al. Alterations of the gut microbiota with antibiotics protects dopamine neuron loss and improve motor deficits in a pharmacological rodent model of Parkinson’s disease. Exp. Neurol. 325, 113159 (2020).
  • Bakker GJ , Nieuwdorp M . Fecal microbiota transplantation: therapeutic potential for a multitude of diseases beyond Clostridium difficile . Microbiol. Spectr. 5(4), doi: 10.1128/microbiolspec.bad-0008-2017 (2017).
  • Wortelboer K , Nieuwdorp M , Herrema H . Fecal microbiota transplantation beyond Clostridioides difficile infections. EBioMedicine 44, 716–729 (2019).
  • Zhong Z , Chen W , Gao H et al. Fecal microbiota transplantation exerts a protective role in MPTP-induced Parkinson’s disease via the TLR4/PI3K/AKT/NF-κB pathway stimulated by α-synuclein. Neurochem. Res. 46, 3050–3058 (2021).
  • Sun J , Xu J , Ling Y et al. Fecal microbiota transplantation alleviated Alzheimer’s disease-like pathogenesis in APP/PS1 transgenic mice. Transl. Psychiatry 9(1), 189 (2019).

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