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Helicobacter hepaticus augmentation triggers Dopaminergic degeneration and motor disorders in mice with Parkinson’s disease

Molecular Psychiatry volume 28, pages 1337–1350 (2023)Cite this article

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Abstract

Gut dysbiosis contributes to Parkinson’s disease (PD) pathogenesis. Gastrointestinal disturbances in PD patients, along with gut leakage and intestinal inflammation, take place long before motor disorders. However, it remains unknown what bacterial species in gut microbiomes play the key role in driving PD pathogenesis. Here we show that Helicobacter hepaticus (H. hepaticus), abundant in gut microbiota from rotenone-treated human α-Synuclein gene (SNCA) transgenic mice and PD patients, initiates α-Synuclein pathology and motor deficits in an AEP-dependent manner in SNCA mice. Chronic Dextran sodium sulfate (DSS) treatment, an inflammatory inducer in the gut, activates AEP (asparagine endopeptidase) that cleaves α-Synuclein N103 and triggers its aggregation, promoting inflammation in the gut and the brain and motor defects in SNCA mice. PD fecal microbiota transplant or live H. hepaticus administration into antibiotics cocktail (Abx)-pretreated SNCA mice induces α-Synuclein pathology, inflammation in the gut and brain, and motor dysfunctions, for which AEP is indispensable. Hence, Helicobacter hepaticus enriched in PD gut microbiomes may facilitate α-Synuclein pathologies and motor impairments via activating AEP.

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Fig. 1: Microbiome analysis in SNCA and SNCA/AEP KO mouse stool reveals an alteration in the microbial community.
Fig. 2: Microbiota profiling, comparative biomarker discovery and correlation analysis.
Fig. 3: DSS induces constipation and PD-like pathogenesis in the gut of SNCA mice.
Fig. 4: PD patients FMT elicits dopaminergic loss, inflammation and motor disorders in Abx-pretreated SNCA mice.
Fig. 5: Active H. Hepaticus triggers dopaminergic loss, inflammation and motor disorders in Abx-pretreated SNCA mice.
Fig. 6: Active H. Hepaticus triggers PD pathologies and motor disorders in SNCA mice.

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References

  1. Armstrong MJ, Okun MS. Diagnosis and treatment of Parkinson Disease: a review. JAMA. 2020;323:548–60.

    PubMed  Google Scholar 

  2. Dwyer Z, Chaiquin M, Landrigan J, Ayoub K, Shail P, Rocha J, et al. The impact of dextran sodium sulphate and probiotic pre-treatment in a murine model of Parkinson’s disease. J Neuroinflammation. 2021;18:20.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Vendrik KEW, Ooijevaar RE, de Jong PRC, Laman JD, van Oosten BW, van Hilten JJ, et al. Fecal microbiota transplantation in neurological disorders. Front Cell Infect Microbiol. 2020;10:98.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Svensson E, Horvath-Puho E, Thomsen RW, Djurhuus JC, Pedersen L, Borghammer P, et al. Vagotomy and subsequent risk of Parkinson’s disease. Ann Neurol. 2015;78:522–9.

    PubMed  Google Scholar 

  5. Devos D, Lebouvier T, Lardeux B, Biraud M, Rouaud T, Pouclet H, et al. Colonic inflammation in Parkinson’s disease. Neurobiol Dis. 2013;50:42–48.

    CAS  PubMed  Google Scholar 

  6. Holmqvist S, Chutna O, Bousset L, Aldrin-Kirk P, Li W, Bjorklund T, et al. Direct evidence of Parkinson pathology spread from the gastrointestinal tract to the brain in rats. Acta Neuropathol. 2014;128:805–20.

    PubMed  Google Scholar 

  7. Ahn EH, Kang SS, Liu X, Chen G, Zhang Z, Chandrasekharan B, et al. Initiation of Parkinson’s disease from gut to brain by delta-secretase. Cell Res. 2020;30:70–87.

    PubMed  Google Scholar 

  8. Kim S, Kwon SH, Kam TI, Panicker N, Karuppagounder SS, Lee S, et al. Transneuronal propagation of pathologic alpha-synuclein from the gut to the brain models Parkinson’s Disease. Neuron. 2019;103:627–41 e627.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Peng C, Trojanowski JQ, Lee VM. Protein transmission in neurodegenerative disease. Nat Rev Neurol. 2020;16:199–212.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Sampson T. The impact of indigenous microbes on Parkinson’s disease. Neurobiol Dis. 2020;135:104426.

    CAS  PubMed  Google Scholar 

  11. Sandhu KV, Sherwin E, Schellekens H, Stanton C, Dinan TG, Cryan JF. Feeding the microbiota-gut-brain axis: diet, microbiome, and neuropsychiatry. Transl Res. 2017;179:223–44.

    CAS  PubMed  Google Scholar 

  12. Dong S, Sun M, He C, Cheng H. Brain-gut-microbiota axis in Parkinson’s disease: a historical review and future perspective. Brain Res Bull. 2022;183:84–93.

    CAS  PubMed  Google Scholar 

  13. Sampson TR, Debelius JW, Thron T, Janssen S, Shastri GG, Ilhan ZE, et al. Gut microbiota regulate motor deficits and neuroinflammation in a model of Parkinson’s Disease. Cell. 2016;167:1469–80 e1412.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Janezic S, Threlfell S, Dodson PD, Dowie MJ, Taylor TN, Potgieter D, et al. Deficits in dopaminergic transmission precede neuron loss and dysfunction in a new Parkinson model. Proc Natl Acad Sci USA. 2013;110:E4016–25.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Wang Q, Luo Y, Ray Chaudhuri K, Reynolds R, Tan EK, Pettersson S. The role of gut dysbiosis in Parkinson’s disease: mechanistic insights and therapeutic options. Brain. 2021;144:2571–93.

    PubMed  Google Scholar 

  16. Yang X, Qian Y, Xu S, Song Y, Xiao Q. Longitudinal analysis of fecal microbiome and pathologic processes in a rotenone induced mice model of Parkinson’s Disease. Front Aging Neurosci. 2017;9:441.

    PubMed  Google Scholar 

  17. Fox JG, Li X, Yan L, Cahill RJ, Hurley R, Lewis R, et al. Chronic proliferative hepatitis in A/JCr mice associated with persistent Helicobacter hepaticus infection: a model of helicobacter-induced carcinogenesis. Infect Immun. 1996;64:1548–58.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Falsafi T, Mahboubi M. Helicobacter hepaticus, a new pathogenic species of the Helicobacter genus: Similarities and differences with H. pylori. Iran J Microbiol. 2013;5:185–94.

    PubMed  PubMed Central  Google Scholar 

  19. Danne C, Powrie F. Helicobacter hepaticus polysaccharide induces an anti-inflammatory response in intestinal macrophages. Micro Cell. 2018;5:208–11.

    CAS  Google Scholar 

  20. Kleine M, Worbs T, Schrem H, Vondran FW, Kaltenborn A, Klempnauer J, et al. Helicobacter hepaticus induces an inflammatory response in primary human hepatocytes. PLoS One. 2014;9:e99713.

    PubMed  PubMed Central  Google Scholar 

  21. Cahill RJ, Foltz CJ, Fox JG, Dangler CA, Powrie F, Schauer DB. Inflammatory bowel disease: an immunity-mediated condition triggered by bacterial infection with Helicobacter hepaticus. Infect Immun. 1997;65:3126–31.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Chin EY, Dangler CA, Fox JG, Schauer DB. Helicobacter hepaticus infection triggers inflammatory bowel disease in T cell receptor alphabeta mutant mice. Comp Med. 2000;50:586–94.

    CAS  PubMed  Google Scholar 

  23. Hamada T, Yokota K, Ayada K, Hirai K, Kamada T, Haruma K, et al. Detection of Helicobacter hepaticus in human bile samples of patients with biliary disease. Helicobacter. 2009;14:545–51.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Ananieva O, Nilsson I, Vorobjova T, Uibo R, Wadstrom T. Immune responses to bile-tolerant helicobacter species in patients with chronic liver diseases, a randomized population group, and healthy blood donors. Clin Diagn Lab Immunol. 2002;9:1160–4.

    PubMed  PubMed Central  Google Scholar 

  25. Li DN, Matthews SP, Antoniou AN, Mazzeo D, Watts C. Multistep autoactivation of asparaginyl endopeptidase in vitro and in vivo. J Biol Chem. 2003;278:38980–90.

    CAS  PubMed  Google Scholar 

  26. Zhang Z, Kang SS, Liu X, Ahn EH, Zhang Z, He L, et al. Asparagine endopeptidase cleaves alpha-synuclein and mediates pathologic activities in Parkinson’s disease. Nat Struct Mol Biol. 2017;24:632–42.

    PubMed  PubMed Central  Google Scholar 

  27. Kang SS, Ahn EH, Zhang Z, Liu X, Manfredsson FP, Sandoval IM, et al. alpha-Synuclein stimulation of monoamine oxidase-B and legumain protease mediates the pathology of Parkinson’s disease. EMBO J. 2018;37:12.

    Google Scholar 

  28. Zhang Z, Song M, Liu X, Kang SS, Kwon IS, Duong DM, et al. Cleavage of tau by asparagine endopeptidase mediates the neurofibrillary pathology in Alzheimer’s disease. Nat Med. 2014;20:1254–62.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Leuzy A, Cicognola C, Chiotis K, Saint-Aubert L, Lemoine L, Andreasen N, et al. Longitudinal tau and metabolic PET imaging in relation to novel CSF tau measures in Alzheimer’s disease. Eur J Nucl Med Mol Imaging. 2019;46:1152–63.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Blennow K, Chen C, Cicognola C, Wildsmith KR, Manser PT, Bohorquez SMS, et al. Cerebrospinal fluid tau fragment correlates with tau PET: a candidate biomarker for tangle pathology. Brain. 2020;143:650–60.

    PubMed  Google Scholar 

  31. Chen C, Ahn EH, Kang SS, Liu X, Alam A, Ye K. Gut dysbiosis contributes to amyloid pathology, associated with C/EBPbeta/AEP signaling activation in Alzheimer’s disease mouse model. Sci Adv. 2020;6:eaba0466.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Chen C, Zhou Y, Wang H, Alam A, Kang SS, Ahn EH, et al. Gut inflammation triggers C/EBPbeta/delta-secretase-dependent gut-to-brain propagation of Abeta and Tau fibrils in Alzheimer’s disease. EMBO J. 2021;40:e106320.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Chen C, Liao J, Xia Y, Liu X, Jones R, Haran J et al. Gut microbiota regulate Alzheimer’s disease pathologies and cognitive disorders via PUFA-associated neuroinflammation. Gut. 2022;71:2233–52.

  34. Pan-Montojo F, Schwarz M, Winkler C, Arnhold M, O’Sullivan GA, Pal A, et al. Environmental toxins trigger PD-like progression via increased alpha-synuclein release from enteric neurons in mice. Sci Rep. 2012;2:898.

    PubMed  PubMed Central  Google Scholar 

  35. Unger MM, Spiegel J, Dillmann KU, Grundmann D, Philippeit H, Burmann J, et al. Short chain fatty acids and gut microbiota differ between patients with Parkinson’s disease and age-matched controls. Parkinsonism Relat Disord. 2016;32:66–72.

    PubMed  Google Scholar 

  36. Poutahidis T, Kearney SM, Levkovich T, Qi P, Varian BJ, Lakritz JR, et al. Microbial symbionts accelerate wound healing via the neuropeptide hormone oxytocin. PLoS One. 2013;8:e78898.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Bain CC, Oliphant CJ, Thomson CA, Kullberg MC, Mowat AM. Proinflammatory role of monocyte-derived CX3CR1(int) macrophages in helicobacter hepaticus-induced colitis. Infect Immun. 2018;86:2.

    Google Scholar 

  38. Erdman SE, Rao VP, Poutahidis T, Rogers AB, Taylor CL, Jackson EA, et al. Nitric oxide and TNF-alpha trigger colonic inflammation and carcinogenesis in Helicobacter hepaticus-infected, Rag2-deficient mice. Proc Natl Acad Sci USA. 2009;106:1027–32.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Kishimoto Y, Zhu W, Hosoda W, Sen JM, Mattson MP. Chronic mild gut inflammation accelerates brain neuropathology and motor dysfunction in alpha-synuclein mutant mice. Neuromolecular Med. 2019;21:239–49.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Klingelhoefer L, Reichmann H. Pathogenesis of Parkinson disease–the gut-brain axis and environmental factors. Nat Rev Neurol. 2015;11:625–36.

    CAS  PubMed  Google Scholar 

  41. Nuzum ND, Loughman A, Szymlek-Gay EA, Hendy A, Teo WP, Macpherson H. Gut microbiota differences between healthy older adults and individuals with Parkinson’s disease: a systematic review. Neurosci Biobehav Rev. 2020;112:227–41.

    PubMed  Google Scholar 

  42. Danne C, Ryzhakov G, Martinez-Lopez M, Ilott NE, Franchini F, Cuskin F, et al. A large polysaccharide produced by helicobacter hepaticus induces an anti-inflammatory gene signature in macrophages. Cell Host Microbe. 2017;22:733–45 e735.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Sterzenbach T, Lee SK, Brenneke B, von Goetz F, Schauer DB, Fox JG, et al. Inhibitory effect of enterohepatic Helicobacter hepaticus on innate immune responses of mouse intestinal epithelial cells. Infect Immun. 2007;75:2717–28.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Eckmann L. Animal models of inflammatory bowel disease: lessons from enteric infections. Ann N Y Acad Sci. 2006;1072:28–38.

    CAS  PubMed  Google Scholar 

  45. Fulling C, Dinan TG, Cryan JF. Gut microbe to brain signaling: what happens in vagus. Neuron. 2019;101:998–1002.

    CAS  PubMed  Google Scholar 

  46. Ahn EH, Lei K, Kang SS, Wang ZH, Liu X, Hong W, et al. Mitochondrial dysfunction triggers the pathogenesis of Parkinson’s disease in neuronal C/EBPbeta transgenic mice. Mol Psychiatry. 2021;26:7838–50.

    CAS  PubMed  Google Scholar 

  47. Sun MF, Shen YQ. Dysbiosis of gut microbiota and microbial metabolites in Parkinson’s Disease. Ageing Res Rev. 2018;45:53–61.

    CAS  PubMed  Google Scholar 

  48. Cardoso SM, Empadinhas N. The microbiome-mitochondria dance in prodromal Parkinson’s Disease. Front Physiol. 2018;9:471.

    PubMed  PubMed Central  Google Scholar 

  49. Bischoff SC, Barbara G, Buurman W, Ockhuizen T, Schulzke JD, Serino M, et al. Intestinal permeability–a new target for disease prevention and therapy. BMC Gastroenterol. 2014;14:189.

    PubMed  PubMed Central  Google Scholar 

  50. Ploger S, Stumpff F, Penner GB, Schulzke JD, Gabel G, Martens H, et al. Microbial butyrate and its role for barrier function in the gastrointestinal tract. Ann N Y Acad Sci. 2012;1258:52–59.

    PubMed  Google Scholar 

  51. Wu Z, Xia Y, Wang Z, Su Kang S, Lei K, Liu X, et al. C/EBPbeta/delta-secretase signaling mediates Parkinson’s disease pathogenesis via regulating transcription and proteolytic cleavage of alpha-synuclein and MAOB. Mol Psychiatry. 2021;26:568–85.

    CAS  PubMed  Google Scholar 

  52. Chen ZJ, Liang CY, Yang LQ, Ren SM, Xia YM, Cui L, et al. Association of Parkinson’s Disease with microbes and microbiological therapy. Front Cell Infect Microbiol. 2021;11:619354.

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Alam A, Leoni G, Quiros M, Wu H, Desai C, Nishio H, et al. The microenvironment of injured murine gut elicits a local pro-restitutive microbiota. Nat Microbiol. 2016;1:15021.

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This study was supported in part by the Emory Gnotobiotic Animal (EGAC), which is subsidized by the Emory University School of Medicine and is one of the Emory Integrated Core Facilities. Additional support was provided by the Rodent Behavioral Core (RBC), which is subsidized by the Emory University School of Medicine and is one of the Emory Integrated Core Facilities; the Emory Integrated Genomics Core (EIGC), which is subsidized by the Emory University School of Medicine and is one of the Emory Integrated Core Facilities; as well as Emory HPLC Bioanalytical Core (EHBC), which was supported by the Department of Pharmacology, Emory University School of Medicine. Drs. Zhi-Dong Jiang and Herbert L. Dupont from University of Texas School of Public Health and Medical School, Baylor St. Luke’s Medical Center, Baylor College of Medicine, Houston, TX, USA provided PD and age-matched HC fecal samples.

Funding

This work was supported by a grant from the National Institute of Health (R01, AG065177) to SSK. Additional support was provided by the Georgia Clinical & Translational Science Alliance of the National Institutes of Health under Award Number UL1TR002378 and by Basic Science Research Program through the National Research Foundation of Korea (NRF), which is funded by the Ministry of Education (2021R1F1A1063591).

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Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, 30322, USA

    Eun Hee Ahn, Xia Liu, Seong Su Kang & Keqiang Ye

  2. Department of Physiology, College of Medicine, Hallym University, Hallymdaehak-gil, Chuncheon-si, Gangwon-Do, 24252, South Korea

    Eun Hee Ahn

  3. Microbiology, Immunology & Molecular Genetics, University of Kentucky, Office - MN 376, Medical Science Building, 800 Rose Street, Lexington, KY, USA

    Ashfaqul M. Alam

  4. Faculty of Life and Health Sciences, Shenzhen Institute of Advanced Technology, Shenzhen, 518055, Guangdong, China

    Keqiang Ye

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Contributions

KY conceived the project, designed the experiments, analyzed the data and wrote the manuscript. EHA, SSK and AMA designed and performed most of the experiments and analyzed the data. XL conducted genotype and breed the transgenic mice. AMA assisted with data analysis and interpretation and critically read the manuscript.

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Correspondence to Seong Su Kang or Keqiang Ye.

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The experimental protocol was approved by the Emory University Institutional Animal Care and Ethical Committee.

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Ahn, E.H., Liu, X., Alam, A.M. et al. Helicobacter hepaticus augmentation triggers Dopaminergic degeneration and motor disorders in mice with Parkinson’s disease. Mol Psychiatry 28, 1337–1350 (2023). https://doi.org/10.1038/s41380-022-01910-2

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