. Snc, origine des signes moteurs. Toutefois, il est désormais clairement établi que les lésions de la maladie de Parkinson ne se limitent pas au système nerveux central mais qu'elles touchent aussi des systèmes nerveux périphériques

, Unité Inserm 913 du centre d'investigation clinique et du CHU de Nantes, ont réalisé des biopsies intestinales sur des patients parkinsoniens. Après avoir identifié les neurones entériques par immuno-marquage, ces biopsies ont révélé des lésions typiques de la maladie, équivalentes à celles retrouvées dans le SNC. En effet, des agrégats d'alpha-synucléine, agent responsable de la dégénérescence neuronale sont présents dans les plexus myentérique et sous-muqueux du SNE, Afin d'analyser les neurones entériques, des gastro-entérologues et leurs collaborateurs de l

, A. marquage permettant le comptage du nombre de neurones et l'identification des prolongements B : identification des inclusions pathologiques (neurites de Lewy) dans certains prolongements identifiés par le marquage des neurofilaments. Echelle 30 µM, Immunomarquage du plexus sous-muqueux prélevé à partir de biopsies coliques

. Manuel-d'anatomie and . De-physiologie-humaines, , vol.19

K. Umeda, T. Matsui, and M. Nakayama, Establishment and characterization of cultured epithelial cells lacking expression of ZO-1, J Biol Chem, vol.279, pp.44785-44794, 2004.

S. Tsukita and M. Furuse, Pores in the wall: claudins constitute tight junction strands containing aqueous pores, J Cell Biol, vol.149, pp.13-16, 2000.

M. G. Laukoetter, P. Nava, and W. Y. Lee, JAM-A regulates permeability and inflammation in the intestine in vivo, J Exp Med, vol.204, pp.3067-3076, 2007.

C. L. Bevins and N. H. Salzman, Panethcells, antimicrobial peptides and maintenance of intestinal homeostasis, Nat Rev Microbiol, vol.9, pp.356-368, 2011.

M. Ramasundara, S. T. Leach, D. A. Lemberg, and A. S. Day, Defensins and inflammation : the role of defensins in inflammatory bowel disease, J Gastroenterol Hepatol, vol.24, pp.202-208, 2009.

T. Ganz, Defensins: antimicrobial peptides of innate immunity, Nat Rev Immunol, vol.3, pp.710-720, 2003.

L. Elesevier-masson--octobre, Chapitre 10 « motricité digestive, 2014.

&. Neurone and . Neurosciences, Anatomie du systeme nerveux enterique novembre, vol.3, 2010.

L. ,

L. ,

C. Cherbuy, M. Thomas, and P. Langella, « Le microbiote intestinal : une composante santé qui évolue avec l'âge. » -Innovations agronomiques 33, pp.37-46, 2013.

«. Flore-microbienne-intestinale,

B. De-rambaud-jean-claude and . Jean-paul, Corthier Gérard -Chapitre « établissement et composition

. Xx, . Li, ;. Yanpin, . Yang, ;. Haiming et al., Effects of dietary fiber levels on cecal microbiota composition in geese, 2018.

L. Yurkovetskiy, M. Burrows, A. A. Khan, and L. Graham, Gender bias in autoimmunity is influenced by microbiota, Immunity, vol.39, issue.2, pp.400-412, 2013.

O. Koren, J. K. Goodrich, and T. C. Cullender, Host remodeling of the gut microbiome and metabolic changes during pregnancy, Cell, issue.150, 2012.

S. Panda, El khader I 1 , Casellas F 2 and al. Short-term effect of antibiotics on human gut microbiota, 2014.

. Veiga-p-1, C. Juste, and P. Lepercq, Correlation between faecal microbial community structure and cholesterol-to-coprostanol conversion in the human gut, FEMS Microbiology Letters, vol.242, issue.1, pp.81-87, 2005.

. Manuel-d'anatomie and . De-physiologie-humaines, , vol.9

, Fabielle Angel et michel Neunlist, Neurones intrinsèques de l'intestin : de la structure à la fonction, pp.1-5, 1995.

, Medecine / sciences : Sensibilité viscérale digestive, pp.1107-1122, 1994.

. The, . England, T. Of-medecine, . Enteric-nervous, R. K. System et al., , pp.1106-1114, 1996.

J. B. Furness, The organisation of the autonomic nervous system: peripheral connections. Autonomic Neurosciences, Basic and Clinical, vol.125, pp.81-85, 2006.

, Neurones intrinsèques de l'intestin : de la structure à la fonction, vol.3, 1996.

M. B. Hansen, The enteric nervous system I: organisation and classification, Pharmacology & Toxicology, vol.92, issue.3, pp.105-113, 2003.

J. N. Langley and R. Magnus, Some observations of the movements of the intestine before and after degenerative section of the mesenteric nerves, J. Physiol, vol.33, pp.34-51, 1905.

D. Grundy, Fundamentals of neurogastroenterology: basic science, Gastroenterology, vol.130, issue.5, pp.1391-411, 2006.

T. Unit--michel, N. Et-malvyne, and R. ,

N. M. Le-douarin, E. Dupin, and C. Ziller, Genetic and epigenetic control in neural crest development, Curr Opin Genet Dev, vol.4, pp.685-95, 1994.

, Society For Neuroscience, vol.7, 2013.

M. Kim, Y. Qie, J. Park, and C. H. Kim, Gut microbial metabolites fuel host antibody responses, Cell Host Microbe, vol.20, pp.202-214, 2016.

C. Landman-ab and E. , Quévrain a , Gut microbiota: Description, role and pathophysiologic implications La Revue de Médecine Interne, vol.37, pp.418-423, 2016.

Y. K. Mao, D. L. Kasper, B. Wang, P. Forsythe, J. Bienenstock et al., Bacteroides fragilis polysaccharide A is necessary and sufficient for acute activation of intestinal sensory neurons, Nat Common, vol.4, 2013.

. Clayburgh-dr-1, T. A. Barrett, Y. Tang, J. B. Meddings, L. J. Van-eldik et al., « Epithelial myosin light chain kinase-dependent barrier dysfunction mediates T cell activation-induced diarrhea in vivo, J Clin Invest, vol.115, issue.10, pp.2702-2717, 2005.

J. R. Turner and A. , PKC-dependent regulation of transepithelial resistance : roles of MLC and MCL kinase, Am J physiol, vol.277, pp.554-562, 1999.

C. R. Weber and R. , Epithelial myosin light chain kinase activation induces mucosal interleukin-13 expression to alter tight junction ion selectivity. », J Biol Chem, vol.285, pp.12037-12046, 2010.

M. Bruewer, M. Utech, A. I. Ivanov, A. M. Hopkins, C. A. Parkos et al., Interferon-? induces internalization of epithelial tight junction proteins via a macropinocytosis-like process, FASEB J, vol.19, pp.923-933, 2005.

D. Scheuner, Secreted amyloid beta-protein similar to that in the senile plaques of Alzheimer's disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease, Nat Med, vol.2, issue.8, pp.864-70, 1996.

G. T. Bramblett, M. Goedert, R. Jakes, S. E. Merrick, J. Q. Trojanowski et al., Abnormal tau phosphorylation at Ser396 in Alzheimer's disease recapitulates development and contributes to reduced microtubule binding, Neuron, vol.10, issue.6, pp.1089-99, 1993.

S. W. Scheff, Alzheimer's disease-related synapse loss in the cingulate cortex, J Alzheimers Dis, vol.3, issue.5, pp.495-505, 2001.

R. Cacabelos, L. Fernandez-novoa, V. Lombardi, Y. Kubota, and M. Takeda, Molecular genetics of Alzheimer's disease and aging, Methods Find Exp Clin Pharmacol, 2005.

C. Smith, J. Carney, and S. , Excess brain protein oxidation and enzyme dysfunction in normal aging and in Alzheimer disease, Proc Natl Acad Sci USA, vol.88, issue.23, pp.10540-10543, 1991.

V. H. Cornejo and C. Hetz, The unfolded protein response in Alzheimer's disease, Seminars in Immunopathology, vol.35, p.277, 2013.

R. S. Stowers, L. J. Megeath, and J. Gorska-andrzejak, Axonal transport of mitochondria to synapses depends on milton, a novel Drosophila protein, Neuron, vol.19, pp.1063-77, 2002.

P. T. Francis, Glutamatergic systems in Alzheimer's disease, Int J Geriatr Psychiatry, vol.18, pp.15-21, 2003.

M. R. Hynd, H. L. Scott, and P. R. Dodd, Glutamate-mediated exci-totoxicity and neurodegeneration in Alzheimer's disease, Neurochem Int, vol.45, pp.583-95, 2004.

E. M. Snyder, Y. Nong, and C. G. Almeida, Regulation of NMDA receptor traf cking by amyloid-beta, Nat Neurosci, vol.8, pp.1051-1059, 2005.

J. A. Luchsinger, Adiposity, hyperinsulinemia, dia-betes and Alzheimer's disease: an epidemiological perspective, Eur J Pharmacol, vol.585, pp.119-148, 2008.

D. Cao, H. Lu, and T. L. Lewis, Intake of sucrose-sweetened water induces insulin resistance and exacerbates memory deficits and amyloidosis in a transgenic mouse model of Alzheimer disease, J Biol Chem, vol.282, pp.36275-82, 2007.

C. Amouyal and F. Andreelli, Insulinorésistance et maladie d'Alzheimer -Médecine des maladies métaboliques -septembre, vol.3, pp.393-396, 2009.

, Service de diabétologie-endocrinologie-nutrition

M. M. Breteler, Vascular involvement in cognitive decline and dementia. Epidemiologic evidence from the Rotterdam Study and the Rotterdam Scan Study, Ann. N. Y. Acad. Sci, vol.903, pp.457-465, 2000.

W. G. Honer, I. Prohovnik, G. Smith, and L. R. Lucas, Scopolamine reduces frontal cortex perfusion, J. Cereb. Blood Flow Metab, vol.8, issue.5, pp.635-641, 1988.

R. Ehehalt, P. Keller, C. Haass, C. Thiele, and K. Simons, Amyloidogenic processing of the Alzheimer beta-amyloid precursor protein depends on lipid rafts, J Cell Biol, vol.160, pp.113-136, 2003.

N. Zilka, Z. Kazmerova, and S. Jadhav, Who fans the flames of Alzheimer's disease brains? Misfolded tau on the crossroad of neurodegenerative and inflammatory pathways, J Neuroinflammation, vol.9, p.47, 2012.

J. Tse, Gut microbiota, nitric oxide, and microglia as prerequisites for neurodegenerative disorders, 2017.

C. Roubaud-baudron and P. Krolak-salmon, Impact of chronic Helicobacter pylori infection on Alzheimer's disease: preliminary results » 2012 -Neurobiol Aging, vol.33, pp.1009-1011, 2012.

V. Braniste, M. Al-asmakh, C. Kowal, F. Anuar, A. Abbaspour et al., The gut microbiota influences blood-brain barrier permeability in mice, Sci. Transl. Med, vol.6, issue.263, pp.263-158, 2014.

D. Erny, A. L. Hrab?-de-angelis, and D. Jaitin, Host microbiota constantly control maturation and function of microglia in the CNS » -Nat Neurosci, vol.18, pp.965-977, 2015.

, Calsolaro V 1 , Edison P 2 « Neuroinflammation in Alzheimer's disease: Current evidence and future directions » -Alzheimers Dement, vol.12, pp.719-751, 2016.

E. Barrett, R. P. Ross, P. W. O'toole, G. F. Fitzgerald, and C. Stanton, Gamma-Aminobutyric acid production by culturable bacteria from the human intestine, J Appl Microbiol, vol.113, pp.411-418, 2012.

M. Lyte, Probiotics function mechanistically as delivery vehicles for neuroactive compounds: microbial endocrinology in the design and use of probiotics, Bioessays, vol.33, pp.574-81, 2011.

L. Möhle, Ly6C hi Monocytes Provide a Link between Antibiotic-Induced Changes in Gut Microbiota and Adult Hippocampal Neurogenesis -Cell Rep, vol.15, pp.1945-1956, 2016.

E. E. Fröhlich-a and A. , Cognitive impairment by antibiotic-induced gut dysbiosis: Analysis of gut microbiota-brain communication, Brain, Behavior, and Immunity, vol.56, pp.140-155, 2016.

, Serge Rivest « TREM2 enables amyloid ? clearance by microglia » -Cell Res, vol.25, pp.535-536, 2015.

H. Zheng, C. Liu, and Y. Atagi, Opposing Roles of the Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) and TREM-like Transcript 2 (TREML2) in Microglia Activation » -Neurobiol Aging, vol.42, pp.132-141, 2016.

. Thirumangalakudi-l-1, A. Prakasam, and R. Zhang, « High cholesterol-induced neuroinflammation and amyloid precursor protein processing correlate with loss of working memory in mice. » -J Neurochem, vol.106, pp.475-85, 2008.

M. Blaut, Relationship of prebiotics and food to intestinal microflora, Eur J Nutr, vol.41, issue.1, pp.11-16, 2002.

P. D. Cani, A. M. Neyrinck, and F. Fava, Selective increases of bifidobacteria in gut microflora improve high-fat-diet-induced diabetes in mice through a mechanism associated with endotoxaemia, Diabetologia, vol.50, pp.2374-83, 2007.

P. Cani, R. Bibiloni, and K. Knauf, Changes in gut microbiota control metabolic endotoxemiainduced inflammation in high-fat diet-induced obesity and diabetes in mice, Diabetes, 2008.
URL : https://hal.archives-ouvertes.fr/inserm-00410066

P. Jørgensen, « A Possible Link between Food and Mood: Dietary Impact on Gut Microbiota and Behavior in BALB/c Mice, 2014.

S. Yehuda, S. Rabinovitz, D. I. Mostofsky, and D. I. , Essential fatty acids are mediators of brain biochemistry and cognitive functions, J Neurosci Res, vol.56, pp.565-570, 1999.

S. Yoshida, Synaptic vesicle ultrastructural changes in the rat hippocampus induced by a combination of alpha-linolenate deficiency and a learning task, J Neurochem, vol.68, pp.1261-1268, 1997.

S. Yoshida, A. Sato, and H. Okuyama, Pathophysiological effects of dietary essential fatty acid balance on neural systems, Jpn J Pharmacol, vol.77, pp.11-22, 1998.

S. Laye, Polyunsaturated fatty acids, neuroinflammation and well being, Prostaglandins Leukot Essent Fatty Acids, vol.82, pp.295-303, 2010.

C. Kuratko, E. Barrett, E. Nelson, and N. Salem, The Relationship of Docosahexaenoic Acid (DHA) with Learning and Behavior in Healthy Children: A Review, Nutrients, vol.5, pp.2777-2810, 2013.

J. C. Mccann and B. N. Ames, Is docosahexaenoic acid, an n-3 long-chain polyunsaturated fatty acid, required for development of normal brain function? An overview of evidence from cognitive and behavioral tests in humans and animals, Am. J. Clin. Nutr, vol.82, pp.281-295, 2005.

G. Hussain and F. Schmitt, Fatting the brain: a brief of recent research, Front Cell Neurosci, vol.7, p.144, 2013.

Z. Amtul, M. Uhrig, and R. F. Rozmahel, Beyreuther K. « Structural insight into the differential effects of omega-3 and omega-6 fatty acids on the production of Abeta peptides and amyloid plaques, J. Biol. Chem, vol.286, pp.6100-6107, 2011.

R. Molteni, R. J. Barnard, and Z. Ying, A high-fat, refined sugar diet reduces hippocampal brainderived neurotrophic factor, neuronal plasticity, and learning, Neuroscience, vol.112, issue.4, pp.803-817, 2002.

K. S. Krabbe, A. R. Nielsen, and R. Krogh-madsen, Brain-derived neurotrophic factor (BDNF) and type 2 diabetes. Diabetologia, vol.50, pp.431-439, 2006.

D. Wang, Role of intestinal microbiota in the generation of polyphenol-derived phenolic acid mediated attenuation of Alzheimer's disease ?-amyloid oligomerization, Mol Nutr Food Res, vol.59, issue.6, pp.1025-1065, 2015.

R. Carratu and M. , Are Retinoids a Promise for Alzheimer's Disease Management?, Current Medicinal Chemistry, vol.19, issue.7, pp.6119-6125, 2012.

. Moreira, Lipoic acid and N-acetyl cysteine decrease mitochondrial-related oxidative stress in Alzheimer disease patient fibroblasts, J. Alzheimers Dis, vol.12, pp.195-206, 2007.

P. I. Moreira, Mitochondria: a therapeutic target in neurodegeneration, Biochim. Biophys. Acta, vol.1802, pp.212-220, 2010.
URL : https://hal.archives-ouvertes.fr/hal-00562943

L. Quadro, M. V. Gamble, and S. Vogel, Retinol and retinol-binding protein : gut integrity and circulating immunoglobulins, J Infect Dis, vol.182, issue.1, pp.97-102, 2000.

K. Touyarot, D. Bonhomme, P. Roux, S. Alfos, P. Lafenetre et al., A midlife vitamin A supplementation prevents age-related spatial memory deficits and hippocampal neurogenesis alterations through CRABP-I, PLoS ONE, vol.8, 2013.

A. Finamore, M. Massimi, D. L. Conti, and E. Mengheri, Zinc deficiency induces membrane barrier damage and increases neutrophil trans-migration in Caco-2 cells, J Nutr, vol.138, issue.9, pp.1664-1670, 2008.

G. Guerrier, C. Veysseyre, A. Nourian, D. Graveriau, and R. Carron, Inhibition in vitro par le gluconate de zinc de la dégranulation des basophiles humains sensibilisés au pollen des graminées, Rev Fr Allergol, vol.27, issue.1, pp.1-5, 1987.

L. Zuo and M. S. Motherwell, The impact of reactive oxygen species and genetic mitochondrial mutations in Parkinson's disease, Gene, vol.532, pp.18-23, 2013.

J. Trinh and M. Farrer, Advances in the genetics of Parkinson disease, Nat Rev Neurol, vol.9, pp.445-54, 2013.

I. Baldi, S. Cordier, X. Coumoul, A. Elbaz, L. Gamet-payrastre et al., Pesticides, effets sur la santé. Expertise collec-tive. Synthèse et recommandations, 2013.

J. R. Richardson, Y. Quan, T. B. Sherer, J. T. Greenamyre, and G. W. Miller, Paraquat neurotoxicity is distinct from that of MPTP and rote-none, Toxicol Sci, vol.88, pp.193-201, 2005.

P. Foley and P. Riederer, Influence of neurotoxins and oxidative stress on the onset and progression of Parkinson's disease, J Neurol, vol.247, pp.82-94, 2000.

S. Bharath, M. Hsu, D. Kaur, S. Rajagopalan, and J. K. Andersen, Glu-tathione, iron and Parkinson's disease, Biochem Pharmacol, vol.64, pp.1037-1085, 2002.

, Systemic exposure to paraquat and maneb models early Parkinson's disease in young adult rats Francesca Cicchetti, Nicolas Lapointe, Neurobiology of Disease, vol.20, pp.360-371, 2005.

J. Kawamata and S. Shimohama, Stimulating nicotinic receptors trigger multiple pathways attenuating cytotoxicity in models of Alzheimer's and Parkinson's diseases, J Alzheimers Dis, vol.24, pp.95-109, 2011.

J. W. Langston, P. Ballard, J. W. Tetrud, and I. Irwin, Chronic Parkinsonism in humans due to a product of meperidine-analog synthesis, Science, vol.219, pp.979-80, 1983.

T. Chanyachukul, K. Yoovathaworn, W. Thongsaard, S. Chong-thammakun, P. Navasumrit et al., Attenuation of paraquat-induced motor behavior and neurochemical disturbances by Lvaline in vivo, Toxicol Lett, vol.150, pp.259-69, 2004.

A. L. Mccormack, D. Monte, and D. A. , Effects of L-dopa and other amino acids against paraquatinduced nigrostriatal degeneration, J Neurochem, vol.85, pp.82-88, 2003.

R. J. Dinis-oliveira, J. A. Duarte, A. Sanchez-navarro, F. Remiao, M. L. Bastos et al., Paraquat poisonings: mechanisms of lung toxicity, clinical features, and treatment, Crit Rev Toxicol, vol.38, pp.13-71, 2008.

A. Moretto and C. Colosio, The role of pesticide exposure in the genesis of Parkinson's disease: epidemiological studies and experimental data, Toxicology, vol.307, pp.24-34, 2013.

L. H. Sanders, T. Greenamyre, and J. , Oxidative damage to macromolecules in human Parkinson disease and the rotenone model, Free Radic Biol Med, vol.62, pp.111-131, 2013.

. Pan-montojo-f-1, M. Schwarz, C. Winkler, and M. Arnhold, Environmental toxins trigger PDlike progression via increased alpha-synuclein release from enteric neurons in mice, » Sci Rep, vol.2, p.898, 2012.

. Holmqvist-s-1, « Direct evidence of Parkinson pathology spread from the gastrointestinal tract to the brain in rats, Acta Neuropathol, vol.128, issue.6, pp.805-825, 2014.

A. G. Kanthasamy, M. Kitazawa, A. Kanthasamy, and V. Anantharam, Dieldrin-induced neurotoxicity: relevance to Parkinson's disease pathogenesis, Neurotoxicology, vol.26, pp.701-720, 2005.

V. Felice, E. Quigley, A. Sullivan, G. O'keeffe, O. 'mahony et al., Microbiota-gut-brain signalling in Parkinson's disease: Implications for non-motor symptoms, 2016.

T. Lebouvier, M. Neunlist, S. Bruley, E. Varannes, A. Coron et al., Philippe Damier and Pascal Derkinderen -Colonic biopsies to assess the neuropathology of Parkinson's disease and its relationship with symptoms -Plos One, 2010.

S. M. Dobbs and R. J. Dobbs, « Peripheral aetiopathogenic drivers and mediators of Parkinson's disease and co-morbidities: role of gastrointestinal microbiot, J Neurovirol, vol.22, pp.22-32, 2016.