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1、Brain-gut-microbiota axis in Parkinsons diseaseAgata Mulak,Bruno BonazAgata Mulak,Department of Gastroenterology and Hepatology,Wroclaw Medical University,50-556 Wroclaw,PolandBruno Bonaz,Grenoble Institut des Neurosciences(GIN),INSERM U836,38043 Grenoble,France Bruno Bonaz,Clinique Universitaire dH

2、pato-Gastroentrologie,CHU de Grenoble,38043 Grenoble,France Author contributions:Mulak A designed and wrote the paper;Bonaz B designed,wrote and reviewed the paper.Conflict-of-interest statement:There is no conflict of interest.Open-Access:This article is an open-access article which was selected by

3、 an in-house editor and fully peer-reviewed by external reviewers.It is distributed in accordance with the Creative Commons Attribution Non Commercial(CC BY-NC 4.0)license,which permits others to distribute,remix,adapt,build upon this work non-commercially,and license their derivative works on diffe

4、rent terms,provided the original work is properly cited and the use is non-commercial.See:http:/creativecommons.org/licenses/by-nc/4.0/Correspondence to:Agata Mulak,MD,PhD,Department of Gastroenterology and Hepatology,Wroclaw Medical University,Borowska 213,50-556 Wroclaw,Poland.agata.mulakwp.plTele

5、phone:+48-71-7332120 Fax:+48-71-7332129Received:March 2,2015Peer-review started:March 3,2015First decision:May 18,2015Revised:May 28,2015Accepted:August 31,2015 Article in press:August 31,2015Published online:October 7,2015 AbstractParkinsons disease(PD)is characterized by alpha-synucleinopathy that

6、 affects all levels of the brain-gut axis including the central,autonomic,and enteric nervous systems.Recently,it has been recognized that the brain-gut axis interactions are significantly modulated by the gut microbiota via immunological,neuroendocrine,and direct neural mechanisms.Dys-regulation of

7、 the brain-gut-microbiota axis in PD may be associated with gastrointestinal manifestations frequently preceding motor symptoms,as well as with the pathogenesis of PD itself,supporting the hypothesis that the pathological process is spread from the gut to the brain.Excessive stimulation of the innat

8、e immune system resulting from gut dysbiosis and/or small in-testinal bacterial overgrowth and increased intestinal permeability may induce systemic inflammation,while activation of enteric neurons and enteric glial cells may contribute to the initiation of alpha-synuclein misfolding.Additionally,th

9、e adaptive immune system may be disturbed by bacterial proteins cross-reacting with human antigens.A better understanding of the brain-gut-microbiota axis interactions should bring a new insight in the pathophysiology of PD and permit an earlier diagnosis with a focus on peripheral biomarkers within

10、 the enteric nervous system.Novel therapeutic options aimed at modifying the gut microbiota composition and enhancing the intestinal epithelial barrier integrity in PD patients could influence the initial step of the following cascade of neurodegeneration in PD.Key words:Brain-gut-microbiota axis;En

11、teric nervous system;Gastrointestinal dysfunction;Gut microbiota;Parkinsons disease The Author(s)2015.Published by Baishideng Publishing Group Inc.All rights reserved.Core tip:Parkinsons disease(PD)is characterized by alpha-synucleinopathy affecting all levels of the brain-gut axis.Both clinical and

12、 neuropathological evidences indicate that neurodegenerative changes in PD are accompanied by gastrointestinal symptoms that may precede or follow the central nervous system impairment.Dysregulation of the brain-gut-microbiota axis may significantly contribute to the pathogenesis of PD.The gut seems

13、 to play a critical role in the pathophysiology of PD representing a rout of entry for a putative environmental factor to initiate the pathological REVIEWSubmit a Manuscript:http:/ Desk:http:/ 7,2015|Volume 21|Issue 37|WJG|World J Gastroenterol 2015 October 7;21(37):10609-10620 ISSN 1007-9327(print)

14、ISSN 2219-2840(online)2015 Baishideng Publishing Group Inc.All rights reserved.process.The close relationship between gut dysbiosis,intestinal permeability and neurological dysfunction suggests that the gut microbiota modification may provide a promising therapeutic option in PD.Mulak A,Bonaz B.Brai

15、n-gut-microbiota axis in Parkinsons disease.World J Gastroenterol 2015;21(37):10609-10620 Available from:URL:http:/ DOI:http:/dx.doi.org/10.3748/wjg.v21.i37.10609INTRODUCTIONParkinsons disease(PD)is a multicentric neurodegenerative disorder characterized by the accumulation and aggregation of alfasy

16、nuclein(syn)in the substantia nigra in the central nervous system(CNS)and in other neural structures1,2.The classical motor symptoms like bradykinesia,resting tremor,rigidity and late postural instability result from the death of dopaminegenerating cells in the substantia nigra.There is also a wide

17、spectrum of nonmotor manifestations involving for example olfactory(loss of smell),gastrointestinal(GI),cardiovascular,and urogenital systems3.It has become evident that the different levels of the braingut axis including the autonomic nervous system(ANS)and the enteric nervous system(ENS)may be aff

18、ected in PD48.Recently,it has been also recognized that the braingut axis interactions may be essentially influenced by the gut microbiota912.On the one hand,dysregulation of the braingutmicrobiota axis in PD may result in GI dysfunction,which is present in over 80%of PD subjects13.On the other hand

19、,this dysregulation may also significantly contribute to the pathogenesis of PD itself,supporting the hypothesis that the pathological process is spread from the gut to the brain4,7.INTERACTIONS WITHIN THE BRAIN-GUT-MICROBIOTA AXISBidirectional communication between the CNS and the GI tract the brai

20、ngut axis occurs both in health and disease.The neural network for the control of GI functions involves the intrinsic and extrinsic nervous systems and forms a hierarchic fourlevel integrative organization14,15.The first level is the ENS represented by neurons of the myenteric(Auerbachs)and submucos

21、al(Meissners)plexi and enteric glial cells(EGCs)16.Local reflexes,such as the migrating motor complex and peristaltic reflex,are under the ENS control through intrinsic primary afferent neurons(IPANs).The IPANs,located in the myenteric and submucosal plexi,project dentritic processes that synapse wi

22、th motor neurons and interneurons.The primary excitatory enteric motor neurons and interneurons are cholinergic.Neurons expressing VIP and/or NO elicit smooth muscle relaxation,and submucosal VIP neurons also stimulate intestinal secretion17.Enteric dopaminergic neurons,which may inhibit intestinal

23、motility,are also present and distributed along an oralaboral gradient within the GI tract17.Dopaminergic neurons account for 14%20%of the enteric neurons of the upper GI tract,whereas their proportion decreases to 1%6%in the lower small intestine and large bowel17.The second level is the prevertebr

24、al ganglia modulating many peripheral visceral reflex responses18.The third level is the ANS within the spinal cord origin of the sympathetic(T5L2)and sacral(S2S4)parasympathetic nervous systems and the brainstem with the nucleus tractus solitarius(NTS)and dorsal motor nucleus of the vagus nerve(DMV

25、N),which receives and gives origin to the afferent and efferent fibers of the vagus nerve(VN),respectively.The DMVN influence is most prominent in the upper GI tract,where cholinergic myenteric neurons mediate vagal excitatory effect,and VIP/NO neurons mediate inhibitory reflexes19.The fourth level

26、includes higher brain centers.Information from the cortical and subcortical centers,including the basal ganglia,funnels down to specific brainstem nuclei,from where many GI functions are controlled.Disturbances at every level of that neural control may affect modulation of the GI functions including

27、 mechanisms at the local enteric reflexes,and extrinsic neural control15.Recently,a role of the enteric microbiota,including both commensal and pathogenic organisms,in the braingut axis interactions has been essentially recognized10.This has been reflected by a revised nomenclature to the more inclu

28、sive braingutenteric microbiota axis9.The impact of the gut microflora on the braingut axis regulation involves immunological,neuroendocrine,and direct neural mechanisms12.The gut microbiota is known to upregulate local and systemic inflammation due to lipopolysaccharides(LPS)from pathogenic bacteri

29、a and synthesis of proinflammatory cytokines.Excessive stimulation of the innate immune system resulting from gut dysbiosis and/or small intestinal bacterial overgrowth and increased intestinal permeability may produce systemic and/or CNS inflammation20.Additionally,the adaptive immune system may be

30、 disturbed by bacterial proteins crossreacting with human antigens.The gut bacteria are able to synthesize numerous neurotransmitters and neuromodulators such as aminobutyric acid,serotonin,dopamine or shortchain fatty acids12,21.The production of these neurochemicals enables also intracellular comm

31、unication between the members of the microbiota.Therefore,the existence of socalled“microbial organ-specific nervous system”could be even speculated21.Bacterial enzymes may also produce neurotoxic metabolites such as Dlactic acid and ammonia20.The direct neural communication between the gut and the

32、brain occurs via the VN,10610October 7,2015|Volume 21|Issue 37|WJG|Mulak A et al.Brain-gut-microbiota axis in PDas bacteria can stimulate afferent neurons of the ENS22.Vagal signals from the gut can evoke an antiinflammatory response protecting against microbialinduced sepsis in a nicotinic acetylch

33、oline receptor 7 subunitdependent manner.Many of the effects of the gut microbiota or potential probiotics on brain function have been shown to be dependent on vagal activation10,11,22.Furthermore,bacterial colonization of the gut plays a major role in the postnatal development and maturation of the

34、 immune,endocrine and even neural systems23.These processes are key factors underpinning CNS signaling.Dysfunction of the braingutmicrobiota axis has been implicated in stressrelated disorders such as depression,anxiety,irritable bowel syndrome,and inflammatory bowel disease,as well as neurodevelopm

35、ental disorders such as autism12,2326.GASTROINTESTINAL DYSFUNCTION IN PARKINSONS DISEASEAmong many causes of parkinsonism,including multiple system atrophy,progressive supranuclear palsy or corticobasal degeneration,GI symptoms have been best characterized in the classical PD13.In the study of Edwar

36、ds et al27 evaluating the frequency of various GI symptoms in 98 patients with PD,abnormal salivation,dysphagia,nausea,constipation and defecatory dysfunction were present in 70%,52%,24%,29%,and 66%of subjects,respectively.Among the studied parameters,only PD activity and duration correlated with GI

37、 dysfunction.No correlation was found between the GI symptoms and patients age,gender,antiparkinsonian treatment,level of activity or dietary fiber intake27.Hypersalivation typical in PD results not from salivary hypersecretion(in fact saliva production is even diminished),but from decreased swallow

38、ing frequency.Swallowing dysfunction may be symptomatic in up to 50%of PD patients28.Apart from common oropharyngeal dysfunction described in videofluoroscopy in more than 85%of PD cases,significant dysfunction in either the esophageal body or lower esophageal sphincter has been also revealed in 61%

39、73%of patients during esophageal manometry2830.A serious complication of dysphagia in PD is an aspiration pneumonia occuring with a frequency ranging from 15%to 56%31.Impaired gastric emptying is an important manifestation of PD and is characterized by symptoms such as postprandial bloating or abdom

40、inal discomfort,early satiety and nausea.In patients with both early and advanced PD electrogastrography has confirmed gastric motility abnormalities32.Reduced amplitude of stomach contractions in PD can be also detected using realtime magnetic resonance imaging33.However,symptoms of the upper GI dy

41、sfunction do not always correlate with objective measurements of gastroparesis34.Delayed gastric emptying may also have potentially relevant pharmacokinetic implication causing an impaired absorption of Ldopa and thus worsening motor fluctuations35.In addition,PD has been associated with a higher pr

42、evalence of ulcer disease and Helicobacter pylori infection36.Uncomfortable sensation of abdominal bloating experienced by some individuals with PD,especially as an“off”phenomenon,could be the consequence of small bowel dysmotility shown by manometry37.Moreover,observed dysmotility may predispose fo

43、r small intestinal bacterial overgrowth(SIBO),the prevalence of which is increased in PD patients38.Constipation,the most prominent GI dysfunction of PD,seems to be an early manifestation of the disease process itself6,13,37,3941.Increased colon transit time has been recorded in both treated and unt

44、reated subjects,and even in PD patients without symptomatic constipation42.In sever cases it may lead to megacolon43.Interestingly,a retrospective analysis exploring the association between the frequency of bowel movements and further risk for PD revealed an increased risk of PD in men with infreque

45、nt bowel movements44.Defecatory dysfunction characterized by excessive straining and incomplete evacuation are another common and distressing problems in PD45,46.Pelvic floor dyssynergia in PD has been confirmed using anorectal manometry,defecography,and anal sphincter electromyography in more than

46、65%of patients27,42,47.PATHOPHYSIOLOGY OF GASTROINTESTINAL DYSFUNCTION IN PARKINSONS DISEASEThe pathophysiology of GI dysfunction in PD may reflect both central and peripheral derangements.While dopaminergic deficiency secondary to nigrostriatal damage may be responsible for some aspects of GI sympt

47、oms in PD,it is quite clear that the additional sites of involvement play an important role as well13.The lesions of the medullar,spinal and peripheral autonomic nervous system present in PD could be sufficient to induce GI disturbances48,49.The involvement of the basal ganglia,the central pattern g

48、enerator of swallowing,the DMVN,and the median raphe nucleus of the pons have been described in PD.Neurodegeneration and dysfunction of the locus ceruleus(LC)in PD has been also observed50.The LC is the major brain noradrenergic candidate for modulating the migrating motor complex(MMC)pattern and it

49、 has been shown that lesions of the LC in rats increase the duration of MMC51.The LC has close connections with the Barrington nucleus that sends descending projections to the sacral parasympathetic command of the distal colon and bladder functions52.Disturbances in the neural network involving the

50、LC and the frontal cortex,hippocampus,as well as the spinal cord may contribute 10611October 7,2015|Volume 21|Issue 37|WJG|Mulak A et al.Brain-gut-microbiota axis in PD10612October 7,2015|Volume 21|Issue 37|WJG|and/or peripheral mechanisms due to postganglionic lesions.Recent reports have shown that