人体生理学 (11).pdf

International Journal of Molecular SciencesReviewMicrobiome-Gut-Brain Axis and Toll-Like Receptorsin Parkinsons DiseaseValentina Caputi1,2and Maria Cecilia Giron1,*ID1Pharmacology Building,Department of Pharmaceutical and Pharmacological Sciences,University ofPadova,35131 Padova,Italy;valentina.caputiucc.ie2APC Microbiome Ireland,University College Cork,T12YT20 Cork,Ireland*Correspondence:cecilia.gironunipd.it;Tel.:+39-049-827-5091;Fax:+39-049-827-5093Received:3 May 2018;Accepted:3 June 2018;Published:6 June 2018?Abstract:Parkinsons disease(PD)is a progressively debilitating neurodegenerative diseasecharacterized by-synucleinopathy,which involves all districts of the brain-gut axis,includingthe central,autonomic and enteric nervous systems.The highly bidirectional communicationbetween the brain and the gut is markedly influenced by the microbiome through integratedimmunological,neuroendocrine and neurological processes.The gut microbiota and its relevantmetabolites interact with the host via a series of biochemical and functional inputs,thereby affectinghost homeostasis and health.Indeed,a dysregulated microbiota-gut-brain axis in PD might lie atthe basis of gastrointestinal dysfunctions which predominantly emerge many years prior to thediagnosis,corroborating the theory that the pathological process is spread from the gut to the brain.Toll-like receptors(TLRs)play a crucial role in innate immunity by recognizing conserved motifsprimarily found in microorganisms and a dysregulation in their signaling may be implicated in-synucleinopathy,such as PD.An overstimulation of the innate immune system due to gut dysbiosisand/or small intestinal bacterial overgrowth,together with higher intestinal barrier permeability,may provoke local and systemic inflammation as well as enteric neuroglial activation,ultimatelytriggering the development of alpha-synuclein pathology.In this review,we provide the currentknowledge regarding the relationship between the microbiota-gutbrain axis and TLRs in PD.A betterunderstanding of the dialogue sustained by the microbiota-gut-brain axis and innate immunity viaTLR signaling should bring interesting insights in the pathophysiology of PD and provide noveldietary and/or therapeutic measures aimed at shaping the gut microbiota composition,improvingthe intestinal epithelial barrier function and balancing the innate immune response in PD patients,in order to influence the early phases of the following neurodegenerative cascade.Keywords:enteric microbiota;brain-gut axis;Parkinsons disease;toll-like receptors;innateimmunity;central nervous system;enteric nervous system;gastrointestinal dysfunctions;probiotics;pharmacological treatment;-synuclein;gut dysbiosis;neurons;microglia;glial cells;intestinalbarrier permeability1.IntroductionParkinsons disease(PD)is acknowledged as the second most common neurodegenerativedisorder,estimated to affect 12 per 1000 of the population worldwide 1.About seven to tenmillion people in the world suffer from PD 2.This figure is expected to double in the near future,circa 2030,due to aging of the population 3.The etiology of PD still remains unclear.However,the slow progression of the disease evolves years before the diagnosis is ascertained,involving variousneuroanatomical areas,arising from an assortment of genetic and environmental factors,and exhibitinga large array of debilitating symptoms.From a histopathological perspective,PD is hallmarked byInt.J.Mol.Sci.2018,19,1689;doi:10.3390/ of 19a distinctive depauperation of dopaminergic neurons in the substantia nigra pars compacta(SNc)with consequent dopamine deficiency within the striatum and by the manifestation of intracellulareosinophilic inclusions,the so called Lewy bodies and Lewy neurites in the remaining neurons.Lewy pathology is characterized by intracellular insoluble aggregates of misfolded-synuclein andimplicates not only the brain but is also widespread in the spinal cord and peripheral nervous system,including sympathetic ganglia,enteric nervous system(ENS),salivary glands,adrenal medulla,vagusnerve,cutaneous nerves and the sciatic nerve 46.The progressive dopamine deficit in the basalganglia determines the characteristic parkinsonian triad of motor symptomsrigidity,bradykinesiaand tremor.However,other significant non-motor symptoms have been receiving increasing attentionfor the more negative impact in the quality of life of PD patients in comparison to motor symptoms.These non-motor symptomsinvolve neuropsychiatric disorders(e.g.,cognitive impairment,depression,apathy,psychosis),sleep disturbances,sensory alterations(pain,olfactory impairment),and thecommon gastrointestinal(GI)dysfunction reported by more than 80%of PD patients 7.The first-lineintervention in PD management is the administration of dopamine modulators even if they can exertserious side effects,produce limited benefits on alleviating non-motor disturbances and often fail to beeffective in the later stages of PD 68.In the last decade,emerging evidence has revealed the presence of an intense dialogue between thebrain and the GI system,the so-called brain-gut axis.Disruption of this complex relationship has beenshown to be associated to the pathogenesis of several disorders,ranging from irritable bowel syndrome(IBS),liver disease and chronic abdominal pain syndromes,to depression,anxiety,autism spectrumdisorders,dementia and PD.The brain-gut(or gut-brain axis)crosstalk can occur in a bidirectionalfashion:firstly,through a gut quiver on central nervous system(CNS)activities(e.g.,changes inmood,cognition or perception due to functional GI disorders 9,10,or subsequent to the release of guthormones 11,or following serious GI inflammatory diseases such as acute pancreatitis1214);secondly,through a central quiver on gut activities(e.g.,stress-induced GI dysfunction 15).Indeed,a common alignment of both brain and gut can be identified in neurobiological disorders(e.g.,neurodegeneration or gliosis)16.Traditionally,the brain-gut axis was viewed as a flux of information,mediated by neurohormonesand inflammatory factors,travelling between the central,autonomic and enteric nervous systems(CNS,ANS and ENS,respectively)with the concurrent participation of the neuroendocrine andneuroimmune systems.Several studies have focused on the role of the CNS in modulating the intestinal inflammationthrough both parts of the ANS,the sympathetic and parasympathetic nervous system 17,18.The inflammatory state of peripheral tissues is conveyed to the brain through afferent nerves which inturn suppress cytokine production,improve intestinal barrier integrity and limit gut inflammation 18.Recent studies performed in animal models of acute and chronic pancreatitis have shown that thestimulation of primary afferent capsaicin-sensitive neurons or treatment with peptides(e.g.,calcitoningene-related peptide)before the exposure to harmful factors,can activate an adaptive mechanismcalled“preconditioning”which is able to reduce pancreatitis development 1921.Sensory neurons areinvolved in gastroprotection and regulation of visceral blood flow and their stimulation by capsaicincan potentially inhibit the progression of inflammation,by improving the endogenous release of nitricoxide(NO)and thus the pancreatic blood flow 2224.In recent years,several preclinical studieshighlighted that certain psychoactive molecules can modulate the endocannabinoid system in the gutand possibly impact the pathogenesis of inflammatory bowel disease,as well as its extra intestinalmanifestations such as pancreatitis 25,26.It has been demonstrated by Warzecha et al.25 thatanandamide reduces mucosal oxidative stress,inhibits the inflammatory process and preserves theintegrity of gastric mucosa in stress-induced gastric ulcers 25.These effects are partly mediatedby capsaicin-sensitive sensory nerves 25 and,in the case of acute pancreatitis,the protective actionof anandamide depends on the phase of the inflammation 27,28.Thus,the modulation of theendocannabinoid system may be useful to treat gut-brain motor dysfunction in PD.Int.J.Mol.Sci.2018,19,16893 of 19Changes in the ANS occurred in conjunction with intestinal inflammation,however,disorderssuch as IBS are also linked to inflammatory abnormalities of the ENS 17.The ENS is the largestnervous system outside the CNS,which autonomously regulates numerous functions of the GI tract,either independently through neuro-glial circuits in the myenteric and submucosal plexus,or byinput of sympathetic and parasympathetic pathways to/from the brain.The enteric neurons andglial cells form a vast communication network in close relationship with the gut microbiota and thusthe ENS can easily be affected by microbiome alterations and be involved in GI disorders as wellas in neurodegenerative diseases.Therefore,the ENS could represent an entry point for pathogensorconverselyfor therapeutic interventions based on diet and/or commensal microbes-derivedmolecules 29.Lately,it is becoming increasingly clear that a third player,such as the gut microbiota,can significantly influence the gut-brain crosstalk,having a marked impact on digestive processes,immune responses,emotional status,perception and cognitive functions 16.The microbiota-gut-brainaxis has attracted much attention regarding the pathogenesis of PD,in which GI dysfunction appearsabout twenty years before motor impairments.Although PD patients manifest both gut dysmotilityand altered microbial composition,it is still unclear which condition comes first and what role the gutand the gut microbiota have in PD progression.In addition to maintaining gut homeostasis and several essential host physiological functions,the gut microbiota is a producer of an assortment of Toll-like receptor(TLR)ligands,which can exertproinflammatory effects under certain conditions.Despite microbial-derived components being potentTLR ligands,the gut has a high tolerance to TLR ligands because epithelial cells express minimal TLRsunder physiological conditions 30.In contrast,altered gut microbiota and disrupted gut epithelialbarrier activate TLRs which in turn trigger downstream signaling pathways,promoting inflammationand oxidative stress in both the gut and brain of PD patients.Thus,gut microbiota and TLRs couldrepresent potential targets for PD treatment.The exact mechanisms by which gut microbiota contribute to PD are still poorly understood,despite the role of gut microbiota in the development of PD being well documented.Here,we firstdescribe the functional aspects of gut microbiota observed in PD.Then,we review the role of TLRsassociated with PD and their potential as a new target of dietary and/or therapeutic interventions.2.Microbiota-Gut-Brain Axis and Host HealthOver the last decade,an increasing amount of literature has focused on the codevelopment of thegut microbiota with the human host since birth and on their mutual shaping clearly relying on thehost genome,nutrition and lifestyle 31.While the association of neuropsychiatric disorders with GIdisturbances dates back to Hippocrates,a clear demonstration of the essential cooperation betweenbrain and microbes was first described by the impressive amelioration of symptoms in patientsaffected by hepatic encephalopathy following treatment with nonadsorbable oral antibiotics 32.The gut microbiota is now being referred to as a new organ or an emergent system,which comprisesa number of microorganisms(bacteria,archaea,fungi,and viruses)comparable to the number ofcells residing in the human body 33.In particular,the enteric microbiota,distributed along thehuman GI tract,displays similar results in terms of relative abundance and distribution betweenhealthy adults,although the microbe profile is quite stable and unique for each individual,and can beconsidered a personal microbic fingerprint or enterotype 34.Firmicutes and Bacteriodetes are the mostdominant phyla(about 51%and 48%,respectively),with Actinobacteria(including the Bifidobacteriagenera),Cyanobacteria,Lentisphaerae,Fusobacteria,Spirochaetes,Proteobacteria,and Verrucomicrobia phylaexisting in relatively low abundance 35.Although a relative consistency in microbial composition inhealthy people is usually maintained over time,small daily variations are found in each individualunless exposed to disrupting agents or conditions,such as antibiotics,colonization by foreigncommensal microbes,marked changes in diet or lifestyle,or infectious or noninfectious disease 3638.The magnitude and the length of the disruption might affect the capability of microbiota to recoverInt.J.Mol.Sci.2018,19,16894 of 19and return to the original composition once the dysfunction is resolved,however repeated harmfulstimuli will weaken its recovery with potential downstream outcomes on host physiology 38.Aging is a critical window for not only the gut and brain function but also for the composition ofenteric microbiota that in turn may have serious consequences on health integrity in these latter stagesof life 38.The bidirectional dialogue between the gut and the brain involves different mechanisms,includingthe enteric and central neural network,neuroendocrine-hypothalamic-pituitary-adrenal axis,immunesystem,several neurotransmitters and neural regulators directly produced by gut bacteria,and barrierpaths such as intestinal mucosal barrier and blood-brain barrier.The enteric microbiota is implicated inthe upregulation of the local and systemic inflammatory response induced by lipopolysaccharides(LPS)derived from pathogens and the related production of proinflammatory mediators.The dysregulationof immune response to environmental and/or microbial agents is associated with the onset ofinflammatory bowel disease in genetically susceptible individuals 39.On the other hand,expositionto low amounts of LPS in early life can affect the ability of the immune cells to produce the cytokines,increasing the resistance of the organism to systemic diseases such as pancreatic inflammation 40.Gut dysbiosis and/or small intestinal overgrowth(SIBO)increase intestinal permeability andbacterial translocation,determining an immune systems overresponse and consequent systemicand/or central nervous system(CNS)inflammation.Enteric bacterial cells possess the capacityto produce numerous neuroactive molecules,such as serotonin,catecholamines,glutamate,-amminobutyric acid(GABA)and short-chain-fatty acids(SCFAs)4143.It has been proposed thatthe variety of neurotransmitters,neuromodulators and neurohormones produced by microorganismsare the“words”of a common language that enables a sophisticated synergic communication 44.However,considering the extreme complexity of this communication network,it remains to bedetermined whether microbial neurochemicals are generated at an adequate level in respect to hostproduction to exert any kind of effect,or can be delivered to central neurocircuits through systemiccirculation 41,42.Although some reports indicate the ability of bacteria to modulate the le