Tinokutendai nekushanyira Nature.com. Shanduro yebrowser yauri kushandisa ine rutsigiro rushoma rweCSS. Kuti uwane mhedzisiro yakanaka, tinokurudzira kushandisa shanduro itsva yebrowser yako (kana kudzima compatibility mode muInternet Explorer). Panguva ino, kuti tive nechokwadi chekuti rutsigiro rwuripo, tiri kuratidza saiti iyi pasina styling kana JavaScript.
Kuongororwa kwekutanga kwe essential tremor (ET) kunogona kuva kwakaoma, kunyanya kana kuchisiyaniswa nezvirwere zvine hutano (HC) neParkinson's disease (PD). Munguva pfupi yapfuura, kuongororwa kwemasampuli etsvina ye gut microbiota ne metabolites ayo kwakapa nzira itsva dzekuwanikwa kwe biomarkers itsva dzezvirwere zve neurodegenerative. Short-chain fatty acids (SCFA), se metabolite huru ye flora yemudumbu, inoderera mutsvina muPD. Zvisinei, fecal SCFA haisati yambodzidzwa muET. Taive nechinangwa chekuongorora huwandu hweSCFAs mutsvina muET, kuongorora hukama hwadzo nezviratidzo zvekiriniki uye gut microbiota, uye kuona kugona kwadzo kuongorora. Fecal SCFA ne gut microbiota zvakayerwa mu37 ETs, 37 new PDs, uye 35 HCs. Kuzvimba, kusashanda zvakanaka kwe autonomic, uye kuomarara kwe tremor zvakayerwa uchishandisa zviyero. Fecal levels ye propionate, butyrate, uye isobutyrate yaive yakaderera muET pane muHC. Musanganiswa wepropionic, butyric uye isobutyric acids wakasiyanisa ET neHC neAUC ye0.751 (95% CI: 0.634–0.867). Fecal isovaleric acid uye isobutyric acid levels zvaive zvakaderera muET pane muPD. Isovaleric acid neisobutyric acid zvinosiyanisa pakati peET nePD neAUC ye0.743 (95% CI: 0.629–0.857). Fecal propionate inobatanidzwa zvakasiyana nekuzvimbirwa uye kusagadzikana kwe autonomic. Isobutyric acid neisovaleric acid zvine chekuita nekuomarara kwededera. Kuderera kweSCFA dzefecal kwakabatana nekudzikira kwehuwandu hweFaecalibacterium neStreptobacterium muET. Saka, huwandu hweSCFA mutsvina hunoderera muET uye hunobatanidzwa nekuoma kwemufananidzo wekiriniki uye shanduko mu intestinal microbiota. Fecal propionate, butyrate, isobutyrate, uye isovalerate zvinogona kunge zviri zviratidzo zvekuongorora uye zvakasiyana zveET.
Kudedera kwesimba (ET) chirwere chisingaperi chetsinga dzeropa chinoenderera mberi chinoratidzwa nekudedera kwemakumbo ekumusoro, izvo zvinogonawo kukanganisa dzimwe nhengo dzemuviri dzakadai semusoro, tambo dzenzwi, uye makumbo epasi 1. Zviratidzo zvekurapa zveET zvinosanganisira kwete zviratidzo zvekufamba chete asiwo zvimwe zviratidzo zvisiri zvekufamba, kusanganisira chirwere chemudumbu 2. Zvidzidzo zvakawanda zvakaitwa kuti zviongorore hunhu hwechirwere uye hwemuviri hwekudengenyeka kwesimba, asi nzira dzakajeka dzezvirwere hadzina kuzivikanwa3,4; Zvidzidzo zvechangobva kuitwa zvinoratidza kuti kusashanda zvakanaka kwe microbiota-gut-brain axis kunogona kukonzera zvirwere zvetsinga, uye kune humbowo huri kukura hwekubatana kunogona kuitika pakati pe gut microbiota nezvirwere zvetsinga5,6. Zvakakosha, mune imwe nyaya, kuisirwa kwefecal microbiota kwakavandudza essential tremor ne irritable bowel syndrome mumurwere, izvo zvinogona kuratidza hukama hwepedyo pakati pe gut microbiota ne essential tremor. Pamusoro pezvo, takawanawo shanduko dzakati mu gut microbiota muvarwere vane ET, izvo zvinotsigira basa rakakosha re gut dysbiosis mu ET8.
Nezve dysbiosis yemudumbu muzvirwere zve neurodegenerative, PD ndiyo inonyanya kudzidzwa5. Microbiota isina kuenzana inogona kuwedzera kupinda kwemudumbu uye kumutsa intestinal glia, zvichikonzera alpha-synucleinopathies9,10,11. PD neET dzine zvimwe zvinhu zvakafanana, zvakaita sekuwanda kwekudengenyeka kwakafanana muvarwere veET nePD, kutenderera kwekuzorora kwakabatana (kutetemeka kwakajairika muPD), uye kutetemeka kwepamuviri (kunowanikwa zvakanyanya muvarwere veET), zvichiita kuti zviome kusiyanisa pakati pavo. matanho ekutanga 12. Naizvozvo, tinoda nekukurumidza kuvhura hwindo rinobatsira kusiyanisa pakati peET nePD. Muchirevo ichi, kudzidza dysbiosis chaiyo yemudumbu uye shanduko dzemetabolite dzakabatana muET uye kuona kusiyana kwavo kubva kuPD kunogona kuva zviratidzo zvinogona kuwanikwa zvekuongorora uye kuongororwa kwakasiyana kweET.
Ma "short-chain fatty acids" (SCFAs) ndiwo ma "metabolites" makuru anogadzirwa ne "intestinal bacterial fermentation" ye "dietary fiber" uye anofungidzirwa kuti anoita basa rakakosha mukudyidzana kwe "gut-brain" ne "gut-brain"13,14. Ma "SCFAs" anotorwa ne "colon cells" oendeswa kuchiropa kuburikidza ne "portal venous system", uye mamwe ma "SCFAs" anopinda mu "systemic circulation". Ma "SCFAs" ane mhedzisiro yemunzvimbo pakuchengetedza kusimba kwe "intestinal barrier" uye kukurudzira "innate immunity" mu "intestinal mucosa"15. Anewo mhedzisiro yenguva refu pa "blood-brain barrier" (BBB) ​​​​nekukurudzira mapuroteni akamanikana uye kumutsa ma "neurons" nekukurudzira ma "G protein-coupled receptors" (GPCRs) kuti ayambuke BBB16. Acetate, propionate, uye butyrate ndiwo ma "SCFAs" akawanda mu "colon". Zvidzidzo zvekare zvakaratidza kudzikira kwe "fecal levels" ye "acetic, propionic" uye "butyric acids" mu "varwere vane chirwere cheParkinson's"17. Zvisinei, "fecal levels" ye "SCFAs" haina kumbodzidzwa muvarwere vane ET.
Saka, chidzidzo chedu chaive nechinangwa chekuona shanduko chaiyo muSCFA yetsvina muvarwere vane ET uye kusiyana kwayo nevarwere vane PD, kuongorora hukama hweSCFA yetsvina nezviratidzo zveET uye microbiota yemudumbu, pamwe nekuona kugona kwekuongorora nekusiyanisa kwemasampuli etsvina. KZhK. Kuti tigadzirise zvinhu zvinovhiringidza zvine chekuita nemishonga inorwisa PD, takasarudza varwere vane chirwere cheParkinson chitsva senzira dzekudzivirira chirwere.
Hunhu hwevanhu nekiriniki hwe37 ET, 37 PD, uye 35 HCs zvakapfupikiswa muTafura 1. ET, PD, uye HCs zvakaenzaniswa nezera, bonde, uye BMI. Mapoka matatu aya aivewo nehuwandu hwakafanana hwekusvuta, kunwa doro uye kunwa kofi netii. Chibodzwa cheWexner (P = 0.004) uye chibodzwa cheHAMD-17 (P = 0.001) cheboka rePD chaive chakakwirira pane cheboka reHC, uye chibodzwa cheHAMA (P = 0.011) uye chibodzwa cheHAMD-17 (P = 0.011) cheboka reET chaive chakakwirira kupfuura cheboka reHC. Kufamba kwechirwere muboka reET kwaive kwenguva yakareba kupfuura muboka rePD (P<0.001).
Paiva nemusiyano wakakura muhuwandu hwetsvina yepropionic acid (P = 0.023), acetic acid (P = 0.039), butyric acid (P = 0.020), isovaleric acid (P = 0.045), uye isobutyric acid (P = 0.015). . Mune imwe ongororo yakatevera, huwandu hwepropionic acid (P = 0.023), butyric acid (P = 0.007), uye isobutyric acid (P = 0.040) muboka reET hwakanga hwakaderera zvakanyanya pane hwevari muboka reHC. Varwere vane ET vaiva nehuwandu hwakaderera hweisovalerate (P = 0.014) uye isobutyrate (P = 0.005) pane varwere vane PD. Pamusoro pezvo, huwandu hwechikafu chepropionic acid (P = 0.013), acetic acid (P = 0.016), uye butyric acid (P = 0.041) hwakaderera muvarwere vane PD pane muvarwere vane CC (Mufananidzo 1 neTafura Yekuwedzera 1).
ag inomiririra kuenzanisa kweboka repropionic acid, acetic acid, butyric acid, isovaleric acid, valeric acid, caproic acid uye isobutyric acid, zvichiteerana. Paive nemisiyano yakakura muhuwandu hwefecal propionic acid, acetic acid, butyric acid, isovaleric acid uye isobutyric acid pakati pemapoka matatu. ET essential tremor, Parkinson's disease, healthy HC control, SCFA. Misiyano yakakosha inoratidzwa ne *P < 0.05 uye **P < 0.01.
Tichifunga nezvemusiyano uripo pakati peboka reET neboka rePD, takaongorora varwere 33 vane PD yekutanga uye varwere 16 vane ET (chirwere chinopfuura makore 3) kuti tiwedzere kuenzanisa (Tafura Yekuwedzera 2). Zvakabuda zvakaratidza kuti huwandu hweET mufecal propionic acid hwakanga hwakaderera zvakanyanya pane hweHA (P=0.015). Musiyano uripo pakati peET neHC yebutyric acid neisobutyric acid hauna kukosha, asi mafambiro acho achiri kuonekwa (P=0.082). Mazinga eFecal isobutyrate aive akaderera zvakanyanya muvarwere vane ET zvichienzaniswa nevarwere vane PD (P=0.030). Musiyano uripo pakati peET nePD yeisovaleric acid hauna kukosha, asi pakanga pachine mafambiro (P=0.084). Propionic acid (P = 0.023), acetic acid (P = 0.020), uye butyric acid (P = 0.044) zvaive zvakaderera zvakanyanya muvarwere vePD pane muvarwere veHC. Mhedzisiro iyi (Mufananidzo Wekuwedzera 1) inowanzoenderana nemigumisiro mikuru. Musiyano uripo pakati pemuenzaniso wese neboka revarwere vekutanga unogona kunge uri nekuda kwehukuru hudiki hwemuenzaniso muboka revarwere, zvichikonzera simba shoma rehuwandu hwedata.
Takazoongorora kana huwandu hweSCFA mutsvina huchigona kusiyanisa varwere vane ET nevarwere vane CU kana PD. Zvichienderana neROC analysis, musiyano muAUC yehuwandu hwepropionate waive 0.668 (95% CI: 0.538-0.797), izvo zvakaita kuti zvikwanisike kusiyanisa varwere vane ET neHC. Varwere vane ET neGC vanogona kusiyaniswa nehukuru hwebutyrate neAUC ye0.685 (95% CI: 0.556–0.814). Kusiyana kwehuwandu hweisobutyric acid kunogona kusiyanisa varwere vane ET neHC neAUC ye0.655 (95% CI: 0.525–0.786). Pakubatanidza mazinga epropionate, butyrate neisobutyrate, AUC yakakwira ye0.751 (95% CI: 0.634–0.867) yakawanikwa nekunzwa kwe74.3% uye kujeka kwe72.9% (Mufananidzo 2a). Kuti tisiyanise pakati pevarwere veET nePD, AUC yemazinga eisovaleric acid yaive 0.700 (95% CI: 0.579–0.822) uye yemazinga eisobutyric acid yaive 0.718 (95% CI: 0.599–0.836). Musanganiswa wemazinga eisovaleric acid neisobutyric acid waiva neAUC yakakwira ye0.743 (95% CI: 0.629–0.857), kunzwikwa kwe74.3% uye kujeka kwe62.9% (Mufananidzo 2b). Pamusoro pezvo, takaongorora kana huwandu hweSCFA mutsvina yevarwere vane chirwere cheParkinson hwakasiyana nehunhu hwevanodzora. Sekureva kweROC analysis, AUC yekuziva varwere vane PD zvichibva pamusiyano wehuwandu hwepropionic acid yaive 0.687 (95% CI: 0.559-0.814), ine kunzwisisika kwe68.6% uye specificity ye68.7%. Kusiyana kwehuwandu hweacetate kunogona kusiyanisa varwere vePD kubva kuHCs vane AUC ye0.674 (95% CI: 0.542–0.805). Varwere vane PD vanogona kusiyaniswa kubva kuCU chete nehukuru hwebutyrate neAUC ye0.651 (95% CI: 0.515–0.787). Pakubatanidza huwandu hwepropionate, acetate nebutyrate, AUC ye0.682 (95% CI: 0.553–0.811) yakawanikwa (Mufananidzo 2c).
Kusarurwa neChechi yeOrthodox yeRussia vachipesana neET neHC; b Kusarurwa kweROC vachipesana neET nePD; c Kusarurwa kweROC vachipesana nePD neHC; Kudedera kweET, chirwere cheParkinson, kudzorwa kweHC kwakanaka, SCFA.
Muvarwere vane ET, huwandu hweasidhi yefecal isobutyric hwakanga husina hukama neFTM score (r = -0.349, P = 0.034), uye huwandu hweasidhi yefecal isovaleric hwakanga husina hukama neFTM score (r = -0.421, P = 0.001) uye TETRAS score. (r = -0.382, P = 0.020). Muvarwere vane ET nePD, huwandu hwepropionate yefecal hwakanga husina hukama neSCOPA-AUT scores (r = -0.236, P = 0.043) (Mufananidzo 3 neTable Supplementary 3). Pakanga pasina hukama hwakakosha pakati penzira yechirwere neSCFA muboka reET (P ≥ 0.161) kana boka rePD (P ≥ 0.246) (Table Supplementary 4). Muvarwere vane PD, huwandu hwe caproic acid mufecal hwakabatana zvakanaka ne MDS-UPDRS scores (r = 0.335, P = 0.042). Pakati pevatori vechikamu vese, huwandu hwe fecal propionate (r = −0.230, P = 0.016) uye huwandu hwe acetate (r = −0.210, P = 0.029) hwakanga hwakafanana zvakanyanya ne Wexner scores (Mufananidzo 3 ne Supplementary Table 3).
Mazinga e isobutyric acid emufecal akanga asina hukama nema FTM scores, isovaleric acid yakanga isina hukama nema FTM ne TETRAS scores, propionic acid yakanga isina hukama nema SCOPA-AUT scores, caproic acid yakanga isina hukama nema MDS-UPDRS scores, uye propionic acid yakanga isina hukama nema FTM ne TETRAS scores. TETRAS ne acetic acid zvakanga zvisina hukama nema Wexner score. MDS-UPDRS Association yakatsigira vhezheni ye Unified Parkinson's Disease Rating Scale, Mini-Mental State Examination MMSE, Hamilton Depression Rating Scale HAMD-17, zvinhu 17, Hamilton Anxiety Rating Scale HAMA, HY Hoehn ne Yahr stages, SCFA, SCOPA - AUT Parkinson's Disease Autonomic Symptom Outcome Scale, FTM Fana-Tolosa-Marin Clinical Tremor Rating Scale, TETRAS Research Group (TRG) Essential Tremor Rating Scale. Misiyano yakakosha inoratidzwa ne *P < 0.05 uye **P < 0.01.
Takaongorora zvakare kusarura kwe gut microbiota tichishandisa LEfSE analysis uye takasarudza genus relative abundance data level kuti tiongorore zvakare. Kuenzanisa kwakaitwa pakati peET neHC uye pakati peET nePD. Spearman correlation analysis yakazoitwa pahuwandu hwe gut microbiota nefecal SCFA levels mumapoka maviri ekuenzanisa.
Faecalibacterium (yakabatana nebutyric acid, r = 0.408, P < 0.001), Lactobacillus (yakabatana nebutyric acid, r = 0.283, P = 0.016), Streptobacterium (yakabatana nepropionic acid, r = 0.327) yaivepo mukuongororwa kweET neCA. , P = 0.005; yakabatana nebutyric acid, r = 0.374, P = 0.001; inoenderana ne isobutyric acid, r = 0.329, P = 0.005), Howardella (inoenderana ne propionic acid, r = 0.242, P = 0.041), Raoultella (inoenderana ne propionate, r = 0.249, P = 0.035), uye Candidatus Arthromitus (inoenderana ne isobutyric acid, r = 0.302, P = 0.010) inoderera mu ET uye inoenderana zvakanaka nemazinga e SCFA yetsvina. Zvisinei, kuwanda kwe Stenotropomonas kwakawedzera mu ET uye kwakabatana zvisina kunaka nemazinga e isobutyrate yetsvina (r = -0.250, P = 0.034). Mushure mekugadziriswa kwe FDR, hukama huripo pakati pe Faecalibacterium, Catenibacter, ne SCFA chete ndihwo hwakaramba hwakakosha (P ≤ 0.045) (Mufananidzo 4 ne Supplementary Table 5).
Kuongororwa kwekubatana kweET neHC. Mushure mekugadziriswa kweFDR, kuwanda kweFaecalibacterium (yakabatana zvakanaka nebutyrate) neStreptobacterium (yakabatana zvakanaka nepropionate, butyrate, uye isobutyrate) kwakawanikwa kwakaderera muET uye kwakabatana zvakanaka nemazinga eSCFA yetsvina. b Kuongororwa kwekubatana kweET nePD. Mushure mekugadziriswa kweFDR, hapana hukama hwakakosha hwakawanikwa. ET essential tremor, chirwere cheParkinson, healthy HC control, SCFA. Misiyano yakakosha inoratidzwa ne *P < 0.05 uye **P < 0.01.
Pakuongorora ET nePD, Clostridium trichophyton yakawanikwa yakawedzera muET uye yakabatana nefecal isovaleric acid (r = -0.238, P = 0.041) uye isobutyric acid (r = -0.257, P = 0.027). ). Mushure mekugadziriswa kweFDR, chero ipi zvayo yakaramba yakakosha (P≥0.295) (Mufananidzo 4 neTafura Yekuwedzera 5).
Chidzidzo ichi chidzidzo chakakwana chinoongorora huwandu hweSCFA mutsvina uye chinohubatanidza nekuchinja kwe microbiota yemudumbu uye kuomarara kwezviratidzo muvarwere vane ET zvichienzaniswa nevarwere vane CU nePD. Takaona kuti huwandu hweSCFA mutsvina hwakaderera muvarwere vane ET uye hwakabatana nekuomarara kwekiriniki uye shanduko dzakati wandei mu microbiota yemudumbu. Kuwanda kwemafuta acids mapfupi (SCFAs) mutsvina kunosiyanisa ET kubva kuGC nePD.
Zvichienzaniswa nevarwere veGC, varwere veET vane huwandu hwakaderera hwepropionic, butyric, uye isobutyric acids mutsvina. Kusanganiswa kwepropionic, butyric uye isobutyric acids kwakasiyanisa ET neHC neAUC ye0.751 (95% CI: 0.634–0.867), kunzwa kwe74.3% uye specificity ye72.9%, zvichiratidza kushandiswa kwavo se biomarkers yekuongorora basa rinogona kuitwa neET. Ongororo yakawedzerwa yakaratidza kuti huwandu hwepropionic acid mutsvina hwakanga hwakabatana zvisina kunaka neWexner score uye SCOPA-AUT score. Mazinga eisobutyric acid mutsvina akabatana zvakasiyana neFTM scores. Kune rumwe rutivi, kudzikira kwemazinga ebutyrate muET kwakabatana nekudzikira kwehuwandu hwemicrobiota inogadzira SCFA, Faecalibacterium, uye Categorybacter. Pamusoro pezvo, kudzikira kwehuwandu hweCatenibacter muTS kwakabatanawo nekudzikira kwemazinga epropionic neisobutyric acid mutsvina.
MaSCFA mazhinji anogadzirwa muura anotorwa nemacolonocytes kunyanya kuburikidza ne H+-dependent kana sodium-dependent monocarboxylate transporters. Ma short-chain fatty acids anotorwa anoshandiswa senzvimbo yesimba kumacolonocytes, nepo ayo asina metabolized mumacolonocytes anotakurwa kuenda ku portal circulation 18. MaSCFA anogona kukanganisa kufamba kwemudumbu, kuwedzera mashandiro emudumbu, uye kukanganisa metabolism yemudumbu uye immune system19. Zvakamboonekwa kuti huwandu hwe butyrate, acetate, uye propionate hwakaderera muvarwere vePD zvichienzaniswa neHCs17, izvo zvinoenderana nezvatakawana. Chidzidzo chedu chakawana kudzikira kweSCFA muvarwere vane ET, asi zvishoma zvinozivikanwa nezvebasa reSCFAs mu pathology yeET. Butyrate nepropionate zvinogona kusunga kuGPCRs uye kukanganisa GPCR-dependent signaling senge MAPK neNF-κB20 signaling. Pfungwa huru ye gut-brain axis ndeyekuti maSCFA anoburitswa nema infectious microbes anogona kukanganisa host signaling, nokudaro achikanganisa mashandiro emudumbu neuropi. Nekuti butyrate nepropionate zvine simba rekudzivirira pane histone deacetylase (HDAC) activity21 uye butyrate inogonawo kushanda se ligand ye transcription factors, zvine simba guru pa metabolism yemugadziri wemuviri, differentiation uye proliferation, kunyanya nekuda kwesimba razvo pakutonga kwemajini22. Zvichibva pauchapupu hunobva kuSCFA nezvirwere zve neurodegenerative, butyrate inoonekwa senzira yekurapa nekuda kwekugona kwayo kugadzirisa HDAC activity isina kunaka, izvo zvinogona kukonzera kufa kwedopaminergic neuron muPD23,24,25. Zvidzidzo zvemhuka zvakaratidzawo kugona kwebutyric acid kudzivirira dopaminergic neuron degeneration uye kugadzirisa mafambiro ekufamba muPD models26,27. Propionic acid yakawanikwa ichideredza mhinduro dzekuzvimba uye kuchengetedza kuvimbika kweBBB28,29. Zvidzidzo zvakaratidza kuti propionic acid inokurudzira kupona kwedopaminergic neurons mukupindura kurotenone toxicity muPD models30 uye kuti kupiwa nemuromo kwepropionic acid kunonunura kurasikirwa kwedopaminergic neuron uye kutadza kufamba kwemakonzo ane PD31. Zvishoma zvinozivikanwa nezvebasa reisobutyric acid. Zvisinei, ongororo yakaitwa munguva pfupi yapfuura yakawana kuti kupinda mumasero embeva ane B. ovale kwakawedzera huwandu hweSCFA mudumbu (kusanganisira acetate, propionate, isobutyrate, uye isovalerate) uye huwandu hweGABA mudumbu, zvichiratidza kuti pane hukama hwakasimbiswa pakati pe microbiota yemudumbu uye huwandu hweSCFA mudumbu. 32. MuET, shanduko dzisina kujairika dzezvirwere mucerebellum dzinosanganisira shanduko muPurkinje cell axons uye dendrites, kufamba uye kurasikirwa kwemasero ePurkinje, shanduko mubasket cell axons, kusagadzikana mukubatana kwefiber inokwira nekugoverwa kwemasero ePurkinje, uye shanduko muGABA receptors mu dentate bone. nuclei, izvo zvinotungamira kudzikira kweGABAergic output kubva kucerebellum3,4,33. Hazvisati zvajeka kana maSCFA akabatana nePurkinje cell neurodegeneration uye kudzikira kwekugadzirwa kweGABA yecerebellar. Mhedzisiro yedu inoratidza hukama hwakasimba pakati peSCFA neET, asi dhizaini yekudzidza kwechikamu chepakati haibvumiri chero mhedziso nezvehukama hwechikonzero pakati peSCFA nemaitiro echirwere cheET; Zvimwe zvidzidzo zvekutevera kwenguva refu zvinodiwa, kusanganisira kuyerwa kwetsvina yeSCFA, pamwe nekuongorora mashandiro emhuka.
MaSCFA anofungidzirwa kuti anokurudzira kugadzikana kwemhasuru dzemudumbu. Kushaikwa kweSCFA kunowedzera zviratidzo zvekuvharirwa, uye kuwedzerwa kweSCFA kunogona kuvandudza zviratidzo zvekuvharirwa PD35. Zvatakawana zvinoratidzawo hukama hwakakosha pakati pekuderera kwehuwandu hweSCFA mutsvina uye kuwedzera kwekuvharirwa uye kusashanda zvakanaka kwemuviri muvarwere vane ET. Imwe nyaya yakawana kuti kuisirwa kwe microbiota kwakavandudza essential tremble uye irritable bowel syndrome mumurwere we7, zvichiratidza hukama hwepedyo pakati pe gut microbiota ne ET. Nokudaro, tinotenda kuti fecal SCFA/microbiota inogona kukanganisa kufamba kwemudumbu uye autonomic nervous system function.
Chidzidzo ichi chakawana kuti kudzikira kwemazinga eSCFA mutsvina muET kwakabatana nekudzikira kwehuwandu hweFaecalibacterium (inobatanidzwa nebutyrate) neStreptobacterium (inobatanidzwa nepropionate, butyrate, uye isobutyrate). Mushure mekugadziriswa kweFDR, hukama uhwu hunoramba hwakakosha. Faecalibacterium neStreptobacterium tupukanana tunogadzira SCFA. Faecalibacterium inozivikanwa setupukanana tunogadzira butyrate36, nepo zvigadzirwa zvikuru zvekuvirisa Catenibacter zviri acetate, butyrate uye lactic acid37. Faecalibacterium yakaonekwa mu100% yemapoka ese eET neHC; huwandu hwepakati hweboka reET hwaive 2.06% uye hweboka reHC hwaive 3.28% (LDA 3.870). Bacterium yeboka yakaonekwa mu21.6% (8/37) yeboka reHC uye mumuenzaniso mumwe chete weboka reET (1/35). Kuderera uye kusaonekwa kwe streptobacteria muET kunogonawo kuratidza hukama nehutachiona hwechirwere ichi. Huwandu hwepakati hwemhando dzeCatenibacter muboka reHC hwaive 0.07% (LDA 2.129). Pamusoro pezvo, mabhakitiriya e lactic acid akabatana nekuchinja kwefecal butyrate (P=0.016, P=0.096 mushure mekugadziriswa kweFDR), uye arthritis candidate yakabatana nekuchinja kweisobutyrate (P=0.016, P=0.072 mushure mekugadziriswa kweFDR). Mushure mekugadziriswa kweFDR, maitiro ekubatana chete ndiwo anoramba aripo, izvo zvisina kukosha muhuwandu. Lactobacilli inozivikanwawo seSCFA (acetic acid, propionic acid, isobutyric acid, butyric acid) vagadziri 38 uye Candidatus Arthromitus inyanzvi chaiyo yekusiyanisa masero eT helper 17 (Th17), neTh1/2 neTregs zvine chekuita ne immune balance /Th1739. . Ongororo yakaitwa munguva pfupi yapfuura inoratidza kuti huwandu hwakakwira hwe pseudoarthritis yetsvina hunogona kukonzera kuzvimba kwekoloni, kusashanda zvakanaka kwezvidziviriro zvemudumbu, uye kuzvimba kwemuviri. 40. Mazinga eClostridium trichoides akawedzera muET zvichienzaniswa nePD. Kuwanda kweClostridium trichoides kwakawanikwa kusina hukama hwakanaka ne isovaleric acid ne isobutyric acid. Mushure mekugadziriswa kweFDR, zvese zvakaramba zvichikosha (P≥0.295). Clostridium pilosum ibhakitiriya inozivikanwa kuti ine hukama nekuzvimba uye inogona kukonzera kusashanda zvakanaka kwezvidziviriro zvemudumbu41. Ongororo yedu yapfuura yakashuma shanduko mu microbiota yemudumbu yevarwere vane ET8. Pano tinotaurawo shanduko muSCFA muET uye tinoona hukama huripo pakati pe dysbiosis yemudumbu nekuchinja muSCFA. Kudzikira kwemazinga eSCFA kwakabatana zvakanyanya ne dysbiosis yemudumbu uye kutetemeka kwakanyanya muET. Mhedzisiro yedu inoratidza kuti gut-brain axis inogona kuita basa rakakosha mu pathogenesis yeET, asi zvimwe zvidzidzo mumhando dzemhuka zvinodiwa.
Zvichienzaniswa nevarwere vane PD, varwere vane ET vane mazinga akaderera e isovaleric ne isobutyric acids mutsvina yavo. Musanganiswa we isovaleric acid ne isobutyric acid wakawana ET muPD neAUC ye0.743 (95% CI: 0.629–0.857), kunzwa kwe74.3% uye specificity ye62.9%, zvichiratidza basa ravo se biomarkers mukuongorora kwakasiyana kwe ET. . Fecal isovaleric acid levels yakabatana zvakasiyana ne FTM ne TETRAS scores. Fecal isobutyric acid levels yakabatana zvakasiyana ne FTM scores. Kuderera kwe isobutyric acid levels kwakabatana nekudzikira kwehuwandu hwe catobacteria. Zvishoma zvinozivikanwa nezvemabasa e isovaleric acid ne isobutyric acid. Ongororo yapfuura yakaratidza kuti kupinda mumapoka emakonzo ane B. ovale kwakawedzera huwandu hweSCFAs dzemudumbu (kusanganisira acetate, propionate, isobutyrate, uye isovalerate) uye huwandu hweGABA mudumbu, zvichiratidza hukama hwemudumbu pakati pe microbiota nehuwandu hweSCFA/neurotransmitter mudumbu32. Zvinofadza kuti, huwandu hwe isobutyric acid hwakaonekwa hwakafanana pakati pemapoka ePD neHC, asi hwakasiyana pakati pemapoka eET nePD (kana HC). Isobutyric acid inogona kusiyanisa pakati peET nePD neAUC ye0.718 (95% CI: 0.599–0.836) uye kuona ET neNC neAUC ye0.655 (95% CI: 0.525–0.786). Pamusoro pezvo, huwandu hwe isobutyric acid hunoenderana nekuomarara kwekudengenyeka, zvichisimbisa hukama hwayo neET. Mubvunzo wekuti isobutyric acid yemuromo inogona kuderedza kuomarara kwekudengenyeka muvarwere vane ET unofanirwa kuongororwa zvakanyanya.
Saka, huwandu hweSCFA mutsvina hunoderera muvarwere vane ET uye hunobatanidzwa nekuoma kweET uye shanduko dzakati wandei mu microbiota yemudumbu. Fecal propionate, butyrate, uye isobutyrate zvinogona kunge zviri zviratidzo zvekuongorora ET, nepo isobutyrate neisovalerate zvingave zvakasiyana zviratidzo zvekuongorora ET. Shanduko mutsvina yeisobutyrate inogona kunge yakanyanya kunanga ET kupfuura shanduko mune dzimwe SCFA.
Chidzidzo chedu chine zvipingamupinyi zvakawanda. Chekutanga, maitiro ekudya uye zvinodiwa zvekudya zvinogona kukanganisa kuratidzwa kwe microbiota, mienzaniso mikuru yekudzidza mumapoka akasiyana inodiwa, uye zvidzidzo zvemangwana zvinofanira kuunza ongororo dzakakwana uye dzakarongeka dzezvekudya dzakadai semibvunzo yekudya inodiwa kakawanda. Chechipiri, dhizaini yekudzidza kwezvikamu zvakasiyana inodzivisa chero mhedziso maererano nehukama hwechikonzero pakati peSCFA nemaitiro echirwere cheET. Zvimwe zvidzidzo zvekutevera kwenguva refu zvine kuyerwa kwakatevedzana kweSCFA dzetsvina zvinodiwa. Chechitatu, kugona kwekuongorora uye kusiyanisa kwemazinga eSCFA etsvina kunofanirwa kusimbiswa uchishandisa sampuli dzakazvimiririra kubva kuET, HC, uye PD. Mamwe sampuli dzetsvina dzakazvimirira dzinofanira kuongororwa mune ramangwana. Chekupedzisira, varwere vane PD muboka redu vaive nenguva pfupi yechirwere kupfuura varwere vane ET. Takanyanya kufananidza ET, PD neHC nezera, bonde uye BMI. Tichifunga nezvemusiyano wechirwere pakati peboka reET neboka rePD, takaongororawo varwere makumi matatu nematatu vane PD yekutanga uye varwere gumi nevatanhatu vane ET (nguva yechirwere ≤makore matatu) kuti tiwedzere kuenzanisa. Musiyano wepakati pemapoka muSCFA waiwanzoenderana nedata redu rekutanga. Pamusoro pezvo, hatina kuwana hukama pakati penguva yechirwere nekuchinja kweSCFA. Zvisinei, mune ramangwana, zvingave zvakanaka kutsvaga varwere vane PD neET pakutanga kwenguva pfupi yechirwere kuti vapedzise kusimbiswa kwechirwere mumuenzaniso mukuru.
Nzira yekudzidza iyi yakatenderwa neKomiti yeMaitiro eChipatara cheRuijin yakabatana neShanghai Jiao Tong University School of Medicine (RHEC2018-243). Mvumo yakanyorwa yakawanikwa kubva kune vese vatori vechikamu.
Pakati paNdira 2019 naZvita 2022, vanhu 109 (37 ET, 37 PD, uye 35 HC) vanobva kuMovement Disorder Center Clinic yeRuijin Hospital, yakabatana neShanghai Jiao Tong University School of Medicine, vakabatanidzwa muchidzidzo ichi. Zviyero zvaive: (1) makore 25-85, (2) varwere vane ET vakaongororwa zvichienderana nezviyero zveMDS Working Group 42 uye PD vakaongororwa zvichienderana nezviyero zveMDS 43, (3) varwere vese vakanga vasiri kutora mishonga yekurwisa PD vasati vatora samples. (4) Boka reET rakatora β-blockers chete kana kuti vasina mishonga ine chekuita nayo vasati vatora samples dzetsvina. HCs dzakaenderana nezera, murume kana mukadzi, uye body mass index (BMI) dzakasarudzwawo. Zvinodiwa zvekusatora mishonga iyi zvaive: (1) vanhu vanodya miriwo chete, (2) kusadya zvakanaka, (3) zvirwere zvisingaperi zvemudumbu (kusanganisira chirwere chemudumbu chinozvimba, maronda emudumbu kana duodenal), (4) zvirwere zvisingaperi (kusanganisira bundu rakaipa), kutadza kushanda kwemoyo, kutadza kushanda kweitsvo, zvirwere zveropa) (5) Nhoroondo yekuvhiyiwa kukuru kwemudumbu, (6) Kudya yogati nguva dzose kana nguva dzose, (7) Kushandisa chero mishonga yeprobiotics kana mishonga inorwisa mabhakitiriya kwemwedzi mumwe chete, (8) Kushandisa kwenguva refu mishonga yecorticosteroids, proton pump inhibitors, statins, metformin, mishonga inodzvinyirira immune kana mishonga inorwisa kenza uye (9) kutadza kushanda zvakanaka kwepfungwa kunokanganisa miedzo yekiriniki.
Vanhu vese vakapa ruzivo rwenhoroondo yezvekurapa, huremu uye kureba kuti vaverenge BMI, uye vakaongororwa netsinga dzemuviri uye kuongororwa kwekiriniki senge Hamilton Anxiety Rating Scale (HAMA) 44 anxiety score, Hamilton Depression Rating Scale-17 score (HAMD-17) 45. kushungurudzika, kuoma kwekuzvimba vachishandisa Wexner Constipation Scale 46 uye Bristol Stool Scale 47 uye cognitive performance vachishandisa Mini-Mental State Examination (MMSE) 48. Chikero cheKuongorora Zviratidzo zveAutonomic zveParkinson's Disease (SCOPA-AUT) 49 chakaongorora kusashanda zvakanaka kwemuviri muvarwere vane ET nePD. Chikero cheFana-Tolos-Marin Clinical Tremor Rating Scale (FTM) uye Essential Tremor Rating Scale (TETRAS) 50 Chikero cheTremor Study (TRG) 50 chakaongororwa muvarwere vane ET; Kinson's Disease Rating Scale (MDS-), chakatsigirwa neUnited Parkinson's Disease Association; UPDRS version 51 uye Hoehn and Yahr (HY) version 52 zvakaongororwa.
Mumwe nemumwe wevatori vechikamu akakumbirwa kuti atore sampuro yetsvina mangwanani achishandisa mudziyo wekutora tsvina. Tumira midziyo muchando woichengeta pa -80°C usati wagadziriswa. Ongororo yeSCFA yakaitwa zvichienderana nekushanda kweTiangene Biotechnology (Shanghai) Co., Ltd. 400 mg yemasampuli matsva etsvina akatorwa kubva kune mumwe nemumwe munhu uye akaongororwa achishandisa maSCFA mushure mekukuya nekuita sonication. MaSCFA akasarudzwa mutsvina akaongororwa achishandisa gas chromatography-mass spectrometry (GC-MS) uye liquid chromatography-tandem MS (LC-MS/MS).
DNA yakatorwa kubva mu200 mg samples uchishandisa QIAamp® Fast DNA Stool Mini Kit (QIAGEN, Hilden, Germany) zvichienderana nemirairo yemugadziri. Kuumbwa kwe microbial kwakawanikwa nekutevera 16 S rRNA gene paDNA yakabviswa kubva mutsvina nekuwedzera V3-V4 region. Edza DNA nekushandisa sampuro pa 1.2% agarose gel. Polymerase chain reaction (PCR) amplification ye 16S rRNA gene yakaitwa uchishandisa universal bacterial primers (357 F na 806 R) uye two-step amplicon library yakavakwa paNovaseq platform.
Zvichienderana zvinoramba zvichiitika zvinoratidzwa seavhareji ± kutsauka kwakajairwa, uye zvichienderana zvinoratidzwa senhamba nemaperesenti. Takashandisa bvunzo yaLevene kuyedza homogeneity yezvichienderana. Kuenzanisa kwakaitwa tichishandisa bvunzo dzet dzine tailed mbiri kana ongororo yekuchinja (ANOVA) kana zvichienderana zvaiwanzo kugoverwa, uye bvunzo dzeMann-Whitney U dzisina parameter kana fungidziro dzekugara dzakatyorwa. Takashandisa nzvimbo iri pasi pe receiver operating characteristic (ROC) curve (AUC) kuti tiongorore mashandiro ekuongorora emuenzaniso uye kuongorora kugona kweSCFA kusiyanisa varwere vane ET kubva kune avo vane HC kana PD. Kuti tiongorore hukama huripo pakati peSCFA nekuoma kwekiriniki, takashandisa Spearman correlation analysis. Kuongororwa kwestatistike kwakaitwa tichishandisa SPSS software (vhezheni 22.0; SPSS Inc., Chicago, IL) ne level yekukosha (kusanganisira P value neFDR-P) yakaiswa pa 0.05 (two-sided).
MaS sequences gumi nematanhatu akaongororwa achishandisa musanganiswa weTrimmomatic (vhezheni 0.35), Flash (vhezheni 1.2.11), UPARSE (vhezheni v8.1.1756), mothur (vhezheni 1.33.3) uye R (vhezheni 3.6.3) software. Raw 16S rRNA gene data yakagadziriswa uchishandisa UPARSE kugadzira operational taxonomic units (OTUs) ine 97% identity. Taxonomies dzakatsanangurwa uchishandisa Silva 128 sedatabhesi rekutarisa. Generic level ye relative abundance data yakasarudzwa kuti iongororwe zvakanyanya. Linear discriminant analysis (LDA) efSE analysis (LEfSE) yakashandiswa kuenzanisa mapoka (ET vs. HC, ET vs. PD) ne α threshold ye0.05 uye effect size threshold ye2.0. Discriminant genera yakawanikwa neLEfSE analysis yakashandiswazve paSpearman correlation analysis yeSCFA.
Kuti uwane rumwe ruzivo nezve dhizaini yekudzidza, ona Natural Research Report Abstract yakabatana nechinyorwa chino.
Data re 16S rakachekwa rakachengetwa muNational Center for Biotechnology Information (NCBI) BioProject database (SRP438900: PRJNA974928), URL: https://www.ncbi.nlm.nih.gov/Traces/study/?acc= SRP438900&o. =acc_s% 3Aa. Mamwe mashoko akakodzera anowanikwa kumunyori anoenderana kana akakumbirwa zvine musoro, akadai sekushandira pamwe kwesainzi uye kuchinjana kwedzidzo nemapurojekiti akazara ekutsvagisa. Hapana kutumirwa kwedata kune vamwe vanhu pasina mvumo yedu kunotenderwa.
Kodhi yakavhurika chete ine musanganiswa weTrimmomatic (vhezheni 0.35), Flash (vhezheni 1.2.11), UPARSE (vhezheni v8.1.1756), mothur (vhezheni 1.33.3) uye R (vhezheni 3.6.3), uchishandisa marongero akajairika kana chikamu "Nzira". Ruzivo rwakawedzerwa rwekujekesa runogona kupihwa kumunyori anoenderana kana paine chikumbiro chakanaka.
Pradeep S naMehanna R. Matambudziko emudumbu mumatambudziko ekufamba kwe hyperkinetic uye ataxia. Akabatana nechirwere cheParkinson. kuvhiringidzika. 90, 125–133 (2021).
Louis, ED naFaust, PL Pathology yekutetemeka kwemuviri: kuora kwetsinga dzemuviri uye kurongeka patsva kwekubatana kwetsinga dzemuviri. Nat. Pastor Nirol. 16, 69–83 (2020).
Gironell, A. Kudedera kwechinhu chikuru chirwere cheGaba dysfunction here? Ehe. internationality. Rev. Neuroscience. 163, 259–284 (2022).
Dogra N., Mani RJ naKatara DP Mutsetse wegut-brain: nzira mbiri dzekuzivisa chirwere cheParkinson. Masero emasero. Neurobiology. 42, 315–332 (2022).
Quigley, EMM. Kubatana kwe microbiota-brain-gut uye zvirwere zvinokanganisa tsinga. zvazvino. Nellore. Neuroscience. Reports 17, 94 (2017).
Liu, XJ, Wu, LH, Xie, WR naHe, XX Fecal microbiota transplantation panguva imwe chete inovandudza essential tremor uye irritable bowel syndrome muvarwere. Geriatric Psychology 20, 796–798 (2020).
Zhang P. nevamwe. Shanduko dzakati wandei mu intestinal microbiota mu essential tremble uye kusiyana kwadzo ne Parkinson's disease. NPJ Parkinson's disease. 8, 98 (2022).
Luo S, Zhu H, Zhang J naWang D. Basa guru re microbiota mukudzora ma neuronal-glial-epithelial units. Kuramba hutachiona. 14, 5613–5628 (2021).
Emin A. nevamwe. Pathology ye duodenal alpha-synuclein uye intestinal gliosis muchirwere cheParkinson chinofambira mberi. kufamba. kuvhiringidzika. https://doi.org/10.1002/mds.29358 (2023).
Skorvanek M. nevamwe. Masoja ekudzivirira chirwere ealpha-synuclein 5G4 anoziva chirwere cheParkinson's pachena uye chirwere cheParkinson's prodromal mucosa yemudumbu. kufamba. kuvhiringidzika. 33, 1366–1368 (2018).
Algarni M naFasano A. Kuitika kamwe chete kwekudengenyeka kwemuviri uye chirwere cheParkinson. Kubatana nechirwere cheParkinson. kuvhiringidzika. 46, С101–С104 (2018).
Sampson, TR nevamwe. Gut microbiota inodzora kushaya simba kwemuviri uye kuzvimba kweuropi mumhando dzechirwere cheParkinson. Cell 167, 1469–1480.e1412 (2016).
Unger, MM nevamwe. Maacids emafuta mapfupi uye ma microbiota emudumbu zvakasiyana pakati pevarwere vane chirwere cheParkinson nevaya vane makore akafanana. Zvinobatanidzwa nechirwere cheParkinson. kuvhiringidzika. 32, 66–72 (2016).
Bleacher E, Levy M, Tatirovsky E naElinav E. MaMetabolites anodzorwa ne microbiome panzvimbo yekudzivirira muviri. J. Immunology. 198, 572–580 (2017).