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Ukuxilongwa kwangoko kwe-essential tremble (ET) kunokuba nzima, ingakumbi xa kwahlulwe kulawulo olusempilweni (HC) kunye nesifo sikaParkinson (PD). Kutshanje, uhlalutyo lweesampuli zesitulo se-gut microbiota kunye ne-metabolites zayo lubonelele ngeendlela ezintsha zokufumanisa ii-biomarkers ezintsha zezifo ze-neurodegenerative. I-Short-chain fatty acids (SCFA), njenge-metabolite ephambili ye-intestinal flora, iyancipha kwi-lice kwi-PD. Nangona kunjalo, i-fecal SCFA ayikaze ifundwe kwi-ET. Sijonge ukuphanda amanqanaba e-fecal e-SCFAs kwi-ET, ukuvavanya ulwalamano lwazo neempawu zeklinikhi kunye ne-gut microbiota, kunye nokufumanisa amandla azo okuxilonga. I-Fecal SCFA kunye ne-gut microbiota zilinganiswe kwi-ET ezingama-37, ii-PD ezintsha ezingama-37, kunye ne-HC ezingama-35. Ukuqunjelwa, ukungasebenzi kakuhle kwe-autonomic, kunye nobunzima bokungcangcazela kuhlolwe kusetyenziswa izikali. Amanqanaba e-fecal e-propionate, i-butyrate, kunye ne-isobutyrate ayephantsi kwi-ET kunakwi-HC. Udibaniso lwee-asidi ze-propionic, i-butyric kunye ne-isobutyric lwahlula i-ET kwi-HC ene-AUC ye-0.751 (95% CI: 0.634–0.867). Amanqanaba e-asidi ye-isovaleric ye-fecal kunye ne-isobutyric acid ayephantsi kwi-ET kunakwi-PD. I-asidi ye-Isovaleric kunye ne-isobutyric acid zahlula phakathi kwe-ET kunye ne-PD ene-AUC ye-0.743 (95% CI: 0.629–0.857). I-Fecal propionate inxulunyaniswa ngokuchaseneyo nokuqunjelwa kunye nokungasebenzi kakuhle kwe-autonomic. I-asidi ye-Isobutyric kunye ne-asidi ye-isovaleric zinxulumene ngokuchaseneyo nobunzima bokungcangcazela. Ukwehla komxholo we-SCFA ye-fecal kunxulunyaniswa nokwehla kobuninzi be-Faecalibacterium kunye ne-Streptobacterium kwi-ET. Ke ngoko, umxholo we-SCFA kwindle uyancipha kwi-ET kwaye unxulunyaniswa nobunzima bomfanekiso weklinikhi kunye notshintsho kwi-microbiota yamathumbu. I-Propionic acid, i-butyric acid, i-isobutyric acid, kunye ne-isovaleric acid ekwindle zinokuba ziimpawu zokuchonga kunye nokwahlulahlula ze-ET.
I-Essential tremor (ET) sisifo esiqhubekayo nesingapheliyo se-neurodegenerative esibonakaliswa ngokuyintloko kukungcangcazela kwamalungu aphezulu, okunokuchaphazela nezinye iindawo zomzimba ezifana nentloko, iintambo zelizwi, kunye namalungu asezantsi 1. Iimpawu zeklinikhi ze-ET azibandakanyi nje kuphela iimpawu ze-motor kodwa kunye nezinye iimpawu ezingezizo ze-motor, kubandakanya nesifo sesisu 2. Izifundo ezininzi zenziwe ukuze kuhlolwe iimpawu ze-pathological kunye ne-physiological ze-essential tremor, kodwa iindlela ezicacileyo ze-pathophysiological azikachongwa3,4. Izifundo zakutshanje zibonisa ukuba ukungasebenzi kakuhle kwe-microbiota-gut-brain axis kunokubangela izifo ze-neurodegenerative, kwaye kukho ubungqina obukhulayo bonxibelelwano olunokubakho phakathi kwe-gut microbiota kunye nezifo ze-neurodegenerative5,6. Okuphawulekayo kukuba, kwelinye ityala lengxelo, ukufakelwa kwe-fecal microbiota kuphucule zombini i-essential tremor kunye ne-irritable bowel syndrome kwisigulana, okunokubonisa ubudlelwane obusondeleyo phakathi kwe-gut microbiota kunye ne-essential tremor. Ukongeza, sikwafumene utshintsho oluthile kwi-gut microbiota kwizigulana ezine-ET, exhasa kakhulu indima ebalulekileyo ye-gut dysbiosis kwi-ET8.
Ngokuphathelele i-dysbiosis yamathumbu kwizifo ze-neurodegenerative, i-PD yeyona ifundwa kakhulu5. I-microbiota engalinganiyo inokunyusa ukungena kwamathumbu kwaye isebenze i-glia yamathumbu, nto leyo ekhokelela kwi-alpha-synucleinopathies9,10,11. I-PD kunye ne-ET zineempawu ezithile ezihambelanayo, ezifana nokungcangcazela okufanayo kwizigulane ze-ET kunye ne-PD, ukungcangcazela kokuphumla okungaphezulu (ukungcangcazela okuqhelekileyo kwi-PD), kunye nokungcangcazela kwesimo (okufumaneka kakhulu kwizigulane ze-ET), okwenza kube nzima ukwahlula phakathi kwazo. amanqanaba okuqala e-12. Ke ngoko, kufuneka sivule ngokukhawuleza ifestile eluncedo yokwahlula phakathi kwe-ET kunye ne-PD. Kulo mongo, ukufunda i-dysbiosis yamathumbu ethile kunye notshintsho oluhambelanayo lwe-metabolite kwi-ET kunye nokuchonga umahluko wabo kwi-PD kunokuba zii-biomarkers ezinokubakho zokuxilonga kunye nokuchonga umahluko we-ET.
Ii-fatty acids ezimfutshane (ii-SCFA) zezona metabolites ziphambili eziveliswa kukuvutshelwa kwebhaktiriya yamathumbu kwifayibha yokutya kwaye kucingelwa ukuba zidlala indima ebalulekileyo ekusebenzisaneni kwamathumbu nobuchopho13,14. Ii-SCFA zithathwa ziiseli zamathumbu kwaye zithuthelwe esibindini ngenkqubo ye-portal venous, kwaye ezinye ii-SCFA zingena kwi-systemic circulation. Ii-SCFA zinefuthe lasekuhlaleni ekugcineni ukuthembeka komqobo wamathumbu kunye nokukhuthaza ukuzikhusela kwendalo kwi-mucosa yamathumbu15. Zikwanefuthe lexesha elide kumqobo wegazi-ubuchopho (BBB) ​​​​ngokuvuselela iiproteni ezixineneyo kunye nokwenza ii-neurons zisebenze ngokuvuselela ii-receptors ze-G protein-coupled (GPCRs) ukuba zidlule kwi-BBB16. I-Acetate, i-propionate, kunye ne-butyrate zezona zininzi kwi-colon. Izifundo zangaphambili zibonise amanqanaba aphantsi e-acetic, propionic kunye ne-butyric acids kwizigulana ezinesifo sikaParkinson17. Nangona kunjalo, amanqanaba e-SCFA ye-fecal awakaze afundwe kwizigulana ezine-ET.
Ngoko ke, uphando lwethu lwalujolise ekuchongeni utshintsho oluthile kwi-SCFA yendle kwizigulane ezine-ET kunye nomahluko wazo kwizigulane ezine-PD, ukuvavanya ubudlelwane be-SCFA yendle kunye neempawu zeklinikhi ze-SCFA kunye ne-intestinal microbiota, kunye nokuchonga amandla okuxilonga kunye nokwahlulahlula kweesampuli zendle. KZHK. Ukujongana nezinto ezididayo ezinxulumene namayeza okulwa ne-PD, sikhethe izigulane ezinesifo sikaParkinson esitsha njengolawulo lwezifo.
Iimpawu zabantu kunye nezonyango ze-ET ezingama-37, ii-PD ezingama-37, kunye nee-HC ezingama-35 zishwankathelwe kwiTheyibhile 1. Ii-ET, ii-PD, kunye nee-HC zifaniswe ngokweminyaka, isini, kunye ne-BMI. La maqela mathathu nawo ayenemilinganiselo efanayo yokutshaya, ukusela utywala kunye nokusela ikofu kunye neti. Amanqaku e-Wexner (P = 0.004) kunye namanqaku e-HAMD-17 (P = 0.001) eqela le-PD ayephezulu kuneeqela le-HC, kwaye amanqaku e-HAMA (P = 0.011) kunye namanqaku e-HAMD-17 (P = 0.011) eqela le-ET ayephezulu kuneeqela le-HC. Indlela yesifo kwiqela le-ET yayinde kakhulu kunakwiqela le-PD (P<0.001).
Bekukho umahluko omkhulu kumanqanaba endle ye-fecal propionic acid (P = 0.023), i-acetic acid (P = 0.039), i-butyric acid (P = 0.020), i-isovaleric acid (P = 0.045), kunye ne-isobutyric acid (P = 0.015). . Kuhlalutyo oluqhubekayo emva kwe-hoc, amanqanaba e-propionic acid (P = 0.023), i-butyric acid (P = 0.007), kunye ne-isobutyric acid (P = 0.040) kwiqela le-ET ayephantsi kakhulu kunalawo akwiqela le-HC. Izigulane ezine-ET zazinamanqanaba aphantsi e-isovalerate (P = 0.014) kunye ne-isobutyrate (P = 0.005) kunezigulane ezine-PD. Ukongeza, amanqanaba e-fecal propionic acid (P = 0.013), i-acetic acid (P = 0.016), kunye ne-butyric acid (P = 0.041) ayephantsi kwizigulane ezine-PD kunakwizigulane ezine-CC (Umzobo 1 kunye neTheyibhile eyoNgezelelweyo 1).
I-ag imele uthelekiso lweqela le-propionic acid, i-acetic acid, i-butyric acid, i-isovaleric acid, i-valeric acid, i-caproic acid kunye ne-isobutyric acid, ngokwahlukeneyo. Bekukho umahluko omkhulu kumanqanaba e-fecal propionic acid, i-acetic acid, i-butyric acid, i-isovaleric acid kunye ne-isobutyric acid phakathi kwamaqela amathathu. I-ET essential tremor, isifo sikaParkinson, ulawulo lwe-HC olusempilweni, i-SCFA. Umahluko obalulekileyo uboniswe yi *P < 0.05 kunye ne **P < 0.01.
Ukuqwalasela umahluko kwindlela yokugula phakathi kweqela le-ET kunye neqela le-PD, sivavanye izigulane ezingama-33 ezine-PD yokuqala kunye nezigulane ezili-16 ezine-ET (indlela yokugula ≤ iminyaka emi-3) ukuze sithelekise ngakumbi (Itheyibhile eyongezelelweyo 2). Iziphumo zibonise ukuba umxholo we-fecal propionic acid we-ET wawuphantsi kakhulu kunowe-HA (P=0.015). Umahluko phakathi kwe-ET kunye ne-HC kwi-butyric acid kunye ne-isobutyric acid wawungabalulekile, kodwa umkhwa wawusabonwa (P=0.082). Amanqanaba e-isobutyrate ye-fecal ayephantsi kakhulu kwizigulane ezine-ET xa kuthelekiswa nezigulane ezine-PD (P=0.030). Umahluko phakathi kwe-ET kunye ne-PD ye-isovaleric acid wawungabalulekile, kodwa kwakusekho umkhwa (P=0.084). I-Propionic acid (P = 0.023), i-acetic acid (P = 0.020), kunye ne-butyric acid (P = 0.044) beziphantsi kakhulu kwizigulane ze-PD kunakwizigulane ze-HC. Ezi ziphumo (Umfanekiso Ongezelelweyo 1) ngokubanzi zihambelana neziphumo eziphambili. Umahluko kwiziphumo phakathi kwesampuli iyonke kunye neqela elincinci lesigulana sokuqala unokubangelwa bubungakanani obuncinci besampuli kwiqela elincinci, okubangela amandla aphantsi ezibalo zedatha.
Emva koko sihlolisise ukuba amanqanaba e-SCFA endle angahlula izigulane ezine-ET kwizigulane ezine-CU okanye i-PD. Ngokohlalutyo lwe-ROC, umahluko kwi-AUC yamanqanaba e-propionate yayiyi-0.668 (95% CI: 0.538-0.797), nto leyo eyenza kwaba nokwenzeka ukwahlula izigulane ezine-ET kwi-HC. Izigulane ezine-ET kunye ne-GC zinokwahlulwa ngamanqanaba e-butyrate ane-AUC eyi-0.685 (95% CI: 0.556–0.814). Umahluko kumanqanaba e-isobutyric acid unokwahlula izigulane ezine-ET kwi-HC ezine-AUC eyi-0.655 (95% CI: 0.525–0.786). Xa kuhlanganiswa amanqanaba e-propionate, i-butyrate kunye ne-isobutyrate, i-AUC ephezulu ye-0.751 (95% CI: 0.634–0.867) ifunyenwe ngovakalelo lwe-74.3% kunye nokucaciswa kwe-72.9% (Umzobo 2a). Ukwahlula phakathi kwezigulane ze-ET kunye ne-PD, i-AUC yamanqanaba e-isovaleric acid yayiyi-0.700 (95% CI: 0.579–0.822) kwaye kumanqanaba e-isobutyric acid yayiyi-0.718 (95% CI: 0.599–0.836). Ukudityaniswa kwamanqanaba e-isovaleric acid kunye ne-isobutyric acid yayine-AUC ephezulu ye-0.743 (95% CI: 0.629–0.857), ukucaciswa kwe-74.3% kunye nokucaciswa kwe-62.9% (Umzobo 2b). Ukongeza, sihlolisise ukuba amanqanaba e-SCFA kwindle yezigulana ezinesifo sikaParkinson ahlukile nakwezo zilawulayo. Ngokohlalutyo lwe-ROC, i-AUC yokuchonga izigulana ezine-PD ngokusekelwe kumahluko kumanqanaba e-propionic acid yayiyi-0.687 (95% CI: 0.559-0.814), enobuntununtunu be-68.6% kunye nokucaciswa kwe-68.7%. Umahluko kumanqanaba e-acetate unokwahlula izigulana ze-PD kwi-HCs ezine-AUC ye-0.674 (95% CI: 0.542–0.805). Izigulana ezine-PD zinokwahlulwa kwi-CU kuphela ngamanqanaba e-butyrate ane-AUC ye-0.651 (95% CI: 0.515–0.787). Xa kuhlanganiswa amanqanaba e-propionate, acetate kunye ne-butyrate, i-AUC ye-0.682 (95% CI: 0.553–0.811) ifunyenwe (Umzobo 2c).
Ukucalulwa kweCawa yama-Orthodox yaseRashiya ngokuchasene ne-ET kunye ne-HC; b ukucalulwa kweCawa yama-Orthodox yaseRashiya ngokuchasene ne-ET kunye ne-PD; c ukucalulwa kwe-ROC ngokuchasene ne-PD kunye ne-HC. Ukungcangcazela okubalulekileyo kwe-ET, isifo sikaParkinson, ulawulo lwe-HC olusempilweni, i-SCFA.
Kwizigulane ezine-ET, amanqanaba e-isobutyric acid ye-fecal ayenxulumene kakubi namanqaku e-FTM (r = -0.349, P = 0.034), kwaye amanqanaba e-isovaleric acid ye-fecal ayenxulumene kakubi namanqaku e-FTM (r = -0.421, P = 0.001) kunye namanqaku e-TETRAS. (r = -0.382, P = 0.020). Kwizigulane ezine-ET kunye ne-PD, amanqanaba e-fecal propionate ayenxulumene kakubi namanqaku e-SCOPA-AUT (r = -0.236, P = 0.043) (Umzobo 3 kunye neTheyibhile eyoNgezelelweyo 3). Akukho nxulumano lubalulekileyo phakathi kwendlela yesifo kunye ne-SCFA kwiqela le-ET (P ≥ 0.161) okanye kwiqela le-PD (P ≥ 0.246) (Itheyibhile eyoNgezelelweyo 4). Kwizigulane ezine-PD, amanqanaba e-caproic acid ye-fecal adibene kakuhle namanqaku e-MDS-UPDRS (r = 0.335, P = 0.042). Kubo bonke abathathi-nxaxheba, amanqanaba e-fecal propionate (r = −0.230, P = 0.016) kunye ne-acetate (r = −0.210, P = 0.029) adibene kakubi namanqaku e-Wexner (Umzobo 3 kunye neTheyibhile eyoNgezelelweyo 3).
Amanqanaba e-asidi ye-isobutyric ye-fecal ayenxulumene kakubi namanqaku e-FTM, i-asidi ye-isovaleric yayinxulumene kakubi namanqaku e-FTM kunye ne-TETRAS, i-asidi ye-propionic yayinxulumene kakubi namanqaku e-SCOPA-AUT, i-asidi ye-caproic yayinxulumene kakuhle namanqaku e-MDS-UPDRS, kwaye i-asidi ye-propionic yayinxulumene kakubi namanqaku e-FTM kunye ne-TETRAS. I-TETRAS kunye ne-acetic acid zazinxulumene kakubi namanqaku e-Wexner. I-MDS-UPDRS Association ixhase inguqulelo ye-Unified Parkinson's Disease Rating Scale, i-Mini-Mental State Examination MMSE, i-Hamilton Depression Rating Scale HAMD-17, izinto ezili-17, i-Hamilton Anxiety Rating Scale HAMA, i-HY Hoehn kunye ne-Yahr stages, i-SCFA, i-SCOPA - AUT Parkinson's Disease Autonomic Symptom Outcome Scale, i-FTM Fana-Tolosa-Marin Clinical Tremor Rating Scale, i-TETRAS Research Group (TRG) Essential Tremor Rating Scale. Umahluko obalulekileyo uboniswe yi-*P < 0.05 kunye ne-**P < 0.01.
Siphinde sahlola indlela ecalula ngayo i-gut microbiota sisebenzisa uhlalutyo lwe-LEfSE saza sakhetha inqanaba ledatha yobuninzi be-genus ukuze sihlalutye ngakumbi. Uthelekiso lwenziwe phakathi kwe-ET kunye ne-HC kunye naphakathi kwe-ET kunye ne-PD. Uhlalutyo lolwalamano lwe-Spearman lwenziwa emva koko kubuninzi be-gut microbiota kunye namanqanaba e-fecal SCFA kumaqela amabini othelekiso.
I-Faecalibacterium (enxulumene ne-butyric acid, r = 0.408, P < 0.001), i-Lactobacillus (enxulumene ne-butyric acid, r = 0.283, P = 0.016), i-Streptobacterium (enxulumene ne-propionic acid, r = 0.327) yayikhona kuhlalutyo lwe-ET kunye ne-CA. , P = 0.005; enxulumene ne-butyric acid, r = 0.374, P = 0.001; ihambelana ne-isobutyric acid, r = 0.329, P = 0.005), iHowardella (ihambelana ne-propionic acid, r = 0.242, P = 0.041), iRaoultella (ihambelana ne-propionate, r = 0.249, P = 0.035), kwaye iCandidatus Arthromitus (ihambelana ne-isobutyric acid, r = 0.302, P = 0.010) ifunyenwe inciphile kwi-ET kwaye ihambelana kakuhle namanqanaba e-SCFA yendle. Nangona kunjalo, ubuninzi beStenotropomonas banda kwi-ET kwaye bahambelana kakubi namanqanaba e-isobutyrate yendle (r = -0.250, P = 0.034). Emva kokulungiswa kwe-FDR, kuphela ulwalamano phakathi kweFaecalibacterium, iCatenibacter, kunye ne-SCFA oluhlala lubalulekile (P ≤ 0.045) (Umzobo 4 kunye neTheyibhile eyoNgezelelweyo 5).
Uhlalutyo lokuhambelana kwe-ET kunye ne-HC. Emva kokulungiswa kwe-FDR, ubuninzi beFaecalibacterium (enxulunyaniswa kakuhle ne-butyrate) kunye neStreptobacterium (enxulunyaniswa kakuhle ne-propionate, i-butyrate, kunye ne-isobutyrate) kufunyenwe ukuba kuncitshisiwe kwi-ET kwaye kunxulunyaniswa kakuhle namanqanaba e-SCFA yendle. b Uhlalutyo lokuhambelana kwe-ET kunye ne-PD. Emva kokulungiswa kwe-FDR, akukho nxulumano lubalulekileyo olufunyenweyo. Ukungcangcazela kwe-ET ebalulekileyo, isifo sikaParkinson, ulawulo lwe-HC olusempilweni, i-SCFA. Umahluko obalulekileyo uboniswe yi *P < 0.05 kunye **P < 0.01.
Xa kuhlalutywa i-ET ngokuchasene ne-PD, iClostridium trichophyton ifunyenwe inyukile kwi-ET kwaye inxulumene ne-fecal isovaleric acid (r = -0.238, P = 0.041) kunye ne-isobutyric acid (r = -0.257, P = 0.027). ). Emva kokulungiswa kwe-FDR, nokuba yeyiphi na yahlala ibalulekile (P≥0.295) (Umfanekiso 4 kunye neTheyibhile eyoNgezelelweyo 5).
Olu phononongo luphononongo olupheleleyo oluhlola amanqanaba e-SCFA yendle kwaye luwanxulumanisa notshintsho kwi-microbiota yesisu kunye nobunzima beempawu kwizigulane ezine-ET xa kuthelekiswa nezigulane ezine-CU kunye ne-PD. Sifumanise ukuba amanqanaba e-SCFA yendle anciphile kwizigulane ezine-ET kwaye anxulunyaniswa nobunzima beklinikhi kunye notshintsho oluthile kwi-microbiota yesisu. Amanqanaba aqokelelweyo e-short-chain fatty acids (SCFAs) kwindle ahlula i-ET kwi-GC kunye ne-PD.
Xa kuthelekiswa nezigulane ze-GC, izigulane ze-ET zinezinga eliphantsi le-asidi ye-propionic, i-butyric, kunye ne-isobutyric. Ukudibana kwe-asidi ye-propionic, i-butyric kunye ne-isobutyric kunokwahlula phakathi kwe-ET kunye ne-HC nge-AUC ye-0.751 (95% CI: 0.634–0.867), uvakalelo lwe-74.3% kunye nokucaciswa kwe-72.9%, okubonisa ukusetyenziswa kwazo njengendima enokubakho njengee-biomarkers zokuxilonga ze-ET. Uhlalutyo olongezelelweyo lubonise ukuba amanqanaba e-asidi ye-fecal propionic ayenxulumene kakubi nenqaku le-Wexner kunye nenqaku le-SCOPA-AUT. Amanqanaba e-asidi ye-isobutyric ye-fecal ayenxulumene ngokuchaseneyo namanqaku e-FTM. Kwelinye icala, ukwehla kwamanqanaba e-butyrate kwi-ET kwanxulunyaniswa nokwehla kobuninzi be-microbiota evelisa i-SCFA, i-Faecalibacter, kunye ne-Categorybacter. Ukongeza, ukuncipha kobuninzi be-Catenibacter kwi-ET kwanxulunyaniswa nokuncipha kwamanqanaba e-asidi ye ...
Uninzi lwee-SCFA eziveliswa kwikholoni zithathwa zii-colonocytes ngokuyintloko ngokusebenzisa ii-monocarboxylate ezixhomekeke kwi-H+ okanye ezixhomekeke kwi-sodium. Ii-fatty acids ezifunxwayo ezimfutshane zisetyenziswa njengomthombo wamandla kwiikholoni, ngelixa ezo zingagaywanga kwi-colonocytes zithuthwa ziye kwi-portal circulation 18. Ii-SCFA zinokuchaphazela ukuhamba kwamathumbu, ziphucule umsebenzi wokuthintela amathumbu, kwaye zichaphazele imetabolism yomninimzi kunye nokuzikhusela komzimba19. Ngaphambili kufunyaniswe ukuba ubuninzi be-butyrate, i-acetate, kunye ne-propionate buncitshisiwe kwizigulane ze-PD xa kuthelekiswa ne-HCs17, nto leyo ehambelana neziphumo zethu. Uphononongo lwethu lufumanise ukwehla kwe-SCFA kwizigulane ezine-ET, kodwa kuncinci okwaziwayo malunga nendima ye-SCFA kwi-pathology ye-ET. I-butyrate kunye ne-propionate zinokubophelela kwi-GPCR kwaye zichaphazele i-signaling exhomekeke kwi-GPCR efana ne-MAPK kunye ne-NF-κB20 signaling. Ingcamango esisiseko ye-gut-brain axis kukuba ii-SCFA ezikhutshwa zii-gut microbes zinokuchaphazela i-host signaling, ngaloo ndlela zichaphazela umsebenzi wamathumbu kunye nobuchopho. Ngenxa yokuba i-butyrate kunye ne-propionate zineziphumo ezinamandla zokuthintela umsebenzi we-histone deacetylase (HDAC)21 kwaye i-butyrate inokusebenza njenge-ligand yezinto ezibangela ukubhalwa kwezakhi zofuzo, zineziphumo ezibanzi kwi-metabolism yomninimzi, umahluko kunye nokwanda, ikakhulu ngenxa yempembelelo yazo kulawulo lwezakhi zofuzo22. Ngokusekelwe kubungqina obuvela kwi-SCFA kunye nezifo eziwohlokayo, i-butyrate ithathwa njengonyango ngenxa yokukwazi kwayo ukulungisa umsebenzi we-HDAC ophazamisekileyo, onokuthi ulawule ukufa kwe-dopaminergic neuron kwi-PD23,24,25. Izifundo zezilwanyana zikwabonise amandla e-butyric acid okuthintela ukuwohloka kwe-dopaminergic neuron kunye nokuphucula ukuphazamiseka kokuhamba kwiimodeli ze-PD26,27. I-Propionic acid ifunyenwe ukuba inciphisa iimpendulo zokudumba kwaye ikhusele ukuthembeka kwe-BBB28,29. Izifundo zibonise ukuba i-propionic acid ikhuthaza ukusinda kwee-dopaminergic neurons ekuphenduleni ubuthi be-rotenone kwiimodeli ze-PD30 kwaye ukuphathwa ngomlomo kwe-propionic acid kusindisa ukulahleka kwe-dopaminergic neuron kunye nokusilela kwe-motor kwiimpuku ezine-PD31. Kuncinci okwaziwayo malunga nomsebenzi we-isobutyric acid. Nangona kunjalo, uphando lwakutshanje lufumanise ukuba ukuhlanganiswa kweempuku ezine-B. ovale kwandisa umxholo we-SCFA yamathumbu (kubandakanya i-acetate, i-propionate, i-isobutyrate, kunye ne-isovalerate) kunye noxinzelelo lwe-GABA yamathumbu, nto leyo egxininisa ukuba kukho unxibelelwano olukhoyo phakathi kwe-gut microbiota kunye noxinzelelo lwe-SCFA yamathumbu. 32. Kwi-ET, utshintsho olungaqhelekanga lwe-pathological kwi-cerebellum lubandakanya utshintsho kwi-axons kunye ne-dendrites zeseli zePurkinje, ukufuduka kunye nokulahleka kweeseli zePurkinje, utshintsho kwi-axons zeseli zebhasikithi, kunye nokungaqhelekanga kunxibelelwano lwefayibha olunyukayo kwiiseli zePurkinje. nuclei, okukhokelela ekunciphiseni kokuphuma kwe-GABAergic kwi-cerebellum3,4,33. Akukacaci ukuba ii-SCFA zidibene ne-neurodegeneration yeseli yePurkinje kunye nokwehla kwemveliso ye-GABA ye-cerebellar. Iziphumo zethu zibonisa ubudlelwane obusondeleyo phakathi kwe-SCFA kunye ne-ET; nangona kunjalo, uyilo lwesifundo esinqamlezileyo aluvumeli naziphi na izigqibo malunga nobudlelwane besizathu phakathi kwe-SCFA kunye nenkqubo yesifo se-ET. Izifundo ezongezelelweyo zokulandelela ixesha elide ziyafuneka, kubandakanya ukulinganiswa okulandelelanayo kwe-SCFAs yendle, kunye nezifundo zezilwanyana ezihlola iindlela.
Kucingelwa ukuba ii-SCFA zikhuthaza ukuqiniswa kwemisipha ethambileyo yamathumbu34. Ukungabikho kwe-SCFA kuya kuyenza mandundu iimpawu zokuqhina, kwaye ukongezwa kwe-SCFA kunokuphucula iimpawu zokuqhina kwe-PD35. Iziphumo zethu zikwabonisa unxibelelwano olubalulekileyo phakathi kokuncipha komxholo we-SCFA yendle kunye nokwanda kokuqhina kunye nokungasebenzi kakuhle kwe-autonomic kwizigulane ezine-ET. Ingxelo yetyala elinye ifumanise ukuba ukufakelwa kwe-microbiota kuphucule zombini i-essential tremble kunye ne-irritable bowel syndrome kwisigulane se-7, nto leyo ebonisa ngakumbi ulwalamano olusondeleyo phakathi kwe-gut microbiota kunye ne-ET. Ke ngoko, sikholelwa ukuba i-fecal SCFA/microbiota inokuchaphazela ukuhamba kwamathumbu kunye nokusebenza kwenkqubo ye-autonomic nervous system.
Olu phononongo lufumanise ukuba amanqanaba aphantsi e-SCFAs yendle kwi-ET adibene nokuncipha kobuninzi beFaecalibacterium (enxulunyaniswa ne-butyrate) kunye neStreptobacterium (enxulunyaniswa ne-propionate, i-butyrate, kunye ne-isobutyrate). Emva kokulungiswa kwe-FDR, olu lwalamano luhlala lubalulekile. I-Faecalibacterium kunye neStreptobacterium ziintsholongwane ezivelisa i-SCFA. I-Faecalibacterium yaziwa ngokuba yi-microorganism evelisa i-butyrate36, ngelixa iimveliso eziphambili ze-Catenibacter fermentation yi-acetate, i-butyrate kunye ne-lactic acid37. I-Faecalibacterium ifunyenwe kwi-100% yamaqela e-ET kunye ne-HC; Ubuninzi obuphakathi beqela le-ET yayiyi-2.06% kwaye obo beqela le-HC yayiyi-3.28% (LDA 3.870). Ibhaktiriya yodidi ifunyenwe kwi-21.6% (8/37) yeqela le-HC kwaye kwisampulu enye kuphela yeqela le-ET (1/35). Ukwehla nokungafumaneki kwe-streptobacteria kwi-ET kunokubonisa ulwalamano kunye nesifo esibangela isifo. Ubuninzi obuphakathi beentlobo zeCatenibacter kwiqela le-HC yayiyi-0.07% (LDA 2.129). Ukongeza, iibhaktheriya ze-lactic acid zazinxulunyaniswa notshintsho kwi-butyrate yendle (P=0.016, P=0.096 emva kohlengahlengiso lwe-FDR), kwaye umviwa we-arthritis wayenxulunyaniswa notshintsho kwi-isobutyrate (P=0.016, P=0.072 emva kohlengahlengiso lwe-FDR). Emva kokulungiswa kwe-FDR, kuphela umkhwa wolwalamano oseleyo, ongabalulekanga ngokwezibalo. I-Lactobacilli ikwaziwa ngokuba ngabavelisi be-SCFA (acetic acid, propionic acid, isobutyric acid, butyric acid) 38 kwaye i-Candidatus Arthromitus yi-inducer ethile ye-T helper 17 (Th17) cell differentiation, kunye ne-Th1/2 kunye ne-Tregs ezinxulumene ne-immune balance /Th1739. . Uphononongo lwakutshanje lubonisa ukuba amanqanaba aphezulu e-fecal pseudoarthritis anokuba negalelo ekuvuvukeni kwamathumbu amakhulu, ukungasebenzi kakuhle kwe-intestinal barrier, kunye nokuvuvukala komzimba 40. I-Clostridium trichophyton yonyuswe kwi-ET xa kuthelekiswa ne-PD. Ubuninzi be-Clostridium trichoides bufunyenwe bunxulumene kakubi ne-isovaleric acid kunye ne-isobutyric acid. Emva kokulungiswa kwe-FDR, zombini zahlala zibalulekile (P≥0.295). I-Clostridium pilosum yibhaktheriya eyaziwa ngokuba inxulumene nokuvuvukala kwaye inokuba negalelo ekungasebenzi kakuhle kwe-intestinal barrier41. Uphononongo lwethu lwangaphambili lubike utshintsho kwi-gut microbiota yezigulana ezine-ET8. Apha sikwabika utshintsho kwi-SCFAs kwi-ET kwaye sichonga unxulumano phakathi kwe-gut dysbiosis kunye notshintsho kwi-SCFAs. Amanqanaba e-SCFA anciphileyo anxulumene kakhulu ne-intestinal dysbiosis kunye nobunzima bokungcangcazela kwi-ET. Iziphumo zethu zibonisa ukuba i-gut-brain axis inokudlala indima ebalulekileyo kwi-pathogenesis ye-ET, kodwa kufuneka izifundo ezongezelelweyo kwiimodeli zezilwanyana.
Xa kuthelekiswa nezigulana ezine-PD, izigulana ezine-ET zinamanqanaba aphantsi e-isovaleric kunye ne-isobutyric acids kwindle yazo. Ukudibana kwe-isovaleric acid kunye ne-isobutyric acid kuchonge i-ET kwi-PD nge-AUC ye-0.743 (95% CI: 0.629–0.857), uvakalelo lwe-74.3% kunye nokucaciswa kwe-62.9%, okubonisa indima yazo enokubakho njengee-biomarkers ekuxilongweni okuhlukileyo kwe-ET. . Amanqanaba e-isovaleric acid ye-fecal adibene ngokuchaseneyo namanqaku e-FTM kunye ne-TETRAS. Amanqanaba e-isobutyric acid ye-fecal adibene ngokuchaseneyo namanqaku e-FTM. Ukwehla kwamanqanaba e-isobutyric acid kudibene nokwehla kobuninzi be-catobacteria. Kuncinci okwaziwayo ngemisebenzi ye-isovaleric acid kunye ne-isobutyric acid. Uphononongo lwangaphambili lubonise ukuba ukuhlanganiswa kweempuku ngeBacteroides ovale kwandisa umxholo we-SCFA yamathumbu (kubandakanya i-acetate, i-propionate, i-isobutyrate, kunye ne-isovalerate) kunye noxinzelelo lwe-GABA yamathumbu, nto leyo egxininisa unxibelelwano lwamathumbu phakathi kwe-microbiota kunye noxinzelelo lwe-SCFA/neurotransmitter yamathumbu32. Okunomdla kukuba, amanqanaba e-isobutyric acid abonwe afana phakathi kwamaqela e-PD kunye ne-HC, kodwa ahluke phakathi kwamaqela e-ET kunye ne-PD (okanye i-HC). I-Isobutyric acid inokwahlula phakathi kwe-ET kunye ne-PD ene-AUC ye-0.718 (95% CI: 0.599–0.836) kwaye ichonge i-ET kunye ne-NC ene-AUC ye-0.655 (95% CI: 0.525–0.786). Ukongeza, amanqanaba e-isobutyric acid ahambelana nobunzima bokungcangcazela, okuqinisa ngakumbi ulwalamano lwayo ne-ET. Umbuzo wokuba ingaba i-isobutyric acid yomlomo inokunciphisa ubunzima bokungcangcazela kwizigulana ezine-ET ifanelwe luphononongo olongezelelweyo.
Ngoko ke, umxholo we-SCFA yendle uyancipha kwizigulane ezine-ET kwaye unxulunyaniswa nobunzima beklinikhi be-ET kunye notshintsho oluthile kwi-microbiota yamathumbu. I-Fecal propionate, i-butyrate, kunye ne-isobutyrate zinokuba zii-biomarkers zokuxilonga ze-ET, ngelixa i-isobutyrate kunye ne-isovalerate zinokuba zii-biomarkers zokuxilonga ezahlukileyo ze-ET. Utshintsho kwi-isobutyrate yendle lunokuba luchaneke ngakumbi kwi-ET kunotshintsho kwezinye ii-SCFA.
Uphononongo lwethu lunemida eliqela. Okokuqala, iipateni zokutya kunye nokukhetha ukutya kunokuchaphazela ukubonakaliswa kwe-microbiota, kufuneka iisampulu zophando ezinkulu kwiindawo ezahlukeneyo, kwaye izifundo ezizayo kufuneka ziveze uphando olupheleleyo nolucwangcisiweyo lokutya olufana nemibuzo yesiqhelo sokutya. Okwesibini, uyilo lophando olunqamlezileyo luthintela naziphi na izigqibo malunga nobudlelwane obubangela phakathi kwee-SCFA kunye nophuhliso lwe-ET. Izifundo ezilandelelanayo zexesha elide ezinokulinganiswa ngokulandelelana kwee-SCFA zendle ziyafuneka. Okwesithathu, amandla okuxilonga kunye nokwahlulahlula kwamanqanaba e-SCFA yendle kufuneka aqinisekiswe kusetyenziswa iisampulu ezizimeleyo ezivela kwi-ET, HC, kunye ne-PD. Iisampulu zendle ezizimeleyo ngakumbi kufuneka zivavanywe kwixesha elizayo. Okokugqibela, izigulane ezine-PD kwiqela lethu zazinexesha elifutshane kakhulu lesifo kunezigulane ezine-ET. Ngokuyintloko silinganise i-ET, i-PD kunye ne-HC ngokweminyaka, isini kunye ne-BMI. Ngenxa yomahluko kwindlela yesifo phakathi kweqela le-ET kunye neqela le-PD, sikwafunde izigulane ezingama-33 ezine-PD yokuqala kunye nezigulane ezili-16 ezine-ET (ubude besifo ≤ iminyaka emi-3) ukuze sithelekise ngakumbi. Umahluko phakathi kweqela kwi-SCFA ngokubanzi wawuhambelana nedatha yethu ephambili. Ukongeza, asifumananga nxibelelwano phakathi kobude bexesha lesifo kunye notshintsho kwi-SCFA. Nangona kunjalo, kwixesha elizayo, kungangcono ukuqesha izigulane ezine-PD kunye ne-ET kwangethuba ezinexesha elifutshane lesifo ukuze kugqitywe ukuqinisekiswa kwisampulu enkulu.
Le nkqubo yokufunda yamkelwe yikomiti yemigaqo yokuziphatha yeSibhedlele iRuijin, enxulumene neShanghai Jiao Tong University School of Medicine (RHEC2018-243). Imvume ebhaliweyo enolwazi ifunyenwe kubo bonke abathathi-nxaxheba.
Phakathi kukaJanuwari 2019 noDisemba 2022, izifundo ezili-109 (37 ET, 37 PD, kunye ne-35 HC) ezivela kwiKlinikhi yeZiko leMovement Disorder yeSibhedlele iRuijin, edibene neShanghai Jiao Tong University School of Medicine, zibandakanyiwe kolu phononongo. Iikhrayitheriya bezi: (1) iminyaka engama-25–85 ubudala, (2) izigulane ezine-ET zichongiwe ngokwekhrayitheriya yeQela eliSebenzayo le-MDS 42 kunye ne-PD zichongiwe ngokwekhrayitheriya ye-MDS 43, (3) zonke izigulane bezingathathi amayeza okulwa ne-PD ngaphambi kokuba ziqokelelwe iisampulu. (4) Iqela le-ET lithathe kuphela ii-β-blockers okanye akukho mayeza anxulumene noko ngaphambi kokuba ziqokelele iisampulu zesitulo. Ii-HCs ezihambelana nobudala, isini, kunye ne-body mass index (BMI) nazo zikhethiwe. Iikhrayitheriya zokukhutshwa kwezi zinto zazizi: (1) abantu abatya imifuno kuphela, (2) ukutya okungondleki kakuhle, (3) izifo ezingapheliyo zendlela yokugaya ukutya (kubandakanya isifo samathumbu esidumbileyo, izilonda zesisu okanye ze-duodenal), (4) izifo ezingapheliyo ezinzima (kubandakanya iithumba ezinobungozi), ukusilela kwentliziyo, ukungaphumeleli kwezintso, izifo zegazi) (5) Imbali yotyando olukhulu lwesisu, (6) Ukutya iyogathi rhoqo okanye rhoqo, (7) Ukusetyenziswa kweprobiotics okanye ii-antibiotics inyanga e-1, (8) Ukusetyenziswa rhoqo kwe-corticosteroids, ii-proton pump inhibitors, ii-statins, i-metformin, ii-immunosuppressants okanye amayeza okubulala umhlaza kunye (9) ukuphazamiseka kwengqondo okuphazamisana nezilingo zeklinikhi.
Zonke izifundo zibonelele ngembali yezonyango, ubunzima kunye nobude ukuze kubalwe i-BMI, kwaye zenze uvavanyo lwe-neurological kunye novavanyo lweklinikhi olufana ne-Hamilton Anxiety Rating Scale (HAMA) 44 anxiety score, i-Hamilton Depression Rating Scale-17 score (HAMD-17) 45. ukudakumba, ubunzima bokuqhinwa kusetyenziswa i-Wexner Constipation Scale 46 kunye ne-Bristol Stool Scale 47 kunye nokusebenza kwengqondo kusetyenziswa i-Mini-Mental State Examination (MMSE) 48. I-Scale for the Assessment of Autonomic Symptoms of Parkinson's Disease (SCOPA-AUT) 49 ihlole ukungasebenzi kakuhle kwe-autonomic kwizigulane ezine-ET kunye ne-PD. I-Fan-Tolos-Marin Clinical Tremor Rating Scale (FTM) kunye ne-Essential Tremor Rating Scale (TETRAS) 50 Iqela le-Tremor Study (TRG) 50 lihlolwe kwizigulane ezine-ET; i-Kinson's Disease rating rating scale (MDS-UPDRS) version 51 kunye ne-Hoehn and Yahr (HY) grade 52 zihlolwe.
Umthathi-nxaxheba ngamnye ucelwe ukuba aqokelele isampuli yendle kusasa esebenzisa isitya sokuqokelela indle. Dlulisa izikhongozeli emkhenkceni aze azigcine kwi--80°C ngaphambi kokuba zicutshungulwe. Uhlalutyo lwe-SCFA lwenziwe ngokwemisebenzi eqhelekileyo yeTiangene Biotechnology (Shanghai) Co., Ltd. Iisampuli zendle ezintsha ezingama-400 mg zaqokelelwa kumntu ngamnye zaza zahlalutywa kusetyenziswa ii-SCFA emva kokusila kunye nokulungiselela kwangaphambili. Ii-SCFA ezikhethiweyo kwindle zahlalutywa kusetyenziswa i-gas chromatography-mass spectrometry (GC-MS) kunye ne-liquid chromatography-tandem MS (LC-MS/MS).
I-DNA ikhutshwe kwiisampulu ezingama-200 mg kusetyenziswa i-QIAamp® Fast DNA Stool Mini Kit (QIAGEN, Hilden, eJamani) ngokwemiyalelo yomenzi. Ulwakhiwo lwe-microbial luchongiwe ngokulandelana kwe-16 S rRNA gene kwi-DNA ehlukaniswe kwindle ngokwandisa ummandla we-V3-V4. Vavanya i-DNA ngokusebenzisa isampuli kwi-1.2% agarose gel. Ukwandiswa kwe-Polymerase chain reaction (PCR) ye-16S rRNA gene kwenziwe kusetyenziswa ii-universal bacterial primers (357 F kunye ne-806 R) kunye nelayibrari ye-amplicon enamanyathelo amabini eyakhiwe kwiqonga le-Novaseq.
Iinguqu eziqhubekayo zibonakaliswa njenge-mean ± standard deviation, kwaye iinguqu zezigaba zibonakaliswa njengeenombolo kunye neepesenti. Sisebenzise uvavanyo lukaLevene ukuvavanya i-homogeneity yeenguqu. Uthelekiso lwenziwe kusetyenziswa uvavanyo lwe-t olunemisila emibini okanye uhlalutyo lwe-variance (ANOVA) ukuba iinguqu zihlala zisasazwa kunye novavanyo lwe-Mann-Whitney U olungeyo-parametric ukuba uqikelelo lwe-normality okanye i-homoscedasticity luphulwe. Sisebenzise indawo ephantsi kwe-receiver operating characteristic (ROC) curve (AUC) ukulinganisa ukusebenza kwe-diagnostic yemodeli kunye nokuhlola amandla e-SCFA okwahlula izigulane ezine-ET kwabo bane-HC okanye i-PD. Ukuhlola ubudlelwane phakathi kwe-SCFA kunye nobunzima beklinikhi, sisebenzise uhlalutyo lwe-Spearman correlation. Uhlalutyo lwezibalo lwenziwe kusetyenziswa isoftware ye-SPSS (inguqulelo 22.0; SPSS Inc., eChicago, IL) kunye nenqanaba lokubaluleka (kubandakanya ixabiso le-P kunye ne-FDR-P) elibekwe kwi-0.05 (emacala amabini).
Ii-sequences ze-S ezili-16 zihlalutywe kusetyenziswa indibaniselwano ye-Trimmomatic (inguqulelo 0.35), i-Flash (inguqulelo 1.2.11), i-UPARSE (inguqulelo v8.1.1756), i-mothur (inguqulelo 1.33.3) kunye ne-R (inguqulelo 3.6.3). Idatha ye-gene ye-rRNA ye-16S engaqhelekanga icutshungulwe kusetyenziswa i-UPARSE ukuvelisa iiyunithi ze-taxonomic ezisebenzayo (ii-OTU) ezine-97% yobunikazi. Ii-taxonomies zichazwe kusetyenziswa i-Silva 128 njengesiseko sedatha. Inqanaba eliqhelekileyo ledatha yobuninzi obuhambelanayo likhethiwe ukuze kuhlalutywe ngakumbi. Uhlalutyo lobungakanani besiphumo se-Linear discriminant analysis (LDA) (LEfSE) lusetyenziselwe ukuthelekisa phakathi kwamaqela (ET vs. HC, ET vs. PD) kunye nomda we-α we-0.05 kunye nomda wesiphumo we-2.0. I-Dispriminant genera echongiweyo yi-LEfSE analysis isetyenzisiwe ngakumbi kuhlalutyo lolwalamano lwe-Spearman lwe-SCFA.
Ukuze ufumane ulwazi oluthe kratya malunga noyilo lophando, jonga i-Natural Research Report Abstract enxulumene neli nqaku.
Idatha yokulandelelana kwe-Raw 16S igcinwa kwisiseko sedatha se-BioProject seZiko leSizwe loLwazi lweBiotechnology (NCBI) (SRP438900: PRJNA974928), i-URL: https://www.ncbi.nlm.nih.gov/Traces/study/?acc= SRP438900&o. =acc_s% 3Aa. Ezinye iinkcukacha ezifanelekileyo ziyafumaneka kumbhali ohambelanayo xa kuceliwe, njengentsebenziswano yesayensi kunye nokutshintshiselana ngezifundo kunye neeprojekthi zophando ezipheleleyo. Akukho kudluliselwa kwedatha kumaqela esithathu ngaphandle kwemvume yethu okuvunyelweyo.
Ikhowudi yomthombo ovulekileyo kuphela ngokudibanisa iTrimmomatic (inguqulelo 0.35), iFlash (inguqulelo 1.2.11), iUPARSE (inguqulelo v8.1.1756), i-mothur (inguqulelo 1.33.3) kunye ne-R (inguqulelo 3.6.3), kusetyenziswa useto oluzenzekelayo okanye icandelo elithi “Indlela”. Ulwazi olongezelelweyo olucacisayo lunokunikezelwa kumbhali ohambelanayo xa kuceliwe ngokufanelekileyo.
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