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Ukuxilongwa kusenesikhathi kwe-essential tremble (ET) kungaba yinselele, ikakhulukazi uma kuqhathaniswa nezilawuli ezinempilo (HC) kanye nesifo sikaParkinson (PD). Muva nje, ukuhlaziywa kwamasampula esidleke se-gut microbiota kanye nama-metabolite ayo kuhlinzeke ngezindlela ezintsha zokuthola ama-biomarker amasha ezifo ze-neurodegenerative. Ama-fatty acid ama-short-chain (SCFA), njenge-metabolite eyinhloko yezitshalo zamathumbu, ancipha endle ku-PD. Kodwa-ke, i-fecal SCFA ayikaze ifundwe ku-ET. Sasihlose ukuphenya amazinga e-fecal e-SCFAs ku-ET, sihlole ubudlelwano bawo nezimpawu zomtholampilo kanye ne-gut microbiota, futhi sinqume ikhono lawo lokuxilonga elingaba khona. I-Fecal SCFA kanye ne-gut microbiota kwalinganiswa kuma-ET angu-37, ama-PD amasha angu-37, kanye nama-HC angu-35. Ukuqunjelwa, ukungasebenzi kahle kwe-autonomic, kanye nobunzima bokuthuthumela kwahlolwa kusetshenziswa izikali. Amazinga e-fecal e-propionate, i-butyrate, kanye ne-isobutyrate ayephansi ku-ET kunaku-HC. Inhlanganisela yama-asidi e-propionic, i-butyric kanye ne-isobutyric yahlukanisa i-ET ne-HC ene-AUC engu-0.751 (95% CI: 0.634–0.867). Amazinga e-asidi ye-isovaleric ye-fecal kanye ne-isobutyric acid ayephansi ku-ET kunaku-PD. I-asidi ye-Isovaleric kanye ne-isobutyric acid zihlukanisa phakathi kwe-ET ne-PD ene-AUC engu-0.743 (95% CI: 0.629–0.857). I-Fecal propionate ihlotshaniswa ngokuphambene nokuqunjelwa kanye nokungasebenzi kahle kwe-autonomic. I-asidi ye-Isobutyric kanye ne-isovaleric acid zihlobene ngokuphambene nobunzima bokuthuthumela. Ukwehla kwama-SCFA e-fecal kuhlotshaniswa nokwehla kobuningi be-Faecalibacterium kanye ne-Streptobacterium ku-ET. Ngakho-ke, okuqukethwe kwe-SCFA endle kwehla ku-ET futhi kuhlotshaniswa nobunzima besithombe somtholampilo kanye nezinguquko ku-microbiota yamathumbu. I-Fecal propionate, i-butyrate, i-isobutyrate, kanye ne-isovalerate kungaba yizimpawu zokuxilonga ezingasetshenziswa ekuxilongeni nasekuhlukaniseni i-ET.
Ukuthuthumela Okubalulekile (ET) kuyisifo esiqhubekayo nesingapheli se-neurodegenerative esibonakala kakhulu ngokuthuthumela kwezingxenye ezingaphezulu zomzimba, okungathinta nezinye izingxenye zomzimba njengekhanda, izintambo zezwi, kanye nezingxenye ezingezansi zomzimba 1. Izici zezokwelapha ze-ET azihlanganisi nje kuphela izimpawu ze-motor kodwa nezinye izimpawu ezingezona eze-motor, okuhlanganisa nesifo se-gastrointestinal 2. Izifundo eziningi zenziwe ukuhlola izici ze-pathological kanye nezomzimba ze-essential tremb, kodwa izindlela ezicacile ze-pathophysiological azikatholakali3,4; Izifundo zakamuva ziphakamisa ukuthi ukungasebenzi kahle kwe-microbiota-gut-brain axis kungabangela izifo ze-neurodegenerative, futhi kunobufakazi obukhulayo bokuxhumana okungaba khona phakathi kwe-gut microbiota kanye nezifo ze-neurodegenerative5,6. Okuphawulekayo, embikweni wesinye isigameko, ukufakelwa kwe-fecal microbiota kuthuthukise kokubili ukuthuthumela okubalulekile kanye ne-irritable bowel syndrome esigulini, okungase kubonise ubudlelwano obuseduze phakathi kwe-gut microbiota kanye ne-essential tremb. Ngaphezu kwalokho, sithole nezinguquko ezithile ku-gut microbiota ezigulini ezine-ET, okusekela kakhulu indima ebalulekile ye-gut dysbiosis ku-ET8.
Ngokuphathelene ne-dysbiosis yamathumbu ezifweni ze-neurodegenerative, i-PD iyona efundwa kabanzi5. I-microbiota engalingani ingandisa ukungena kwamathumbu futhi isebenze i-glia yamathumbu, okuholela ku-alpha-synucleinopathies9,10,11. I-PD ne-ET zabelana ngezici ezithile ezivamile, njengokuvama okufanayo kokuthuthumela ezigulini ze-ET ne-PD, ukuthuthumela okuphumula okuphindaphindene (ukuthuthumela okuvamile ku-PD), kanye nokuthuthumela kwesimo (okutholakala kakhulu ezigulini ze-ET), okwenza kube nzima ukuhlukanisa phakathi kwazo. izigaba zokuqala 12. Ngakho-ke, sidinga ngokuphuthumayo ukuvula ifasitela eliwusizo lokuhlukanisa phakathi kwe-ET ne-PD. Kulo mongo, ukufunda i-dysbiosis yamathumbu ethize kanye nezinguquko ze-metabolite ezihambisanayo ku-ET nokuhlonza umehluko wazo ku-PD kungaba yizimpawu ezingenzeka zokuxilongwa kanye nokuxilongwa okuhlukile kwe-ET.
Ama-fatty acid ama-short-chain (ama-SCFA) yiwona ama-metabolites amakhulu akhiqizwa ukuvutshelwa kwamagciwane amathumbu e-fiber yokudla futhi kucatshangwa ukuthi adlala indima ebalulekile ekusebenzisaneni kwamathumbu nobuchopho13,14. Ama-SCFA athathwa ngamaseli e-colon bese ethuthelwa esibindini ngesistimu ye-portal venous, kanti amanye ama-SCFA angena ekujikelezeni kwegazi. Ama-SCFA anemiphumela yendawo ekugcineni ubuqotho bomgoqo wamathumbu nokukhuthaza ukuzivikela kwemvelo ku-mucosa yamathumbu15. Aphinde abe nemiphumela yesikhathi eside kumgoqo wegazi nobuchopho (BBB) ​​​​ngokuvuselela amaprotheni e-tight junction kanye nokwenza ama-neurons asebenze ngokuvuselela ama-receptor e-G protein-coupled (GPCRs) ukuze awele i-BBB16. I-Acetate, i-propionate, kanye ne-butyrate yiwona ama-SCFA amaningi kakhulu ku-colon. Izifundo zangaphambilini zibonise amazinga e-fecal e-acetic, propionic kanye ne-butyric acid ezigulini ezinesifo sikaParkinson17. Kodwa-ke, amazinga e-fecal e-SCFA awakaze afundwe ezigulini ezine-ET.
Ngakho-ke, ucwaningo lwethu lwaluhlose ukuhlonza izinguquko ezithile ku-SCFA yendle ezigulini ezine-ET kanye nomehluko wazo ezigulini ezine-PD, ukuhlola ubudlelwano be-SCFA yendle nezimpawu zomtholampilo ze-ET kanye ne-microbiota yamathumbu, kanye nokunquma amakhono okuxilonga angaba khona kanye nokwehluka kwamasampula endle. KZhK. Ukuze sibhekane nezici ezididayo ezihambisana nemithi yokulwa ne-PD, sikhethe iziguli ezinesifo sikaParkinson esisanda kuqala njengezilawuli zezifo.
Izici zezibalo kanye nezemitholampilo zama-ET angu-37, ama-PD angu-37, kanye nama-HC angu-35 zifingqiwe kuThebula 1. Ama-ET, ama-PD, kanye nama-HC afaniswe nobudala, ubulili, kanye ne-BMI. La maqembu amathathu nawo ayenezilinganiso ezifanayo zokubhema, ukuphuza utshwala kanye nokuphuza ikhofi netiye. Isikolo se-Wexner (P = 0.004) kanye nesikolo se-HAMD-17 (P = 0.001) seqembu le-PD sasiphezulu kuneseqembu le-HC, kanti isikolo se-HAMA (P = 0.011) kanye nesikolo se-HAMD-17 (P = 0.011) seqembu le-ET sasiphezulu kuneseqembu le-HC. Inkambo yesifo eqenjini le-ET yayinde kakhulu kunaseqenjini le-PD (P<0.001).
Kube nomehluko omkhulu emazingeni endle e-fecal propionic acid (P = 0.023), i-acetic acid (P = 0.039), i-butyric acid (P = 0.020), i-isovaleric acid (P = 0.045), kanye ne-isobutyric acid (P = 0.015). . Ekuhlaziyweni okuqhubekayo kwangemva kwe-hoc, amazinga e-propionic acid (P = 0.023), i-butyric acid (P = 0.007), kanye ne-isobutyric acid (P = 0.040) eqenjini le-ET ayephansi kakhulu kunalawo eqenjini le-HC. Iziguli ezine-ET zazinamazinga aphansi e-isovalerate (P = 0.014) kanye ne-isobutyrate (P = 0.005) kuneziguli ezine-PD. Ngaphezu kwalokho, amazinga e-fecal propionic acid (P = 0.013), i-acetic acid (P = 0.016), kanye ne-butyric acid (P = 0.041) ayephansi ezigulini ezine-PD kunasezigulini ezine-CC (Isithombe 1 kanye neThebula Elingeziwe 1).
I-ag imele ukuqhathaniswa kweqembu le-propionic acid, i-acetic acid, i-butyric acid, i-isovaleric acid, i-valeric acid, i-caproic acid kanye ne-isobutyric acid, ngokulandelana. Kwakukhona umehluko omkhulu emazingeni e-fecal propionic acid, i-acetic acid, i-butyric acid, i-isovaleric acid kanye ne-isobutyric acid phakathi kwamaqembu amathathu. Ukuthuthumela okubalulekile kwe-ET, isifo sikaParkinson, ukulawulwa kwe-HC okunempilo, i-SCFA. Umehluko omkhulu ukhonjiswa yi-*P < 0.05 kanye ne-**P < 0.01.
Uma sibheka umehluko endleleni yesifo phakathi kweqembu le-ET neqembu le-PD, sihlole iziguli ezingu-33 ezine-PD yokuqala kanye neziguli ezingu-16 ezine-ET (indlela yesifo engaphansi kweminyaka emi-3) ukuze siqhathanise kabanzi (Ithebula Elingeziwe 2). Imiphumela ibonise ukuthi okuqukethwe kwe-fecal propionic acid ye-ET kwakuphansi kakhulu kunokwe-HA (P=0.015). Umehluko phakathi kwe-ET ne-HC ye-butyric acid kanye ne-isobutyric acid wawungabalulekile, kodwa ukuthambekela kusabonakala (P=0.082). Amazinga e-Fecal isobutyrate ayephansi kakhulu ezigulini ezine-ET uma kuqhathaniswa neziguli ezine-PD (P=0.030). Umehluko phakathi kwe-ET ne-PD ye-isovaleric acid wawungabalulekile, kodwa kwakusekhona ukuthambekela (P=0.084). I-Propionic acid (P = 0.023), i-acetic acid (P = 0.020), kanye ne-butyric acid (P = 0.044) zaziphansi kakhulu ezigulini ze-PD kunasezigulini ze-HC. Le miphumela (Isithombe Esingeziwe 1) ngokuvamile ihambisana nemiphumela eyinhloko. Umehluko emiphumeleni phakathi kwesampula iyonke kanye neqembu elincane lesiguli sokuqala ungase ube ngenxa yobukhulu besampula obuncane eqenjini elincane, okuholela emandleni aphansi ezibalo zedatha.
Ngokulandelayo sihlole ukuthi amazinga e-SCFA endle angahlukanisa yini iziguli ezine-ET neziguli ezine-CU noma i-PD. Ngokusho kokuhlaziywa kwe-ROC, umehluko ku-AUC yamazinga e-propionate wawungu-0.668 (95% CI: 0.538-0.797), okwenza kwaba nokwenzeka ukuhlukanisa iziguli ezine-ET ne-HC. Iziguli ezine-ET ne-GC zingahlukaniswa ngamazinga e-butyrate ane-AUC engu-0.685 (95% CI: 0.556–0.814). Umehluko emazingeni e-isobutyric acid ungahlukanisa iziguli ezine-ET ne-HC ezine-AUC engu-0.655 (95% CI: 0.525–0.786). Lapho kuhlanganiswa amazinga e-propionate, i-butyrate kanye ne-isobutyrate, i-AUC ephezulu engu-0.751 (95% CI: 0.634–0.867) yatholakala ngokuzwela okungu-74.3% kanye nokucaciswa okungu-72.9% (Isithombe 2a). Ukuze kuhlukaniswe phakathi kweziguli ze-ET kanye ne-PD, i-AUC yamazinga e-isovaleric acid yayingu-0.700 (95% CI: 0.579–0.822) kanye namazinga e-isobutyric acid yayingu-0.718 (95% CI: 0.599–0.836). Inhlanganisela yamazinga e-isovaleric acid kanye ne-isobutyric acid yayine-AUC ephezulu engu-0.743 (95% CI: 0.629–0.857), ukuzwela okungu-74.3% kanye nokucaciswa okungu-62.9% (Isithombe 2b). Ngaphezu kwalokho, sihlole ukuthi amazinga e-SCFA endle yeziguli ezinesifo sikaParkinson ahluke yini ezilawulwayo. Ngokusho kokuhlaziywa kwe-ROC, i-AUC yokuhlonza iziguli ezine-PD ngokusekelwe ekwehlukeni kwamazinga e-propionic acid yayingu-0.687 (95% CI: 0.559-0.814), enozwela oluyi-68.6% kanye nokucaciswa okungu-68.7%. Umehluko kumazinga e-acetate ungahlukanisa iziguli ze-PD kuma-HC ane-AUC engu-0.674 (95% CI: 0.542–0.805). Iziguli ezine-PD zingahlukaniswa kusuka ku-CU kuphela ngamazinga e-butyrate ane-AUC engu-0.651 (95% CI: 0.515–0.787). Lapho kuhlanganiswa amazinga e-propionate, i-acetate kanye ne-butyrate, i-AUC engu-0.682 (95% CI: 0.553–0.811) yatholakala (Isithombe 2c).
ukubandlululwa yiSonto Lobu-Orthodox LaseRussia ngokumelene ne-ET kanye ne-HC; b ukubandlululwa kwe-ROC ngokumelene ne-ET kanye ne-PD; c ukubandlululwa kwe-ROC ngokumelene ne-PD kanye ne-HC; ukuthuthumela okubalulekile kwe-ET, isifo sikaParkinson, ukulawulwa kwe-HC okunempilo, i-SCFA.
Ezigulini ezine-ET, izinga le-asidi ye-isobutyric ye-fecal lalihlobene kabi ne-FTM score (r = -0.349, P = 0.034), kanti izinga le-asidi ye-isovaleric ye-fecal lalihlobene kabi ne-FTM score (r = -0.421, P = 0.001) kanye ne-TETRAS score. (r = -0.382, P = 0.020). Ezigulini ezine-ET kanye ne-PD, amazinga e-fecal propionate ayehlobene kabi ne-SCOPA-AUT scores (r = -0.236, P = 0.043) (Isithombe 3 kanye neThebula Elingeziwe 3). Kwakungekho ukuhlobana okuphawulekayo phakathi kwenkambo yesifo kanye ne-SCFA eqenjini le-ET (P ≥ 0.161) noma eqenjini le-PD (P ≥ 0.246) (Ithebula Elingeziwe 4). Ezigulini ezine-PD, amazinga e-fecal caproic acid ahlotshaniswa kahle namaphuzu e-MDS-UPDRS (r = 0.335, P = 0.042). Kubo bonke ababambiqhaza, amazinga e-fecal propionate (r = −0.230, P = 0.016) kanye ne-acetate (r = −0.210, P = 0.029) ahlotshaniswa kabi namaphuzu e-Wexner (Isithombe 3 kanye neThebula Elingeziwe 3).
Amazinga e-fecal isobutyric acid ahlobene kabi namaphuzu e-FTM, i-isovaleric acid ihlobene kabi namaphuzu e-FTM kanye ne-TETRAS, i-propionic acid ihlobene kabi namaphuzu e-SCOPA-AUT, i-caproic acid ihlobene kahle namaphuzu e-MDS-UPDRS, kanti i-propionic acid ihlobene kabi namaphuzu e-FTM kanye ne-TETRAS. I-TETRAS kanye ne-acetic acid zihlobene kabi namaphuzu e-Wexner. I-MDS-UPDRS Association ixhase inguqulo ye-Unified Parkinson's Disease Rating Scale, i-Mini-Mental State Examination MMSE, i-Hamilton Depression Rating Scale HAMD-17, izinto ezingu-17, i-Hamilton Anxiety Rating Scale HAMA, izigaba ze-HY Hoehn kanye ne-Yahr, 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. Umehluko omkhulu uboniswa yi-*P < 0.05 kanye ne-**P < 0.01.
Siphinde sahlola uhlobo lokubandlulula lwe-gut microbiota sisebenzisa ukuhlaziywa kwe-LEfSE futhi sakhetha izinga ledatha yobuningi bohlobo ukuze sihlaziye kabanzi. Ukuqhathaniswa kwenziwa phakathi kwe-ET ne-HC kanye naphakathi kwe-ET ne-PD. Ukuhlaziywa kokuxhumana kwe-Spearman kwabe sekwenziwa ngobuningi bobukhulu be-gut microbiota kanye namazinga e-fecal SCFA emaqenjini amabili okuqhathanisa.
I-Faecalibacterium (ehlobene ne-butyric acid, r = 0.408, P < 0.001), i-Lactobacillus (ehlobene ne-butyric acid, r = 0.283, P = 0.016), i-Streptobacterium (ehlobene ne-propionic acid, r = 0.327) yayikhona ekuhlaziyweni kwe-ET kanye ne-CA. , P = 0.005; ehlobene ne-butyric acid, r = 0.374, P = 0.001; ihlobene ne-isobutyric acid, r = 0.329, P = 0.005), i-Howardella (ihlobene ne-propionic acid, r = 0.242, P = 0.041), i-Raoultella (ihlobene ne-propionate, r = 0.249, P = 0.035), kanye ne-Candidatus Arthromitus (ihlobene ne-isobutyric acid, r = 0.302, P = 0.010) yehla ku-ET futhi ihlobene kahle namazinga e-fecal SCFA. Kodwa-ke, ukugcwala kwe-Stenotropomonas kwanda ku-ET futhi kwahlotshaniswa kabi namazinga e-fecal isobutyrate (r = -0.250, P = 0.034). Ngemuva kokulungiswa kwe-FDR, kuphela ukuhlobana phakathi kwe-Faecalibacterium, i-Catenibacter, ne-SCFA okwahlala kubalulekile (P ≤ 0.045) (Isithombe 4 kanye neThebula Elingeziwe 5).
Ukuhlaziywa kokuhambisana kwe-ET ne-HC. Ngemva kokulungiswa kwe-FDR, ubuningi be-Faecalibacterium (ehlotshaniswa kahle ne-butyrate) kanye ne-Streptobacterium (ehlotshaniswa kahle ne-propionate, i-butyrate, kanye ne-isobutyrate) kwatholakala ukuthi kwehla ku-ET futhi kuhlotshaniswa kahle namazinga e-fecal SCFA. b Ukuhlaziywa kokuhambisana kwe-ET ne-PD. Ngemva kokulungiswa kwe-FDR, akukho ukuhlangana okubalulekile okutholiwe. Ukuthuthumela okubalulekile kwe-ET, isifo sikaParkinson, ukulawulwa kwe-HC okunempilo, i-SCFA. Umehluko obalulekile ukhonjiswa yi-*P < 0.05 kanye ne-**P < 0.01.
Lapho kuhlaziywa i-ET uma kuqhathaniswa ne-PD, i-Clostridium trichophyton itholakale ikhuphukile ku-ET futhi ihlobene ne-fecal isovaleric acid (r = -0.238, P = 0.041) kanye ne-isobutyric acid (r = -0.257, P = 0.027). ). Ngemva kokulungiswa kwe-FDR, noma yikuphi kwalokhu kwahlala kubalulekile (P≥0.295) (Isithombe 4 kanye neThebula Elingeziwe 5).
Lolu cwaningo luwucwaningo oluphelele oluhlola amazinga e-SCFA yendle futhi luwahlobanise noshintsho ku-microbiota yamathumbu kanye nobunzima bezimpawu ezigulini ezine-ET uma kuqhathaniswa neziguli ezine-CU kanye ne-PD. Sithole ukuthi amazinga e-SCFA yendle ancishisiwe ezigulini ezine-ET futhi ahlotshaniswa nobunzima bezokwelapha kanye nezinguquko ezithile ku-microbiota yamathumbu. Amazinga endle aqongelelekayo ama-fatty acids amafushane (ama-SCFA) ahlukanisa i-ET ne-GC kanye ne-PD.
Uma kuqhathaniswa neziguli ze-GC, iziguli ze-ET zinamazinga aphansi endle yama-propionic, butyric, kanye nama-isobutyric acid. Ukuhlanganiswa kwama-propionic, butyric kanye nama-isobutyric acid kwahlukanisa i-ET kanye ne-HC nge-AUC engu-0.751 (95% CI: 0.634–0.867), ukuzwela okungu-74.3% kanye nokucaciswa okungu-72.9%, okubonisa ukusetshenziswa kwazo njengezimpawu zokuxilonga zendima engaba khona ye-ET. Ukuhlaziywa okwengeziwe kubonise ukuthi amazinga e-fecal propionic acid ayehlobene kabi ne-Wexner score kanye ne-SCOPA-AUT score. Amazinga e-fecal isobutyric acid ayehlobene ngokuphambene namaphuzu e-FTM. Ngakolunye uhlangothi, ukwehla kwamazinga e-butyrate ku-ET kwakuhlotshaniswa nokwehla kobuningi be-microbiota ekhiqiza i-SCFA, i-Faecalibacterium, kanye ne-Categorybacter. Ngaphezu kwalokho, ukwehla kobuningi be-Catenibacter ku-ET kwakuhlotshaniswa nokwehla kwamazinga e-fecal propionic kanye ne-isobutyric acid.
Ama-SCFA amaningi akhiqizwa emathunjini athathwa ama-colonocyte ikakhulukazi ngama-transporter e-monocarboxylate ancike ku-H+ noma i-sodium-dependent. Ama-fatty acid amafushane adonswayo asetshenziswa njengomthombo wamandla wama-colonocyte, kanti lawo angagaywa kuma-colonocyte athuthwa ayiswe emgudwini wokujikeleza kwegazi 18. Ama-SCFA angathonya ukuhamba kwamathumbu, athuthukise ukusebenza kwesithiyo samathumbu, futhi athonye imetabolism yomnikazi kanye nokuzivikela komzimba 19. Ngaphambilini kwatholakala ukuthi amazinga endle e-butyrate, i-acetate, kanye ne-propionate ancishisiwe ezigulini ze-PD uma kuqhathaniswa nama-HCs17, okuhambisana nemiphumela yethu. Ucwaningo lwethu luthole ukwehla kwama-SCFA ezigulini ezine-ET, kodwa kuncane okwaziwayo ngendima yama-SCFA ekwelapheni kwe-ET. I-butyrate kanye ne-propionate zingabopha kuma-GPCR futhi zithonye ukusayinwa okuncike ku-GPCR njenge-MAPK kanye ne-NF-κB20 signaling. Umqondo oyisisekelo we-gut-brain axis ukuthi ama-SCFA akhishwa ngamagciwane emathunjini angathonya ukusayinwa komnikazi, ngaleyo ndlela athonye ukusebenza kwamathumbu kanye nobuchopho. Ngenxa yokuthi i-butyrate kanye ne-propionate zinemiphumela enamandla yokuvimbela umsebenzi we-histone deacetylase (HDAC)21 futhi i-butyrate nayo ingasebenza njenge-ligand yezici zokubhala, zinemiphumela ebanzi kumetabolism yomnikazi, ukuhlukanisa kanye nokwanda, ikakhulukazi ngenxa yethonya lazo ekulawulweni kwezakhi zofuzo22. Ngokusekelwe ebufakazini obuvela ku-SCFA kanye nezifo ze-neurodegenerative, i-butyrate ibhekwa njengekhambi lokwelapha ngenxa yekhono layo lokulungisa umsebenzi we-HDAC ophazamisekile, okungase kuholele ekufeni kwe-dopaminergic neuron ku-PD23,24,25. Izifundo zezilwane zibonise nekhono le-butyric acid lokuvimbela ukuwohloka kwe-dopaminergic neuron nokuthuthukisa ukuphazamiseka kokunyakaza kumamodeli e-PD26,27. I-Propionic acid itholakale inciphisa izimpendulo zokuvuvukala futhi ivikele ubuqotho be-BBB28,29. Izifundo zibonise ukuthi i-propionic acid ikhuthaza ukusinda kwama-dopaminergic neurons ekuphenduleni ubuthi be-rotenone kumamodeli e-PD 30 nokuthi ukuphathwa ngomlomo kwe-propionic acid kusindisa ukulahlekelwa yi-dopaminergic neuron kanye nokuntuleka kwe-motor kumagundane ane-PD 31. Kuncane okwaziwayo ngomsebenzi we-isobutyric acid. Kodwa-ke, ucwaningo lwamuva nje luthole ukuthi ukuhlanganiswa kwamagundane ane-B. ovale kwandisa okuqukethwe kwe-SCFA yamathumbu (kufaka phakathi i-acetate, i-propionate, i-isobutyrate, kanye ne-isovalerate) kanye nokuhlushwa kwe-GABA yamathumbu, okuqokomisa ukuthi kusungulwe ukuxhumana phakathi kwe-gut microbiota kanye nokuhlushwa kwe-SCFA yamathumbu kwama-neurotransmitters32. Ku-ET, izinguquko ezingavamile ze-pathological ku-cerebellum zifaka phakathi izinguquko kuma-axons nama-dendrites eseli le-Purkinje, ukufuduka kanye nokulahlekelwa amaseli e-Purkinje, izinguquko kuma-axons eseli lebhasikidi, ukungalingani ekuxhumaneni kwe-fiber ekhuphukayo nokusatshalaliswa kwamaseli e-Purkinje, kanye nezinguquko kuma-receptors e-GABA ku-nuclei yethambo le-dentate, okuholela ekunciphiseni kokukhishwa kwe-GABAergic kusuka ku-cerebellum3,4,33. Akukacaci ukuthi ama-SCFA ahlotshaniswa nokuwohloka kwe-neurogeneis kweseli le-Purkinje kanye nokwehla kokukhiqizwa kwe-GABA ye-cerebellar. Imiphumela yethu iphakamisa ubudlelwano obuqinile phakathi kwe-SCFA ne-ET, kodwa ukwakheka kocwaningo oluhlanganisa izingxenye ezithile akuvumeli noma yiziphi iziphetho mayelana nobudlelwano obubangela phakathi kwe-SCFA kanye nenqubo yesifo se-ET; Kudingeka izifundo ezengeziwe zokulandelela isikhathi eside, okuhlanganisa ukulinganiswa okulandelanayo kwama-SCFA endle, kanye nezifundo zezilwane ezihlola izindlela.
Ama-SCFA kucatshangwa ukuthi akhuthaza ukugoba kwemisipha ebushelelezi yamathumbu amakhulu. Ukuntuleka kwe-SCFA kuzokwandisa izimpawu zokugoba, futhi ukwengezwa kwe-SCFA kungathuthukisa izimpawu zokugoba kwe-PD35. Imiphumela yethu iphinde ikhombise ubudlelwano obubalulekile phakathi kokwehla kokuqukethwe kwe-SCFA yendle kanye nokwanda kokugoba kanye nokungasebenzi kahle kwe-autonomic ezigulini ezine-ET. Umbiko wecala elilodwa uthole ukuthi ukufakelwa kwe-microbiota kuthuthukise kokubili ukuthuthumela okubalulekile kanye ne-irritable bowel syndrome esigulini esingu-7, okuphakamisa ngokwengeziwe ubudlelwano obuseduze phakathi kwe-gut microbiota kanye ne-ET. Ngakho-ke, sikholelwa ukuthi i-fecal SCFA/microbiota ingathinta ukunyakaza kwamathumbu omnikazi kanye nokusebenza kwesistimu yezinzwa ezizimele.
Ucwaningo luthole ukuthi amazinga aphansi e-SCFAs yamathumbu ku-ET ahlotshaniswa nokuncipha kwenani le-Faecalibacterium (elihlotshaniswa ne-butyrate) kanye ne-Streptobacterium (elihlotshaniswa ne-propionate, i-butyrate, kanye ne-isobutyrate). Ngemva kokulungiswa kwe-FDR, lobu budlelwano buhlala bubalulekile. I-Faecalibacterium kanye ne-Streptobacterium zingama-microorganism akhiqiza i-SCFA. I-Faecalibacterium yaziwa njenge-microorganism ekhiqiza i-butyrate36, kuyilapho imikhiqizo eyinhloko yokubiliswa kwe-Catenibacter yi-acetate, i-butyrate kanye ne-lactic acid37. I-Faecalibacterium itholakale ku-100% wamaqembu e-ET kanye ne-HC; inani eliphakathi nendawo leqembu le-ET lalingu-2.06% kanti elamaqembu e-HC lalingu-3.28% (LDA 3.870). Igciwane lesigaba litholakale ku-21.6% (8/37) weqembu le-HC futhi kusampula eyodwa kuphela yeqembu le-ET (1/35). Ukwehla nokungatholakali kwe-streptobacteria ku-ET kungabonisa futhi ukuhambisana nesifo esibangela izifo. Ubuningi obuphakathi bezinhlobo ze-Catenibacter eqenjini le-HC babungu-0.07% (LDA 2.129). Ngaphezu kwalokho, amabhaktheriya e-lactic acid ahlotshaniswa noshintsho ku-butyrate yendle (P=0.016, P=0.096 ngemuva kokulungiswa kwe-FDR), kanti umuntu onesifo samathambo wahlotshaniswa noshintsho ku-isobutyrate (P=0.016, P=0.072 ngemuva kokulungiswa kwe-FDR). Ngemuva kokulungiswa kwe-FDR, kusala umkhuba wokuxhumana kuphela, okungabalulekile ngokwezibalo. Ama-Lactobacilli ayaziwa nangokuthi abakhiqizi be-SCFA (acetic acid, propionic acid, isobutyric acid, butyric acid) 38 kanti i-Candidatus Arthromitus iyisisusa esithile sokwehluka kwamaseli e-T helper 17 (Th17), kanye ne-Th1/2 kanye ne-Tregs ezihlotshaniswa nebhalansi yomzimba /Th1739. . Ucwaningo lwamuva nje lubonisa ukuthi amazinga aphezulu e-fecal pseudoarthritis angabangela ukuvuvukala kwamathumbu, ukungasebenzi kahle kwesithiyo samathumbu, kanye nokuvuvukala komzimba 40. Amazinga e-Clostridium trichoides akhuphukile ku-ET uma kuqhathaniswa ne-PD. Ubuningi be-Clostridium trichoides butholakale buhlobene kabi ne-isovaleric acid kanye ne-isobutyric acid. Ngemva kokulungiswa kwe-FDR, kokubili kwahlala kubalulekile (P≥0.295). I-Clostridium pilosum iyibhaktheriya eyaziwa ngokuthi ihlotshaniswa nokuvuvukala futhi ingabangela ukungasebenzi kahle kwesithiyo samathumbu 41. Ucwaningo lwethu lwangaphambilini lubike izinguquko ku-microbiota yamathumbu eziguli ezine-ET8. Lapha siphinde sibike izinguquko ku-SCFA ku-ET futhi sithole ubudlelwano phakathi kwe-dysbiosis yamathumbu kanye nezinguquko ku-SCFA. Amazinga e-SCFA anciphile ahlotshaniswa kakhulu ne-dysbiosis yamathumbu kanye nobunzima bokuthuthumela ku-ET. Imiphumela yethu iphakamisa ukuthi i-axis yobuchopho nobuchopho ingadlala indima ebalulekile ekuqaliseni kwe-ET, kodwa kudingeka izifundo ezengeziwe kumamodeli ezilwane.
Uma kuqhathaniswa neziguli ezine-PD, iziguli ezine-ET zinamazinga aphansi e-isovaleric kanye ne-isobutyric acid endle yazo. Ukuhlanganiswa kwe-isovaleric acid kanye ne-isobutyric acid kuthole i-ET ku-PD nge-AUC engu-0.743 (95% CI: 0.629–0.857), ukuzwela okungu-74.3% kanye nokucaciswa okungu-62.9%, okuphakamisa indima yazo engaba khona njenge-biomarkers ekuxilongweni okuhlukile kwe-ET. . Amazinga e-Fecal isovaleric acid ahlobene ngokuphambene namaphuzu e-FTM kanye ne-TETRAS. Amazinga e-Fecal isobutyric acid ahlobene ngokuphambene namaphuzu e-FTM. Ukwehla kwamazinga e-isobutyric acid kuhlotshaniswa nokwehla kobuningi be-catobacteria. Kuncane okwaziwayo ngemisebenzi ye-isovaleric acid kanye ne-isobutyric acid. Ucwaningo lwangaphambilini lukhombisile ukuthi ukuhlanganiswa kwamagundane ane-B. ovale kwandisa inani lama-SCFA amathumbu (kufaka phakathi i-acetate, i-propionate, i-isobutyrate, kanye ne-isovalerate) kanye nokugcwala kwe-GABA yamathumbu, okugqamisa ukuxhumana kwamathumbu phakathi kwe-microbiota kanye nokugcwala kwe-SCFA/neurotransmitter yamathumbu32. Ngokuthakazelisayo, amazinga e-isobutyric acid abonwe ayefana phakathi kwamaqembu e-PD kanye ne-HC, kodwa ayehlukile phakathi kwamaqembu e-ET kanye ne-PD (noma i-HC). I-Isobutyric acid ingahlukanisa phakathi kwe-ET kanye ne-PD nge-AUC engu-0.718 (95% CI: 0.599–0.836) futhi ihlonze i-ET kanye ne-NC nge-AUC engu-0.655 (95% CI: 0.525–0.786). Ngaphezu kwalokho, amazinga e-isobutyric acid ahlobene nobunzima bokuthuthumela, okuqinisa kakhulu ukuhlangana kwayo ne-ET. Umbuzo wokuthi ngabe i-isobutyric acid yomlomo inganciphisa ubunzima bokuthuthumela ezigulini ezine-ET kufanele ufundwe kabanzi.
Ngakho-ke, okuqukethwe yi-fecal SCFA kuyancipha ezigulini ezine-ET futhi kuhlotshaniswa nobunzima be-ET kanye nezinguquko ezithile ku-microbiota yamathumbu. I-Fecal propionate, i-butyrate, kanye ne-isobutyrate kungaba ama-biomarker okuxilonga i-ET, kanti i-isobutyrate kanye ne-isovalerate kungaba ama-biomarker okuxilonga ahlukile e-ET. Izinguquko ku-fecal isobutyrate zingase zibe ngqo kakhulu ku-ET kunezinguquko kwamanye ama-SCFA.
Ucwaningo lwethu lunemikhawulo eminingana. Okokuqala, amaphethini okudla kanye nezintandokazi zokudla kungathinta ukubonakaliswa kwe-microbiota, kudingeka amasampula amakhulu ocwaningo kubantu abahlukene, futhi izifundo zesikhathi esizayo kufanele zethule izinhlolovo zokudla eziphelele nezihlelekile njengemibuzo yemvamisa yokudla. Okwesibili, ukwakheka kocwaningo oluhlanganisa izingxenye kuvimbela noma yiziphi iziphetho mayelana nobudlelwano obuyimbangela phakathi kwe-SCFA nenqubo yesifo se-ET. Izifundo ezengeziwe zokulandelela zesikhathi eside ezinezilinganiso ezilandelanayo ze-SCFAs zamathumbu ziyadingeka. Okwesithathu, amakhono okuxilonga nokuhlukanisa amazinga e-SCFA yamathumbu kufanele aqinisekiswe kusetshenziswa amasampula azimele avela ku-ET, HC, kanye ne-PD. Amasampula amaningi azimele endle kufanele ahlolwe esikhathini esizayo. Okokugcina, iziguli ezine-PD eqenjini lethu zazinesikhathi esifushane kakhulu sesifo kuneziguli ezine-ET. Ngokuyinhloko sifanise i-ET, i-PD kanye ne-HC ngobudala, ubulili kanye ne-BMI. Njengoba sinikezwe umehluko wenkambo yesifo phakathi kweqembu le-ET neqembu le-PD, siphinde safunda iziguli ezingu-33 ezine-PD yokuqala kanye neziguli ezingu-16 ezine-ET (ubude besifo ≤ iminyaka engu-3) ukuze siqhathanise okwengeziwe. Umehluko phakathi kwamaqembu ku-SCFA wawuvame ukuhambisana nedatha yethu eyinhloko. Ngaphezu kwalokho, asitholanga ukuhlobana phakathi kobude besikhathi sesifo kanye nezinguquko ku-SCFA. Kodwa-ke, esikhathini esizayo, kungaba ngcono ukuqasha iziguli ezine-PD kanye ne-ET zisesenesikhathi esifushane sesifo ukuze kuqedwe ukuqinisekiswa kusampula enkulu.
Iphrothokholi yocwaningo yamukelwe yiKomidi Lokuziphatha leSibhedlela saseRuijin elixhumene neShanghai Jiao Tong University School of Medicine (RHEC2018-243). Imvume ebhaliwe enolwazi yatholakala kubo bonke abahlanganyeli.
Phakathi kukaJanuwari 2019 noDisemba 2022, izifundo ezingu-109 (37 ET, 37 PD, kanye no-35 HC) ezivela eMovement Disorder Center Clinic yaseRuijin Hospital, exhumene neShanghai Jiao Tong University School of Medicine, zafakwa kulolu cwaningo. Izindinganiso zaziyi: (1) iminyaka engu-25-85, (2) iziguli ezine-ET zahlolwa ngokwemigomo ye-MDS Working Group 42 kanye ne-PD zahlolwa ngokwemigomo ye-MDS 43, (3) zonke iziguli zazingaphuzi imithi yokulwa ne-PD ngaphambi kokuqoqwa kwamasampula. (4) Iqembu le-ET lathatha ama-β-blockers kuphela noma alikho imithi ehlobene ngaphambi kokuqoqa amasampula esitulo. Ama-HC ahambisana nobudala, ubulili, kanye ne-body mass index (BMI) nawo akhethiwe. Izindlela zokukhishwa kwakuyilezi: (1) abantu abadla imifino kuphela, (2) ukudla okungondleki kahle, (3) izifo ezingamahlalakhona zomgudu wokugaya ukudla (kufaka phakathi isifo samathumbu esivuvukalayo, izilonda zesisu noma ze-duodenal), (4) izifo ezingamahlalakhona ezinzima (kufaka phakathi izimila ezimbi), ukwehluleka kwenhliziyo, ukwehluleka kwezinso, izifo zegazi) (5) Umlando wokuhlinzwa okukhulu kokugaya ukudla, (6) Ukusetshenziswa kwe-yogurt okungamahlalakhona noma okuvamile, (7) Ukusetshenziswa kwanoma yimaphi ama-probiotic noma ama-antibiotic inyanga eyi-1, (8) Ukusetshenziswa okungamahlalakhona kwama-corticosteroids, ama-proton pump inhibitors, ama-statin, i-metformin, ama-immunosuppressants noma imithi yokulwa nomdlavuza kanye (9) ukukhubazeka okukhulu kwengqondo okuphazamisa izivivinyo zemitholampilo.
Zonke izifundo zinikeze umlando wezokwelapha, isisindo kanye nolwazi lokuphakama ukuze kubalwe i-BMI, futhi zahlolwa ngemizwa kanye nokuhlolwa kwezokwelapha njenge-Hamilton Anxiety Rating Scale (HAMA) 44 anxiety score, i-Hamilton Depression Rating Scale-17 score (HAMD-17) 45. ukucindezeleka, ubukhali bokuqunjelwa kusetshenziswa i-Wexner Constipation Scale 46 kanye ne-Bristol Stool Scale 47 kanye nokusebenza kwengqondo kusetshenziswa i-Mini-Mental State Examination (MMSE) 48. I-Scale for the Assessment of Autonomic Symptoms of Parkinson's Disease (SCOPA-AUT) 49 ihlole ukungasebenzi kahle kwe-autonomic ezigulini ezine-ET kanye ne-PD. I-Fana-Tolos-Marin Clinical Tremor Rating Scale (FTM) kanye ne-Essential Tremor Rating Scale (TETRAS) 50 I-Tremor Study Group (TRG) 50 ihlolwe ezigulini ezine-ET; i-Kinson's Disease Rating Scale (MDS-), exhaswe yi-United Parkinson's Disease Association; i-UPDRS version 51 kanye ne-Hoehn and Yahr (HY) version 52 ihlolwe.
Umhlanganyeli ngamunye ucelwe ukuthi aqoqe isampula yendle ekuseni esebenzisa isitsha sokuqoqa indle. Dlulisa izitsha eqhweni bese uzigcina ku--80°C ngaphambi kokucutshungulwa. Ukuhlaziywa kwe-SCFA kwenziwe ngokwemisebenzi ejwayelekile ye-Tiangene Biotechnology (Shanghai) Co., Ltd. Amasampula endle amasha angu-400 mg aqoqwe kumuntu ngamunye futhi ahlaziywa kusetshenziswa ama-SCFA ngemva kokugaya nokukhipha i-sonication. Ama-SCFA akhethiwe endle ahlaziywa kusetshenziswa i-gas chromatography-mass spectrometry (GC-MS) kanye ne-liquid chromatography-tandem MS (LC-MS/MS).
I-DNA ikhishwe kumasampula angu-200 mg kusetshenziswa i-QIAamp® Fast DNA Stool Mini Kit (QIAGEN, Hilden, Germany) ngokwemiyalelo yomenzi. Ukwakheka kwama-microbial kunqunywe ngokulandelana kwe-16 S rRNA gene ku-DNA ehlukaniswe nendle ngokukhulisa indawo ye-V3-V4. Hlola i-DNA ngokusebenzisa isampula ku-1.2% agarose gel. Ukukhuliswa kwe-polymerase chain reaction (PCR) kwe-16S rRNA gene kwenziwa kusetshenziswa ama-universal bacterial primers (357 F kanye ne-806 R) kanye nomtapo wezincwadi we-amplicon onezinyathelo ezimbili owakhiwe epulatifomu ye-Novaseq.
Izinguquko eziqhubekayo zivezwa njengokuphambuka okujwayelekile okungu-±, kanti izinguquko zesigaba zivezwa njengezinombolo namaphesenti. Sisebenzise ukuhlolwa kukaLevene ukuhlola ukulingana kwezinguquko. Ukuqhathaniswa kwenziwe kusetshenziswa ukuhlolwa kwe-t okunemisila emibili noma ukuhlaziywa kokuhlukahluka (i-ANOVA) uma izinguquko zivame ukusatshalaliswa, kanye nokuhlolwa kwe-Mann-Whitney U okungeyona i-parametric uma ukuqagela okujwayelekile noma kwe-homoscedasticity kwephulwe. Sisebenzise indawo engaphansi kwe-receiver operating characteristic (ROC) curve (AUC) ukuze silinganise ukusebenza kokuxilonga kwemodeli futhi sihlole ikhono le-SCFA lokuhlukanisa iziguli ezine-ET kulabo abane-HC noma i-PD. Ukuze sihlole ubudlelwano phakathi kwe-SCFA nobunzima bezokwelapha, sisebenzise ukuhlaziywa kokuxhumana kwe-Spearman. Ukuhlaziywa kwezibalo kwenziwe kusetshenziswa isofthiwe ye-SPSS (inguqulo 22.0; SPSS Inc., Chicago, IL) ngezinga lokubaluleka (kufaka phakathi inani le-P kanye ne-FDR-P) elibekwe ku-0.05 (ezinhlangothini ezimbili).
Ama-sequence angu-16 S ahlaziywe kusetshenziswa inhlanganisela ye-Trimmomatic (inguqulo 0.35), i-Flash (inguqulo 1.2.11), i-UPARSE (inguqulo v8.1.1756), i-mothur (inguqulo 1.33.3) kanye ne-R (inguqulo 3.6.3). Idatha yezakhi zofuzo ze-rRNA ze-Raw 16S icutshungulwe kusetshenziswa i-UPARSE ukukhiqiza amayunithi e-taxonomic operational (OTUs) anobunikazi obungu-97%. Ama-taxonomies acacisiwe kusetshenziswa i-Silva 128 njengesizindalwazi sokubhekisela. Izinga elijwayelekile ledatha yobuningi obuhlobene likhethiwe ukuze kuhlaziywe okwengeziwe. Ukuhlaziywa kosayizi womphumela we-Linear discriminant analysis (LDA) (LEfSE) kusetshenziswe ukuqhathanisa phakathi kwamaqembu (ET vs. HC, ET vs. PD) ngomkhawulo we-α ongu-0.05 kanye nomkhawulo wosayizi womphumela ongu-2.0. I-Dispriminant genera ekhonjwe ukuhlaziywa kwe-LEfSE yasetshenziswa futhi ekuhlaziyweni kokuxhumana kwe-Spearman kwe-SCFA.
Ukuze uthole ulwazi olwengeziwe mayelana nomklamo wocwaningo, bheka i-Natural Research Report Abstract ehlotshaniswa nalesi sihloko.
Idatha yokulandelelana kwe-Raw 16S igcinwa kusizindalwazi se-National Center for Biotechnology Information (NCBI) BioProject (SRP438900: PRJNA974928), i-URL: https://www.ncbi.nlm.nih.gov/Traces/study/?acc= SRP438900&o. =acc_s% 3Aa. Eminye imininingwane efanele iyatholakala kumbhali ohambisanayo uma kucelwa ngokufanele, njengokubambisana kwesayensi kanye nokushintshana kwezemfundo namaphrojekthi ocwaningo aphelele. Akukho ukudluliselwa kwedatha kubantu besithathu ngaphandle kwemvume yethu okuvunyelwe.
Ikhodi yomthombo ovulekile kuphela ngenhlanganisela ye-Trimmomatic (inguqulo 0.35), i-Flash (inguqulo 1.2.11), i-UPARSE (inguqulo v8.1.1756), i-mothur (inguqulo 1.33.3) kanye ne-R (inguqulo 3.6.3), kusetshenziswa izilungiselelo ezizenzakalelayo noma isigaba esithi “Indlela”. Ulwazi olwengeziwe lokucacisa lunganikezwa umbhali ohambisanayo uma kucelwa ngokufanele.
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