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Ukuhlolwa kwangaphambilini kokuthuthumela okuqakathekileko (ET) kungaba yinselele, khulukhulu lokha nakuhlukaniswa nezilawuli eziphilileko (HC) kanye nobulwelwe be-Parkinson (PD). Mhlapha nje, ukuhlaziywa kwamasampula wethumbu we-gut microbiota kanye nama-metabolites wawo kunikele ngeendlela ezitjha zokutholakala kwama-biomarkers amatjha wezifo eziphathelene nokuwohloka kwemizwa. Amafutha we-Short-chain (SCFA), njenge-metabolite ekulu yeentjalo zamathumbu, anciphiswa ethuvini ku-PD. Kodwana, i-SCFA yendle ayikaze ifundwe ku-ET. Besihlose ukuphenya amazinga we-SCFAs ku-ET, ukuhlola ubudlelwano bawo namatshwayo wezokwelapha kanye nama-microbiota wamathumbu, begodu sithole ikghono lawo lokuhlola. I-SCFA yendle kanye nama-gut microbiota kwalinganiswa kuma-ET ama-37, ama-PD amatjha ama-37, kanye nama-HC ama-35. Ukuqunjelwa, ukungasebenzi kuhle, kanye nobukhulu bokuthuthumela kwahlolwa kusetjenziswa iinkali. Amazinga we-propionate, i-butyrate, ne-isobutyrate begade aphasi ku-ET kunase-HC. Inhlanganisela ye-propionic, butyric kanye ne-isobutyric acids yahlukanisa i-ET kusuka ku-HC nge-AUC ye-0.751 (95% CI: 0.634–0.867). Amazinga we-isovaleric acid yendle kanye ne-isobutyric acid bekaphasi ku-ET kunaku-PD. I-isovaleric acid ne-isobutyric acid zihlukanisa hlangana ne-ET ne-PD nge-AUC ye-0.743 (95% CI: 0.629–0.857). I-propionate yendle ihlotjaniswa ngokuphambene nokuqunjelwa nokusebenza komzimba. I-isobutyric acid kanye ne-isovaleric acid zihlobene ngokuphambene nobukhulu bokuthuthumela. Ukwehla kwe-SCFAs yethumbu kwahlotjaniswa nokwehla kwe-Faecalibacterium ne-Streptobacterium ku-ET. Ngalokho, okuqukethwe kwe-SCFA ethuvini kwehla ku-ET begodu kuhlotjaniswa nobukhulu besithombe somtholampilo nokutjhuguluka kwe-microbiota yamathumbu. I-fecal propionate, i-butyrate, i-sobutyrate, kanye ne-isovalerate kungaba zii-biomarkers zokuhlola nokuhlukahlukana kwe-ET.
Ukuthuthumela okuqakathekileko (ET) mkhuhlane oqhubekako, ongapheliko wokuwohloka kwemizwa obonakala khulu ngokuthuthumela kwamalunga angaphezulu, okungathinta nezinye iindawo zomzimba ezifana nehloko, iintambo zephimbo, kanye namalunga angaphasi 1 . Iimpawu zezokwelapha ze-ET azihlanganisi amatshwayo weenthuthi kwaphela kodwana nezinye iimphawu ezingezizo zeenthuthi, okufakahlangana ubulwelwe be-gastrointestinal 2 . Iimfundo ezinengi zenziwe ukuhlola ubujamo bokugula nomzimba bokuthuthumela okuqakathekileko, kodwana iindlela ezicacileko zomzimba azikatholwa3,4; Iimfundo zamva nje zitjengisa bona ukungasebenzi kuhle kwe-microbiota-gut-brain axis kungaba nomthelela emalwelweni we-neurodegenerative, begodu kunobufakazi obukhulako bokuhlobana okungaba khona phakathi kwe-gut microbiota kanye nama-neurodegenerative diseases5,6. Ngokuphawulekako, embikweni wecala elilodwa, ukufakelwa kwe-microbiota yendle kwenze ngcono kokubili ukuthuthumela okuqakathekileko kanye nesifo samathumbu esithukutheleko esigulini, okungatjengisa ubudlelwano obuseduze phakathi kwe-gut microbiota nokuthuthumela okuqakathekileko. Ukungezelela, sithole amatjhuguluko athileko ema-gut microbiota eengulini ezine-ET, okusekela khulu indima eqakathekileko ye-gut dysbiosis ku-ET8.
Malungana nokungasebenzi kuhle kwamathumbu emalwelweni we-neurodegenerative, i-PD ngiyo efundwa khulu5. I-microbiota engalinganiko ingakhuphula ukungena kwamathumbu begodu yenze i-glia yamathumbu isebenze, okurholela ekutheni kube nama-alpha-synucleinopathies9,10,11. I-PD ne-ET zihlanganyela ezinye izinto ezifanako, ezifana nokuvama okufanako kokuthuthumela eengulini ze-ET ne-PD, ukuthuthumela okudlulako kokuphumula (ukuthuthumela okujayelekileko ku-PD), nokuthuthumela kokuma (okutholakala khulu eengulini ze-ET), okwenza kube budisi ukuhlukanisa hlangana nazo. amazinga wokuthoma 12. Ngalokho-ke, sitlhoga ukuvula ifasitela eliwusizo ukuhlukanisa phakathi kwe-ET ne-PD. Ngalokhu, ukufunda nge-dysbiosis yamathumbu kanye nokutjhuguluka kwe-metabolite okuhlobene nayo ku-ET nokukhomba umehluko wawo ku-PD kungaba ziimpawu ezingaba khona zokuxilonga nokuhlolwa okuhlukileko kwe-ET.
Ama-esidi wamafutha amafitjhani (ama-SCFA) zizinto ezikulu ezikhiqizwa kuvutshelwa kwamagciwani wamathumbu wefayibha yokudla begodu kucatshangwa bona zidlala indima eqakathekileko ekusebenzisaneni kwamathumbu nobuchopho13,14. Ama-SCFA athathwa ngamaseli wekoloni bese adluliselwa esibindini nge-portal venous system, begodu amanye ama-SCFA angena emjikelezweni wesistimu. Ama-SCFA anemiphumela yendawo ekugcineni ubuqotho besithiyo samathumbu nokukhuthaza ukuzivikela okuzalwa ngaphakathi kwe-mucosa yamathumbu15. Zibuye zibe nemiphumela yesikhathi eside emgodleni weengazi nobuchopho (BBB) ​​ngokuvuselela amaphrotheyini ahlangana ngokuqinileko nokuvuselela ama-neuron ngokuvuselela ama-G protein-coupled receptors (ama-GPCR) ukuwela i-BBB16. I-Acetate, i-propionate, ne-butyrate zii-SCFA ezinengi khulu ekholoni. Iimfundo zangaphambilini zitjengise ukwehla kwamazinga we-acetic, propionic kanye ne-butyric acid eengulini ezine-Parkinson's disease17. Kodwana, amazinga we-SCFA wendle azange afundwe eengulini ezine-ET.
Ngalokho, irhubhululo lethu belihlose ukukhomba amatjhuguluko athileko we-SCFA yendle eengulini ezine-ET nokuhluka kwazo eengulini ezine-PD, ukuhlola ubudlelwano be-SCFA yendle namatshwayo wezokwelapha we-ET kanye ne-microbiota yamathumbu, kanye nokuthola amandla wokuhlola nokuhlukahlukana kwamasampula wendle. KZhK. Ukutjheja izinto ezididako ezihlobene nemithi yokulwisana ne-PD, sikhethe iingulani ezine-Parkinson's disease njengezilawuli zesifo.
Iimfanelo ze-demographic nezokwelapha zama-ET ama-37, ama-PD ama-37, nama-HC ama-35 zifingqiwe kuThebuli 1. Ama-ET, ama-PD, nama-HC afaniswa ngobudala, ubulili, kanye ne-BMI. Amaqembu amathathu nawo bekanezinga elifanako lokubhema, ukusela utjwala nokusela ikofi netiye. Isikolo se-Wexner (P = 0.004) kanye nesikolo se-HAMD-17 (P = 0.001) sesiqhema se-PD beziphezulu kunalezo zesiqhema se-HC, begodu isikolo se-HAMA (P = 0.011) kanye nesikolo se-HAMD-17 (P = 0.011) sesiqhema se-ET beziphezulu kunalezo zesiqhema se-HC. Indlela yobulwelwe esiqhemeni se-ET beyide khulu kunasesiqhemeni se-PD (P<0.001).
Bekunomehluko oqakathekileko emazingeni we-fecal propionic acid (P = 0.023), i-acetic acid (P = 0.039), i-butyric acid (P = 0.020), isovaleric acid (P = 0.045), kanye ne-isobutyric acid (P = 0.015). . Ekuhlaziyweni okuragela phambili, amazinga we-propionic acid (P = 0.023), i-butyric acid (P = 0.007), kanye ne-isobutyric acid (P = 0.040) esiqhemeni se-ET begade aphasi khulu kunalawo asesiqhemeni se-HC. Iingulani ezine-ET bezinamazinga aphasi we-isovalerate (P = 0.014) kanye ne-isobutyrate (P = 0.005) ukudlula iingulani ezine-PD. Ukungezelela, amazinga we-fecal propionic acid (P = 0.013), i-acetic acid (P = 0.016), kanye ne-butyric acid (P = 0.041) begade aphasi eengulini ezine-PD kunezigulini ezine-CC (Umfanekiso 1 kanye neThebula elingezelelweko 1) .
i-ag imele ukumadanisa isiqhema se-propionic acid, i-acetic acid, i-butyric acid, isovaleric acid, valeric acid, i-caproic acid kanye ne-isobutyric acid, ngokulandelana. Bekunomehluko omkhulu emazingeni we-propionic acid, i-acetic acid, i-butyric acid, i-isovaleric acid kanye ne-isobutyric acid hlangana namakoro amathathu. ET ukuthuthumela okuqakathekileko, isifo se-Parkinson, ukulawulwa kwe-HC okunepilo, i-SCFA. Umehluko oqakathekileko utjengiswa yi-*P <0.05 kanye ne-**P <0.01.
Nasicabangela umehluko wendlela yobulwelwe hlangana nesiqhema se-ET nesiqhema se-PD, sifunde iingulani ezingama-33 ezine-PD yokuthoma kanye nezigulani ezili-16 ezine-ET (indlela yesifo Ngemva kwalokho sihlolisise bona amazinga we-SCFA wethumbu angahlukanisa na iingulani ezine-ET ezigulini ezine-CU nofana i-PD. Ngokuya ngokuhlaziywa kwe-ROC, umehluko ku-AUC yamazinga we-propionate bekungu-0.668 (95% CI: 0.538-0.797), okwenza bona kube nokwenzeka ukuhlukanisa iingulani ezine-ET ukusuka ku-HC. Iingulani ezine-ET ne-GC zingahlukaniswa ngamazinga we-butyrate nge-AUC ye-0.685 (95% CI: 0.556–0.814). Umehluko emazingeni we-isobutyric acid ungahlukanisa iingulani ezine-ET ukusuka ku-HC nge-AUC ye-0.655 (95% CI: 0.525–0.786). Lokha nakuhlanganiswa amazinga we-propionate, butyrate kanye ne-isobutyrate, i-AUC ephezulu ye-0.751 (95% CI: 0.634–0.867) yatholakala ngokuzwela kwe-74.3% kanye nokukhethekileko kwe-72.9% (Umfanekiso 2a). Ukuhlukanisa hlangana nezigulani ze-ET ne-PD, i-AUC yamazinga we-isovaleric acid bekungu-0.700 (95% CI: 0.579–0.822) begodu amazinga we-isobutyric acid bekungu-0.718 (95% CI: 0.599–0.836). Ukuhlanganiswa kwamazinga we-isovaleric acid kanye ne-isobutyric acid bekune-AUC ephezulu ye-0.743 (95% CI: 0.629–0.857), ukuzwela kwe-74.3% kanye nokukhethekileko kwe-62.9% (Umfanekiso 2b). Ukungezelela, sihlole bona amazinga we-SCFA ethuvini lezigulani ezinesifo se-Parkinson ahlukile na ebantwini abalawulayo. Ngokuya ngokuhlaziywa kwe-ROC, i-AUC yokukhomba iingulani ezine-PD ngokuya ngomehluko wamazinga we-propionic acid bekungu-0.687 (95% CI: 0.559-0.814), ngokuzwela okungu-68.6% nokukhethekileko okungu-68.7%. Umehluko emazingeni we-acetate ungahlukanisa iingulani ze-PD kuma-HC ane-AUC ye-0.674 (95% CI: 0.542–0.805). Iingulani ezine-PD zingahlukaniswa ne-CU kwaphela ngamazinga we-butyrate nge-AUC ye-0.651 (95% CI: 0.515–0.787). Lokha nakuhlanganiswa amazinga we-propionate, i-acetate kanye ne-butyrate, i-AUC ye-0.682 (95% CI: 0.553–0.811) yatholakala (Isithombe 2c).
ukubandlululwa yiBandla le-Russian Orthodox ngokumelene ne-ET ne-HC; b Ukubandlululwa kwe-ROC ngokumelene ne-ET ne-PD; c Ukubandlululwa kwe-ROC ngokumelene ne-PD ne-HC; ET ukuthuthumela okuqakathekileko, isifo se-Parkinson, ukulawulwa kwe-HC okunepilo, i-SCFA.
Ezigulini ezine-ET, izinga le-sobutyric acid yendle belihlobene kumbi ne-FTM score (r = -0.349, P = 0.034), begodu izinga le-isovaleric acid ye-fecal belihlobene kumbi ne-FTM score (r = -0.421, P = 0.001) kanye ne-TETRAS score. (r = -0.382, P = 0.020). Eengulini ezine-ET ne-PD, amazinga we-fecal propionate bekahlobene kumbi nama-SCOPA-AUT scores (r = −0.236, P = 0.043) (Umfanekiso 3 kanye neThebula elingezelelweko 3). Bekungakabi nokuhlobana okuqakathekileko hlangana nendlela yobulwelwe ne-SCFA esiqhemeni se-ET (P ≥ 0.161) nofana esiqhemeni se-PD (P ≥ 0.246) (Ithebula elingezelelweko 4). Eengulini ezine-PD, amazinga we-fecal caproic acid ahlotjaniswa kuhle namaphuzu we-MDS-UPDRS (r = 0.335, P = 0.042). Kibo boke abahlanganyeli, amazinga we-fecal propionate (r = −0.230, P = 0.016) kanye ne-acetate (r = −0.210, P = 0.029) bekahlotjaniswa kumbi namaphuzu we-Wexner (Umfanekiso 3 kanye neThebula eliNgezelelweko 3).
Amazinga we-sobutyric acid yendle bekahlobene kumbi namaphuzu we-FTM, i-isovaleric acid beyihlobene kumbi namaphuzu we-FTM kanye ne-TETRAS, i-propionic acid beyihlotjaniswa kumbi namaphuzu we-SCOPA-AUT, i-caproic acid beyihlobene kuhle namaphuzu we-MDS-UPDRS, begodu i-propionic acid beyihlotjaniswa kumbi namaphuzu we-FTM kanye ne-TETRAS. I-TETRAS kanye ne-acetic acid bezihlobene kumbi ne-Wexner score. I-MDS-UPDRS Association isekelwe ngenguqulo 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 i-HAMA, i-HY Hoehn kanye ne-Yahr izigaba, i-SCCOFA SFA, APAUTONOmic Parkinson's Disease Autonomic Disease I-Symptom Outcome Scale, i-FTM Fana-Tolosa-Marin Clinical Tremor Rating Scale, i-TETRAS Research Group (TRG) Essential Tremor Rating Scale. Umehluko oqakathekileko utjengiswa yi-*P <0.05 kanye ne-**P <0.01.
Siragele phambili nokuhlola ubujamo bokubandlulula kwama-gut microbiota ngokusebenzisa ukuhlaziywa kwe-LEfSE begodu sakhetha izinga ledatha yobunengi bomhlobo wokuhlaziywa okungeziweko. Ukumadanisa kwenziwa hlangana ne-ET ne-HC begodu hlangana ne-ET ne-PD. Ukuhlaziywa kokuhlobana kwe-Spearman kwenziwa ngobunengi obuhlobeneko be-gut microbiota kanye namazinga we-SCFA we-fecal emaqenjini amabili wokumadanisa.
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) bezikhona ekuhlaziyweni kwe-CA ne-ET. , P = 0.005; ehlotjaniswa ne-butyric acid, r = 0.374, P = 0.001; ihlobana ne-isobutyric acid, r = 0.329, P = 0.005), i-Howardella (ihlobana ne-propionic acid, r = 0.242, P = 0.041), i-Raoultella (ihambelana ne-propionate, r = 0.249, P = 0.035), kanye ne-Candidatus Arthromitus (ihambelana ne-propionic acid, r = 0.249, 0.302, P = 0.010) yehla ku-ET begodu ihlobene kuhle namazinga we-SCFA wendle. Kodwana, ubunengi be-Stenotropomonas kwanda ku-ET begodu bebuhlobene kumbi namazinga we-isobutyrate wendle (r = -0.250, P = 0.034). Ngemva kokulungiswa kwe-FDR, ukuhlobana hlangana kwe-Faecalibacterium, i-Catenibacter, ne-SCFA kwahlala kuqakathekile (P ≤ 0.045) (Umfanekiso 4 kanye neThebula eliNgezelelweko 5).
Ukuhlaziywa kokuhlobana kwe-ET ne-HC. Ngemva kokulungisa i-FDR, ubunengi be-Faecalibacterium (ehlobene kuhle ne-butyrate) kanye ne-Streptobacterium (ehlobene kuhle ne-propionate, i-butyrate, ne-isobutyrate) kwatholakala bona kwehliswe ku-ET begodu kuhlotjaniswa kuhle namazinga we-SCFA wendle. b Ukuhlaziywa kokuhlobana kwe-ET ne-PD. Ngemva kokulungisa i-FDR, akukho ukuhlobana okuqakathekileko okutholakele. ET ukuthuthumela okuqakathekileko, isifo se-Parkinson, ukulawulwa kwe-HC okunepilo, i-SCFA. Umehluko oqakathekileko utjengiswa yi-*P <0.05 kanye ne-**P <0.01.
Lokha nakuhlaziywa i-ET ngokuqathaniswa ne-PD, i-Clostridium trichophyton yatholakala ikhuphukile ku-ET begodu ihlobene ne-isovaleric acid yendle (r = -0.238, P = 0.041) kanye ne-isobutyric acid (r = -0.257, P = 0.027). ). Ngemva kokulungiswa kwe-FDR, enye yahlala iqakathekile (P≥0.295) (Umfanekiso 4 kanye neThebula lokuNgezelelako 5).
Irhubhululo leli lirhubhululo elipheleleko elihlola amazinga we-SCFA wendle begodu liwahlobanise namatjhuguluko we-gut microbiota kanye nobukhulu beempawu eengulini ezine-ET naziqathaniswa nezigulani ezine-CU ne-PD. Sithole bona amazinga we-SCFA wendle ehliswe eengulini ezine-ET begodu ahlotjaniswa nobujamo bezokwelapha kanye namatjhuguluko athileko we-gut microbiota. Amazinga we-fecal aqongelelweko wama-short-chain fatty acids (ama-SCFA) ahlukanisa i-ET kusuka ku-GC ne-PD.
Nayiqathaniswa nezigulani ze-GC, izigulani ze-ET zinamazinga aphasi we-propionic, butyric, kanye ne-isobutyric acids. Ukuhlanganiswa kwama-propionic, butyric kanye ne-isobutyric acids kwahlukanisa i-ET ne-HC nge-AUC ye-0.751 (95% CI: 0.634–0.867), ukuzwela kwe-74.3% kanye nokukhethekileko kwe-72.9%, okutjengisa ukusetjenziswa kwawo njenge-biomarkers yokuhlola indima engaba khona ye-ET. Ukuhlaziywa okuragela phambili kutjengise bona amazinga we-propionic acid yendle ahlotjaniswa kumbi ne-Wexner score kanye ne-SCOPA-AUT score. Amazinga we-isobutyric acid yendle ahlotjaniswa ngokuphambene namaphuzu we-FTM. Ngakelinye ihlangothi, ukwehla kwamazinga we-butyrate ku-ET bekuhlotjaniswa nokwehla kwama-microbiota akhiqiza i-SCFA, i-Faecalibacterium, kanye ne-Categorybacter. Ukungezelela, ukwehla kobunengi be-Catenibacter ku-ET nakho kwahlotjaniswa nokwehla kwamazinga we-fecal propionic kanye ne-isobutyric acid.
Inengi lama-SCFA akhiqizwa ngaphakathi kwamathumbu athathwa ma-colonocytes khulukhulu ngokusebenzisa i-H+-dependent nofana i-sodium-dependent monocarboxylate transporters. Ama-esidi wamafutha amafitjhani asetjenziswa njengomthombo wamandla wama-colonocytes, kuthi lawo angasebenziseki ema-colonocytes athuthwa aye emjikelezweni we-portal 18 . Ama-SCFA angathonya ukunyakaza kwamathumbu, athuthukise ukusebenza kwesithiyo samathumbu, begodu abe nomthelela ekusebenzeni kwegazi kanye nokuzivikela komzimba19. Kwatholakala ngaphambilini bona ukugxila kwe-butyrate, i-acetate, kanye ne-propionate yehlile eengulini ze-PD nayiqathaniswa ne-HCs17, okuhambisana nemiphumela yethu. Irhubhululo lethu lithole ukwehla kwama-SCFA eengulini ezine-ET, kodwana kuncani okwaziwako ngendima yama-SCFA ekuguleni kwe-ET. I-Butyrate ne-propionate zingabophelela kuma-GPCR begodu zibe nomthelela ekuboniseni okuthembele ku-GPCR njenge-MAPK kanye ne-NF-κB20 signaling. Umqondo oyisisekelo we-gut-brain axis kukuthi ama-SCFA akhiqizwa ziinlwanyana ze-gut angathonya ukuthunyelwa kwe-host, ngaleyo ndlela athonye ukusebenza kwamathumbu nobuchopho. Ngombana i-butyrate ne-propionate zinemiphumela enamandla yokuvimbela umsebenzi we-histone deacetylase (HDAC)21 begodu i-butyrate nayo ingasebenza njenge-ligand yezinto zokutlola, inemiphumela ebanzi ekusebenzeni kwe-host, ukuhlukaniswa nokwanda, khulukhulu ngebanga lomthelela wazo ekulawuleni izakhi zofuzo22 . Ngokuya ngobufakazi obuvela ku-SCFA kanye namalwelwe we-neurodegenerative, i-butyrate ithathwa njengendlela yokwelapha ngebanga lekghono layo lokulungisa ukusebenza kwe-HDAC okukhubazekileko, okungabangela ukufa kwe-dopaminergic neuron ku-PD23,24,25. Iimfundo zeenlwana zibuye zitjengise ikghono le-butyric acid lokukhandela ukuwohloka kwe-dopaminergic neuron nokwenza ngcono ukuphazamiseka kokunyakaza kumamodeli we-PD26,27. I-esidi ye-propionic itholakele bona inciphisa ukuphendula kokuvuvuka begodu ivikela ubuqotho be-BBB28,29. Iimfundo zitjengise bona i-propionic acid ikhuthaza ukuphila kwama-neuron we-dopaminergic ngokuphendula ebuthini be-rotenone kumamodeli we-PD 30 nokuthi ukuphathwa kwe-propionic acid ngomlomo kusindisa ukulahlekelwa kwe-dopaminergic neuron kanye nokutlhayela kweenthuthi emagundeni ane-PD 31 . Kuncani okwaziwako ngomsebenzi we-sobutyric acid. Kodwana, irhubhululo lamuva nje lithole bona ukukoloniswa kwamagundane nge-B. ovale kwandisa okuqukethwe kwe-SCFA yamathumbu (okufaka hlangana i-acetate, propionate, isobutyrate, kanye ne-isovalerate) kanye nokugxila kwe-GABA yamathumbu, okuveza bona kukhona ukuhlobana hlangana kwe-gut microbiota ne-intestinal SCFA. ukugxila kwama-neurotransmitter32. Ku-ET, amatjhuguluko angakajayeleki we-cerebellum afaka hlangana amatjhuguluko kuma-axon wamaseli we-Purkinje nama-dendrite, ukufuduswa nokulahlekelwa kwamaseli we-Purkinje, amatjhuguluko kuma-axon wamaseli webhasikidi, ukungajayeleki ekukhuphukeni kokuxhumana kwefayibha nokusabalalisa amaseli we-Purkinje, kanye namatjhuguluko kuma-receptors we-GABA ethambweni elinamazinyo. i-nuclei, okurholela ekwehleni kwe-GABAergic okuvela e-cerebellum3,4,33. Akukacaci bona ama-SCFA ahlotjaniswa nokuwohloka kwemizwa yamaseli we-Purkinje kanye nokwehla kokukhiqizwa kwe-GABA ye-cerebellar. Imiphumela yethu iveza ukuhlobana okuqinileko hlangana ne-SCFA ne-ET, kodwana umklamo wesifundo esiphambukileko awuvumeli nanyana ngiziphi iinphetho malungana nobudlelwano obubangelako hlangana ne-SCFA nekambiso yesifo se-ET; Iimfundo ezilandelako ezilandelako ziyatlhogeka, okufaka hlangana ukulinganisa okulandelanako kwama-SCFA wendle, kanye neemfundo zeenlwana ezihlola iindlela.
Ama-SCFA acatshangwa bona akhuthaza ukunciphisa kwemisipha ebushelelezi yekoloni34. Ukutlhogeka kwe-SCFA kuzokuthuthukisa amatshwayo wokuqunjelwa, begodu ukungezelelwa nge-SCFA kungenza ngcono amatshwayo wokuqunjelwa PD35. Imiphumela yethu ibuye itjengise ukuhlobana okuqakathekileko hlangana nokwehla kokuqukethwe kwe-SCFA yendle nokunyuka kokuqunjelwa nokungasebenzi kuhle kweziguli ezine-ET. Umbiko owodwa wecala uthole bona ukufakelwa kwe-microbiota kwenze ngcono kokubili ukuthuthumela okuqakathekileko kanye nesifo samathumbu esithukutheleko esigulini 7, okuveza ubuhlobo obuseduze phakathi kwe-gut microbiota ne-ET. Ngalokho-ke, sikholelwa bona i-SCFA/microbiota yethumbu ingathonya ukunyakaza kwamathumbu womsingathi nokusebenza kwehlelo lezinzwa elizimeleko.
Irhubhululo lithole bona ukwehla kwamazinga we-SCFAs yethumbu ku-ET ahlotjaniswa nokwehla kobunengi be-Faecalibacterium (ehlobene ne-butyrate) kanye ne-Streptobacterium (ehlobene ne-propionate, butyrate, kanye ne-isobutyrate). Ngemva kokulungiswa kwe-FDR, ubudlelwano lobu buhlala buqakathekile. I-Faecalibacterium ne-Streptobacterium ziinlwana ezikhiqiza i-SCFA. I-Faecalibacterium yaziwa ngokuthi yi-microorganism ekhiqiza i-butyrate36, kuthi imikhiqizo ekulu yokuvutshelwa kwe-Catenibacter yi-acetate, i-butyrate kanye ne-lactic acid37. I-Fecalibacterium yatholakala ku-100% yamaqembu we-ET ne-HC; ubunengi obuphakathi beqembu le-ET bekuyi-2.06% kuthi leqembu le-HC bekungu-3.28% (LDA 3.870). Ibhaktheriya yesigaba yatholakala ku-21.6% (8/37) yesiqhema se-HC begodu kusampula yinye kwaphela yesiqhema se-ET (1/35). Ukwehla nokungabonakali kwe-streptobacteria ku-ET kungatjengisa ukuhlobana nokutheleleka kwesifo. Ubunengi obuphakathi bemihlobo ye-Catenibacter esiqhemeni se-HC bekungu-0.07% (LDA 2.129). Ukungezelela, amagciwane we-lactic acid ahlotjaniswa namatjhuguluko we-fecal butyrate (P=0.016, P=0.096 ngemva kokulungiswa kwe-FDR), begodu i-arthritis candidate yahlotjaniswa namatjhuguluko ku-isobutyrate (P=0.016, P=0.072 ngemva kokulungiswa kwe-FDR). Ngemva kokulungiswa kwe-FDR, kusele umkhuba wokuhlobana kwaphela, okungakaqakatheki ngokwezibalo. I-Lactobacilli nayo yaziwa ngokuthi yi-SCFA (acetic acid, propionic acid, isobutyric acid, butyric acid) abakhiqizi 38 begodu i-Candidatus Arthromitus yi-inducer ethileko ye-T helper 17 (Th17) cell differentiation, nge-Th1/2 kanye ne-Tregs ezihlotjaniswa nokulinganisela kwamasotja womzimba /Th173. . Irhubhululo lakamuva litjengisa bona amazinga aphakemeko we-pseudoarthritis yendle angafaka isandla ekuvuvukeni kwekoloni, ukungasebenzi kuhle kwesithiyo samathumbu, kanye nokuvuvuka komzimba 40 . Amazinga we-Clostridium trichoides akhuphuka ku-ET nayiqathaniswa ne-PD. Ubunengi be-Clostridium trichoides kwatholakala bona buhlobene kumbi ne-isovaleric acid kanye ne-isobutyric acid. Ngemva kokulungiswa kwe-FDR, kokubili kwahlala kuqakathekile (P≥0.295). I-Clostridium pilosum libhaktheriya elaziwa ngokuhlotjaniswa nokuvuvuka begodu lingaba nomthelela ekusebenzisekeni kuhle kwesithiyo samathumbu41. Irhubhululo lethu langaphambilini libike amatjhuguluko ema-microbiota wamathumbu wezigulani ezine-ET8. Lapha siphinde sibike amatjhuguluko ku-SCFA ku-ET begodu sikhombe ukuhlobana hlangana nokugula kwamathumbu namatjhuguluko ku-SCFA. Ukwehla kwamazinga we-SCFA kuhlotjaniswa khulu nokugandeleleka kwamathumbu nokuthuthumela okukhulu ku-ET. Imiphumela yethu iveza bona i-gut-brain axis ingadlala indima eqakathekileko ekuthomeni kwe-ET, kodwana iimfundo ezingezelelweko emamodelini weenlwana ziyatlhogeka.
Nayiqathaniswa nezigulani ezine-PD, izigulani ezine-ET zinamazinga aphasi we-isovaleric kanye ne-isobutyric acids ethuvini lazo. Ukuhlanganiswa kwe-isovaleric acid kanye ne-isobutyric acid kwaveza i-ET ku-PD nge-AUC ye-0.743 (95% CI: 0.629–0.857), ukuzwela kwe-74.3% kanye nokukhethekileko kwe-62.9%, okuveza indima yabo engaba khona njenge-biomarkers ekuhlolweni okuhlukileko kwe-ET. . Amazinga we-isovaleric acid yendle bekahlobene ngokuphambene namaphuzu we-FTM kanye ne-TETRAS. Amazinga we-isobutyric acid yendle ahlotjaniswa ngokuphambene namaphuzu we-FTM. Ukwehla kwamazinga we-isobutyric acid kwahlotjaniswa nokwehla kwenani lama-catobacteria. Kuncani okwaziwako ngemisebenzi ye-isovaleric acid ne-isobutyric acid. Irhubhululo langaphambilini litjengise bona ukukoloniswa kwamagundane nge-B. ovale kwandisa inani lama-SCFAs wamathumbu (okufaka hlangana i-acetate, propionate, isobutyrate, kanye ne-isovalerate) kanye nokugxila kwe-GABA yamathumbu, okuveza ukuhlobana kwamathumbu hlangana ne-microbiota kanye nokugxila kwe-SCFA/neurotransmitter yamathumbu32. Ngokukarisako, amazinga we-isobutyric acid abonwako bekafana hlangana namaqembu we-PD ne-HC, kodwana ahlukile hlangana namaqembu we-ET ne-PD (nofana i-HC). I-Isobutyric acid ingakwazi ukuhlukanisa phakathi kwe-ET ne-PD nge-AUC ye-0.718 (95% CI: 0.599–0.836) begodu ikhombe i-ET ne-NC nge-AUC ye-0.655 (95% CI: 0.525–0.786). Ukungezelela, amazinga we-isobutyric acid ahlobana nobukhulu bokuthuthumela, okuqinisa ukuhlobana kwayo ne-ET. Umbuzo wokobana ingabe i-isobutyric acid yomlomo ingehlisa ubudisi bokuthuthumela eengulini ezine-ET kufanele ifundwe ngokunabileko.
Ngalokho, okuqukethwe kwe-SCFA yethumbu kwehliswa eengulini ezine-ET begodu kuhlotjaniswa nobukhulu bezokwelapha be-ET kanye namatjhuguluko athileko we-microbiota yamathumbu. I-fecal propionate, i-butyrate, kanye ne-isobutyrate kungaba ma-biomarker wokuhlola i-ET, lokha i-sobutyrate ne-isovalerate kungaba zii-biomarker zokuhlola ezihlukileko ze-ET. Amatjhuguluko we-isobutyrate yendle angaba ngqo khulu ku-ET ukudlula amatjhuguluko kwamanye ama-SCFA.
Irhubhululo lethu linemikhawulo eminengi. Kokuthoma, amaphetheni wokudla nokukhetha ukudla kungaba nomthelela ekuvezweni kwe-microbiota, amasampula amakhulu wokufunda ebantwini abahlukahlukeneko ayatlhogeka, begodu iimfundo zesikhathi esizako kufanele zethule iimfundo zokudla ezipheleleko nezihlelekileko ezifana namaphepha wemibuzo wokudla okuvamileko. Kwesibili, umklamo wesifundo esiphambukileko uvimbela nanyana ngiziphi iinphetho malungana nobudlelwano obubangelwako hlangana ne-SCFA kanye nekambiso yesifo se-ET. Iimfundo ezilandelako zesikhathi eside ezineenlinganiso ezilandelelanako zama-SCFA wendle ziyatlhogeka. Okwesithathu, amakghono wokuhlola nokuhlukahlukana kwamazinga we-SCFA wendle kufanele aqinisekiswe kusetjenziswa amasampula azijameleko avela ku-ET, HC, kanye ne-PD. Amasampula amanengi wethumbu azijameleko kufanele ahlolwe esikhathini esizako. Ekugcineni, iingulani ezine-PD esiqhemeni sethu bezinesikhathi esifitjhani khulu sesifo ukudlula iingulani ezine-ET. Simadanise khulu i-ET, i-PD ne-HC ngokweminyaka, ubulili kanye ne-BMI. Njengombana kunikelwe umehluko wendlela yobulwelwe hlangana nesiqhema se-ET nesiqhema se-PD, siphinde safunda iingulani ezingama-33 ezine-PD yokuthoma kanye nezigulani ezili-16 ezine-ET (isikhathi sesifo ≤3 iminyaka) ukumadanisa okungeziweko. Umehluko phakathi kwamaqembu ku-SCFA bewuhambisana nedatha yethu yokuthoma. Ukungezelela, asitholanga ukuhlobana hlangana nesikhathi sesifo nokutjhuguluka kwe-SCFA. Kodwana, esikhathini esizako, kungaba kuhle ukubutha iingulani ezine-PD ne-ET ekuthomeni ngesikhathi esifitjhani sobulwelwe ukuqedela ukuqinisekiswa ngesampula ekulu.
Iphrothokholi yokufunda yavunywa yiKomidi yokuZiphatha ye-Ruijin Hospital ehlangene ne-Shanghai Jiao Tong University School of Medicine (RHEC2018-243). Imvumo etloliweko enolwazi yatholwa kibo boke abahlanganyeli.
Hlangana noTjhirhweni 2019 noNobayeni 2022, abantu abali-109 (37 ET, 37 PD, kanye nama-35 HC) abavela e-Movement Disorder Center Clinic ye-Ruijin Hospital, ehlangene ne-Shanghai Jiao Tong University School of Medicine, bafakwa esifundweni lesi. Iinqophiso beziyi: (1) iminyaka ema-25 ukuya kwema-85, (2) iingulani ezine-ET zahlolwa ngokuya kwendlela ye-MDS Working Group 42 begodu i-PD yahlolwa ngokuya kwendlela ye-MDS 43, (3) zoke iingulani bezingathathi iindakamizwa ezilwa ne-PD ngaphambi kokuhlala esihlalweni. ukubuthelela amasampula. (4) Isiqhema se-ET sathatha ama-β-blockers kwaphela nofana singathathi iindakamizwa ezihlobeneko ngaphambi kokubuthelela amasampula wethumbu. Ama-HC afana neminyaka, ubulili, kanye ne-body mass index (BMI) nawo akhethwa. Iindlela zokukhipha bekuyi: (1) abantu abadla imifino, (2) ukudla okumbi, (3) amalwelwe angapheliko wesisu (okufaka hlangana amalwelwe wokuvuvuka kwamathumbu, amathumbu wesisu nofana we-duodenal), (4) amalwelwe angapheliko amakhulu (okufaka hlangana amathumba amambi), ukuhluleka kwehliziyo, ukuhluleka kweenso, amalwelwe weengazi) (5) amalwelwe wamathumbu amakhulu ukuhlinzwa, (6) Ukusetjenziswa kwe-yogurt okungapheliko nofana njalo, (7) Ukusetjenziswa kwananyana ngimiphi i-probiotics nofana ama-antibiotics inyanga eyodwa, (8) Ukusetjenziswa okungapheliko kwama-corticosteroids, ama-proton pump inhibitors, ama-statins, i-metformin, ama-immunosuppressants nofana imithi yokulwisana nomdlavuza kanye (9) nokukhubazeka okukhulu kwengqondo okuphazamisa imithi yezokwelapha.
Boke abafundi banikela ngomlando wezamaphilo, ilwazi lobunzima nobude ukubala i-BMI, begodu benza ukuhlolwa kwemizwa nokuhlolwa kwezokwelapha okufana ne-Hamilton Anxiety Rating Scale (HAMA) 44 anxiety score, i-Hamilton Depression Rating Scale-17 score (HAMD-17) 45. ukugandeleleka, ubukhulu bokuqunjelwa ngokusebenzisa ukuqunjelwa 46 kanye ne-Bristol Stool Scale 47 nokusebenza kwengqondo kusetjenziswa i-Mini-Mental State Examination (MMSE) 48 . I-Scale for the Assessment of Autonomic Symptoms of Parkinson's Disease (SCOPA-AUT) 49 ihlole ukungasebenzi kuhle kwe-autonomic eengulini ezine-ET 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 zahlolwa eengulini ezine-ET; i-Kinson's Disease Rating Scale (MDS-), esekelwe yi-United Parkinson's Disease Association; I-UPDRS inguqulo 51 kanye ne-Hoehn no-Yahr (HY) inguqulo 52 zahlolwa.
Umhlanganyeli ngamunye wacelwa bona athathe isampula yesitulo ekuseni asebenzisa isitja sokubuthelela isitulo. Dlulisela iintjalo zibe seqhweni bese uzibeka ku--80°C ngaphambi kokusebenza. Ukuhlaziywa kwe-SCFA kwenziwa ngokuya ngemisebenzi ejayelekileko ye-Tiangene Biotechnology (Shanghai) Co., Ltd. Ama-400 mg wamasampula wethuvi amatjha aqoqwe esifundweni ngasinye begodu ahlaziywa kusetjenziswa ama-SCFA ngemva kokugaya nokuzwakala. Ama-SCFA akhethiweko endle ahlaziywa kusetjenziswa i-gas chromatography-mass spectrometry (GC-MS) kanye ne-liquid chromatography-tandem MS (LC-MS/MS).
I-DNA yakhishwa emasampula angama-200 mg kusetjenziswa i-QIAamp® Fast DNA Stool Mini Kit (QIAGEN, Hilden, Germany) ngokuya kwemilayo yomkhiqizi. Ukwakheka kwama-microbial kwatholwa ngokulandelana kwejini le-16 S rRNA ku-DNA ehlukaniswe ethuvini ngokukhulisa indawo ye-V3-V4. Hlola i-DNA ngokusebenzisa isampula ku-1.2% ye-agarose gel. Ukukhuliswa kwe-polymerase chain reaction (PCR) kwe-16S rRNA gene kwenziwa kusetjenziswa ama-primers we-universal bacterial (357 F kanye ne-806 R) kanye nelayibhrari ye-amplicon enezinyathelo ezimbili eyakhiwe kuplatifomu ye-Novaseq.
Iintjhuguluko eziragako zivezwa njengesilinganiso ± ukuphambuka okujayelekileko, begodu iintjhuguluko ezihlukahlukeneko zivezwa njengeenomboro namaphesente. Sisebenzise ukuhlolwa kwaka-Levene ukuhlola ukufana kokuhluka. Ukumadanisa kwenziwa kusetjenziswa ukuhlolwa kwe-t okunemisila emibili nofana ukuhlaziywa kokuhlukahluka (i-ANOVA) nangabe amatjhuguluko bekasakazwe ngokujayelekileko, kanye nokuhlolwa kwe-Mann-Whitney U okungekho emthethweni nangabe ukucabanga okujayelekileko nofana kwe-homoscedasticity kwephulwe. Sisebenzise indawo engaphasi kwe-receiver operating characteristic (ROC) curve (AUC) ukulinganisa ukusebenza kokuhlola kwemodeli nokuhlola ikghono le-SCFA lokuhlukanisa iingulani ezine-ET kilabo abane-HC nofana i-PD. Ukuhlola ubudlelwano phakathi kwe-SCFA nobukhulu bomtholampilo, sisebenzise ukuhlaziywa kokuhlobana kwe-Spearman. Ukuhlaziywa kwezibalo kwenziwa kusetjenziswa isofthiwe ye-SPSS (inguqulo 22.0; SPSS Inc., Chicago, IL) ngezinga lokuqakatheka (okufaka hlangana inani le-P kanye ne-FDR-P) ebekwe ku-0.05 (amahlangothi amabili).
Ukulandelana kwe-16 S kwahlaziywa kusetjenziswa inhlanganisela ye-Trimmomatic (inguqulo 0.35), Flash (inguqulo 1.2.11), UPARSE (inguqulo v8.1.1756), mothur (inguqulo 1.33.3) kanye ne-R (inguqulo 3.6.3) isofthiwe. Idatha yezakhi zofuzo ze-16S rRNA eluhlaza yasetjenzwa kusetjenziswa i-UPARSE ukwenza amayunithi we-operational taxonomic (ama-OTU) ane-97% yobunikazi. Ukuhlukaniswa kwavezwa kusetjenziswa i-Silva 128 njengedathabheyisi yokubhekisela. Izinga elijwayelekileko ledatha yobunengi obuhlobeneko lakhethelwa ukuhlaziywa okungeziweko. Ukuhlaziywa kobukhulu bomthelela (i-LDA) kwasetjenziselwa ukumadanisa hlangana namaqembu (ET vs. HC, ET vs. PD) ngomkhawulo we-α we-0.05 kanye nomkhawulo wobukhulu bomphumela we-2.0. Iinhlobo ezihlukileko ezikhonjwe ngokuhlaziywa kwe-LEfSE zabuye zasetjenziselwa ukuhlaziywa kokuhlobana kwe-Spearman kwe-SCFA.
Ukuthola ilwazi elinabileko ngomklamo wesifundo, qala i-Abstract yoMbiko weRhubhululo leMvelo ehlotjaniswa ne-atikili le.
Idatha yokulandelana kwe-16S engakalungiswa igcinwa ku-National Center for Biotechnology Information (NCBI) i-BioProject database (SRP438900: PRJNA974928), i-URL: https://www.ncbi.nlm.nih.gov/Traces/study/?acc= SRP438900&Po. =acc_s% 3Aa. Eminye idatha efaneleko iyatholakala kumtloli ohambelana naye ngesibawo esizwakalako, njengokusebenzisana kwezesayensi nokutjhentjhana kwezefundo namaphrojekthi wokurhubhulula apheleleko. Akukho ukudluliselwa kwedatha kwabanye abantu ngaphandle kwemvumo yethu okuvunyelweko.
Ikhodi yomthombo ovulekileko kwaphela ngokuhlanganiswa kwe-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), usebenzisa amasethingi akhethiweko nofana isigaba esithi “Indlela”. Ilwazi elengeziweko elicacisako linganikelwa umtloli ohambelana naye ngesibawo esizwakalako.
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