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Kuzindikira msanga kwa essential tremor (ET) kungakhale kovuta, makamaka ngati kusiyanitsa ndi matenda athanzi (HC) ndi matenda a Parkinson (PD). Posachedwapa, kusanthula zitsanzo za ndowe za microbiota ya m'matumbo ndi metabolites zake kwapereka njira zatsopano zopezera zizindikiro zatsopano za matenda a neurodegenerative. Short-chain fatty acids (SCFA), monga metabolite yayikulu ya zomera za m'matumbo, imachepa m'chimbudzi mu PD. Komabe, SCFA ya m'chimbudzi sinaphunzirepo mu ET. Cholinga chathu chinali kufufuza kuchuluka kwa ma SCFA mu chimbudzi mu ET, kuwunika ubale wawo ndi zizindikiro zachipatala ndi microbiota ya m'matumbo, ndikupeza luso lawo lozindikira matenda. SCFA ya m'chimbudzi ndi microbiota ya m'matumbo zinayesedwa mu ET 37, PD zatsopano 37, ndi HC 35. Kudzimbidwa, kusagwira ntchito bwino kwa autonomic, ndi kuopsa kwa tremor zinayesedwa pogwiritsa ntchito sikelo. Kuchuluka kwa propionate, butyrate, ndi isobutyrate mu chimbudzi kunali kotsika mu ET kuposa mu HC. Kuphatikiza kwa ma asidi a propionic, butyric ndi isobutyric kunasiyanitsa ET ndi HC yokhala ndi AUC ya 0.751 (95% CI: 0.634–0.867). Ma asidi a Fecal isovaleric ndi isobutyric acid anali otsika mu ET kuposa mu PD. Isovaleric acid ndi isobutyric acid zimasiyanitsa pakati pa ET ndi PD yokhala ndi AUC ya 0.743 (95% CI: 0.629–0.857). Fecal propionate imagwirizanitsidwa molakwika ndi kudzimbidwa komanso kusagwira ntchito bwino kwa autonomic. Isobutyric acid ndi isovaleric acid zimagwirizanitsidwa molakwika ndi kugwedezeka kwamphamvu. Kuchepa kwa kuchuluka kwa SCFA m'chimbudzi kunagwirizanitsidwa ndi kuchepa kwa kuchuluka kwa Faecalibacterium ndi Streptobacterium mu ET. Chifukwa chake, kuchuluka kwa SCFA m'chimbudzi kumachepa mu ET ndipo kumalumikizidwa ndi kuopsa kwa chithunzi chachipatala komanso kusintha kwa microbiota ya m'matumbo. Propionic acid, butyric acid, isobutyric acid, ndi isovaleric acid m'ndowe zingakhale zizindikiro zodziwira matenda komanso zosiyana za ET.
Kugwedezeka kwakukulu (ET) ndi matenda osatha komanso osatha a neurodegenerative omwe amadziwika makamaka ndi kugwedezeka kwa miyendo yakumtunda, komwe kungakhudzenso ziwalo zina za thupi monga mutu, mawu, ndi miyendo yakumunsi 1. Zizindikiro zachipatala za ET sizimangophatikizapo zizindikiro za kayendedwe ka thupi komanso zizindikiro zina zosakhala zoyendetsa thupi, kuphatikizapo matenda am'mimba 2. Kafukufuku wambiri wachitika kuti afufuze momwe matenda ndi thupi zimakhudzira kugwedezeka kwakukulu, koma njira zomveka bwino za pathophysiological sizinadziwike3,4. Kafukufuku waposachedwapa akusonyeza kuti kusagwira ntchito bwino kwa microbiota-gut-brain axis kungayambitse matenda a neurodegenerative, ndipo pali umboni wokulirapo wa kulumikizana komwe kungachitike pakati pa microbiota ya m'mimba ndi matenda a neurodegenerative5,6. Chodziwika bwino, mu lipoti lina, kuyika fecal microbiota m'malo mwa fecal kunathandiza kuti kugwedezeka kwakukulu komanso irritable bowel syndrome zikhale bwino kwa wodwala, zomwe zingasonyeze ubale wapafupi pakati pa microbiota ya m'mimba ndi essential tremor. Kuphatikiza apo, tapezanso kusintha kwina kwa microbiota ya m'matumbo mwa odwala omwe ali ndi ET, komwe kumathandizira kwambiri ntchito yofunika ya dysbiosis ya m'matumbo mu ET8.
Ponena za dysbiosis ya m'matumbo m'matenda a neurodegenerative, PD ndiyo yomwe imaphunziridwa kwambiri5. Microbiota yosalinganika imatha kuwonjezera kulowa kwa m'matumbo ndikuyambitsa glia ya m'matumbo, zomwe zimapangitsa kuti alpha-synucleinopathies9,10,11. PD ndi ET zili ndi makhalidwe ena ofanana, monga kuchuluka kwa kugwedezeka kwa odwala a ET ndi PD, kugwedezeka kopumula kophatikizana (kugwedezeka kwachizolowezi mu PD), ndi kugwedezeka kwa positi (komwe kumapezeka kwambiri mwa odwala a ET), zomwe zimapangitsa kuti zikhale zovuta kusiyanitsa pakati pawo. magawo oyambirira 12. Chifukwa chake, tikufunika mwachangu kutsegula zenera lothandiza kuti tisiyanitse pakati pa ET ndi PD. Pachifukwa ichi, kuphunzira dysbiosis yeniyeni ya m'matumbo ndi kusintha kwa metabolite komwe kumachitika mu ET ndikuzindikira kusiyana kwawo ndi PD kungakhale zizindikiro zomwe zingagwiritsidwe ntchito pozindikira ndi kuzindikira kusiyana kwa ET.
Ma asidi amafuta afupiafupi (SCFAs) ndi ma metabolites akuluakulu omwe amapangidwa ndi kuwiritsa kwa mabakiteriya m'matumbo a ulusi wazakudya ndipo amaganiziridwa kuti amagwira ntchito yofunika kwambiri pakuyanjana kwa m'matumbo ndi ubongo13,14. Ma SCFA amatengedwa ndi maselo a m'matumbo ndikusamutsidwa kupita ku chiwindi kudzera mu portal venous system, ndipo ma SCFA ena amalowa m'magazi. Ma SCFA ali ndi zotsatira zakomweko pakusunga umphumphu wa chotchinga cha m'matumbo ndikulimbikitsa chitetezo chamthupi m'matumbo15. Amakhalanso ndi zotsatira za nthawi yayitali pa chotchinga cha magazi ndi ubongo (BBB) ​​​​mwa kuyambitsa mapuloteni olumikizana mwamphamvu ndikuyambitsa ma neuron mwa kuyambitsa ma receptors a G protein-coupled (GPCRs) kuti awoloke BBB16. Acetate, propionate, ndi butyrate ndi ma SCFA ochulukirapo m'matumbo. Kafukufuku wakale wasonyeza kuchepa kwa ma acetic, propionic ndi butyric acid m'matumbo mwa odwala omwe ali ndi matenda a Parkinson17. Komabe, kuchuluka kwa SCFA m'matumbo sikunaphunzirepo mwa odwala omwe ali ndi ET.
Motero, kafukufuku wathu cholinga chake chinali kuzindikira kusintha kwapadera kwa SCFA ya m'chimbudzi mwa odwala omwe ali ndi ET ndi kusiyana kwawo ndi odwala omwe ali ndi PD, kuwunika ubale wa SCFA ya m'chimbudzi ndi zizindikiro zachipatala za SCFA ndi microbiota ya m'mimba, komanso kuzindikira kuthekera kozindikira ndi kusiyanitsa kwa zitsanzo za m'chimbudzi. KZHK. Pofuna kuthana ndi zinthu zosokoneza zokhudzana ndi mankhwala oletsa PD, tinasankha odwala omwe ali ndi matenda a Parkinson omwe angoyamba kumene ngati njira zowongolera matenda.
Makhalidwe a anthu ndi azachipatala a ma ET 37, ma PD 37, ndi ma HC 35 afotokozedwa mwachidule mu Gome 1. Ma ET, ma PD, ndi ma HC adagwirizana ndi zaka, kugonana, ndi BMI. Magulu atatuwa analinso ndi kuchuluka kofanana kwa kusuta, kumwa mowa ndi kumwa khofi ndi tiyi. Chiwerengero cha Wexner (P = 0.004) ndi chiwerengero cha HAMD-17 (P = 0.001) cha gulu la PD chinali chokwera kuposa cha gulu la HC, ndipo chiwerengero cha HAMA (P = 0.011) ndi chiwerengero cha HAMD-17 (P = 0.011) cha gulu la ET chinali chokwera kuposa cha gulu la HC. Kuchuluka kwa matendawa mu gulu la ET kunali kotalika kwambiri kuposa gulu la PD (P <0.001).
Panali kusiyana kwakukulu pa kuchuluka kwa ma asidi a propionic acid m'chimbudzi (P = 0.023), acetic acid (P = 0.039), butyric acid (P = 0.020), isovaleric acid (P = 0.045), ndi isobutyric acid (P = 0.015). . Mu kusanthula kwina pambuyo pa hoc, kuchuluka kwa asidi a propionic (P = 0.023), butyric acid (P = 0.007), ndi isobutyric acid (P = 0.040) m'gulu la ET kunali kotsika kwambiri kuposa omwe ali m'gulu la HC. Odwala omwe ali ndi ET anali ndi ma isovalerate otsika (P = 0.014) ndi isobutyrate (P = 0.005) kuposa odwala omwe ali ndi PD. Kuphatikiza apo, kuchuluka kwa asidi wa propionic acid (P = 0.013), acetic acid (P = 0.016), ndi butyric acid (P = 0.041) kunali kotsika mwa odwala omwe ali ndi PD kuposa odwala omwe ali ndi CC (Chithunzi 1 ndi Table Supplementary 1).
ag ikuyimira kufananiza kwa gulu la propionic acid, acetic acid, butyric acid, isovaleric acid, valeric acid, caproic acid ndi isobutyric acid, motsatana. Panali kusiyana kwakukulu pamlingo wa fecal propionic acid, acetic acid, butyric acid, isovaleric acid ndi isobutyric acid pakati pa magulu atatuwa. ET essential tremor, Parkinson's disease, healthy HC control, SCFA. Kusiyana kwakukulu kukuwonetsedwa ndi *P < 0.05 ndi **P < 0.01.
Poganizira kusiyana kwa matenda pakati pa gulu la ET ndi gulu la PD, tinayesa odwala 33 omwe anali ndi PD yoyambirira ndi odwala 16 omwe anali ndi ET (njira ya matenda ≤ zaka 3) kuti tiyerekezerenso (Table Yowonjezera 2). Zotsatira zake zinasonyeza kuti kuchuluka kwa propionic acid mu ET kunali kotsika kwambiri kuposa kwa HA (P=0.015). Kusiyana pakati pa ET ndi HC kwa butyric acid ndi isobutyric acid sikunali kofunikira, koma kusinthaku kunawonedwabe (P= 0.082). Kuchuluka kwa isobutyrate mu fecal kunali kotsika kwambiri mwa odwala omwe ali ndi ET poyerekeza ndi odwala omwe ali ndi PD (P= 0.030). Kusiyana pakati pa ET ndi PD kwa isovaleric acid sikunali kofunikira, koma panalibe kusintha (P= 0.084). Propionic acid (P = 0.023), acetic acid (P = 0.020), ndi butyric acid (P = 0.044) zinali zochepa kwambiri mwa odwala PD kuposa odwala HC. Zotsatirazi (Chithunzi Chowonjezera 1) nthawi zambiri zimagwirizana ndi zotsatira zazikulu. Kusiyana kwa zotsatira pakati pa chitsanzo chonse ndi gulu laling'ono la odwala oyambirira kungakhale chifukwa cha kukula kochepa kwa chitsanzo m'gulu laling'ono, zomwe zimapangitsa kuti deta ikhale yochepa.
Kenako tinafufuza ngati kuchuluka kwa SCFA m'chimbudzi kungasiyanitse odwala omwe ali ndi ET ndi odwala omwe ali ndi CU kapena PD. Malinga ndi kusanthula kwa ROC, kusiyana kwa AUC ya kuchuluka kwa propionate kunali 0.668 (95% CI: 0.538-0.797), zomwe zinapangitsa kuti zikhale zotheka kusiyanitsa odwala omwe ali ndi ET ndi HC. Odwala omwe ali ndi ET ndi GC amatha kusiyanitsidwa ndi kuchuluka kwa butyrate ndi AUC ya 0.685 (95% CI: 0.556–0.814). Kusiyana kwa kuchuluka kwa isobutyric acid kumatha kusiyanitsa odwala omwe ali ndi ET ndi HC ndi AUC ya 0.655 (95% CI: 0.525–0.786). Pophatikiza milingo ya propionate, butyrate ndi isobutyrate, AUC yapamwamba ya 0.751 (95% CI: 0.634–0.867) idapezeka ndi kukhudzidwa kwa 74.3% ndi kutsimikizika kwa 72.9% (Chithunzi 2a). Kuti tisiyanitse pakati pa odwala a ET ndi PD, AUC ya milingo ya isovaleric acid inali 0.700 (95% CI: 0.579–0.822) ndipo ya milingo ya isobutyric acid inali 0.718 (95% CI: 0.599–0.836). Kuphatikiza kwa milingo ya isovaleric acid ndi isobutyric acid kunali ndi AUC yapamwamba ya 0.743 (95% CI: 0.629–0.857), kukhudzidwa kwa 74.3% ndi kutsimikizika kwa 62.9% (Chithunzi 2b). Kuphatikiza apo, tinayang'ana ngati kuchuluka kwa SCFA m'chimbudzi cha odwala omwe ali ndi matenda a Parkinson kunali kosiyana ndi kwa anthu olamulira. Malinga ndi kusanthula kwa ROC, AUC yodziwira odwala omwe ali ndi PD kutengera kusiyana kwa kuchuluka kwa propionic acid inali 0.687 (95% CI: 0.559-0.814), yokhala ndi kukhudzidwa kwa 68.6% ndi kudziwika kwa 68.7%. Kusiyana kwa kuchuluka kwa acetate kumatha kusiyanitsa odwala a PD ndi ma HC omwe ali ndi AUC ya 0.674 (95% CI: 0.542–0.805). Odwala omwe ali ndi PD amatha kusiyanitsidwa ndi CU kokha ndi kuchuluka kwa butyrate ndi AUC ya 0.651 (95% CI: 0.515–0.787). Mukaphatikiza kuchuluka kwa propionate, acetate ndi butyrate, AUC ya 0.682 (95% CI: 0.553–0.811) idapezeka (Chithunzi 2c).
Kusankha Tchalitchi cha Orthodox cha ku Russia motsutsana ndi ET ndi HC; b kusankha Tchalitchi cha Orthodox cha ku Russia motsutsana ndi ET ndi PD; c kusankha ROC motsutsana ndi PD ndi HC. ET essential tremor, matenda a Parkinson, kulamulira bwino HC, SCFA.
Kwa odwala omwe ali ndi ET, kuchuluka kwa asidi wa chimbudzi kunali kosagwirizana ndi FTM score (r = -0.349, P = 0.034), ndipo kuchuluka kwa asidi wa chimbudzi kunali kosagwirizana ndi FTM score (r = -0.421, P = 0.001) ndi TETRAS score. (r = -0.382, P = 0.020). Kwa odwala omwe ali ndi ET ndi PD, kuchuluka kwa propionate wa chimbudzi kunali kosagwirizana ndi SCOPA-AUT scores (r = -0.236, P = 0.043) (Chithunzi 3 ndi Table Supplementary 3). Panalibe mgwirizano wofunikira pakati pa matenda ndi SCFA m'gulu la ET (P ≥ 0.161) kapena gulu la PD (P ≥ 0.246) (Table Supplementary 4). Kwa odwala omwe ali ndi PD, kuchuluka kwa caproic acid m'chiwindi kunali kogwirizana bwino ndi ziwerengero za MDS-UPDRS (r = 0.335, P = 0.042). Kwa onse omwe adatenga nawo mbali, kuchuluka kwa fecal propionate (r = −0.230, P = 0.016) ndi acetate (r = −0.210, P = 0.029) kunali kogwirizana molakwika ndi ziwerengero za Wexner (Chithunzi 3 ndi Gome Lowonjezera 3).
Magazi a isobutyric acid ochokera ku fecal anali osagwirizana ndi ma FTM scores, isovaleric acid inali yosagwirizana ndi ma FTM ndi ma TETRAS scores, propionic acid inali yogwirizana ndi ma SCOPA-AUT scores, caproic acid inali yogwirizana ndi ma MDS-UPDRS scores, ndipo propionic acid inali yogwirizana ndi ma FTM ndi ma TETRAS scores. TETRAS ndi acetic acid zinali zosagwirizana ndi ma Wexner score. MDS-UPDRS Association inathandizira mtundu wa Unified Parkinson's Disease Rating Scale, Mini-Mental State Examination MMSE, Hamilton Depression Rating Scale HAMD-17, zinthu 17, Hamilton Anxiety Rating Scale HAMA, HY Hoehn ndi Yahr stages, SCFA, SCOPA - AUT Parkinson's Disease Autonomic Symptom Outcome Scale, FTM Fana-Tolosa-Marin Clinical Tremor Rating Scale, TETRAS Research Group (TRG) Essential Tremor Rating Scale. Kusiyana kwakukulu kukuwonetsedwa ndi *P < 0.05 ndi **P < 0.01.
Tinafufuzanso za kusiyana kwa ma microbiota a m'matumbo pogwiritsa ntchito kusanthula kwa LEfSE ndipo tinasankha mulingo wa deta yokhudzana ndi kuchuluka kwa majini kuti tiwunikenso. Kuyerekeza kunapangidwa pakati pa ET ndi HC komanso pakati pa ET ndi PD. Kusanthula kwa ubale wa Spearman kenako kunachitika pa kuchuluka kwa ma microbiota a m'matumbo ndi fecal SCFA m'magulu awiri oyerekeza.
Faecalibacterium (yogwirizana ndi butyric acid, r = 0.408, P < 0.001), Lactobacillus (yogwirizana ndi butyric acid, r = 0.283, P = 0.016), Streptobacterium (yogwirizana ndi propionic acid, r = 0.327) inalipo mu kusanthula kwa ET ndi CA. , P = 0.005; yogwirizana ndi butyric acid, r = 0.374, P = 0.001; Zimagwirizana ndi isobutyric acid, r = 0.329, P = 0.005), Howardella (yogwirizana ndi propionic acid, r = 0.242, P = 0.041), Raoultella (yogwirizana ndi propionate, r = 0.249, P = 0.035), ndipo Candidatus Arthromitus (yogwirizana ndi isobutyric acid, r = 0.302, P = 0.010) idapezeka kuti yatsika mu ET ndipo imagwirizana bwino ndi milingo ya SCFA ya ndowe. Komabe, kuchuluka kwa Stenotropomonas kudakwera mu ET ndipo kudagwirizana molakwika ndi milingo ya isobutyrate ya ndowe (r = -0.250, P = 0.034). Pambuyo pa kusintha kwa FDR, kulumikizana kokha pakati pa Faecalibacterium, Catenibacter, ndi SCFA kudatsalabe kofunika (P ≤ 0.045) (Chithunzi 4 ndi Table Yowonjezera 5).
Kusanthula kwa mgwirizano wa ET ndi HC. Pambuyo pa kusintha kwa FDR, kuchuluka kwa Faecalibacterium (kogwirizana ndi butyrate) ndi Streptobacterium (kogwirizana ndi propionate, butyrate, ndi isobutyrate) kunapezeka kuti kwachepa mu ET ndipo kogwirizana ndi milingo ya SCFA ya m'mimba. b Kusanthula kwa mgwirizano wa ET ndi PD. Pambuyo pa kusintha kwa FDR, palibe mgwirizano wofunikira womwe unapezeka. ET essential tremor, matenda a Parkinson, HC control wathanzi, SCFA. Kusiyana kwakukulu kukuwonetsedwa ndi *P < 0.05 ndi **P < 0.01.
Pofufuza ET motsutsana ndi PD, Clostridium trichophyton idapezeka kuti yawonjezeka mu ET ndipo imagwirizana ndi fecal isovaleric acid (r = -0.238, P = 0.041) ndi isobutyric acid (r = -0.257, P = 0.027). ). Pambuyo pa kusintha kwa FDR, chilichonse mwa izi chinakhalabe chofunikira (P≥0.295) (Chithunzi 4 ndi Table Supplementary 5).
Kafukufukuyu ndi kafukufuku wokwanira womwe umafufuza kuchuluka kwa SCFA m'chimbudzi ndipo umawagwirizanitsa ndi kusintha kwa microbiota ya m'mimba ndi kuopsa kwa zizindikiro mwa odwala omwe ali ndi ET poyerekeza ndi odwala omwe ali ndi CU ndi PD. Tapeza kuti kuchuluka kwa SCFA m'chimbudzi kunachepa mwa odwala omwe ali ndi ET ndipo kunagwirizanitsidwa ndi kuopsa kwa matenda komanso kusintha kwina kwa microbiota m'matumbo. Kuchuluka kwa mafuta acids afupiafupi (SCFAs) m'chimbudzi kumasiyanitsa ET ndi GC ndi PD.
Poyerekeza ndi odwala GC, odwala a ET ali ndi milingo yotsika ya ma asidi a propionic, butyric, ndi isobutyric m'chimbudzi. Kuphatikiza kwa ma asidi a propionic, butyric ndi isobutyric kumatha kusiyanitsa pakati pa ET ndi HC ndi AUC ya 0.751 (95% CI: 0.634–0.867), kukhudzidwa kwa 74.3% ndi kudziwika kwa 72.9%, kusonyeza kuti kugwiritsidwa ntchito kwawo ngati gawo lomwe lingakhalepo ngati zizindikiro zodziwira matenda a ET. Kusanthula kwina kunawonetsa kuti milingo ya propionic acid m'chimbudzi inali yosagwirizana ndi Wexner score ndi score ya SCOPA-AUT. Milingo ya isobutyric acid m'chimbudzi inali yogwirizana ndi FTM scores. Kumbali ina, kuchepa kwa milingo ya butyrate mu ET kunalumikizidwa ndi kuchepa kwa kuchuluka kwa microbiota yopanga SCFA, Faecalibacterium, ndi Categorybacter. Kuphatikiza apo, kuchepa kwa kuchuluka kwa Catenibacter mu ET kunalumikizidwanso ndi kuchepa kwa milingo ya propionic ndi isobutyric acid m'chimbudzi.
Ma SCFA ambiri opangidwa m'matumbo amatengedwa ndi ma colonocytes makamaka kudzera mu ma transporter a monocarboxylate omwe amadalira H+ kapena sodium. Ma acid afupiafupi omwe amatengedwa amagwiritsidwa ntchito ngati gwero lamphamvu la ma colonocytes, pomwe omwe sanagayidwe mu ma colonocytes amasamutsidwa kupita ku portal circulation 18. Ma SCFA amatha kusintha kuyenda kwa matumbo, kukulitsa ntchito yotchinga matumbo, komanso kusintha kagayidwe kake ndi chitetezo chamthupi19. Kale zidapezeka kuti kuchuluka kwa butyrate, acetate, ndi propionate m'matumbo kunachepa mwa odwala a PD poyerekeza ndi HCs17, zomwe zikugwirizana ndi zotsatira zathu. Kafukufuku wathu adapeza kuchepa kwa SCFA mwa odwala omwe ali ndi ET, koma zochepa zomwe zimadziwika za udindo wa SCFA mu matenda a ET. Butyrate ndi propionate zimatha kumangirira ku GPCRs ndikukhudza ma signaling omwe amadalira GPCR monga MAPK ndi NF-κB20 signaling. Lingaliro loyambira la gut-brain axis ndilakuti ma SCFA omwe amatulutsidwa ndi ma virus m'matumbo amatha kusintha ma signaling a host, motero amakhudza ntchito ya m'matumbo ndi ubongo. Popeza butyrate ndi propionate zimakhala ndi mphamvu zoletsa ntchito ya histone deacetylase (HDAC)21 ndipo butyrate imathanso kugwira ntchito ngati ligand pazinthu zolembera, zimakhala ndi zotsatira zambiri pa kagayidwe kachakudya ka munthu, kusiyana kwake, ndi kuchulukana kwake, makamaka chifukwa cha mphamvu zake pa kayendetsedwe ka majini22. Kutengera umboni wochokera ku SCFA ndi matenda a neurodegenerative, butyrate imaonedwa kuti ndi njira yochiritsira chifukwa cha kuthekera kwake kukonza ntchito ya HDAC yolakwika, yomwe ingayambitse imfa ya dopaminergic neuron mu PD23,24,25. Kafukufuku wa nyama wawonetsanso kuthekera kwa butyric acid kupewa kuchepa kwa dopaminergic neuron ndikukonza zovuta zoyenda mu PD models26,27. Propionic acid yapezeka kuti imachepetsa mayankho otupa ndikuteteza umphumphu wa BBB28,29. Kafukufuku wasonyeza kuti propionic acid imalimbikitsa kupulumuka kwa dopaminergic neurons poyankha poizoni wa rotenone mu PD models 30 ndipo kupereka propionic acid pakamwa kumapulumutsa kutayika kwa dopaminergic neuron ndi kusowa kwa mphamvu zoyendetsa m'makoswe omwe ali ndi PD 31. Sizikudziwika zambiri za ntchito ya isobutyric acid. Komabe, kafukufuku waposachedwapa adapeza kuti kukhazikika kwa mbewa ndi B. ovale kunawonjezera kuchuluka kwa SCFA m'matumbo (kuphatikiza acetate, propionate, isobutyrate, ndi isovalerate) ndi kuchuluka kwa GABA m'matumbo, zomwe zikuwonetsa kuti pali mgwirizano pakati pa microbiota ya m'matumbo ndi kuchuluka kwa SCFA m'matumbo. 32. Pa ET, kusintha kosazolowereka kwa matenda mu cerebellum kumaphatikizapo kusintha kwa ma axon ndi ma dendrites a maselo a Purkinje, kusamuka ndi kutayika kwa maselo a Purkinje, kusintha kwa ma axon a maselo a basket, ndi zolakwika pakulumikizana kwa ulusi wokwera ku maselo a Purkinje. nuclei, zomwe zimapangitsa kuchepa kwa kutulutsa kwa GABAergic kuchokera ku cerebellum3,4,33. Sizikudziwikabe ngati ma SCFA amagwirizana ndi kuwonongeka kwa mitsempha ya maselo a Purkinje ndi kuchepa kwa kupanga kwa GABA ya cerebellar. Zotsatira zathu zikusonyeza ubale wapafupi pakati pa SCFA ndi ET; komabe, kapangidwe ka kafukufuku wodutsa magawo osiyanasiyana sikulola malingaliro aliwonse okhudza ubale womwe ulipo pakati pa SCFA ndi njira ya matenda a ET. Maphunziro ena otsatira a nthawi yayitali amafunikira, kuphatikiza kuyeza kwa ma SCFA a ndowe, komanso maphunziro a nyama omwe amafufuza njira.
Ma SCFA akuganiziridwa kuti amalimbikitsa kugwira ntchito kwa minofu yosalala ya m'matumbo34. Kusowa kwa SCFA kungapangitse zizindikiro za kudzimbidwa kukhala zochulukirapo, ndipo kuwonjezera SCFA kungathandize zizindikiro za kudzimbidwa kukhala zocheperako. Zotsatira zathu zikuwonetsanso mgwirizano waukulu pakati pa kuchepa kwa kuchuluka kwa SCFA m'chimbudzi ndi kuwonjezeka kwa kudzimbidwa komanso kusagwira ntchito bwino kwa thupi mwa odwala omwe ali ndi ET. Lipoti lina linapeza kuti kusamutsa microbiota kunathandiza kugwedezeka kwa essential tremor ndi irritable bowel syndrome mwa odwala 7, zomwe zikusonyezanso kuti pali ubale wapakati pa gut microbiota ndi ET. Chifukwa chake, tikukhulupirira kuti fecal SCFA/microbiota ingakhudze kuyenda kwa matumbo a m'nyumba komanso ntchito ya autonomic nervous system.
Kafukufukuyu adapeza kuti kuchepa kwa ma SCFA a ndowe mu ET kunagwirizana ndi kuchepa kwa kuchuluka kwa Faecalibacterium (yogwirizana ndi butyrate) ndi Streptobacterium (yogwirizana ndi propionate, butyrate, ndi isobutyrate). Pambuyo pa kukonza kwa FDR, ubalewu umakhalabe wofunika. Faecalibacterium ndi Streptobacterium ndi tizilombo toyambitsa matenda tomwe timapanga SCFA. Faecalibacterium imadziwika kuti ndi tizilombo toyambitsa matenda topanga butyrate36, pomwe zinthu zazikulu za Catenibacter fermentation ndi acetate, butyrate ndi lactic acid37. Faecalibacterium idapezeka mu 100% ya magulu onse a ET ndi HC; Kuchuluka kwapakati kwa gulu la ET kunali 2.06% ndipo kwa gulu la HC kunali 3.28% (LDA 3.870). Bacterium ya gululi idapezeka mu 21.6% (8/37) ya gulu la HC ndipo mu chitsanzo chimodzi chokha cha gulu la ET (1/35). Kuchepa ndi kusapezeka kwa mabakiteriya a streptobacteria mu ET kungasonyezenso kugwirizana ndi matenda opatsirana. Kuchuluka kwapakati kwa mitundu ya Catenibacter mu gulu la HC kunali 0.07% (LDA 2.129). Kuphatikiza apo, mabakiteriya a lactic acid adalumikizidwa ndi kusintha kwa butyrate ya m'mimba (P=0.016, P=0.096 pambuyo pa kusintha kwa FDR), ndipo wodwala matenda a nyamakazi adalumikizidwa ndi kusintha kwa isobutyrate (P=0.016, P=0.072 pambuyo pa kusintha kwa FDR). Pambuyo pa kukonza kwa FDR, njira yokhayo yolumikizirana imatsalira, yomwe siili yofunika kwambiri pa ziwerengero. Lactobacilli amadziwikanso kuti ndi opanga SCFA (acetic acid, propionic acid, isobutyric acid, butyric acid) 38 ndipo Candidatus Arthromitus ndi chinthu choyambitsa kusiyana kwa maselo a T helper 17 (Th17), ndi Th1/2 ndi Tregs zogwirizana ndi chitetezo chamthupi /Th1739. . Kafukufuku waposachedwapa akusonyeza kuti kuchuluka kwa matenda a pseudoarthritis m'matumbo kungathandize kutupa kwa m'matumbo, kusagwira bwino ntchito kwa chotchinga cha m'mimba, komanso kutupa kwa thupi lonse 40. Clostridium trichophyton inawonjezeka mu ET poyerekeza ndi PD. Kuchuluka kwa Clostridium trichoides kunapezeka kuti sikukugwirizana bwino ndi isovaleric acid ndi isobutyric acid. Pambuyo pa kusintha kwa FDR, zonse ziwiri zinakhalabe zofunika (P≥0.295). Clostridium pilosum ndi bakiteriya wodziwika kuti amagwirizana ndi kutupa ndipo angathandize kusokoneza chotchinga cha m'mimba 41. Kafukufuku wathu wakale adanenanso za kusintha kwa microbiota ya m'matumbo mwa odwala omwe ali ndi ET8. Pano tikuwonetsanso kusintha kwa ma SCFA mu ET ndikupeza mgwirizano pakati pa dysbiosis ya m'matumbo ndi kusintha kwa ma SCFA. Kutsika kwa SCFA kumakhudzana kwambiri ndi dysbiosis ya m'matumbo ndi kugwedezeka kwamphamvu mu ET. Zotsatira zathu zikusonyeza kuti mzere wa m'mimba ndi ubongo ukhoza kukhala ndi gawo lofunika kwambiri pakupanga kwa ET, koma maphunziro ena m'mitundu ya nyama akufunika.
Poyerekeza ndi odwala omwe ali ndi PD, odwala omwe ali ndi ET ali ndi milingo yotsika ya isovaleric ndi isobutyric acid m'chimbudzi chawo. Kuphatikiza kwa isovaleric acid ndi isobutyric acid kunazindikira ET mu PD ndi AUC ya 0.743 (95% CI: 0.629–0.857), kukhudzidwa kwa 74.3% ndi kudziwika kwa 62.9%, zomwe zikusonyeza kuti ndi gawo lawo ngati ma biomarker pakuzindikira kusiyana kwa ET. . Magawo a isovaleric acid a fecal anali ogwirizana mosiyana ndi ma FTM ndi ma TETRAS. Magawo a isobutyric acid a fecal anali ogwirizana mosiyana ndi ma FTM. Kuchepa kwa milingo ya isobutyric acid kunalumikizidwa ndi kuchepa kwa kuchuluka kwa ma catobacteria. Sizikudziwika zambiri za ntchito za isovaleric acid ndi isobutyric acid. Kafukufuku wakale adawonetsa kuti kukhazikika kwa mbewa ndi Bacteroides ovale kunawonjezera kuchuluka kwa SCFA m'matumbo (kuphatikiza acetate, propionate, isobutyrate, ndi isovalerate) ndi kuchuluka kwa GABA m'matumbo, zomwe zikuwonetsa kulumikizana kwa m'matumbo pakati pa microbiota ndi kuchuluka kwa SCFA/neurotransmitter m'matumbo32. Chosangalatsa ndichakuti, kuchuluka kwa isobutyric acid komwe kunawonedwa kunali kofanana pakati pa magulu a PD ndi HC, koma kunali kosiyana pakati pa magulu a ET ndi PD (kapena HC). Asidi ya Isobutyric ikhoza kusiyanitsa pakati pa ET ndi PD ndi AUC ya 0.718 (95% CI: 0.599–0.836) ndikuzindikira ET ndi NC ndi AUC ya 0.655 (95% CI: 0.525–0.786). Kuphatikiza apo, kuchuluka kwa isobutyric acid kumagwirizana ndi kuopsa kwa kugwedezeka, zomwe zimalimbitsa kwambiri mgwirizano wake ndi ET. Funso loti ngati isobutyric acid ya pakamwa ingachepetse kuopsa kwa kugwedezeka kwa odwala omwe ali ndi ET liyenera kuphunziridwanso.
Motero, kuchuluka kwa SCFA m'chimbudzi kumachepa mwa odwala omwe ali ndi ET ndipo kumalumikizidwa ndi kuopsa kwa ET komanso kusintha kwina kwa matumbo a microbiota. Fecal propionate, butyrate, ndi isobutyrate zitha kukhala zizindikiro zodziwira matenda a ET, pomwe isobutyrate ndi isovalerate zitha kukhala zizindikiro zosiyana zodziwira matenda a ET. Kusintha kwa isobutyrate m'chimbudzi kungakhale kodziwika bwino pa ET kuposa kusintha kwa ma SCFA ena.
Kafukufuku wathu ali ndi zoletsa zingapo. Choyamba, njira zodyera ndi zomwe amakonda pakudya zitha kukhudza momwe ma microbiota amaonekera, zitsanzo zazikulu za kafukufuku m'magulu osiyanasiyana zimafunika, ndipo maphunziro amtsogolo ayenera kuyambitsa kafukufuku wathunthu komanso wokonzedwa bwino wazakudya monga mafunso okhudzana ndi kuchuluka kwa chakudya. Chachiwiri, kapangidwe ka kafukufuku wophatikizana kamaletsa mfundo zilizonse zokhudzana ndi ubale womwe ulipo pakati pa ma SCFA ndi chitukuko cha ET. Maphunziro ena otsatira a nthawi yayitali okhala ndi miyeso yotsatizana ya ma SCFA akufunika. Chachitatu, kuthekera kozindikira ndi kusiyanitsa kwa kuchuluka kwa ma SCFA a chimbudzi kuyenera kutsimikiziridwa pogwiritsa ntchito zitsanzo zodziyimira pawokha kuchokera ku ET, HC, ndi PD. Zitsanzo zambiri zodziyimira pawokha za chimbudzi ziyenera kuyesedwa mtsogolo. Pomaliza, odwala omwe ali ndi PD m'gulu lathu anali ndi nthawi yochepa kwambiri ya matenda kuposa odwala omwe ali ndi ET. Tidagwirizanitsa kwambiri ET, PD ndi HC ndi zaka, jenda ndi BMI. Popeza kusiyana kwa njira ya matenda pakati pa gulu la ET ndi gulu la PD, tidaphunziranso odwala 33 omwe ali ndi PD yoyambirira ndi odwala 16 omwe ali ndi ET (nthawi ya matenda ≤ zaka 3) kuti tiyerekezerenso. Kusiyana pakati pa magulu mu SCFA nthawi zambiri kunali kogwirizana ndi deta yathu yoyamba. Kuphatikiza apo, sitinapeze mgwirizano uliwonse pakati pa nthawi ya matenda ndi kusintha kwa SCFA. Komabe, mtsogolomu, zingakhale bwino kulemba odwala omwe ali ndi PD ndi ET pachiyambi pomwe ali ndi nthawi yochepa ya matenda kuti amalize kutsimikizira mu chitsanzo chachikulu.
Ndondomeko ya kafukufukuyu idavomerezedwa ndi komiti ya makhalidwe abwino ya chipatala cha Ruijin, chomwe chili ku Shanghai Jiao Tong University School of Medicine (RHEC2018-243). Chilolezo cholembedwa kuchokera kwa onse omwe adatenga nawo mbali chidaperekedwa.
Pakati pa Januwale 2019 ndi Disembala 2022, anthu 109 (37 ET, 37 PD, ndi 35 HC) ochokera ku Movement Disorder Center Clinic ya Ruijin Hospital, yogwirizana ndi Shanghai Jiao Tong University School of Medicine, adaphatikizidwa mu kafukufukuyu. Zofunikira zinali: (1) zaka 25-85, (2) odwala omwe ali ndi ET adapezeka malinga ndi zofunikira za MDS Working Group 42 ndipo PD adapezeka malinga ndi zofunikira za MDS 43, (3) odwala onse sanali kumwa mankhwala oletsa PD asanatenge zitsanzo. (4) Gulu la ET lidatenga β-blockers yokha kapena palibe mankhwala okhudzana ndi izi asanatenge zitsanzo za chopondapo. Ma HC ogwirizana ndi zaka, jenda, ndi index ya body mass (BMI) adasankhidwanso. Zofunikira zochotsera mankhwalawa zinali izi: (1) anthu osadya nyama, (2) zakudya zosapatsa thanzi, (3) matenda osatha a m'mimba (kuphatikizapo matenda otupa m'matumbo, zilonda zam'mimba kapena duodenal), (4) matenda osatha (kuphatikizapo zotupa zoyipa), kulephera kwa mtima, kulephera kwa impso, matenda a magazi) (5) Mbiri ya opaleshoni yayikulu ya m'mimba, (6) Kudya yogurt kosatha kapena nthawi zonse, (7) Kugwiritsa ntchito ma probiotics kapena maantibayotiki kwa mwezi umodzi, (8) Kugwiritsa ntchito mankhwala oletsa kutupa, ma proton pump inhibitors, ma statins, metformin, ma immunosuppressants kapena mankhwala oletsa khansa komanso (9) kulephera kwa ubongo komwe kumasokoneza mayeso azachipatala.
Ophunzira onse adapereka chidziwitso cha mbiri yachipatala, kulemera ndi kutalika kuti awerengere BMI, ndipo adayesedwa ndi mitsempha ndikuwunika zachipatala monga Hamilton Anxiety Rating Scale (HAMA) 44 anxiety score, Hamilton Depression Rating Scale-17 score (HAMD-17) 45. kupsinjika maganizo, kuopsa kwa kudzimbidwa pogwiritsa ntchito Wexner Constipation Scale 46 ndi Bristol Stool Scale 47 ndi magwiridwe antchito anzeru pogwiritsa ntchito Mini-Mental State Examination (MMSE) 48. The Scale for the Assessment of Autonomic Symptoms of Parkinson's Disease (SCOPA-AUT) 49 idafufuza kusagwira bwino ntchito kwa autonomic mwa odwala omwe ali ndi ET ndi PD. The Fan-Tolos-Marin Clinical Tremor Rating Scale (FTM) ndi Essential Tremor Rating Scale (TETRAS) 50 The Tremor Study Group (TRG) 50 idawunikidwa mwa odwala omwe ali ndi ET; Kinson's disease rating scale (MDS-UPDRS) version 51 ndi Hoehn ndi Yahr (HY) grade 52 zidawunikidwa.
Wophunzira aliyense anapemphedwa kuti atenge chitsanzo cha ndowe m'mawa pogwiritsa ntchito chidebe chosonkhanitsira ndowe. Samutsani zidebezo mu ayezi ndikuzisunga pa -80°C musanazigwiritse ntchito. Kusanthula kwa SCFA kunachitika motsatira ntchito zachizolowezi za Tiangene Biotechnology (Shanghai) Co., Ltd. Zitsanzo za ndowe zatsopano za 400 mg zinasonkhanitsidwa kuchokera kwa munthu aliyense ndikuwunikidwa pogwiritsa ntchito ma SCFA atatha kupukutidwa ndi kusamalidwa. Ma SCFA osankhidwa mu ndowe adawunikidwa pogwiritsa ntchito gas chromatography-mass spectrometry (GC-MS) ndi liquid chromatography-tandem MS (LC-MS/MS).
DNA inatengedwa kuchokera ku zitsanzo za 200 mg pogwiritsa ntchito QIAamp® Fast DNA Stool Mini Kit (QIAGEN, Hilden, Germany) malinga ndi malangizo a wopanga. Kapangidwe ka tizilombo toyambitsa matenda kanadziwika mwa kutsata jini ya 16 S rRNA pa DNA yochotsedwa ku ndowe mwa kukulitsa dera la V3-V4. Yesani DNA poyendetsa chitsanzocho pa gel ya agarose ya 1.2%. Kukulitsa kwa polymerase chain reaction (PCR) kwa jini ya 16S rRNA kunachitika pogwiritsa ntchito ma primer a bacterial bacterial (357 F ndi 806 R) ndi laibulale ya amplicon ya magawo awiri yomangidwa pa nsanja ya Novaseq.
Zosintha zopitilira zimafotokozedwa ngati mean ± standard deviation, ndipo zosintha zamagulu zimafotokozedwa ngati manambala ndi maperesenti. Tinagwiritsa ntchito mayeso a Levene kuti tiyese homogeneity ya kusiyana. Kuyerekeza kunachitika pogwiritsa ntchito mayeso a t awiri kapena kusanthula kusiyana (ANOVA) ngati zosintha nthawi zambiri zimagawidwa komanso mayeso a Mann-Whitney U osagwiritsa ntchito parametric ngati malingaliro a normality kapena homoscedasticity adaphwanyidwa. Tinagwiritsa ntchito dera lomwe lili pansi pa receiver operating characteristic (ROC) curve (AUC) kuti tiyese magwiridwe antchito a diagnostic a model ndikuwunika kuthekera kwa SCFA kusiyanitsa odwala omwe ali ndi ET ndi omwe ali ndi HC kapena PD. Kuti tiwone ubale pakati pa SCFA ndi kuopsa kwa matenda, tinagwiritsa ntchito Spearman correlation analysis. Kusanthula kwa ziwerengero kunachitika pogwiritsa ntchito pulogalamu ya SPSS (version 22.0; SPSS Inc., Chicago, IL) ndi mulingo wofunikira (kuphatikiza P value ndi FDR-P) womwe wakhazikitsidwa pa 0.05 (two-sided).
Ma sequence 16 a S adasanthulidwa pogwiritsa ntchito pulogalamu ya Trimmomatic (mtundu 0.35), Flash (mtundu 1.2.11), UPARSE (mtundu v8.1.1756), mothur (mtundu 1.33.3) ndi R (mtundu 3.6.3). Deta ya majini a rRNA a Raw 16S idakonzedwa pogwiritsa ntchito UPARSE kuti ipange mayunitsi ogwirira ntchito a taxonomic (OTUs) okhala ndi 97% identity. Ma Taxonomies adatchulidwa pogwiritsa ntchito Silva 128 ngati database yowunikira. Mulingo wamba wa deta yochuluka yokhudzana ndi ubale unasankhidwa kuti ufufuzidwenso. Linear discriminant analysis (LDA) efSE analysis (LEfSE) idagwiritsidwa ntchito poyerekeza magulu (ET vs. HC, ET vs. PD) yokhala ndi α threshold ya 0.05 ndi effect size threshold ya 2.0. Discriminant genera yomwe idadziwika ndi LEfSE analysis idagwiritsidwanso ntchito pa Spearman correlation analysis ya SCFA.
Kuti mudziwe zambiri zokhudza kapangidwe ka kafukufukuyu, onani Chidule cha Lipoti la Kafukufuku Wachilengedwe chogwirizana ndi nkhaniyi.
Deta yosanjidwa ya 16S imasungidwa mu database ya National Center for Biotechnology Information (NCBI) BioProject (SRP438900: PRJNA974928), URL: https://www.ncbi.nlm.nih.gov/Traces/study/?acc= SRP438900&o. =acc_s% 3Aa. Deta ina yofunikira imapezeka kwa wolemba woyenerera ngati pakufunika kutero, monga mgwirizano wa sayansi ndi kusinthana kwa maphunziro ndi mapulojekiti ofufuza athunthu. Sikololedwa kusamutsa deta kwa anthu ena popanda chilolezo chathu.
Khodi yotseguka yokha ndi kuphatikiza kwa Trimmomatic (mtundu 0.35), Flash (mtundu 1.2.11), UPARSE (mtundu v8.1.1756), mothur (mtundu 1.33.3) ndi R (mtundu 3.6.3), pogwiritsa ntchito makonda okhazikika kapena gawo la "Njira". Zambiri zowonjezera zitha kuperekedwa kwa wolemba woyenerera ngati pakufunika kutero.
Pradeep S ndi Mehanna R. Matenda a m'mimba mu matenda oyenda ndi ataxia. Ogwirizana ndi matenda a Parkinson. chisokonezo. 90, 125–133 (2021).
Louis, ED ndi Faust, PL Matenda a kugwedezeka kofunikira: kuwonongeka kwa mitsempha ndi kukonzanso kulumikizana kwa mitsempha. Nat. Pastor Nirol. 16, 69–83 (2020).
Gironell, A. Kodi kugwedezeka kwa essential ndi vuto lalikulu la kusokonezeka kwa Gaba? Inde. mayiko osiyanasiyana. Rev. Neuroscience. 163, 259–284 (2022).
Dogra N., Mani RJ ndi Katara DP Mzere wa m'mimba ndi ubongo: njira ziwiri zolumikizirana ndi matenda a Parkinson. Mamolekyulu a m'maselo. Neurobiology. 42, 315–332 (2022).
Quigley, EMM. Mzere wa microbiota-ubongo-matumbo ndi matenda owononga mitsempha. panopa. Nellore. Sayansi ya Neuroscience. Malipoti 17, 94 (2017).
Liu, XJ, Wu, LH, Xie, WR ndi He, XX Kusamutsa tizilombo toyambitsa matenda a fecal microbiota nthawi imodzi kumathandizira kugwedezeka kwamphamvu komanso matenda a m'mimba mwa odwala. Geriatric Psychology 20, 796–798 (2020).
Zhang P. et al. Kusintha kwapadera kwa microbiota ya m'matumbo mu kugwedezeka kwamphamvu ndi kusiyana kwawo ndi matenda a Parkinson. NPJ Matenda a Parkinson. 8, 98 (2022).
Luo S, Zhu H, Zhang J ndi Wang D. Udindo wofunikira wa microbiota pakuwongolera mayunitsi a neuronal-glial-epithelial. Kukana matenda. 14, 5613–5628 (2021).
Emin A. ndi ena. Matenda a duodenal alpha-synuclein ndi intestine gliosis mu matenda a Parkinson omwe akupita patsogolo. kusuntha. kusokonezeka. https://doi.org/10.1002/mds.29358 (2023).
Skorvanek M. ndi ena. Ma antibodies a alpha-synuclein 5G4 amazindikira matenda a Parkinson ndi matenda a Parkinson omwe amapezeka m'matumbo aang'ono. kusuntha. kusokonezeka. 33, 1366–1368 (2018).
Algarni M ndi Fasano A. Kugwirizana kwa kugwedezeka kwamphamvu ndi matenda a Parkinson. Kugwirizana ndi matenda a Parkinson. chisokonezo. 46, С101–С104 (2018).
Sampson, TR ndi ena. Gut microbiota imasintha kufooka kwa kayendedwe ka thupi ndi kutupa kwa mitsempha m'mafano a matenda a Parkinson. Cell 167, 1469–1480.e1412 (2016).
Unger, MM et al. Ma asidi amafuta afupiafupi ndi ma microbiota am'mimba amasiyana pakati pa odwala omwe ali ndi matenda a Parkinson ndi olamulira omwe ali ndi zaka zofanana. Zogwirizana ndi matenda a Parkinson. chisokonezo. 32, 66–72 (2016).
Bleacher E, Levy M, Tatirovsky E ndi Elinav E. Ma Metabolites omwe amayendetsedwa ndi microbiome pa malo olumikizirana chitetezo chamthupi. J. Immunology. 198, 572–580 (2017).