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Kev kuaj mob thaum ntxov ntawm kev tshee hnyo tseem ceeb (ET) tuaj yeem nyuaj, tshwj xeeb tshaj yog thaum sib txawv ntawm cov neeg noj qab haus huv tswj (HC) thiab Parkinson tus kab mob (PD). Tsis ntev los no, kev tshuaj xyuas cov qauv quav rau cov kab mob hauv plab thiab nws cov metabolites tau muab cov txheej txheem tshiab rau kev tshawb pom cov cim tshiab ntawm cov kab mob neurodegenerative. Cov roj fatty acid luv luv (SCFA), ua cov metabolite tseem ceeb ntawm cov kab mob hauv plab, raug txo qis hauv cov quav hauv PD. Txawm li cas los xij, cov quav SCFA yeej tsis tau kawm hauv ET. Peb lub hom phiaj yog tshawb xyuas cov qib quav ntawm SCFAs hauv ET, ntsuas lawv txoj kev sib raug zoo nrog cov tsos mob hauv tsev kho mob thiab cov kab mob hauv plab, thiab txiav txim siab lawv lub peev xwm kuaj mob. Fecal SCFA thiab cov kab mob hauv plab tau ntsuas hauv 37 ETs, 37 PDs tshiab, thiab 35 HCs. Cem quav, autonomic dysfunction, thiab qhov hnyav ntawm kev tshee hnyo tau ntsuas siv cov nplai. Cov qib quav ntawm propionate, butyrate, thiab isobutyrate qis dua hauv ET dua li hauv HC. Kev sib xyaw ua ke ntawm propionic, butyric thiab isobutyric acids ua rau ET thiab HC txawv nrog AUC ntawm 0.751 (95% CI: 0.634–0.867). Fecal isovaleric acid thiab isobutyric acid qib qis dua hauv ET dua li hauv PD. Isovaleric acid thiab isobutyric acid sib txawv ntawm ET thiab PD nrog AUC ntawm 0.743 (95% CI: 0.629–0.857). Fecal propionate yog inversely cuam tshuam nrog kev cem quav thiab kev ua haujlwm tsis zoo ntawm lub cev. Isobutyric acid thiab isovaleric acid yog inversely cuam tshuam nrog qhov hnyav ntawm kev co. Qhov kev txo qis hauv fecal SCFAs yog cuam tshuam nrog kev txo qis hauv qhov ntau ntawm Faecalibacterium thiab Streptobacterium hauv ET. Yog li, cov ntsiab lus ntawm SCFA hauv cov quav txo qis hauv ET thiab yog cuam tshuam nrog qhov hnyav ntawm daim duab kho mob thiab kev hloov pauv hauv cov kab mob hauv plab hnyuv. Fecal propionate, butyrate, isobutyrate, thiab isovalerate tej zaum yuav yog cov cim qhia txog kev kuaj mob thiab kev kuaj mob sib txawv rau ET.
Kev tshee hnyo tseem ceeb (ET) yog ib qho kev mob hlwb uas zuj zus tuaj, uas muaj tus yam ntxwv tshwj xeeb los ntawm kev tshee hnyo ntawm sab saud, uas kuj tseem tuaj yeem cuam tshuam rau lwm qhov ntawm lub cev xws li lub taub hau, cov suab nrov, thiab sab qis 1. Cov yam ntxwv kho mob ntawm ET suav nrog tsis yog tsuas yog cov tsos mob ntawm lub cev xwb tab sis kuj muaj qee cov cim tsis yog lub cev, suav nrog kab mob plab hnyuv 2. Muaj ntau txoj kev tshawb fawb tau ua los tshuaj xyuas cov yam ntxwv pathological thiab physiological ntawm kev tshee hnyo tseem ceeb, tab sis cov txheej txheem pathophysiological meej meej tsis tau txheeb xyuas3,4; Cov kev tshawb fawb tsis ntev los no qhia tias kev ua haujlwm tsis zoo ntawm microbiota-gut-brain axis yuav ua rau muaj kab mob neurodegenerative, thiab muaj pov thawj ntau ntxiv rau qhov kev sib txuas bidirectional ntawm cov kab mob plab thiab cov kab mob neurodegenerative5,6. Qhov tseem ceeb, hauv ib daim ntawv qhia txog rooj plaub, kev hloov pauv fecal microbiota tau txhim kho ob qho tib si kev tshee hnyo tseem ceeb thiab mob plab hnyuv chim siab hauv tus neeg mob, uas yuav qhia txog kev sib raug zoo ntawm cov kab mob plab thiab kev tshee hnyo tseem ceeb. Tsis tas li ntawd, peb kuj pom cov kev hloov pauv tshwj xeeb hauv cov kab mob plab hauv cov neeg mob uas muaj ET, uas txhawb nqa lub luag haujlwm tseem ceeb ntawm dysbiosis plab hauv ET8.
Hais txog kev mob plab hnyuv dysbiosis hauv cov kab mob neurodegenerative, PD yog qhov kev kawm dav tshaj plaws5. Ib qho microbiota tsis sib npaug tuaj yeem ua rau cov kab mob hauv plab hnyuv permeability thiab ua kom cov glia hauv plab hnyuv ua haujlwm, ua rau alpha-synucleinopathies9,10,11. PD thiab ET muaj qee yam ntxwv zoo sib xws, xws li zaus ntawm kev co hauv cov neeg mob ET thiab PD, kev co thaum so (kev co ib txwm muaj hauv PD), thiab kev co postural (feem ntau pom hauv cov neeg mob ET), ua rau nws nyuaj rau qhov sib txawv ntawm lawv. Cov theem thaum ntxov 12. Yog li ntawd, peb xav tau qhib lub qhov rais muaj txiaj ntsig los sib txawv ntawm ET thiab PD. Hauv cov ntsiab lus no, kev kawm txog kev mob plab hnyuv dysbiosis thiab kev hloov pauv metabolite cuam tshuam hauv ET thiab txheeb xyuas lawv qhov sib txawv ntawm PD yuav dhau los ua cov cim qhia rau kev kuaj mob thiab kev kuaj mob sib txawv ntawm ET.
Cov roj fatty acid luv luv (SCFAs) yog cov metabolites tseem ceeb uas tsim los ntawm cov kab mob hauv plab hnyuv ntawm cov khoom noj muaj fiber thiab xav tias ua lub luag haujlwm tseem ceeb hauv kev sib cuam tshuam ntawm lub plab thiab lub hlwb13,14. SCFAs raug coj los ntawm cov hlwb plab hnyuv thiab thauj mus rau lub siab los ntawm lub cev venous, thiab qee cov SCFAs nkag mus rau hauv kev ncig ntawm lub cev. SCFAs muaj cov teebmeem hauv zos ntawm kev tswj hwm kev ncaj ncees ntawm lub plab hnyuv thiab txhawb kev tiv thaiv kab mob hauv plab hnyuv15. Lawv kuj muaj cov teebmeem mus sij hawm ntev ntawm lub hlwb ntshav (BBB) ​​​​los ntawm kev txhawb nqa cov protein sib txuas nruj thiab ua kom cov neurons ua haujlwm los ntawm kev txhawb nqa G protein-coupled receptors (GPCRs) kom hla BBB16. Acetate, propionate, thiab butyrate yog cov SCFAs ntau tshaj plaws hauv plab hnyuv. Cov kev tshawb fawb yav dhau los tau qhia txog cov qib qis ntawm acetic, propionic thiab butyric acids hauv cov neeg mob uas muaj tus kab mob Parkinson17. Txawm li cas los xij, cov qib ntawm SCFAs hauv cov quav tsis tau raug kawm hauv cov neeg mob uas muaj ET.
Yog li, peb txoj kev tshawb fawb yog tsom rau kev txheeb xyuas cov kev hloov pauv tshwj xeeb hauv fecal SCFA hauv cov neeg mob uas muaj ET thiab lawv qhov sib txawv ntawm cov neeg mob uas muaj PD, ntsuas qhov kev sib raug zoo ntawm fecal SCFA nrog cov tsos mob ntawm ET thiab cov kab mob hauv plab hnyuv, nrog rau kev txiav txim siab qhov muaj peev xwm kuaj mob thiab sib txawv ntawm cov qauv kuaj mob fecal. KZhK. Txhawm rau daws cov teeb meem tsis meej pem uas cuam tshuam nrog cov tshuaj tiv thaiv PD, peb tau xaiv cov neeg mob uas muaj tus kab mob Parkinson tshiab ua cov tshuaj tswj kab mob.
Cov yam ntxwv ntawm cov neeg mob thiab kev kho mob ntawm 37 ETs, 37 PDs, thiab 35 HCs tau muab sau ua ke hauv Rooj 1. ETs, PDs, thiab HCs tau sib phim los ntawm hnub nyoog, poj niam txiv neej, thiab BMI. Peb pawg kuj muaj cov feem pua ​​​​​​zoo sib xws ntawm kev haus luam yeeb, haus cawv thiab haus kas fes thiab tshuaj yej. Cov qhab nia Wexner (P = 0.004) thiab HAMD-17 qhab nia (P = 0.001) ntawm pawg PD siab dua li cov ntawm pawg HC, thiab cov qhab nia HAMA (P = 0.011) thiab HAMD-17 qhab nia (P = 0.011) ntawm pawg ET siab dua li ntawm pawg HC. Lub sijhawm ntawm tus kab mob hauv pawg ET ntev dua li ntawm pawg PD (P<0.001).
Muaj qhov sib txawv tseem ceeb hauv cov qib fecal ntawm fecal propionic acid (P = 0.023), acetic acid (P = 0.039), butyric acid (P = 0.020), isovaleric acid (P = 0.045), thiab isobutyric acid (P = 0.015). . Hauv kev tshuaj xyuas tom qab hoc ntxiv, cov qib ntawm propionic acid (P = 0.023), butyric acid (P = 0.007), thiab isobutyric acid (P = 0.040) hauv pawg ET qis dua li cov neeg hauv pawg HC. Cov neeg mob uas muaj ET muaj cov qib qis dua ntawm isovalerate (P = 0.014) thiab isobutyrate (P = 0.005) dua li cov neeg mob uas muaj PD. Ntxiv rau, cov theem ntawm fecal propionic acid (P = 0.013), acetic acid (P = 0.016), thiab butyric acid (P = 0.041) qis dua rau cov neeg mob uas muaj PD dua li cov neeg mob uas muaj CC (Daim Duab 1 thiab Cov Lus Qhia Ntxiv 1).
ag sawv cev rau kev sib piv pawg ntawm propionic acid, acetic acid, butyric acid, isovaleric acid, valeric acid, caproic acid thiab isobutyric acid, raws li. Muaj qhov sib txawv tseem ceeb hauv cov theem ntawm fecal propionic acid, acetic acid, butyric acid, isovaleric acid thiab isobutyric acid ntawm peb pawg. ET tseem ceeb tremor, Parkinson tus kab mob, kev tswj hwm HC noj qab haus huv, SCFA. Qhov sib txawv tseem ceeb yog qhia los ntawm *P < 0.05 thiab **P < 0.01.
Xav txog qhov sib txawv ntawm txoj kev mob ntawm pawg ET thiab pawg PD, peb tau kawm 33 tus neeg mob uas muaj PD thaum ntxov thiab 16 tus neeg mob uas muaj ET (txoj kev mob <3 xyoos) rau kev sib piv ntxiv (Supplementary Table 2). Cov txiaj ntsig tau qhia tias cov ntsiab lus ntawm fecal propionic acid ntawm ET qis dua li ntawm HA (P = 0.015). Qhov sib txawv ntawm ET thiab HC rau butyric acid thiab isobutyric acid tsis tseem ceeb, tab sis tseem pom muaj qhov sib txawv (P = 0.082). Cov theem Fecal isobutyrate qis dua hauv cov neeg mob uas muaj ET piv rau cov neeg mob uas muaj PD (P = 0.030). Qhov sib txawv ntawm ET thiab PD ntawm isovaleric acid tsis tseem ceeb, tab sis tseem muaj qhov sib txawv (P = 0.084). Propionic acid (P = 0.023), acetic acid (P = 0.020), thiab butyric acid (P = 0.044) qis dua hauv cov neeg mob PD dua li cov neeg mob HC. Cov txiaj ntsig no (Daim Duab Ntxiv 1) feem ntau yog sib xws nrog cov txiaj ntsig tseem ceeb. Qhov sib txawv ntawm cov txiaj ntsig ntawm tag nrho cov qauv thiab cov neeg mob thaum ntxov yuav yog vim qhov loj me ntawm cov qauv hauv pawg me, ua rau lub zog txheeb cais qis dua ntawm cov ntaub ntawv.
Tom ntej no peb tau tshuaj xyuas seb cov qib SCFA hauv cov quav puas tuaj yeem paub qhov txawv ntawm cov neeg mob uas muaj ET los ntawm cov neeg mob uas muaj CU lossis PD. Raws li kev tshuaj xyuas ROC, qhov sib txawv ntawm AUC ntawm cov qib propionate yog 0.668 (95% CI: 0.538-0.797), uas ua rau nws muaj peev xwm paub qhov txawv ntawm cov neeg mob uas muaj ET los ntawm HC. Cov neeg mob uas muaj ET thiab GC tuaj yeem paub qhov txawv los ntawm cov qib butyrate nrog AUC ntawm 0.685 (95% CI: 0.556–0.814). Qhov sib txawv ntawm cov qib isobutyric acid tuaj yeem paub qhov txawv ntawm cov neeg mob uas muaj ET los ntawm HC nrog AUC ntawm 0.655 (95% CI: 0.525–0.786). Thaum muab cov theem propionate, butyrate thiab isobutyrate sib xyaw ua ke, AUC siab dua ntawm 0.751 (95% CI: 0.634–0.867) tau txais nrog qhov rhiab heev ntawm 74.3% thiab qhov tshwj xeeb ntawm 72.9% (Daim Duab 2a). Txhawm rau kom paub qhov txawv ntawm cov neeg mob ET thiab PD, AUC rau cov theem isovaleric acid yog 0.700 (95% CI: 0.579–0.822) thiab rau cov theem isobutyric acid yog 0.718 (95% CI: 0.599–0.836). Kev sib xyaw ua ke ntawm cov theem isovaleric acid thiab isobutyric acid muaj AUC siab dua ntawm 0.743 (95% CI: 0.629–0.857), qhov rhiab heev ntawm 74.3% thiab qhov tshwj xeeb ntawm 62.9% (Daim Duab 2b). Ntxiv mus, peb tau tshuaj xyuas seb cov theem SCFA hauv cov quav ntawm cov neeg mob uas muaj tus kab mob Parkinson txawv ntawm cov neeg tswj. Raws li ROC kev tshuaj xyuas, AUC rau kev txheeb xyuas cov neeg mob uas muaj PD raws li qhov sib txawv ntawm cov theem propionic acid yog 0.687 (95% CI: 0.559-0.814), nrog rau qhov rhiab heev ntawm 68.6% thiab qhov tshwj xeeb ntawm 68.7%. Qhov sib txawv ntawm cov theem acetate tuaj yeem sib txawv cov neeg mob PD los ntawm HCs nrog AUC ntawm 0.674 (95% CI: 0.542–0.805). Cov neeg mob uas muaj PD tuaj yeem sib txawv ntawm CU tsuas yog los ntawm cov theem butyrate nrog AUC ntawm 0.651 (95% CI: 0.515–0.787). Thaum muab cov theem propionate, acetate thiab butyrate sib xyaw ua ke, AUC ntawm 0.682 (95% CI: 0.553–0.811) tau txais (Daim duab 2c).
kev ntxub ntxaug los ntawm lub Koom Txoos Orthodox Lavxias tawm tsam ET thiab HC; b ROC kev ntxub ntxaug tawm tsam ET thiab PD; c ROC kev ntxub ntxaug tawm tsam PD thiab HC; ET kev tshee hnyo tseem ceeb, kab mob Parkinson, kev tswj hwm HC noj qab haus huv, SCFA.
Hauv cov neeg mob uas muaj ET, qib fecal isobutyric acid tsis sib raug zoo nrog FTM qhab nia (r = -0.349, P = 0.034), thiab qib fecal isovaleric acid tsis sib raug zoo nrog FTM qhab nia (r = -0.421, P = 0.001) thiab TETRAS qhab nia. (r = -0.382, P = 0.020). Hauv cov neeg mob uas muaj ET thiab PD, qib fecal propionate tsis sib raug zoo nrog SCOPA-AUT qhab nia (r = −0.236, P = 0.043) (Daim Duab 3 thiab Daim Ntawv Qhia Ntxiv 3). Tsis muaj kev sib raug zoo tseem ceeb ntawm kev mob thiab SCFA hauv pawg ET (P ≥ 0.161) lossis pawg PD (P ≥ 0.246) (Daim Ntawv Qhia Ntxiv 4). Hauv cov neeg mob uas muaj PD, cov qib fecal caproic acid tau sib raug zoo nrog MDS-UPDRS cov qhab nia (r = 0.335, P = 0.042). Thoob plaws txhua tus neeg koom nrog, cov qib fecal propionate (r = −0.230, P = 0.016) thiab acetate (r = −0.210, P = 0.029) tau sib raug zoo nrog Wexner cov qhab nia (Daim Duab 3 thiab Cov Lus Qhia Ntxiv 3).
Cov theem ntawm cov kua qaub isobutyric hauv cov quav tsis sib raug zoo nrog cov qhab nia FTM, cov kua qaub isovaleric tsis sib raug zoo nrog cov qhab nia FTM thiab TETRAS, cov kua qaub propionic tsis sib raug zoo nrog cov qhab nia SCOPA-AUT, cov kua qaub caproic tsis sib raug zoo nrog cov qhab nia MDS-UPDRS, thiab cov kua qaub propionic tsis sib raug zoo nrog cov qhab nia FTM thiab TETRAS. TETRAS thiab cov kua qaub acetic tsis sib raug zoo nrog cov qhab nia Wexner. Cov ntawv txhawb nqa los ntawm MDS-UPDRS Association ntawm Unified Parkinson's Disease Rating Scale, Mini-Mental State Examination MMSE, Hamilton Depression Rating Scale HAMD-17, 17 yam khoom, Hamilton Anxiety Rating Scale HAMA, HY Hoehn thiab 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. Qhov sib txawv tseem ceeb yog qhia los ntawm *P < 0.05 thiab **P < 0.01.
Peb tau tshawb nrhiav ntxiv txog qhov xwm txheej ntawm cov kab mob hauv plab siv kev tshuaj xyuas LEfSE thiab xaiv cov ntaub ntawv qib sib piv ntawm cov noob caj noob ces rau kev tshuaj xyuas ntxiv. Kev sib piv tau ua ntawm ET thiab HC thiab ntawm ET thiab PD. Kev tshuaj xyuas Spearman correlation tau ua tiav ntawm qhov sib piv ntawm cov kab mob hauv plab thiab cov qib SCFA hauv ob pawg sib piv.
Faecalibacterium (sib raug zoo nrog butyric acid, r = 0.408, P < 0.001), Lactobacillus (sib raug zoo nrog butyric acid, r = 0.283, P = 0.016), Streptobacterium (sib raug zoo nrog propionic acid, r = 0.327) tau muaj nyob rau hauv kev tshuaj xyuas ntawm ET thiab CA., P = 0.005; sib raug zoo nrog butyric acid, r = 0.374, P = 0.001; sib raug zoo nrog isobutyric acid, r = 0.329, P = 0.005), Howardella (sib raug zoo nrog propionic acid, r = 0.242, P = 0.041), Raoultella (sib raug zoo nrog propionate, r = 0.249, P = 0.035), thiab Candidatus Arthromitus (sib raug zoo nrog isobutyric acid, r = 0.302, P = 0.010) txo qis hauv ET thiab muaj kev sib raug zoo nrog cov qib fecal SCFA. Txawm li cas los xij, Stenotropomonas muaj ntau ntxiv hauv ET thiab muaj kev sib raug zoo nrog cov qib fecal isobutyrate (r = -0.250, P = 0.034). Tom qab kev hloov kho FDR, tsuas yog kev sib raug zoo ntawm Faecalibacterium, Catenibacter, thiab SCFA tseem ceeb (P ≤ 0.045) (Daim duab 4 thiab Daim Ntawv Qhia Ntxiv 5).
Kev tshuaj xyuas kev sib raug zoo ntawm ET thiab HC. Tom qab kev hloov kho FDR, qhov muaj ntau ntawm Faecalibacterium (muaj feem cuam tshuam zoo nrog butyrate) thiab Streptobacterium (muaj feem cuam tshuam zoo nrog propionate, butyrate, thiab isobutyrate) tau pom tias txo qis hauv ET thiab muaj feem cuam tshuam zoo nrog cov qib SCFA hauv quav. b Kev tshuaj xyuas kev sib raug zoo ntawm ET thiab PD. Tom qab kev hloov kho FDR, tsis pom muaj kev sib raug zoo tseem ceeb. ET tseem ceeb tremor, Parkinson tus kab mob, kev tswj hwm HC noj qab haus huv, SCFA. Qhov sib txawv tseem ceeb tau qhia los ntawm *P < 0.05 thiab **P < 0.01.
Thaum tshuaj xyuas ET piv rau PD, Clostridium trichophyton tau pom tias muaj ntau ntxiv hauv ET thiab muaj feem cuam tshuam nrog fecal isovaleric acid (r = -0.238, P = 0.041) thiab isobutyric acid (r = -0.257, P = 0.027). Tom qab kev hloov kho FDR, ob qho tib si tseem ceeb (P≥0.295) (Daim Duab 4 thiab Cov Lus Qhia Ntxiv 5).
Txoj kev tshawb fawb no yog ib txoj kev tshawb fawb dav dav uas tshuaj xyuas cov qib SCFA hauv cov quav thiab sib piv lawv nrog kev hloov pauv hauv cov kab mob hauv plab thiab qhov hnyav ntawm cov tsos mob hauv cov neeg mob uas muaj ET piv rau cov neeg mob uas muaj CU thiab PD. Peb pom tias cov qib SCFA hauv cov quav tau txo qis hauv cov neeg mob uas muaj ET thiab tau cuam tshuam nrog qhov hnyav ntawm kev kho mob thiab kev hloov pauv tshwj xeeb hauv cov kab mob hauv plab. Cov qib sib sau ua ke ntawm cov roj fatty acid luv luv (SCFAs) sib txawv ET ntawm GC thiab PD.
Piv nrog cov neeg mob GC, cov neeg mob ET muaj cov qib qis dua ntawm cov propionic, butyric, thiab isobutyric acids hauv cov quav. Kev sib xyaw ua ke ntawm propionic, butyric thiab isobutyric acids sib txawv ET thiab HC nrog AUC ntawm 0.751 (95% CI: 0.634–0.867), qhov rhiab heev ntawm 74.3% thiab qhov tshwj xeeb ntawm 72.9%, qhia txog lawv siv ua cov cim qhia kev kuaj mob rau lub luag haujlwm ntawm ET. Kev tshuaj xyuas ntxiv qhia tau tias cov qib fecal propionic acid tau sib raug zoo tsis zoo nrog Wexner qhab nia thiab SCOPA-AUT qhab nia. Cov qib Fecal isobutyric acid tau sib raug zoo nrog FTM qhab nia. Ntawm qhov tod tes, qhov txo qis ntawm cov qib butyrate hauv ET tau cuam tshuam nrog qhov txo qis ntawm cov microbiota tsim SCFA, Faecalibacterium, thiab Categorybacter. Tsis tas li ntawd, kev txo qis ntawm Catenibacter ntau hauv ET kuj tau cuam tshuam nrog kev txo qis ntawm cov qib fecal propionic thiab isobutyric acid.
Feem ntau cov SCFAs uas tsim tawm hauv cov hnyuv loj yog cov colonocytes noj los ntawm H+-dependent lossis sodium-dependent monocarboxylate transporters. Cov roj fatty acids luv luv uas nqus tau yog siv los ua lub zog rau cov colonocytes, thaum cov uas tsis tau metabolized hauv cov colonocytes raug thauj mus rau hauv lub portal circulation 18. SCFAs tuaj yeem cuam tshuam rau kev txav mus los ntawm txoj hnyuv, txhim kho kev ua haujlwm ntawm txoj hnyuv, thiab cuam tshuam rau tus tswv tsev metabolism thiab kev tiv thaiv kab mob19. Yav dhau los nws tau pom tias cov quav concentration ntawm butyrate, acetate, thiab propionate tau txo qis hauv cov neeg mob PD piv rau HCs17, uas yog sib xws nrog peb cov txiaj ntsig. Peb txoj kev tshawb fawb pom tias muaj kev txo qis hauv SCFAs hauv cov neeg mob uas muaj ET, tab sis me ntsis paub txog lub luag haujlwm ntawm SCFAs hauv pathology ntawm ET. Butyrate thiab propionate tuaj yeem khi rau GPCRs thiab cuam tshuam rau GPCR-dependent signaling xws li MAPK thiab NF-κB20 signaling. Lub tswv yim yooj yim ntawm lub plab-lub hlwb axis yog tias SCFAs secreted los ntawm cov kab mob plab tuaj yeem cuam tshuam rau tus tswv tsev signaling, yog li cuam tshuam rau txoj hnyuv thiab lub hlwb ua haujlwm. Vim tias butyrate thiab propionate muaj cov teebmeem inhibitory rau histone deacetylase (HDAC) kev ua ub no21 thiab butyrate kuj tuaj yeem ua haujlwm ua ligand rau cov yam ntxwv transcription, lawv muaj cov teebmeem dav dav rau tus tswv tsev metabolism, kev sib txawv thiab kev loj hlob, feem ntau yog vim lawv cov kev cuam tshuam rau kev tswj hwm gene22. Raws li cov pov thawj los ntawm SCFA thiab cov kab mob neurodegenerative, butyrate yog suav hais tias yog tus neeg sib tw kho mob vim nws lub peev xwm los kho qhov tsis zoo HDAC kev ua ub no, uas yuav ua rau dopaminergic neuron tuag hauv PD23,24,25. Kev tshawb fawb tsiaj kuj tau ua pov thawj txog lub peev xwm ntawm butyric acid los tiv thaiv dopaminergic neuron degeneration thiab txhim kho kev txav mus los hauv PD qauv26,27. Propionic acid tau pom tias txwv cov lus teb inflammatory thiab tiv thaiv kev ncaj ncees ntawm BBB28,29. Kev tshawb fawb tau qhia tias propionic acid txhawb nqa kev ciaj sia ntawm dopaminergic neurons hauv kev teb rau rotenone toxicity hauv PD qauv30 thiab tias kev tswj hwm qhov ncauj ntawm propionic acid cawm dopaminergic neuron poob thiab lub cev muaj zog hauv nas nrog PD31. Tsis muaj ntau yam paub txog kev ua haujlwm ntawm isobutyric acid. Txawm li cas los xij, kev tshawb fawb tsis ntev los no pom tias kev ua kom cov nas nrog B. ovale nce cov ntsiab lus SCFA hauv plab hnyuv (suav nrog acetate, propionate, isobutyrate, thiab isovalerate) thiab cov concentration ntawm GABA hauv plab hnyuv, qhia tias qhov txuas tau tsim ntawm cov kab mob hauv plab hnyuv thiab cov concentration ntawm cov neurotransmitters32. Hauv ET, kev hloov pauv tsis zoo hauv cerebellum suav nrog kev hloov pauv hauv Purkinje cell axons thiab dendrites, kev hloov pauv thiab kev poob ntawm Purkinje cell, kev hloov pauv hauv cov pob tawb cell axons, kev tsis zoo hauv kev sib txuas ntawm cov fiber ntau nrog Purkinje cell faib, thiab kev hloov pauv hauv GABA receptors hauv pob txha dentate. nuclei, uas ua rau muaj kev txo qis hauv GABAergic tso zis los ntawm cerebellum3,4,33. Nws tseem tsis meej tias SCFAs puas cuam tshuam nrog Purkinje cell neurodegeneration thiab txo qis cerebellar GABA ntau lawm. Peb cov txiaj ntsig qhia txog kev sib raug zoo ntawm SCFA thiab ET, tab sis kev tsim qauv kev tshawb fawb hla tsis pub muaj kev xaus lus txog kev sib raug zoo ntawm SCFA thiab cov txheej txheem kab mob ntawm ET; Xav tau kev tshawb fawb txuas ntxiv mus ntev, suav nrog kev ntsuas cov quav SCFAs, nrog rau kev tshawb fawb tsiaj txhu tshuaj xyuas cov txheej txheem.
SCFAs xav tias yuav ua rau cov leeg nqaij du ntawm lub plab zom mov zoo li qub34. Yog tias tsis muaj SCFA yuav ua rau cov tsos mob ntawm kev cem quav hnyav zuj zus, thiab kev noj SCFA ntxiv yuav ua rau cov tsos mob ntawm kev cem quav PD35 zoo dua. Peb cov txiaj ntsig kuj qhia txog kev sib raug zoo tseem ceeb ntawm cov ntsiab lus ntawm cov quav SCFA tsawg dua thiab kev cem quav ntau ntxiv thiab kev ua haujlwm tsis zoo ntawm lub cev hauv cov neeg mob uas muaj ET. Ib daim ntawv qhia txog tus neeg mob pom tias kev hloov pauv microbiota tau txhim kho ob qho tib si kev co thiab kev mob plab hnyuv hauv tus neeg mob 7, qhia ntxiv txog kev sib raug zoo ntawm cov kab mob plab thiab ET. Yog li ntawd, peb ntseeg tias cov quav SCFA / microbiota yuav cuam tshuam rau kev txav mus los ntawm lub plab thiab kev ua haujlwm ntawm lub paj hlwb.
Txoj kev tshawb fawb pom tau tias cov qib qis ntawm cov quav SCFAs hauv ET tau cuam tshuam nrog kev txo qis ntawm Faecalibacterium (cuam tshuam nrog butyrate) thiab Streptobacterium (cuam tshuam nrog propionate, butyrate, thiab isobutyrate). Tom qab FDR kho, qhov kev sib raug zoo no tseem ceeb heev. Faecalibacterium thiab Streptobacterium yog cov kab mob tsim SCFA. Faecalibacterium paub tias yog cov kab mob tsim butyrate36, thaum cov khoom tseem ceeb ntawm Catenibacter fermentation yog acetate, butyrate thiab lactic acid37. Faecalibacterium tau pom hauv 100% ntawm ob pawg ET thiab HC; qhov nruab nrab ntawm cov kab mob ntawm pawg ET yog 2.06% thiab ntawm pawg HC yog 3.28% (LDA 3.870). Cov kab mob hauv pawg tau pom hauv 21.6% (8/37) ntawm pawg HC thiab tsuas yog hauv 1 tus qauv ntawm pawg ET (1/35). Qhov txo qis thiab tsis pom ntawm streptobacteria hauv ET kuj tseem yuav qhia txog kev sib raug zoo nrog qhov ua rau muaj kab mob. Qhov nruab nrab ntawm cov kab mob Catenibacter hauv pawg HC yog 0.07% (LDA 2.129). Tsis tas li ntawd, cov kab mob lactic acid tau cuam tshuam nrog kev hloov pauv hauv fecal butyrate (P = 0.016, P = 0.096 tom qab FDR hloov kho), thiab tus neeg mob pob qij txha tau cuam tshuam nrog kev hloov pauv hauv isobutyrate (P = 0.016, P = 0.072 tom qab FDR hloov kho). Tom qab FDR kho, tsuas yog qhov sib raug zoo tseem tshuav, uas tsis tseem ceeb. Lactobacilli kuj paub tias yog SCFA (acetic acid, propionic acid, isobutyric acid, butyric acid) cov neeg tsim khoom 38 thiab Candidatus Arthromitus yog tus neeg tshwj xeeb ntawm T helper 17 (Th17) cell differentiation, nrog Th1/2 thiab Tregs cuam tshuam nrog kev sib npaug ntawm lub cev / Th1739. . Ib txoj kev tshawb fawb tsis ntev los no qhia tau hais tias cov qib siab ntawm cov kab mob fecal pseudoarthritis yuav ua rau mob colonic, ua haujlwm tsis zoo ntawm txoj hnyuv, thiab mob o ntawm lub cev 40. Cov qib Clostridium trichoides tau nce ntxiv hauv ET piv rau PD. Clostridium trichoides muaj ntau heev tau pom tias muaj kev sib raug zoo tsis zoo nrog isovaleric acid thiab isobutyric acid. Tom qab kev hloov kho FDR, ob qho tib si tseem ceeb (P≥0.295). Clostridium pilosum yog ib hom kab mob uas paub tias cuam tshuam nrog kev o thiab tej zaum yuav ua rau mob o ntawm txoj hnyuv41. Peb txoj kev tshawb fawb yav dhau los tau tshaj tawm txog kev hloov pauv hauv cov kab mob plab ntawm cov neeg mob uas muaj ET8. Ntawm no peb kuj tshaj tawm txog kev hloov pauv hauv SCFA hauv ET thiab txheeb xyuas kev sib raug zoo ntawm kev ua haujlwm tsis zoo ntawm txoj hnyuv thiab kev hloov pauv hauv SCFA. Cov qib SCFA txo qis muaj feem cuam tshuam nrog kev ua haujlwm tsis zoo ntawm txoj hnyuv thiab kev co hauv ET. Peb cov txiaj ntsig qhia tau hais tias txoj kab ke ntawm txoj hnyuv thiab lub hlwb yuav ua lub luag haujlwm tseem ceeb hauv kev mob ET, tab sis kev tshawb fawb ntxiv hauv cov qauv tsiaj txhu yog qhov xav tau.
Piv nrog cov neeg mob uas muaj PD, cov neeg mob uas muaj ET muaj cov isovaleric thiab isobutyric acids qis dua hauv lawv cov quav. Kev sib xyaw ua ke ntawm isovaleric acid thiab isobutyric acid tau txheeb xyuas ET hauv PD nrog AUC ntawm 0.743 (95% CI: 0.629–0.857), qhov rhiab heev ntawm 74.3% thiab qhov tshwj xeeb ntawm 62.9%, qhia txog lawv lub luag haujlwm ua biomarkers hauv kev kuaj mob sib txawv ntawm ET. . Fecal isovaleric acid theem tau sib raug zoo nrog FTM thiab TETRAS cov qhab nia. Fecal isobutyric acid theem tau sib raug zoo nrog FTM cov qhab nia. Qhov txo qis hauv isobutyric acid theem tau cuam tshuam nrog qhov txo qis hauv qhov ntau ntawm catobacteria. Me ntsis paub txog cov haujlwm ntawm isovaleric acid thiab isobutyric acid. Ib txoj kev tshawb fawb yav dhau los tau qhia tias kev loj hlob ntawm cov nas nrog B. ovale ua rau muaj ntau cov SCFAs hauv plab hnyuv (xws li acetate, propionate, isobutyrate, thiab isovalerate) thiab cov GABA hauv plab hnyuv ntau ntxiv, qhia txog kev sib txuas ntawm cov kab mob hauv plab hnyuv thiab cov SCFA / neurotransmitter hauv plab hnyuv32. Qhov nthuav yog, cov qib isobutyric acid uas tau pom zoo sib xws ntawm cov pab pawg PD thiab HC, tab sis sib txawv ntawm cov pab pawg ET thiab PD (lossis HC). Isobutyric acid tuaj yeem paub qhov txawv ntawm ET thiab PD nrog AUC ntawm 0.718 (95% CI: 0.599–0.836) thiab txheeb xyuas ET thiab NC nrog AUC ntawm 0.655 (95% CI: 0.525–0.786). Tsis tas li ntawd, cov qib isobutyric acid sib raug zoo nrog qhov hnyav ntawm kev co, ua rau nws muaj kev sib raug zoo nrog ET ntxiv. Lo lus nug txog seb qhov ncauj isobutyric acid puas tuaj yeem txo qhov hnyav ntawm kev co hauv cov neeg mob uas muaj ET tsim nyog kawm ntxiv.
Yog li, cov ntsiab lus ntawm SCFA hauv cov quav raug txo qis rau cov neeg mob uas muaj ET thiab cuam tshuam nrog qhov hnyav ntawm ET thiab kev hloov pauv tshwj xeeb hauv cov kab mob hauv plab hnyuv. Fecal propionate, butyrate, thiab isobutyrate tej zaum yuav yog cov cim qhia txog kev kuaj mob rau ET, thaum isobutyrate thiab isovalerate tej zaum yuav yog cov cim qhia txog kev kuaj mob sib txawv rau ET. Kev hloov pauv hauv fecal isobutyrate tej zaum yuav tshwj xeeb dua rau ET dua li kev hloov pauv hauv lwm yam SCFAs.
Peb txoj kev tshawb fawb muaj ntau yam kev txwv. Ua ntej, cov qauv noj haus thiab kev nyiam zaub mov yuav cuam tshuam rau kev qhia tawm ntawm cov kab mob me me, cov qauv kev tshawb fawb loj dua hauv cov pej xeem sib txawv yog qhov xav tau, thiab kev tshawb fawb yav tom ntej yuav tsum qhia txog kev soj ntsuam kev noj haus kom tiav thiab muaj txheej txheem xws li cov lus nug txog zaus noj mov. Qhov thib ob, txoj kev tsim qauv kev tshawb fawb hla kev txwv tsis pub muaj kev xaus lus txog kev sib raug zoo ntawm SCFA thiab cov txheej txheem kab mob ntawm ET. Xav tau kev tshawb fawb txuas ntxiv mus sij hawm ntev nrog kev ntsuas cov quav SCFAs. Qhov thib peb, kev kuaj mob thiab kev sib txawv ntawm cov qib quav SCFA yuav tsum tau lees paub siv cov qauv ywj pheej los ntawm ET, HC, thiab PD. Yuav tsum kuaj cov qauv quav ywj pheej ntxiv yav tom ntej. Thaum kawg, cov neeg mob uas muaj PD hauv peb pawg neeg muaj lub sijhawm mob luv dua li cov neeg mob uas muaj ET. Peb feem ntau phim ET, PD thiab HC los ntawm hnub nyoog, poj niam txiv neej thiab BMI. Muab qhov sib txawv ntawm kev mob ntawm pawg ET thiab pawg PD, peb kuj tau kawm 33 tus neeg mob uas muaj PD thaum ntxov thiab 16 tus neeg mob uas muaj ET (lub sijhawm mob ≤3 xyoos) rau kev sib piv ntxiv. Qhov sib txawv ntawm pawg hauv SCFA feem ntau yog sib xws nrog peb cov ntaub ntawv tseem ceeb. Ntxiv mus, peb tsis pom muaj kev sib raug zoo ntawm lub sijhawm mob thiab kev hloov pauv hauv SCFA. Txawm li cas los xij, yav tom ntej, nws yuav zoo tshaj plaws los nrhiav cov neeg mob uas muaj PD thiab ET thaum ntxov nrog lub sijhawm mob luv dua kom ua tiav qhov kev lees paub hauv cov qauv loj dua.
Cov txheej txheem kev tshawb fawb tau pom zoo los ntawm Pawg Neeg Saib Xyuas Kev Ncaj Ncees ntawm Ruijin Tsev Kho Mob koom nrog Shanghai Jiao Tong University School of Medicine (RHEC2018-243). Kev pom zoo sau ntawv tau txais los ntawm txhua tus neeg koom nrog.
Nruab nrab ntawm Lub Ib Hlis 2019 thiab Lub Kaum Ob Hlis 2022, 109 tus neeg mob (37 ET, 37 PD, thiab 35 HC) los ntawm Lub Chaw Kho Mob Mob Hlwb ntawm Ruijin Tsev Kho Mob, koom tes nrog Shanghai Jiao Tong University School of Medicine, tau suav nrog hauv txoj kev tshawb fawb no. Cov qauv yog: (1) hnub nyoog 25–85 xyoo, (2) cov neeg mob uas muaj ET tau kuaj pom raws li MDS Working Group cov qauv 42 thiab PD tau kuaj pom raws li MDS cov qauv 43, (3) txhua tus neeg mob tsis tau noj tshuaj tiv thaiv PD ua ntej lub rooj zaum. sau cov qauv. (4) Pawg ET tsuas yog noj β-blockers lossis tsis muaj tshuaj cuam tshuam ua ntej sau cov qauv quav. HCs phim rau hnub nyoog, poj niam txiv neej, thiab lub cev hnyav (BMI) kuj tau raug xaiv. Cov qauv tsis suav nrog yog: (1) cov neeg tsis noj nqaij, (2) kev noj zaub mov tsis zoo, (3) cov kab mob ntev ntawm txoj hnyuv plab (xws li kab mob plab hnyuv, mob plab lossis duodenum), (4) cov kab mob ntev hnyav (xws li cov qog nqaij hlav phem), lub plawv tsis ua haujlwm, lub raum tsis ua haujlwm, cov kab mob ntshav) (5) Keeb kwm ntawm kev phais plab loj, (6) Noj mis nyuj yogurt ntev lossis tsis tu ncua, (7) Siv cov probiotics lossis tshuaj tua kab mob rau 1 lub hlis, (8) Siv cov corticosteroids ntev, cov tshuaj proton twj tso kua mis, statins, metformin, cov tshuaj tiv thaiv kab mob lossis cov tshuaj tiv thaiv kab mob qog noj ntshav thiab (9) kev puas tsuaj loj heev uas cuam tshuam rau kev sim tshuaj.
Txhua tus neeg mob tau muab keeb kwm kho mob, qhov hnyav thiab qhov siab los xam BMI, thiab tau kuaj mob hlwb thiab kev soj ntsuam hauv chaw kho mob xws li Hamilton Anxiety Rating Scale (HAMA) 44 qhov qhab nia kev ntxhov siab, Hamilton Depression Rating Scale-17 qhov qhab nia (HAMD-17) 45. kev nyuaj siab, qhov hnyav ntawm kev cem quav siv Wexner Constipation Scale 46 thiab Bristol Stool Scale 47 thiab kev ua haujlwm ntawm lub hlwb siv Mini-Mental State Examination (MMSE) 48. Lub Scale rau Kev Ntsuam Xyuas Cov tsos mob ntawm Parkinson's Disease (SCOPA-AUT) 49 tau tshuaj xyuas qhov tsis ua haujlwm ntawm lub cev hauv cov neeg mob uas muaj ET thiab PD. Lub Fana-Tolos-Marin Clinical Tremor Rating Scale (FTM) thiab Essential Tremor Rating Scale (TETRAS) 50 Pawg Kawm Tremor (TRG) 50 tau raug tshuaj xyuas hauv cov neeg mob uas muaj ET; Kinson's Disease Rating Scale (MDS-), txhawb nqa los ntawm United Parkinson's Disease Association; UPDRS version 51 thiab Hoehn thiab Yahr (HY) version 52 tau raug tshuaj xyuas.
Txhua tus neeg koom nrog tau raug hais kom sau cov qauv quav thaum sawv ntxov siv lub thawv sau cov quav. Hloov cov thawv rau hauv dej khov thiab khaws cia rau -80 ° C ua ntej ua tiav. Kev tshuaj xyuas SCFA tau ua raws li kev ua haujlwm niaj hnub ntawm Tiangene Biotechnology (Shanghai) Co., Ltd. 400 mg ntawm cov qauv quav tshiab tau sau los ntawm txhua tus neeg thiab tshuaj xyuas siv SCFAs tom qab sib tsoo thiab sonication. Cov SCFAs xaiv hauv cov quav tau tshuaj xyuas siv roj chromatography-mass spectrometry (GC-MS) thiab kua chromatography-tandem MS (LC-MS/MS).
DNA tau rho tawm ntawm 200 mg cov qauv siv QIAamp® Fast DNA Stool Mini Kit (QIAGEN, Hilden, Lub Tebchaws Yelemees) raws li cov lus qhia ntawm cov chaw tsim khoom. Cov kab mob sib xyaw tau txiav txim siab los ntawm kev txheeb xyuas cov noob caj noob ces 16 S rRNA ntawm DNA cais tawm ntawm cov quav los ntawm kev ua kom loj dua thaj tsam V3-V4. Sim cov DNA los ntawm kev khiav cov qauv ntawm 1.2% agarose gel. Polymerase chain reaction (PCR) kev ua kom loj dua ntawm 16S rRNA noob tau ua tiav siv cov tshuaj primers bacterial universal (357 F thiab 806 R) thiab lub tsev qiv ntawv amplicon ob kauj ruam tsim los ntawm lub platform Novaseq.
Cov hloov pauv tas mus li yog qhia ua qhov nruab nrab ± tus qauv sib txawv, thiab cov hloov pauv categorical yog qhia ua cov lej thiab feem pua. Peb siv Levene qhov kev xeem los sim qhov sib xws ntawm cov kev hloov pauv. Kev sib piv tau ua los ntawm kev siv ob-tailed t kev xeem lossis kev tshuaj xyuas ntawm qhov sib txawv (ANOVA) yog tias cov hloov pauv tau faib ua feem ntau, thiab cov kev xeem tsis yog parametric Mann-Whitney U yog tias qhov kev xav zoo li qub lossis homoscedasticity tau ua txhaum. Peb siv thaj chaw hauv qab tus cwj pwm ua haujlwm ntawm tus txais (ROC) nkhaus (AUC) los ntsuas qhov kev ua haujlwm kuaj mob ntawm tus qauv thiab tshuaj xyuas lub peev xwm ntawm SCFA los sib txawv cov neeg mob uas muaj ET los ntawm cov neeg uas muaj HC lossis PD. Txhawm rau tshuaj xyuas kev sib raug zoo ntawm SCFA thiab qhov hnyav ntawm kev kho mob, peb siv Spearman kev tshuaj xyuas kev sib raug zoo. Kev tshuaj xyuas cov ntaub ntawv tau ua tiav siv SPSS software (version 22.0; SPSS Inc., Chicago, IL) nrog qib tseem ceeb (suav nrog P tus nqi thiab FDR-P) teeb tsa ntawm 0.05 (ob sab).
Cov kab ke 16 S tau raug tshuaj xyuas siv kev sib xyaw ua ke ntawm Trimmomatic (version 0.35), Flash (version 1.2.11), UPARSE (version v8.1.1756), mothur (version 1.33.3) thiab R (version 3.6.3) software. Cov ntaub ntawv noob caj noob ces 16S rRNA tau raug ua tiav siv UPARSE los tsim cov chav ua haujlwm taxonomic (OTUs) nrog 97% tus kheej. Taxonomies tau teev tseg siv Silva 128 ua lub hauv paus ntaub ntawv siv. Qib dav dav ntawm cov ntaub ntawv muaj ntau yam tau raug xaiv rau kev tshuaj xyuas ntxiv. Kev tshuaj xyuas qhov loj me ntawm cov nyhuv linear discriminant (LDA) (LEfSE) tau siv rau kev sib piv ntawm cov pab pawg (ET vs. HC, ET vs. PD) nrog qhov α threshold ntawm 0.05 thiab qhov loj me ntawm cov nyhuv threshold ntawm 2.0. Cov noob caj noob ces Discriminant tau txheeb xyuas los ntawm LEfSE kev tshuaj xyuas tau siv ntxiv rau kev tshuaj xyuas Spearman correlation ntawm SCFA.
Yog xav paub ntxiv txog kev tsim txoj kev tshawb fawb, mus saib Natural Research Report Abstract uas cuam tshuam nrog tsab xov xwm no.
Cov ntaub ntawv raw 16S sequencing khaws cia rau hauv National Center for Biotechnology Information (NCBI) BioProject database (SRP438900: PRJNA974928), URL: https://www.ncbi.nlm.nih.gov/Traces/study/?acc= SRP438900&o. =acc_s% 3Aa. Lwm cov ntaub ntawv tseem ceeb muaj rau tus sau ntawv sib xws thaum thov, xws li kev koom tes hauv kev tshawb fawb thiab kev sib pauv kev kawm nrog cov haujlwm tshawb fawb tag nrho. Tsis pub xa cov ntaub ntawv mus rau lwm tus yam tsis tau peb tso cai.
Tsuas yog qhib qhov code nrog kev sib xyaw ua ke ntawm Trimmomatic (version 0.35), Flash (version 1.2.11), UPARSE (version v8.1.1756), mothur (version 1.33.3) thiab R (version 3.6.3), siv cov chaw teeb tsa lossis ntu "Txoj Kev". Cov ntaub ntawv qhia ntxiv tuaj yeem muab rau tus sau ntawv raws li qhov kev thov tsim nyog.
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Louis, ED thiab Faust, PL Kev mob ntawm kev co tseem ceeb: kev puas tsuaj ntawm lub paj hlwb thiab kev rov tsim kho dua tshiab ntawm kev sib txuas ntawm cov hlab ntsha. Nat. Pastor Nirol. 16, 69–83 (2020).
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