Lub plab Microbiome nyob rau hauv Alzheimer's Disease: Peb Paub Thiab Dab Tsi Tseem Yuav Tshawb Nrhiav
Nov 24, 2023
Abstract
Alzheimer's disease (AD), feem ntau ua rau dementia, ua rau muaj kev poob qis hauv kev paub. Tam sim no muaj ob peb txoj kev kho mob zoo rau AD, tab sis kev nkag siab rau cov txheej txheem uas kho qhov pib thiab kev loj hlob ntawm tus kab mob tuaj yeem ua rau cov tswv yim kho mob tshiab. Amyloid beta oligomers thiab plaques, tau aggregates, thiab neuroinflammation ua lub luag haujlwm tseem ceeb hauv neurodegeneration thiab cuam tshuam kev kho mob AD. Cov kev hloov pauv ntawm cov kab mob no tsis tau qhia meej meej, tab sis cov pov thawj tsis ntev los no qhia tau tias lub plab microbiome (GMB) yuav muaj kev cuam tshuam rau cov yam ntxwv no thiab yog li ntawd yuav cuam tshuam rau AD kev loj hlob hauv tib neeg cov neeg mob. Hauv kev tshuaj xyuas no, peb sau cov kev tshawb fawb uas tau txheeb xyuas qhov kev hloov pauv hauv GMB uas cuam tshuam nrog pathophysiology hauv AD cov neeg mob thiab AD nas qauv. Tsis tas li ntawd, peb tham txog kev tshawb pom nrog GMB manipulations hauv AD qauv thiab muaj peev xwm GMB-targeted therapeutics rau AD. Thaum kawg, peb sib tham txog kev noj zaub mov, pw tsaug zog, thiab kev tawm dag zog ua lub peev xwm hloov kho ntawm kev sib raug zoo ntawm GMB thiab AD thiab xaus nrog cov lus qhia yav tom ntej thiab cov lus pom zoo rau kev kawm ntxiv ntawm cov ncauj lus no.
Suab puam nyob cistanche-Anti Alzheimer's kab mob
Ntsiab lus
Lub plab microbiome, Amyloid, Tau, Neuroinflammation, Peripheral immunity, Tib neeg, Nas, Kev kho mob, noj zaub mov, pw tsaug zog, qoj ib ce
Keeb kwm
Alzheimer's disease (AD) yog ib qho kev puas siab puas ntsws neurodegenerative uas yog feem ntau ua rau dementia thiab tam sim no muaj ob peb qhov kev kho mob zoo-kho kho mob [1]. Txhawm rau tsim kho cov kab mob-hloov kho, nws yog qhov tsim nyog kom nkag siab zoo dua cov txheej txheem ntawm kev pib kab mob thiab kev loj hlob. Cov kab mob pathological ntawm AD muaj xws li senile plaques tsim los ntawm amyloid beta (A) peptides, neurofibrillary tangles muaj li ntawm hyperphosphorylated cov ntaub ntawv ntawm microtubule-txuas nrog tau protein, thiab neuroinflammation uas ua rau neurodegeneration [1]. Neuroinflammation tau txuas nrog kev txhim kho thiab kev loj hlob ntawm cov kab mob pathologies. Lub plab microbiome (GMB) yog suav nrog trillions ntawm cov kab mob, archaea, protozoa, kab mob, thiab cov fungi thiab tau pom tias muaj peev xwm tswj tau cov kab mob neuroinflammation hauv ntau yam mob paj hlwb, suav nrog Ntau Yam Sclerosis [2], Parkinson's disease [3, 4] , thiab AD [5–8].
GMB-mediated regulation ntawm neuroinflamation tej zaum yuav tshwm sim los ntawm ncaj qha los yog indirect mechanisms (Fig. 1). Kev hloov pauv hauv GMB tuaj yeem hloov pauv cov metabolites los ntawm microbial thiab peripheral tiv thaiv kab mob, uas tuaj yeem hloov pauv CNS lub cev tiv thaiv kab mob hauv cov ntsiab lus ntawm cov kab mob neurological (Fig. 1) [9]. Thaum cov kev tshawb fawb tsis ntev los no qhia tias cov neeg mob AD muaj qhov hloov pauv GMB piv nrog cov uas tsis muaj AD [10, 11], thiab kev ua haujlwm rau GMB hauv cov qauv nas ntawm AD tuaj yeem hloov pauv pathology thiab neuroinflammation [5-8, 12-14], cov txheej txheem meej los ntawm uas GMB cuam tshuam AD tseem yuav tsum tau piav qhia. Hauv kev tshuaj xyuas no, peb sau cov kev tshawb fawb hauv cov neeg mob AD thiab cov qauv nas ntawm A amyloidosis uas cuam tshuam rau GMB hauv AD pathogenesis (Daim duab 1). Tsis tas li ntawd, peb qhia txog cov neeg muaj peev xwm kho kom haum xeeb ntawm kev sib raug zoo ntawm GMB thiab AD uas xav tau kev kawm ntxiv. Peb kuj tham txog cov tswv yim kho mob microbiome-mediated rau AD uas tuaj yeem hloov kho tus kab mob. Thaum kawg, peb sib tham txog yav tom ntej ntawm GMB kev tshawb fawb hauv AD thiab cov cuab yeej tseem ceeb uas yuav tsum tau ua kom nce qib mus rau lub hom phiaj ntawm kev qhia meej txog lub luag haujlwm ntawm GMB hauv AD.
Cov txiaj ntsig ntawm cistanche tubulosa-Anti Alzheimer tus kab mob
Tib neeg pov thawj ntawm GMB kev hloov pauv hauv AD
Ob qhov kev tshawb fawb thawj zaug hauv 2017 tau pom tias cov tib neeg zoo amyloid / AD cov neeg mob tau hloov pauv GMB piv rau cov tib neeg tsis muaj amyloid / AD. Cattaneo thiab cov npoj yaig (N=83 tag nrho, 40 amyloids zoo nrog kev paub tsis meej, 33 amyloid tsis zoo nrog kev paub tsis meej, 10 amyloid tsis zoo yam tsis muaj kev paub tsis meej) ntsuas ntshav qib ntawm RNAs encoding xaiv cytokines thiab cov quav ntau ntawm Erichsche se (GMBia). /Shigella, Pseudomonas aeruginosa, Eubacterium rectale, Eubacterium hallii, Faecalibacterium prausnitzii, Bacteroides fragilis) siv qPCR le caag (Table 1) [10]. Cov kev tshawb fawb no tau nthuav tawm qhov nce hauv mRNA encoding pro-inflammatory cytokines IL6, CXCL2, NLRP3, thiab IL1 thiab txo qis hauv mRNA encoding anti-inflammatory cytokine IL-10 hauv cov neeg mob amyloid-zoo piv nrog cov neeg amyloid-tsis zoo. Ib qho kev sib raug zoo tau pom ntawm cov pro-inflammatory cytokines thiab Escherichia / Shigella (uas yav tas los cuam tshuam nrog cov tshuaj tiv thaiv kab mob) thiab qhov cuam tshuam tsis zoo nrog Eubacterium rectale (uas yav tas los cuam tshuam nrog cov tshuaj tiv thaiv kab mob). Tsis tas li ntawd, Vogt thiab cov npoj yaig (N=50 tag nrho, 25 AD, 25 kev tswj kev noj qab haus huv), ua tsis ncaj ncees rau 16 s ribosomal RNA amplicon sequencing ntawm DNA cais tawm ntawm cov quav los ntawm cov neeg mob AD nrog dementia thiab noj qab haus huv lub hnub nyoog thiab kev sib deev tswj cov ntsiab lus. (HC) (Table 1) [11]. Ntawm no, qhov txo qis ntawm GMB kab mob sib txawv tau pom hauv cov neeg mob AD, nrog rau kev txo qis hauv Firmicutes thiab Bifidobacterium thiab nce qib ntawm Bacteroidetes piv nrog HC. Txij li thaum cov kev tshawb fawb thawj zaug no, ob qho kev tshawb fawb los ntawm cov pab pawg hauv Suav teb kuj pom muaj kev hloov pauv hauv GMB ntawm cov neeg mob AD thiab HC [15, 16]. Zhuang et al. (N=86, 43 AD, 43 tswj kev noj qab haus huv) pom qhov txo qis hauv Bacteroidetes thiab nce hauv Actinobacteria hauv cov neeg mob AD piv nrog HCs (Table 1) [15]. Liu et al. (N=97 tag nrho, 33 AD, 32 MCI, 32 kev noj qab haus huv tswj) pom qhov txo qis hauv Firmicutes thiab nce hauv Proteobacteria hauv cov neeg mob AD piv nrog cov tswj (Table 1) [16]. Ua ke, cov txiaj ntsig los ntawm cov kev tshawb fawb no qhia tias GMB muaj pes tsawg leeg tau hloov pauv hauv cov neeg mob AD thiab qhov kev hloov GMB tuaj yeem cuam tshuam rau kev nce qib ntawm AD. Txawm li cas los xij, cov kev tshawb fawb no yog kev sib raug zoo thiab cov txiaj ntsig los ntawm tib neeg AD microbiome-mediated therapeutic kev sim tshuaj ntsuam xyuas yuav tsum tau soj ntsuam seb qhov kev hloov pauv hauv GMB ncaj qha cuam tshuam rau AD pathogenesis. Tsis tas li ntawd, zoo li muaj kev pom zoo me ntsis ntawm cov kab mob phyla uas tau hloov pauv hauv cov neeg mob AD hauv cov kev tshawb fawb no. Ntxiv mus, cov neeg mob thiab kev tswj hwm hauv cov kev tshawb fawb luam tawm yog me me (<50 participants/group) and several confounding factors might influence patient GMB composition including geographical location, diet, and environmental exposures. To resolve these confounding issues, we propose that it will be critical to carry out a large, international study that assesses GMB composition between age and sex-matched AD patients (preferably divided by MCI/AD stage) and HCs. It will also be important that stool collection protocols are standardized, and stool consistency is accounted for as this can alter GMB composition results [17].
Cov ntaub ntawv pov thawj ntawm GMB kev hloov pauv hauv AD nas qauv thiab cov teebmeem ntawm GMB manipulations ntawm pathology
Hloov hauv AD nas GMB
Raws li kev hloov pauv ntawm GMB muaj pes tsawg leeg pom hauv cov neeg mob AD, qhov sib txawv ntawm GMB kuj tau pom hauv AD nas qauv, suav nrog 5XFAD [18, 19], APPSwe/PSEN1dE9 (APP/PS1) [20–23], thiab APPSwe/PSEN1L166P (APPPS1-21) [14] qauv piv nrog cov nas qus (Table 2). Brandscheid et al. (2017) qhia txog kev nce hauv Firmicutes thiab txo qis hauv Bacteroidetes phyla ntawm 9 lub lis piam hauv 5XFAD nas piv rau cov nas qus (Table 2) [18]. Ntawm qhov tsis sib xws, Chen et al. (2020) qhia txog qhov txo qis hauv Firmicutes thiab nce Bacteroidetes phyla ntawm 3 lub hlis hauv 5XFAD nas piv nrog cov nas qus (Table 2). Thaum 6 lub hlis, muaj qhov nce hauv Bacteroidetes, Proteobacteria, thiab Deferribacteres [19]. Tsis tas li ntawd, qhov txo qis hauv alpha ntau haiv neeg tau pom [19]. Shen et al. (2017) qhia GMB hauv 3, 6, thiab 8-hli APP/PS1 nas. Cov hnub nyoog-raws li kev hloov pauv hauv GMB uas cuam tshuam nrog amyloid pathology tau pom: nce hauv Odoribacter thiab Helicobacter genera thiab txo qis hauv Prevotella hom (Table 2). Tsis tas li ntawd, qhov txo qis hauv hnub nyoog ntawm GMB ntau haiv neeg kuj tau pom [20]. Chen et al. (2020) tau soj ntsuam GMB cov ntaub ntawv hauv 1, 2, 3, 6, thiab 9-hli APP/ PS1 nas (Table 2). GMB hloov pauv hauv APP/PS1 nas tau pom thaum ntxov li 1 lub hlis thiab nce ntxiv raws sijhawm. Ntawm no, kev nce ntxiv hauv Escherichia-Shigella, Desulfovibrio, Akkermansia, thiab Blautia hauv APP/PS1 nas tau pom nyob rau lub sijhawm [21]. Nyob rau hauv Zhang et al. (2017), Verrucomicrobia thiab Proteobacteria tau pom tias tau nce ntxiv hauv 8–rau 12-hli APP/PS1 nas (Table 2). Txawm li cas los xij, Ruminococcus thiab Butyricicoccus tau txo qis hauv 8–{58}}hli APP/PS1 nas piv nrog cov nas qus. Interestingly, ob peb luv-chain fatty acids (SCFAs) tau txo qis hauv cov quav thiab lub hlwb ntawm APP/PS1 nas piv nrog cov nas qus [22]. Cuervo-Zanata et al. (2021) qhia txog kev sib deev tshwj xeeb hloov pauv hauv APP/PS1 nas piv nrog cov nas qus. Kuj ceeb tias, txiv neej APP / PS1 nas muaj kev hloov pauv loj dua hauv lawv cov GMB profiles piv nrog cov poj niam [23]. Harach et al. (2017) tau tshaj tawm qhov nce ntxiv hauv Bacteroidetes thiab Tenericutes thiab txo qis hauv Firmicutes, Verrucomicrobia, thiab Proteobacteria ntawm 8 lub hlis hauv APPPS1-21 nas piv nrog cov nas qus [14]. Zuag qhia tag nrho, cov kev tshawb fawb no qhia tias muaj feem yuav muaj hnub nyoog thiab kev sib deev-raws li kev hloov pauv hauv GMB muaj pes tsawg leeg thiab ntau haiv neeg ntawm cov qauv nas ntawm A amyloidosis thiab lawv cov tsiaj qus-hom counterparts. Thaum muaj kev txaus siab, muaj qhov tsis txaus ntseeg hauv kev sim ua kom paub tseeb qhov tseem ceeb ntawm cov kab mob tshwj xeeb thiab cov kev hloov pauv hauv kev sib xyaw vim tias cov tsiaj ua qauv thiab cov tsiaj qus-hom counterparts uas nyob hauv cov chaw sib txawv nas, muab cov khoom noj sib txawv, thiab muaj cov keeb kwm sib txawv. feem ntau yeej muaj qhov sib txawv GBMs nyob rau hauv cov cheeb tsam nas.
Fig. 1 (Saib cov lus dab neeg ntawm nplooj ntawv dhau los.)
Table 1 Cov kab mob hloov pauv hauv tib neeg cov neeg mob AD piv rau kev tswj hwm
Table 2 Cov kab mob hloov pauv hauv AD nas qauv piv rau kev tswj hwm
Amyloidosis
Ntxiv rau qhov kev ntsuam xyuas ntawm GMB muaj pes tsawg leeg ntawm AD nas qauv thiab cov nas qus, ntau qhov kev tshawb fawb tau hloov GMB hauv AD nas qauv, feem ntau yog siv cov tshuaj tua kab mob (abx) lossis cov nas nyob hauv thaj chaw tsis muaj kab mob uas cov nas yog devoid ntawm microbes thiab yog li ntawd tsis tsim GMB. Abx tau pom nyob rau hauv ntau tus qauv AD nas los hloov GMB muaj pes tsawg leeg, suav nrog APP/PS1 [5, 6], APPPS1-21 [7, 8, 24], 5XFAD [12, 25, 26], thiab APPNL -G-F [27] cov. Piv txwv li, Minter et al. (2016) [5] nthuav tawm cov nas nyob nruab nrab ntawm P14-P21 nrog cov koob tshuaj ntau ntawm broad spectrum abx cocktail thiab pom qhov hloov pauv hauv GBM muaj pes tsawg leeg nrog kev nce hauv Akkermansia thiab Lachnospiracea thaum muaj hnub nyoog 6 lub hlis piv nrog kev kho tsheb tswj. Qhov tseem ceeb, kev hloov kho Abx hauv GMB muaj pes tsawg leeg yuav tsum muaj abx cocktail, vim tus neeg abx tsis zoo ntawm kev hloov GMB muaj pes tsawg leeg lossis amyloidosis [24]. Ntxiv mus, abx siv nyob rau hauv lub cocktail tsis hla cov ntshav-hlwb barrier, yog li qhia tau hais tias cov teebmeem ntawm A amyloidosis yog kho los ntawm GMB es tsis yog los ntawm cov teebmeem ncaj qha hauv lub hlwb [5–8, 12, 19, 24]. Tsis tas li ntawd, peb txoj kev tshawb fawb tau muab los ntawm APPPS1-21 [13, 14] thiab 5XFAD nas [12] nyob rau hauv cov kab mob tsis muaj kab mob, qhov twg cov nas tsis muaj GMB, thiab muab piv rau cov tsiaj txhu uas tau tsa los uas muaj GMB tsis zoo. GMB perturbation kev tshawb fawb hauv AD qauv tau pom tias kev tswj hwm ntawm GMB nrog abx ua rau txo qis ntawm A deposition tsis hais tus qauv [5–8, 12, 19, 24, 25, 27]. Qhov kev txo qis hauv A deposition (thiab insoluble A qib) tau raug lees paub siv qhov ntau ntawm cov tshuaj tiv thaiv kab mob, western blotting, enzyme-linked immunosorbent assay (ELISA), thiab Meso scale discovery (MSD) assay. Qhov tseem ceeb, qhov txo qis hauv amyloid deposition yog poj niam txiv neej thiab tsuas yog tshwm sim hauv cov txiv neej hauv APPPS1- 21 thiab APP/PS1 nas qauv [7, 8]. Muaj ntau qhov laj thawj rau cov txiaj ntsig ntawm kev sib deev tshwj xeeb uas xav tau kev tshawb nrhiav ntxiv. Piv txwv li, qhov sib txawv ntawm GMB-hormone kev sib cuam tshuam [28, 29] nrog rau qhov sib txawv ntawm kev tiv thaiv kab mob ntawm poj niam txiv neej [30] yuav yog lub luag haujlwm. Qhov tseem ceeb, nws tau raug tshaj tawm tias kev tswj hwm ntawm kev hloov pauv fecal teeb meem (FMT) los ntawm cov tsis-abx kho amyloid qauv nas mus rau hauv kev kho amyloid qauv nas rov kho lawv GMB thiab A pathology, qhia tias GMB perturbations yog qhov tseeb ua rau muaj kev hloov pauv hauv amyloidosis uas tsis yog- abx cov teebmeem ntawm amyloidosis [7, 8]. Qhov kev txo qis rau hauv cov tshuaj amyloid zoo ib yam nrog cov kev hloov pauv hauv cov nas tsis muaj kab mob [12–14]. Cov nas tsis muaj kab mob kuj muaj qhov txo qis hauv amyloid beta pathology, tab sis kuj ceeb tias, cov nyhuv no tsis yog kev sib deev [12–14]. Cov txheej txheem los ntawm kev kho abx txo qis A pathology hauv cov txiv neej tab sis tsis yog poj niam, tsis paub txog qhov sib npaug ntawm amyloid hauv GF nas, tsis paub. Txawm li cas los xij, cov pov thawj tsis ntev los no qhia tau hais tias lub cev tiv thaiv kab mob thiab microglia hauv GF nas yog nyob rau hauv lub xeev tsis paub tab thiab qhov sib txawv ntawm biology ntawm microglia hauv txiv neej thiab poj niam tau tsa hauv SPF vs GF cov xwm txheej yuav txawv heev. Hauv qhov no, Tion et al. (2018) [31] tau tshaj tawm tias cov microbiota cuam tshuam rau kev xeeb tub thiab cov neeg laus microglia hauv kev sib deev tshwj xeeb. Txhawb nqa cov kev tshawb pom no, Gunekaya li al. (2018) [32] tau tshaj tawm tias muaj qhov sib txawv ntawm kev hloov pauv thiab kev txhais lus sib txawv hauv microglia hauv hlwb ntawm cov txiv neej thiab poj niam tsiaj. Ib qho tseem ceeb ntawm cov tsiaj kho nrog GF tsiaj yog qhov sib piv rau cov tsiaj txhu GF uas tsis muaj GBM, abx tsis tas yuav ua rau GBM depletion tab sis theej rau kev hloov pauv ntawm cov kab mob sib xyaw thiab ntau haiv neeg. Qhov tseem ceeb, thaum GF nas recolonized nrog microbiota, amyloid pathology tau rov qab los [13, 14]. Lub tshuab uas GMB cuam tshuam rau amyloidosis zoo li tsis muaj kev hloov pauv hauv amyloid beta ua tshuab, zoo li muaj qhov tsawg kawg nkaus ntawm lub hlwb hloov hauv amyloid precursor protein (APP) lossis beta-secretase 1 (BACE1) ntawm rau-kho nas lossis GF. cov nas thiab cov kab ke uas tsis kho nas [5, 6, 14]. Tshwj xeeb, Harach et al. (2017) tau tshaj tawm tias cov qib ntawm A degrading enzymes, xws li neprilysin thiab insulin-degrading enzymes tau nce hauv GF APPPS1-21 nas piv rau cov pa hauv tsev APPPS1-21 nas [14], thiab yog li, nws Nws yog qhov tseeb tias qhov nce hauv A degrading enzymes tuaj yeem ua lub luag haujlwm rau GF thiab abx kho kom txo qis hauv amyloid pathology.
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Neuroinflamation
Nws tau pom tsis tu ncua tias abx lossis GF-mediated GMB depletion lossis tsis tuaj, raws li, hauv cov qauv amyloidosis ua rau muaj kev hloov pauv hauv microglial inflammatory xeev [5–7, 12–14, 24]. Ntau qhov kev tshawb fawb tau pom tias thaum lub sijhawm cev xeeb tub, microglia tshwm sim los ua tsis tshua muaj kev mob thiab ntau phagocytic raws li tau txiav txim los ntawm RNAseq thiab microglial morphological tsom xam hauv cov ntsiab lus ntawm abx-mediated compositional hloov hauv GMB [6, 7, 24]. Tshwj xeeb, APP / PS1 nas kho nrog abx tau txo cov quav hniav nrog microglia thiab hloov kho microglial morphology uas microglia tau nce cov txheej txheem ntev thiab tus lej, zoo ib yam nrog ntau lub xeev homeostatic [6, 7, 24]. APPPS1-21 nas kho nrog tshuaj tua kab mob muaj qhov zoo sib xws microglial phenotype li abx-kho APP/PS1 nas, thiab tej RNAseq kuj tau qhia tias cov microglia no muaj qhov txo qis hauv microglial cell activation los ntawm gene ontology tsom [7, 8]. Qhov tseem ceeb, kev hloov microglial tau rov qab los thaum abx-kho nas tau muab FMT los ntawm cov nas tsis kho [7, 8]. Ua ke, cov txiaj ntsig no qhia tias microglia nyob rau hauv cov ntsiab lus ntawm abx yuav plam kev ua haujlwm tsis zoo, ua kom zoo dua ntawm phagocytosis, thiab tej zaum yuav yog ib feem ntawm cov txheej txheem uas abx ua rau txo qis hauv amyloid. Lwm daim ntawv pov thawj uas txhawb nqa qhov kev xav no yog tias thaum colony-stimulating factor 1 receptor (CSF1R) antagonists tau muab rau abx-kho nas kom deplete microglia, abx-mediated txo nyob rau hauv amyloid pathology tsis tshwm sim [8]. Qhov no qhia tau hais tias microglia yog ib qho tseem ceeb rau abx-mediated txo nyob rau hauv amyloid pathology. Microglia kuj tseem cuam tshuam rau cov kab mob tsis muaj kab mob AD cov nas piv rau AD nas uas nyob hauv tsev. Harach thiab cov npoj yaig [14] tau pom tias GF APPPS1-21 nas tau txo cov ionized calcium-binding adapter 1 (Iba1) + microglia nyob rau hauv lub hlwb ntawm 3.5 thiab 8 lub hlis piv rau cov nas nyob hauv tsev [14]. Hauv qhov sib piv, Mezo thiab cov npoj yaig [12] pom qhov nce hauv Iba1+microglia hauv GF 5XFAD nas nyob rau hauv hippocampus thaum muaj hnub nyoog 4 hli piv rau 4-hli cov nas nyob hauv tsev. Microglial bulk RNAseq tau nthuav tawm qhov kos npe rau microglial hauv GF 5XFAD cov nas uas muaj kev txhawb nqa ntawm Apoe, Trem2, Axl, Cst7, Cd9, Itgax, thiab Clec7a thiab downregulation ntawm P2ry12. Thaum kawg, GF 5XFAD nas tau muaj txiaj ntsig zoo dua microglial phagocytosis ntawm A piv rau cov nas uas tau tsa los ua ke [12]. Colombo thiab cov npoj yaig siv GF APPPS1-21 nas los qhia tias GMB-los ntawm SCFAs tswj microglial transcriptomic xeev [13]. Thaum GF APPPS1-21 muaj qhov txo qis hauv SCFAs, plaque-associated microglia, thiab A plaques, kev tswj hwm ntawm SCFAs hauv GF APPPS1-21 cov nas ua rau muaj kev nce hauv cov quav hniav nrog microglia thiab A plaques. Nanostring transcriptomic tsom xam tau nthuav tawm ib lub xeev activated microglial, tus cwj pwm los ntawm kev nthuav tawm ntau cov noob hauv APOE-TREM2 txoj hauv kev hauv SCFA-kho GF APPPS1-21 nas. Cov txiaj ntsig no qhia tias SCFAs tau los ntawm plab hnyuv microglial xeev uas tuaj yeem hloov kho A plaques hauv lub hlwb [13]. Thaum cov nas tsis muaj kab mob yog cov qauv tsim nyog rau kev kawm GMB kev pab cuam rau cov kab mob, lawv muaj lub caveat tias lawv muaj ntau yam kev loj hlob tsis xws luag uas yuav cuam tshuam rau tus kab mob phenotype thiab tej zaum yuav tsis muaj feem cuam tshuam [33–35]. Peripheral [36] thiab hauv nruab nrab lub cev tsis muaj zog [34], neurotransmission [37], thiab neurogenesis [38] tuaj yeem hloov pauv los ntawm GF cov xwm txheej thiab tuaj yeem cuam tshuam kev tshawb fawb siv cov qauv no. Nws yog ib qho tseem ceeb los muab GF-raws li GMB manipulation nrog lwm yam tsawg dua GMB manipulations kom paub tseeb qhov tseem ceeb ntawm kev tshawb pom rau tus qauv kab mob. Ntxiv nrog rau microglia, astrocytes yog lwm hom cell hauv lub hlwb uas koom nrog hauv lub cev tiv thaiv kab mob. Cov nyhuv ntawm GMB manipulation ntawm reactive astrocyte modulation nyob rau hauv AD tsis tau tshawb fawb ntau. Cov ntaub ntawv pov thawj tsis ntev los no los ntawm peb pab pawg qhia tias GMB perturbations ntawm abx thiab tsis muaj kab mob ib puag ncig hauv APPPS1-21 nas qauv ntawm amyloidosis txo GFAP + reactive astrocytosis, astrocyte ntxiv C3 qhia, astrocyte recruitment rau amyloid plaques, thiab hloov astrocyte morphology hauv txiv neej nas. FMT los ntawm kev kho tsis tau APPPS1-21 nas mus rau abx-kho APPPS1- 21 nas rov kho cov kev hloov astrocytic uas qhia tias GMB yog qhov tseeb tswj GFAP + astrocyte reactivity rau amyloid plaques [39]. Nyob rau hauv cov ntsiab lus ntawm Ntau Sclerosis (MS), nws tau pom tias cov plab hnyuv metabolites, xws li derivatives ntawm tryptophan (indole, indoxyl-3-sulfate, indole-3-propionic-acid, indole{{92} }}aldehyde) tuaj yeem hloov kho astrocyte reactivity ncaj qha [40]. Rothhammer et al. (2016) tau qhia tias plab-derived tryptophan metabolites tuaj yeem nce aryl hydrocarbon receptor (Ahr) signaling, uas tuaj yeem cuam tshuam astrocytic o hauv EAE qauv ntawm MS [40]. Tsis tas li ntawd nyob rau hauv MS, cov metabolites gut-derived tuaj yeem hloov cov noob qhia hauv lwm lub hlwb CNS, xws li microglia [41] lossis meningeal natural killer (NK) hlwb [42], uas nyob rau hauv lem, tuaj yeem tswj astrocyte reactivity. Lwm txoj kev tshawb fawb los ntawm Rothhammer et al. (2018) tau pom tias tryptophan metabolites hauv plab tuaj yeem hloov kho TGFɑ thiab VEGF-B signaling hauv microglia ntawm Ahr. Cov kev taw qhia no ces tswj lub astrocytic inflammatory xeev. Sanamarco et al. (2021) pom tias GMB tswj kev qhia ntawm IFN- hauv NK hlwb. NK-derived IFN- tswj lub induction ntawm LAMP{107}} TRAIL+ astrocytes, uas induce pro-inflammatory T-cell apoptosis. Tsis tas li ntawd, SCFAs hauv vitro tuaj yeem hloov kho astrocytic gene qhia hauv kev sib deev-raws li [43]. Qhov kev sau ntawm cov kev tshawb fawb no qhia tias GMB muaj peev xwm cuam tshuam rau astrocyte phenotype.
Vim tias astrocytes yog phagocytic hlwb, muaj kev tiv thaiv kab mob, thiab tuaj yeem pab txhawb rau neurodegeneration [44], amyloid [45–48], thiab tau deposition thiab kis [49, 50], nws zoo li GMB-tswj astrocytes tseem ceeb hauv AD. Yog li ntawd, yuav tsum tau ua hauj lwm ntau ntxiv kom nkag siab txog qhov tseem ceeb ntawm GMB-mediated tswj ntawm astrocytosis hauv AD thiab seb GMB-astrocyte axis puas tuaj yeem kho tau.
GMB thiab Ntshav-hlwb barrier / Peripheral tiv thaiv
BBB kev puas tsuaj hauv cov kab mob neurodegenerative yuav yog qhov tseem ceeb rau GMB thiab kev koom tes ntawm cov kab mob peripheral. Tom qab BBB tawg lawm, peripheral immune cells, cytokines, thiab metabolites tuaj yeem nkag mus rau hauv lub hlwb yooj yim dua thiab muaj kev cuam tshuam rau cov hlwb hauv hlwb thiab kev loj hlob ntawm neuropathological [51]. Thaum qhov kev sib txuas ntawm GMB, cov ntshav-hlwb teeb meem, thiab AD tsis tau tsim zoo, muaj kev tshawb fawb qhia tias GMB tuaj yeem tswj BBB permeability los ntawm GMB-derived metabolites [52, 53]. Ib txoj kev tshawb fawb tau pom tias cov nas tsis muaj kab mob tau nce BBB permeability vim tias txo qis ntawm cov protein sib txuas hauv lub cev thaum cev xeeb tub uas pheej mus rau cov neeg laus. Recolonization ntawm cov kab mob tsis muaj kab mob nrog cov pa nas rau kev hloov pauv cov teebmeem no. Tsis tas li ntawd, SCFAs tuaj yeem hloov kho qhov kev nthuav qhia ntawm cov nqaij sib txuas nruj heev, qhia tias GMB hloov pauv hauv SCFA ntau lawm yog cov txheej txheem uas BBB permeability hloov pauv [52]. Lwm txoj kev tshawb fawb tau pom tias qhov sib txawv ntawm GMB-derived metabolite, methylamine trimethylamine N-oxide (TMAO), muaj peev xwm txhim kho BBB kev ncaj ncees los ntawm kev hloov pauv cov lus qhia ntawm annexin A1, cov protein sib txuas nruj. TMAO kuj tseem tuaj yeem txwv LPS-mediated memory impairment los ntawm kev txwv microglial thiab astrocyte-mediated neuroinflammation [53]. Ua ke, cov kev tshawb fawb no qhia tias GMB, los ntawm cov metabolites, tuaj yeem cuam tshuam BBB kev ncaj ncees. BBB kev puas tsuaj tau sau tseg zoo hauv AD, yog li nws muaj peev xwm hais tias GMB dysbiosis tuaj yeem hloov kho cov txheej txheem no thiab ua rau BBB tawg ntau dua. Txawm li cas los xij, kev tshawb fawb ntxiv yog xav tau kom nkag siab ntau dua qhov txuas ntawm GMB, BBB, thiab AD.
Hais txog yuav ua li cas GMB perturbation hloov lub peripheral tiv thaiv kab mob hauv AD qauv, Minter li al. qhia txog kev nce ntshav plasma CCL11, IL1 , IL2, IL3, thiab qia cell factor (SCF) thiab txo IL6 hauv APP/PS1 nas kho nrog rau rau piv rau kev tswj [6]. Tsis tas li ntawd, kev nce hauv kev tswj hwm T hlwb (T-regs) hauv cov ntshav thiab lub hlwb tau pom nyob rau hauv cov nas uas tau kho nrog rau kev tswj hwm [6]. Txawm li cas los xij, tsis muaj qhov sib txawv tseem ceeb hauv CD4 lossis CD8 T-cells [6]. T-regs paub tias txo qhov mob [54], uas yuav ua raws li qhov txo qis neuroinflammation uas tau pom thoob plaws AD qauv hauv cov ntsiab lus ntawm abx lossis GF nas [5–8, 12–14]. Lwm txoj kev tshawb fawb tau pom tias qhov sib txawv ntawm cytokine hauv cov ntshav ntawm 6-kho APPPS1-21 nas yog poj niam txiv neej [7]. Abx-kho txiv neej APPPS1-21 nas tau nce cov ntshav plasma los tiv thaiv cytokines, xws li insulin-zoo li kev loj hlob zoo tshaj plaws khi protein 3, IL6, thiab IL10, thiab txo qis pro-inflammatory cytokines, xws li eotaxin1, IL{{33 }} , IL2, IL3, IL17a, thiab CCL5 piv rau cov tswj. Cov kev hloov peripheral no tau cuam tshuam nrog txo qis A plaque deposition thiab microglial activation nkaus xwb nyob rau hauv txiv neej nas nyob rau hauv lub hlwb [7]. Txawm li cas los xij, poj niam abx-kho nas muaj qhov nce ntxiv hauv cov cytokines, suav nrog IL1, IL5, IL9, thiab IL17a. Tsis tas li ntawd, lwm txoj kev tshawb nrhiav pom qhov txo qis hauv T1+cov cell hauv lub hlwb tom qab kev kho abx hauv 5XFAD nas. Qhov no kuj tseem cuam tshuam nrog txo qis microglial activation. Tsis tas li ntawd, FMT los ntawm 5XFAD nas mus rau WT nas nrog hippocampal A txhaj nce T1+cells hauv hlwb thaum txo T2+cells [55]. Lwm txoj kev tshawb nrhiav pom qhov txo qis hauv IFN- , IL2 , IL1 , thiab IL5 hauv cov ntshav ntawm GF APPPS1-21 cov nas piv rau cov nas nyob hauv tsev [14]. Lwm cov kws tshawb fawb tau pom tias FMT tau rov qab kho qhov txo qis hauv abx-mediated hauv kev loj hlob ntawm fibroblast (bFGF) thiab granulocyte-macrophage colony-stimulating factor (GM-CSF) [8]. Zuag qhia tag nrho, cov kev tshawb fawb no qhia tias muaj plasma cytokine thiab peripheral immune cell hloov hauv GMB perturbed xeev hauv amyloidosis qauv. Txawm li cas los xij, muaj qhov sib txawv ntawm cov kev tshawb fawb ntawm cov cytokines tshwj xeeb tau hloov pauv. Ntau qhov kev nkag siab thiab tsis ncaj ncees yog xav tau los daws qhov sib txawv ntawm cov kev tshawb fawb. Nws yuav tsum tau muab sau tseg tias ntau ntawm cov kev tshawb fawb cytokine tau tham saum toj no yog ua raws li membrane-based cytokine arrays, uas tsuas yog ib nrab-quantitative [5-8], thiab yav tom ntej daim ntawv lo-dawb proteomic/mass spectrometry mus kom ze ntawm fractioned plasma yuav tsim nyog. soj ntsuam tag nrho cov repertoire ntawm soluble yam uas yog modulated los ntawm GMB.
Cov txiaj ntsig ntawm cistanche tubulosa-Anti Alzheimer's kab mob
Vagus nerve-mediated kev sib txuas ntawm plab thiab lub hlwb
Thaum cov khoom lag luam zais cia, xws li cov khoom noj uas tau los ntawm cov plab hnyuv yuav tuaj yeem kho qhov kev sib txuas ntawm plab-hlwb, kuj tseem muaj kev sib txuas ncaj qha ntawm cov hlab ntsha vagus [56]. Cov paj hlwb vagus yog cov paj hlwb ntev tshaj plaws hauv lub cev thiab nthuav tawm ntawm txoj hnyuv loj mus rau lub hlwb. Nws yog ib qho tseem ceeb nyob rau hauv involuntary parasympathetic tswj kev zom, lub plawv dhia, ua pa, thiab lwm yam tseem ceeb functions. Cov hlab ntsha vagus tso cai rau kev sib txuas lus bidirectional ntawm lub plab thiab lub hlwb thiab muaj 80% afferent thiab 20% efferent fibers. Tus, microbiota-derived molecules tuaj yeem cuam tshuam rau lub paj hlwb firing thiab qee qhov ntawm cov molecules tuaj yeem mus rau lub hlwb ntawm cov hlab ntsha vagus [56]. Ntau pawg kab mob taxonomic uas tuaj yeem tsim cov APPNL-G-F tau muab VSL # 3, tsis muaj kev hloov pauv hauv A , glial fibrillary acidic protein (GFAP), Iba1, lossis cov cim proliferative, Ki-67. Qhov tshwm sim no tuaj yeem yog vim 6 lub hlis tuaj yeem lig dhau los pib kho cov kab mob probiotic hauv APPNL-G-F tus qauv uas pathology twb mob hnyav heev thaum muaj hnub nyoog [85, 86]. Hauv kev sib piv, Abdelhamid et al. (2022) tau qhia tias 3-hli APPNL-G-F nas kho nrog Bifidobacterium breve rau 4 lub hlis tau txo A , Iba1, thiab cov cytokines pro-inflammatory, nrog rau nce ADAM10 thiab synaptic proteins [87]. Lub hnub nyoog dhau los ntawm kev kho mob tuaj yeem piav qhia qhov txawv ntawm cov txiaj ntsig piv rau Kaur li al. [85, 87] ib. Ib daim ntawv tshaj tawm ua ntej los ntawm tib pab pawg no tau pom tias txo qis hauv kev tiv thaiv kab mob los ntawm ntau RNAseq hauv Bifidobacterium breve-kho nas txhaj nrog A piv rau kev tswj tsheb [88]. Hauv lwm txoj kev tshawb fawb, Asl et al. (2019) kho A - txhaj nas nrog probiotics (Lactobacillus acidophilus, Bifdobacterium bifdum thiab Bifdobacterium longum) lossis tsheb [89]. Cov neeg tshawb xyuas no tau tshaj tawm tias cov nas uas kho cov kab mob probiotic ua tau zoo dua hauv Morris dej tshawb nrhiav piv rau cov nas tsuag hauv tsheb. Tsis tas li ntawd, cov nas kho tsheb tau txwv LTP uas tau rov qab los nrog probiotics [89]. Ib khub ntawm cov ntaub ntawv los ntawm Bonfli li al. pom cov txiaj ntsig zoo ntawm SLAB51 (Streptococcus thermophilus, Bifdobacteria longum, Bifdobacteria breve, Bifdobacteria infantis, Lactobacilli acidophilus, Lactobacilli plantarum, Lactobacilli paracasei, Lactobacilli delbrueckulii subspill, {3} kev kho mob. - qub 3xTg nas rau 4 lub hlis [90–92]. SLAB51 kev kho mob txhim kho kev ua tau zoo ntawm cov khoom tshiab paub txog kev sim, txo lub hlwb puas, txo A plaques, nce SCFAs, thiab txo cov ntshav cytokine qib [90]. Lwm txoj kev tshawb fawb los ntawm tib pab pawg tau pom tias SLAB51 tuaj yeem muaj kev tiv thaiv los ntawm kev nce Sirtuin-1, protein deacetylase, uas tuaj yeem tiv thaiv cov hlwb los ntawm oxidative stress [91]. Probiotics kuj tseem tuaj yeem ua ke nrog lwm cov kev kho mob zoo, xws li kev tawm dag zog. Abraham et al. (2019) tau pom tias cov tshuaj probiotic (Bifidobacterium longus, Lactobacillus acidophilus, vitamin A, vitamin D, omega 3 fatty acids nyob rau hauv cov roj ntsha cod, thiab cov vitamins B1, B3, B6, B9, B12) ua ke nrog kev tawm dag zog A thiab nce kev txawj ntse. kev ua tau zoo ntawm APP/PS1 nas nyob rau hauv Morris dej maze [93]. Cao et al. (2021) tau qhia tias 4-hli APP/PS1 nas tau kho nrog Bifidobacterium lactic Probio-M8 rau 45 hnub tau pom tsawg dua A plaques, muaj kev hloov pauv ntawm lawv cov GMB muaj pes tsawg leeg, thiab nce kev txawj ntse hauv kev sim Y-maze [94]. Ntxiv nrog rau probiotics, prebiotics kuj tau pom tias muaj txiaj ntsig zoo hauv amyloid qauv ntawm AD. Liu et al. (2021) kho 5XFAD nas nrog prebiotic mannan oligosaccharide rau 8 lub lis piam txij thaum yug los thiab pom tias nws txo qis kev txawj ntse, A plaques, txo oxidative kev nyuaj siab, thiab microglial activation, thiab hloov GMB. Lawv pom tias GMB-induced hloov nyob rau hauv lub hlwb muaj feem yuav kho los ntawm SCFAs raws li supplementation nrog SCFAs ua rau tib yam teebmeem [95]. Chen et al. (2020) kho 5XFAD nas nrog prebiotic R13 uas yog tropomyosin receptor kinase B (TrkB) agonist thiab pom tias cov compound blocks proinflammatory C / EBPB / AEP txoj hauv kev hauv plab thiab txo cov amyloid-positive signals hauv plab, thiab. [19].
Fig. 2 Microbiome-related therapeutic strategies for AD. Cov pov thawj ua ntej los ntawm cov nas thiab tib neeg cov kev tshawb fawb qhia tias probiotics / prebiotics, fecal teeb meem hloov pauv los ntawm cov neeg noj qab haus huv rau cov neeg mob AD, microbiome hloov tshuaj, thiab ncaj qha lub hom phiaj ntawm lub plab microbiome-tswj neuroinflammatory txoj hauv kev tuaj yeem ua rau cov kab mob hloov kho cov tswv yim kho mob thiab tuaj yeem txo cov amyloid, tau, thiab neurodegeneration
Ntxiv rau cov kev tshawb fawb hauv AD qauv nas kuaj probiotics, kuj tseem muaj cov kev sim me me rau cov neeg mob AD. Akbari et al. (2016) (N=60) tau ua ib qho kev soj ntsuam randomized, ob qhov muag tsis pom kev sib piv cov txiaj ntsig hauv AD cov neeg mob tau txais cov mis nyuj probiotic (Lactobacillus acidophilus, Lactobacillus casei, Bifidobacterium bifdum, thiab Lactobacillus fermentum) lossis tswj cov mis nyuj (200 ml / hnub ) rau 12 lub lis piam. Lawv pom tias cov neeg mob probiotic-kho tau muaj kev txhim kho tseem ceeb hauv lawv qhov Mini-Mental State Examination (MMSE) cov qhab nia thiab qhov txo qis hauv cov ntshav plasma malondialdehyde, tus cim ntawm oxidative kev nyuaj siab, thiab txo qis hauv cov ntshav C-reactive protein, ib qho kev qhia dav dav. kev kho mob [96]. Txawm li cas los xij, lwm qhov kev sim los ntawm tib pab pawg (N=60) hauv cov neeg mob hnyav AD tau pom tias 12 lub lis piam ntawm kev kho mob probiotic (Lactobacillus fermentum, Lactobacillus plantarum, Bifdobacterium lactis, Lactobacillus acidophilus, Bifdobacterium bifdum, thiab Bifdobacterium ntev) tsis zoo. los hloov cov qhab nia kev txawj ntse ntawm Kev Ntsuas Koj Qhov Kev Ntsuas Memory piv rau kev tswj hwm. Tsis tas li ntawd, cov probiotics tsis tau hloov cov theem ntawm inflammatory cytokines los yog cov cim ntawm oxidative kev nyuaj siab hauv plasma [97]. Cov txiaj ntsig sib txawv no tuaj yeem yog vim txawv cov qauv ntawm probiotics siv lossis qhov hnyav ntawm AD hauv cov neeg mob suav nrog. Qhov no yuav qhia tau tias cov tshuaj probiotics yuav muaj txiaj ntsig zoo dua ua ntej hauv kab mob thaum pathology tsis hnyav. Raws li qhov kev kwv yees no, Xiao et al. (2020) (N=80) tau ua ib qho kev sim, ob qhov muag tsis pom kev los sim seb cov probiotics puas yuav pab tau zoo hauv cov neeg mob MCI. Cov neeg tshawb xyuas no tau tshaj tawm tias 16 lub lis piam ntawm kev kho mob nrog Bifidobacterium breve A1 ua rau muaj kev txhim kho hauv Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) thiab JMCIS cov kev ntsuam xyuas hauv cov neeg mob MCI piv rau cov placebo [98]. Probiotics kuj tseem yuav muaj txiaj ntsig zoo nrog rau lwm cov kev kho mob. Tamtaji et al. (2019) (N=79) tau qhia tias probiotics (Lactobacillus acidophilus, Bifidobacterium bifdum, thiab Bifidobacterium longum) ua ke nrog selenium supplementation hauv cov neeg mob AD ua rau muaj kev sib koom ua ke hauv MMSE qhab nia, txo qis hauv CRP, txo tag nrho cov antioxidant muaj peev xwm, txo qis cov tshuaj insulin, txo qis LDL, thiab txo cov ntshav triglycerides [99]. Kev ntsuam xyuas meta-kev soj ntsuam cov ntaub ntawv muaj nyob ntawm seb cov probiotics puas yuav kho tau zoo rau AD tau ua los ntawm Den et al. (2020). Los ntawm 5 txoj kev tshawb fawb nrog 297 tus neeg mob, lawv pom tias tag nrho cov probiotics ua rau muaj kev txhim kho ntawm kev paub, txo qis hauv cov ntshav plasma malondialdehyde, thiab txo cov ntshav CRP qib piv rau cov tswj [100]. Zuag qhia tag nrho, cov txiaj ntsig no qhia tias probiotics tuaj yeem muaj txiaj ntsig zoo rau AD. Txawm li cas los xij, ntau lub sij hawm ntev, kev sim loj dua yuav tsum tau ua kom paub tseeb tias lawv muaj txiaj ntsig zoo rau AD raws li cov kev sim tau piav qhia saum toj no yog luv luv nrog cov qauv qis. Tsis tas li ntawd, nrog rau qhov muaj txiaj ntsig zoo ntawm cov ntshav biomarkers rau AD [101], kuaj probiotics ua ntej qhov pib ntawm cov tsos mob yuav yog lub tswv yim zoo tshaj plaws los hloov kho cov kab mob. Tsis tas li ntawd, txawm hais tias tsis muaj ib qho ntawm cov kev tshawb fawb tau sib tham txog kev ntsuas GMB hloov pauv hauv cov neeg mob tom qab kev kho mob probiotic, qhov ua tau zoo ntawm kev tswj hwm probiotic hauv kev hloov kho kev kho mob qhia tau tias hloov GMB tuaj yeem ua tau zoo rau kev hloov kho AD-txog neuropathology thiab kab mob kev loj hlob.
Fecal teeb meem hloov
Lwm lub tswv yim kho mob nrog rau kev tswj hwm ntawm GMB yog fecal matter transplant (FMT) (Fig. 2). FMT tam sim no siv rau Clostridium difcile tus kab mob rov qab los [102], tab sis muaj peev xwm tuaj yeem kho tau rau ntau yam mob uas GMB tau txuas rau kev mob pathological [103, 104]. Hauv AD, ib khub ntawm cov kev tshawb fawb tau luam tawm tsis ntev los no qhia txog qhov ua tau zoo ntawm FMT hauv kev txo cov kab mob hauv AD nas qauv [105, 106]. Sun et al. (2019) tau qhia tias kev tswj hwm FMT los ntawm WT nas rau hauv 6-hli APP / PS1 nas rau 4 lub lis piam ua rau txo qis hauv A , tau hyperphosphorylation, nce qib synaptic proteins, thiab txo qis cyclooxygenase-2 (cox -2) thiab CD11b+microglia [105]. Kim et al. (2019) tau lees paub cov kev tshawb pom no hauv ADLPAPT nas qauv ntawm AD los ntawm kev qhia tias kev kho ADLPAPT nas los ntawm 2 lub hlis ntawm hnub nyoog nrog WT FMT txog 6 lub hlis ntawm hnub nyoog ua rau txo qis hauv A , tau phosphorylation, Iba1+microglia, GFAP + astrocytes, Ly6Chigh monocytes, thiab kev ua tau zoo dua hauv cov ntsiab lus ntshai txias thiab Y maze [106]. Hauv kev sib piv, Dodiya et al. (2022) pom tias FMT los ntawm WT nas mus rau APPPS rau 6-kho tau1-21 nas txij hnub tom qab yug menyuam 25 txog 9 lub lis piam ua rau muaj kev nce hauv amyloid thiab microglial activation [8]. Thaum pom tseeb tsis sib haum rau cov kev tshawb fawb los ntawm Kim et al. thiab Sun et al., FMT kev tshawb fawb los ntawm Dodiya li al. tau ua nyob rau hauv abx-kho tsiaj nrog ib tug perturbed GMB uas nthuav tawm qhov txo qis hauv A amyloidosis thiab microglial activation thiab yog li FMT tsuas yog rov qab kho cov kev txwv no rau cov uas tau pom hauv APPPS1-21 nas yam tsis muaj GBM perturbations. Nrog rau qhov ntawd nyob rau hauv lub siab, xav tau kev tshawb fawb ntau ntxiv hla ntau cov qauv amyloid thiab tau thiab lub sijhawm los txiav txim seb FMT puas tuaj yeem yog lub tswv yim kho mob zoo rau AD.
Lwm hom kev kho mob hloov kho nrog GMB
Cov tshuaj uas tuaj yeem hloov kho GMB tuaj yeem muaj txiaj ntsig zoo rau AD (Fig. 2). Sodium oligomannate (GV-971) tsim los ntawm GreenValley Pharmaceuticals tau tshaj tawm los ntawm Wang li al. (2019) kom txo tau AD pathology hauv 5xFAD nas qauv los ntawm ib lub tshuab uas muaj kev hloov kho GMB [55, 107]. Cov kws tshawb fawb tau tshaj tawm tias GV-971 kho mob suppresses GMB dysbiosis, thiab txo qis peripheral o thiab tom qab neuroinflammation. Tsis tas li ntawd, hauv 36-lub lim tiam, multicenter, randomized theem 3 kev sim tshuaj nyob rau hauv Suav teb (N=818), GV-971 tau ntsib nws thawj qhov kawg [108]. Txawm li cas los xij, txoj kev tshawb no ua tsis tau raws li nws cov ntsiab lus thib ob, tab sis qhov sib xyaw tseem tau pom zoo los ntawm Suav FDA. Kev sim tshuaj thoob ntiaj teb nrog cov chaw hauv North America thiab Europe tau pib tab sis tam sim no raug kaw vim muaj teeb meem nyiaj txiag cuam tshuam txog COVID{12}} kis thoob qhov txhia chaw. Cov kev tshawb fawb ntxiv ntawm qhov sib xyaw no thiab lwm cov tshuaj hloov kho GMB yog qhov txaus siab los txiav txim siab seb GMB hloov kho puas tuaj yeem yog ib qho txiaj ntsig zoo rau kev tsom mus rau AD (Fig. 2).
Ib chav kawm tom ntej ntawm kev kho mob nrog lub peev xwm los tsom rau GMB yog cov kws kho mob probiotics [109–111]. Engineered probiotics genetically manipulate bacterial species to produce be useful metabolites/compounds in response to a particular stimulus [109–111] thiab txog tam sim no tau sim nyob rau hauv cov qauv ntawm cov kab mob plab, xws li kab mob plab plob tsis so tswj [112] thiab Clostridium defile kab mob [113] . Tsis tas li ntawd, cov kab mob tau raug tsim los tso tawm kev kho mob qog noj ntshav [114–116]. Cov chav kawm ntawm kev kho mob no kuj tseem yuav muaj txiaj ntsig zoo hauv cov kab mob hlwb uas GMB koom nrog, xws li AD, PD, thiab MS.
Kev paub Cistanche- Txhim Kho Kev Nco
Lwm lub tswv yim kho mob tseem ceeb uas yog GMB-hais txog yog siv cov khoom loj thiab ib leeg-cell RNAseq los txheeb xyuas lub hlwb-wide thiab cell-type txoj kev tshwj xeeb uas tau tswj hwm los ntawm GMB thiab tsom rau txoj hauv kev / cell hom (Fig. 2). Qhov no tej zaum yuav yog ib txoj hauv kev zoo dua los coj GMB kev tswj hwm raws li cov tswv yim kho mob vim tias muaj kev hloov pauv loj npaum li cas GMB manipulations cuam tshuam rau tib neeg. Txawm li cas los xij, txoj hauv kev tswj hwm los ntawm GMB tej zaum yuav muaj ntau dua. Piv txwv li, Sanmarco et al. (2021) tsis ntev los no tau txheeb xyuas GMB-tswj cov tshuaj tiv thaiv kab mob TRAIL+/LAMP1+astrocyte subtype [42]. Qhov induction ntawm no astrocyte subtype yuav kho tau rau ntau yam kab mob neurological. Cov tswv yim kho zoo sib xws tuaj yeem siv rau GMB-tswj microglial, neuronal, thiab oligodendrocyte subtypes / substrates. Tsis tas li ntawd, kev tswj hwm ntawm GMB-tswj peripheral inflammatory subtypes / substrates tuaj yeem muaj txiaj ntsig zoo. Hom tswv yim no tuaj yeem ua tau los ntawm kev siv adeno-associated vector virus therapy [117] nrog cov cell-hom tshwj xeeb txhawb lossis los ntawm kev siv ligand-conjugated antisense oligonucleotides [118]. Qhov tseem ceeb, rau kev siv lub tswv yim no, yuav tsum tau ua kom zoo dua txhais tau tias ntawm kev kho mob ntawm tes tshwj xeeb. Tsis tas li ntawd, kev hloov kho ntawm txoj hauv kev uas tau txheeb xyuas hauv cov RNAseq tej zaum yuav yog qhov tseem ceeb rau kev kho mob ib yam nkaus. Chen et al. (2020) tau txheeb xyuas tias C / EBP / AEP inflammatory pathway nyob rau hauv lub hlwb yog tswj los ntawm GMB thiab tej zaum yuav cuam tshuam rau amyloid pathology [19]. Kev tsom mus rau txoj hauv kev no tuaj yeem muaj txiaj ntsig zoo rau AD.
Muaj peev xwm txuas ntawm GMB thiab AD uas xav tau kev tshawb nrhiav ntxiv
Kev siv zog kom nkag siab txog lub luag haujlwm ntawm GMB hauv AD yog qhov tshiab nrog thawj cov kev tshawb fawb hauv tib neeg qhia tias GMB hloov pauv hauv cov neeg mob AD piv rau kev tswj hwm kev noj qab haus huv thiab kev tshawb fawb nas qhia GMB kev hloov pauv AD pathology luam tawm xyoo 2016 thiab 2017. Raws li xws li , muaj ntau tus neeg tuaj yeem sib khom lus ntawm kev sib raug zoo ntawm GMB thiab AD pathology uas tseem tsis tau tshawb nrhiav. Hauv seem no, peb piav qhia txog qhov muaj peev xwm sib txuas uas yuav muaj nyob nruab nrab ntawm GMB thiab kev noj haus, kev pw tsaug zog, thiab kev tawm dag zog, thiab kev txhim kho thiab kev loj hlob ntawm AD.
Noj zaub mov
Kev sib txuas ntawm kev noj haus thiab AD yog tsim tau zoo. Cov ntaub ntawv pov thawj epidemiological qhia tau hais tias kev noj zaub mov muaj roj ntau thiab kev rog rog yog txuam nrog kev pheej hmoo ntxiv rau kev tsim AD thiab dementia [119-123]. Tsis tas li ntawd, qhov tshwm sim ntawm AD yog siab dua nyob rau hauv cov teb chaws uas feem ntau noj cov zaub mov muaj roj tsawg uas tsis yog cov zaub mov muaj roj tsawg. Ntau qhov kev tshawb fawb nas tau pom tias AD qauv nas uas noj cov zaub mov muaj roj ntau tau ua rau muaj kev cuam tshuam rau neuropathology. Nce A plaques hauv lub hlwb tom qab noj cov zaub mov muaj roj ntau tau pom hauv APP / PS1 [124, 125], 5XFAD [126], APP23 [127], thiab APPNL-F [128] qauv ntawm amyloidosis. Tsis tas li ntawd, ntau qhov kev tshawb fawb tau pom tias kev noj zaub mov muaj roj ntau tuaj yeem ua rau muaj kev nce hauv neuroinflamation [124, 125, 127, 128] thiab txo qis kev ua haujlwm ntawm AD-txog kev ntsuas tus cwj pwm [125, 127–132]. Txawm li cas los xij, kuj tseem muaj qee qhov kev tshawb fawb uas tsis tau pom muaj txiaj ntsig ntawm kev noj zaub mov muaj roj ntau ntawm AD-txog neuropathology [129, 132, 133]. Qhov sib txawv ntawm qhov tshwm sim hauv cov qauv nas tuaj yeem yog vim tus qauv, poj niam txiv neej, thiab kev kho mob sib txawv. Txawm li cas los xij, tib neeg cov ntaub ntawv qhia, feem ntau, kev noj zaub mov muaj rog thiab rog rog yog qhov muaj feem cuam tshuam rau AD. Hloov pauv, muaj pov thawj qhia tias kev noj zaub mov Mediterranean, uas muaj cov khoom noj uas muaj cog thiab noj qab nyob zoo, tuaj yeem tiv thaiv AD [134–140]. Ballarini et al. (2021) tsis ntev los no tau pom tias kev noj zaub mov ntau dua Mediterranean ua rau muaj cov teeb meem grey ntau dua, nco zoo dua, qis A , thiab qis dua phosphorylated tau [141]. Tsis tas li ntawd, kev noj zaub mov ketogenic, uas suav nrog cov rog rog thiab tsis muaj cov carbohydrates noj, kuj tau pom tias muaj txiaj ntsig zoo hauv AD [142–145]. Cov kev tshawb fawb hauv nas qauv ntawm AD tau pom tias cov khoom noj ketogenic tuaj yeem txhim kho kev nco, txo cov amyloid plaques, thiab txo cov neurodegeneration, thiab neuroinflammation [146-148]. Tsis tas li ntawd, kev noj zaub mov ketogenic tau pom tias hloov GMB muaj pes tsawg leeg thiab kev ua haujlwm ntawm lub paj hlwb, uas tuaj yeem muaj txiaj ntsig zoo rau AD [149]. Interestingly, Nagpal et al. (2019) pom tias kev hloov kho Mediterranean ketogenic noj zaub mov tuaj yeem hloov kho GMB thiab SCFA ntau lawm hauv tib neeg MCI uas cuam tshuam nrog amyloid ntsuas hauv cerebrospinal kua (CSF) [150]. Zuag qhia tag nrho, cov pov thawj pom tseeb tias kev noj haus tuaj yeem cuam tshuam AD kev pheej hmoo thiab kev loj hlob.
Kev noj haus yog ib qho tseem ceeb tshaj plaws uas cuam tshuam GMB muaj pes tsawg leeg. Piv txwv li, Mediterranean, ketogenic, vegan, thiab gluten-dawb noj zaub mov hloov GMB muaj pes tsawg leeg hauv tib neeg [151-157]. Tsis tas li ntawd, GMB ua lub luag haujlwm loj hauv kev txhim kho thiab kev loj hlob ntawm kev rog thiab metabolic syndrome [158, 159]. GMB muaj pes tsawg leeg tau hloov pauv hauv cov neeg rog rog thiab hauv cov nas [160, 161]. Tsis tas li ntawd, GF nas tau txo lub cev rog piv rau cov nas uas tau tsa los ua ke txawm tias lawv xav tau lub zog ntau dua kom tswj tau qhov hnyav tib yam li cov tsiaj txhu uas tau tsa [162]. Tsis tas li ntawd, GF cov nas uas tau noj cov zaub mov muaj roj ntau, cov zaub mov muaj carbohydrates tau nce qhov hnyav dua li cov nas uas tau tsa ua ke [163]. Lwm txoj kev tshawb fawb pom tau hais tias colonization ntawm GF nas nrog cov ntsiab lus cecal los ntawm ntshiv los yog rog pub rau cov nas rog rog uas muaj feem pua ntawm cov rog hauv lub cev ntau dua piv rau cov nas colonized nrog cov ntsiab lus cecal los ntawm cov neeg pub dawb [164]. Ua ke, cov kev tshawb fawb no qhia tias GMB koom nrog kev loj hlob thiab kev loj hlob ntawm kev rog thiab lub zog homeostasis. GMB tuaj yeem tswj cov kab mob peripheral, uas hloov kho txoj kev loj hlob thiab kev loj hlob ntawm kev rog [165-168].
Muaj pov thawj ntseeg ntawm kev sib txuas ntawm kev noj haus, GMB, thiab AD [169, 170]. Kev sib txuas ntawm kev noj haus thiab AD, kev noj haus thiab GMB, thiab GMB thiab AD tau kawm. Txawm li cas los xij, tsis muaj kev sim luam tawm uas tag nrho 3 yam tau kawm ua ke. Nagpal et al. (2019) tau ua ib txoj kev tshawb fawb siv 17 cov neeg mob (11 nrog MCI, 6 qhov kev paub zoo li qub) qhov twg cov neeg mob tau ua raws li kev hloov kho Mediterranean-ketogenic noj rau 6 lub lis piam tom qab 6 lub lis piam ua raws li kev noj haus pom zoo los ntawm American Heart Association. GMB, plasma SCFAs, thiab ntshav AD cov cim tau ntsuas ua ntej thiab tom qab noj mov. Cov kev tshawb fawb no tau qhia tias txhua qhov kev noj haus tau hloov kho GMB thiab SCFA ntau lawm hauv txoj kev sib txawv thiab qee qhov kev hloov pauv no cuam tshuam nrog CSF A -42 [150]. Cov kev tshawb fawb ntev yav tom ntej yuav tsum tau ua los txiav txim siab seb kev noj zaub mov puas tuaj yeem hloov kho AD phenotypes los ntawm GMB. Tsis tas li ntawd, kev sim tsiaj ntau ntxiv yog xav tau los txiav txim siab seb qhov kev hloov pauv GMB puas tsim nyog rau kev noj zaub mov kom hloov pauv AD phenotypes. Muaj ib qho kev sib txuas ntawm cov khoom no hauv cov khoom noj uas hloov GMB, uas tswj cov peripheral thiab neuroinflammation, uas tuaj yeem cuam tshuam kev loj hlob ntawm AD pathology.
Pw tsaug zog
Pw tsaug zog thiab circadian atherosclerosis tsis ua haujlwm yog qhov cuam tshuam loj heev hauv AD [171]. Cov neeg mob AD feem ntau cuam tshuam kev pw tsaug zog-tsim thiab feem ntau tsaug zog thaum hmo ntuj thiab tsaug zog thaum nruab hnub [172]. Lawv kuj siv sij hawm tsawg dua nyob rau hauv qeeb nthwv dej [173, 174] thiab ceev qhov muag txav (REM) pw tsaug zog [175, 176], ob qho tib si tseem ceeb rau kev nco ua ke thiab kev paub [177, 178]. Tsis tas li ntawd, kev pw tsaug zog tsis zoo thiab kev pw tsaug zog tsis zoo tuaj yeem kwv yees AD thiab tom qab dementia [179–181]. Tsis tas li ntawd, cov neeg laus uas paub txog kev paub txog kev pw tsaug zog uas tus kheej qhia txog teeb meem pw tsaug zog feem ntau yuav muaj amyloid pathology hauv lawv lub hlwb ntawm PET scans [182]. Ib qib tau pom tias tau tswj los ntawm kev pw tsaug zog-tsim lub voj voog. Thaum lub paj hlwb interstitial kua (ISF) raug kuaj hauv cov nas uas siv microdialysis, qib A tau nce thaum cov nas tsaug zog thiab txo qis thaum cov nas tsaug zog [183]. Qhov kev tshawb pom no kuj tau lees paub hauv tib neeg cov neeg mob AD [184]. Cov oscillations diurnal nyob rau hauv A theem nyob rau hauv lub hlwb ISF yog dissipated thiab pw tsaug zog-wake voj voog yog cuam tshuam tom qab A plaque tsim nyob rau hauv APP / PS1 nas qauv ntawm amyloidosis. Txawm li cas los xij, amelioration ntawm A plaque pathology nrog A immunotherapy tau kho lub voj voog pw tsaug zog ib txwm thiab lub hnub ci oscillations hauv A qib hauv cov nas [185]. Txoj kev tshawb no ncaj qha cuam tshuam txog A plaque pathology hauv kev pw tsaug zog-wake cycle thiab diurnal A oscillations. Lub diurnal A oscillations kuj tau xav tias yog qhov sib txawv ntawm kev ua haujlwm neuronal ntawm kev pw tsaug zog thiab wakefulness. Thaum pw tsaug zog, kev ua haujlwm neuronal txo qis thiab thaum sawv ntxov, nws nce ntxiv. Kev ua haujlwm neuronal qis dua thaum pw tsaug zog yuav ua rau A ntau dua [186–188]. Pw tsaug zog deprivation exacerbates AD pathology [183, 189, 190], uas qhia meej txog kev pw tsaug zog tsis zoo nrog kev loj hlob ntawm AD. Tsis tas li ntawd, circadian atherosclerosis tsis ua haujlwm yog cuam tshuam hauv AD [191]. Nas qauv ntawm AD qhia circadian tsis ua haujlwm dhau sijhawm [191]. Trana et al. (2011) pom tias circadian dysfunction tuaj yeem kwv yees kev txhim kho yav tom ntej ntawm AD [192]. Tsis tas li ntawd, ib leeg nucleotide polymorphisms hauv Clock gene yog txuam nrog AD [193–195].
Muaj ntau cov ntaub ntawv pov thawj uas qhia tias GMB tuaj yeem cuam tshuam rau kev pw tsaug zog zoo thiab qhov kev pw tsaug zog zoo tuaj yeem cuam tshuam GMB muaj pes tsawg leeg. Antibiotic-mediated perturbation ntawm GMB tuaj yeem ua rau tawg NREM pw tsaug zog [196]. Ntawm qhov tod tes, kev cuam tshuam kev pw tsaug zog tuaj yeem ua rau muaj kev hloov pauv hauv GMB muaj pes tsawg leeg. Voigt et al. (2016) pom tias mutant Moos nas uas cuam tshuam kev pw tsaug zog muaj qhov hloov pauv GMB muaj pes tsawg leeg thiab qis dua taxonomic ntau yam piv rau kev tswj [197]. Cov txiaj ntsig no tau ua rau hnyav dua los ntawm kev haus cawv, qhia tias kev pw tsaug zog tsis zoo nrog rau lwm yam tuaj yeem hloov GMB ntau dua piv rau kev pw tsaug zog tsis zoo ib leeg. Qhov no yuav qhia txog qhov kev xav ntawm ob-ntaus qhov uas pw tsaug zog tsis zoo tuaj yeem cuam tshuam loj rau GMB thiab ua rau nws mus rau ntau yam kab mob. Poroyko et al. (2016) pom qhov hloov pauv hauv GMB muaj pes tsawg leeg tom qab pw tsaug zog tawg tau raug ntxias hauv cov nas qus. Raws li qhov tshwm sim, cov nas no muaj cov ntaub so ntswg adipose thiab txo qis cov tshuaj insulin. Tsis tas li ntawd, colonization los ntawm cov nas pw tsaug zog rau hauv cov tsiaj tsis muaj kab mob ua rau cov phenotypes zoo ib yam, qhia tias GMB tau kho cov teebmeem no [198]. Ib yam li ntawd, kev pw tsaug zog ntev ntev hauv 7- cov nas hnub qub, ua rau GMB muaj kev hloov pauv [199]. Cov txheej txheem uas GMB tuaj yeem cuam tshuam kev pw tsaug zog tuaj yeem yog los ntawm microbial metabolites. Kev tswj hwm ntawm butyrate tau pom los txhawb NREM pw tsaug zog hauv nas thiab nas [200]. Tsis tas li ntawd, feem pua ntawm cov propionate ntau dua nyob rau hauv kev sib raug zoo rau tag nrho SCFA muaj pes tsawg leeg yog txuam nrog ntev uninterrupted tib neeg cov me nyuam mos pw [201]. Kev pw tsaug zog kuj tuaj yeem cuam tshuam qhov mob. Feem ntau, pw tsaug zog nce inflammatory teb. Kev sib txuas ntawm kev pw tsaug zog thiab mob tuaj yeem kho tau los ntawm GMB [202]. Ntxiv rau qhov kev sib txuas ntawm kev cuam tshuam ntawm lub cev kev pw tsaug zog raug cuam tshuam nrog GMB kev hloov pauv, kev pw tsaug zog pathological kuj tseem cuam tshuam nrog kev hloov pauv GMB. Intermittent hypoxia txuam nrog obstructive pw tsaug zog apnea (OSA) yog txuam nrog GMB muaj pes tsawg leeg thiab ntau yam kev hloov pauv [203, 204]. Tsis tas li ntawd, OSA cov neeg mob tau hloov GMB muaj pes tsawg leeg piv rau HCs [205]. Ib yam li ntawd, insomnia thiab narcoleptic cov neeg mob ob leeg tau hloov GMB muaj pes tsawg leeg piv rau HCs [206, 207]. FMT los ntawm cov neeg pub noj qab haus huv tau zoo dua pw tsaug zog hauv cov neeg mob plab plob tsis so tswj [208]. Thaum kawg, ntau yam probiotics / prebiotic formulations txhim kho kev pw tsaug zog [209–213], qhia tias nce cov kab mob muaj txiaj ntsig hauv GMB tuaj yeem cuam tshuam rau kev pw tsaug zog.
Cov pov thawj qhia tias muaj feem yuav muaj kev sib txuas ntawm GMB, pw tsaug zog, thiab AD [214]. Txawm hais tias kev sib txuas ntawm GMB thiab pw tsaug zog thiab pw tsaug zog thiab AD tau kawm, kev sib txuas ntawm GMB, pw tsaug zog, thiab AD ua ke tsis tau kawm ntau. Qhov kev sib raug zoo no yuav nyuaj thiab bidirectional. Kev pw tsaug zog tsis zoo tuaj yeem ua rau lub plab dysbiosis, uas tuaj yeem hloov kho AD pathology. Nws kuj tseem tuaj yeem ua rau lub plab dysbiosis tuaj yeem ua rau muaj kev cuam tshuam txog kev pw tsaug zog, uas tuaj yeem hloov kho AD pathology. Muaj feem yuav muaj kev sib koom ua ke ntawm ob qhov xwm txheej no, uas ua rau AD pathogenesis. Nws yog ib qho tseem ceeb uas qhov kev sib txuas no tau kawm kom nkag siab zoo dua cov txheej txheem ntawm AD kev nce qib thiab rau kev kho lub hom phiaj ntawm kev sib txuas ntawm kev pw tsaug zog-GMB rau AD.
Kev tawm dag zog
Tib neeg cov kev tshawb fawb tau pom tias kev tawm dag zog yog tiv thaiv lub hnub nyoog ntawm kev paub txog kev poob qis thiab AD-txog kev pheej hmoo dementia [215-219]. Cov nyhuv no zoo li kho tau los ntawm kev txhim kho cov neeg laus hippocampal neurogenesis, lub paj hlwb-derived neurotrophic factor signaling, thiab synaptic muaj nuj nqi nrog rau txo qis neuroinflammation [220-222]. Nws yog qhov tseeb tias GMB tuaj yeem kho qhov kev tawm dag zog qhov txiaj ntsig ntawm kev paub. Kev tawm dag zog hloov kho qhov sib xyaw thiab ntau haiv neeg ntawm GMB hauv tib neeg thiab hauv nas [223–226]. Masumoto et al. (2008) [223] yog thawj zaug tshaj tawm tias 5 lub lis piam ntawm kev tawm dag zog hauv nas tau ua rau GMB muaj kev hloov pauv thiab nce hauv cecal butyrate, uas tau rov qab los ntawm lwm pab pawg. Allen et al. (2017) [226] corroborated qhov kev tshawb pom no nyob rau hauv tib neeg nyob rau hauv ib tug longitudinal txoj kev tshawb no, qhov twg sedentary lean thiab rog poj niam kawm koom nyob rau hauv 6 lub lis piam ntawm kev saib xyuas endurance-based aerobic kev cob qhia 3 zaug / lub lis piam thiab rov qab mus rau lawv txoj kev ua neej nyob rau 6 lub lis piam . Allen et al. (2017) [226] tau qhia tias kev tawm dag zog ua haujlwm hauv GMB muaj pes tsawg leeg, thiab cov kev hloov pauv no yog nyob ntawm kev rog rog. Kev qoj ib ce nce fecal SCFA concentrations hauv lean tab sis tsis rog neeg koom. Cov teebmeem no tau thim rov qab tom qab 6 lub lis piam ntawm kev tawm dag zog tawm dag zog qhia tias kev txhawb nqa ntawm kev tawm dag zog yog qhov tsim nyog rau kev tawm dag zog mus sij hawm ntev-vim GMB hloov pauv. Vim hais tias kev tawm dag zog yog kev tiv thaiv hauv AD thiab kev tawm dag zog hloov GMB muaj pes tsawg leeg, nws muaj peev xwm tiv thaiv kev tawm dag zog ntawm kev ua haujlwm ntawm AD yog kho los ntawm GMB. Tsis tas li ntawd, GMB tuaj yeem tswj hwm neurogenesis thiab neuroinflammation, uas yog cov txheej txheem tseem ceeb ntawm kev tawm dag zog vim muaj txiaj ntsig rau kev paub [35, 227]. Txhawm rau nthuav tawm qhov kev sib txuas ntawm kev tawm dag zog, GMB, thiab AD, cov kev tshawb fawb yav tom ntej yuav tsum muaj nyob rau hauv uas AD qauv nas nrog GMB perturbations tau txais kev cob qhia kev tawm dag zog, thiab AD-txog pathophysiology raug soj ntsuam piv rau kev siv AD nas tsis muaj GMB perturbations. Yog tias GMB tau pom tias yog tus neeg nruab nrab tseem ceeb ntawm cov txiaj ntsig kev tawm dag zog rau AD, cov tswv yim kho mob rov hais dua qhov kev tawm dag zog GMB lub xeev yuav pab tau rau AD.
Cistanche ntxiv nyob ze kuv-Kev Txhim Kho Kev Nco
Xaus
GMB yog tus tswj hwm ntawm kev mob hauv lub cev thiab yog li tseem ceeb heev rau kev txhim kho thiab kev loj hlob ntawm cov kab mob uas cuam tshuam nrog peripheral thiab central o [228]. Nkag siab txog cov txheej txheem uas GMB tuaj yeem cuam tshuam AD kev nce qib tuaj yeem nthuav tawm lub hom phiaj kho mob tseem ceeb uas tuaj yeem tswj tau ntau yam kab mob. Txij li thaum cov kev tshawb fawb thawj zaug tau nthuav tawm qhov cuam tshuam loj ntawm GMB hloov pauv hauv AD-txog pathology [5, 6, 14] thiab cov neeg mob AD muaj qhov hloov pauv GMB muaj pes tsawg leeg piv rau kev tswj hwm kev noj qab haus huv [10, 11], tau muaj kev tawg ntawm kev txaus siab hauv lub subfield ntawm AD. Raws li cov kev tshawb fawb txog niaj hnub no, peb tam sim no muaj qhov kev xav tsim nyog uas GMB tswj cov kab mob peripheral thiab hauv nruab nrab o tuaj yeem los ntawm microbial metabolites (Daim duab 1), uas muaj kev cuam tshuam rau AD pathology hauv lub hlwb (Fig. 1). Kev tswj hwm ntawm abx [5–8, 24] lossis cov kab mob tsis muaj kab mob [12–14] hauv cov qauv nas ntawm amyloidosis ua rau txo qis amyloidosis thiab microglial activation. Abx kuj nce cov tshuaj tiv thaiv kab mob T-hlwb hauv cov ntshav thiab lub hlwb [6]. Peripheral immune hloov pauv yuav cuam tshuam rau lub cev tiv thaiv kab mob hauv microglia thiab lwm lub hlwb, uas tuaj yeem cuam tshuam rau amyloidosis thiab neurodegeneration (Fig. 1). Tsis tas li ntawd, SCFAs tsim los ntawm cov kab mob hauv GMB tuaj yeem hloov kho amyloidosis [13]. Txawm hais tias qhov kev pab cuam los ntawm ntau qhov kev tshawb fawb tau ua rau muaj kev xav dav dav ntawm yuav ua li cas GMB tuaj yeem hloov kho AD-txog kab mob, ob peb txoj hauv kev tshwj xeeb tau raug txheeb xyuas. Qhov nce ntawm genomic technologies thiab bioinformatic cov cuab yeej yuav pab tau nyob rau hauv kev rau siab mus nrhiav lub hlwb-wide thiab cell-type txoj kev tshwj xeeb uas cuam tshuam los ntawm GMB thiab ua rau kev hloov kho ntawm AD pathology. Tsis tas li ntawd, cov qauv zoo dua ntawm tib neeg-tseem ceeb ntawm GMB manipulation yog xav tau kom nkag siab zoo dua li cas nas qauv kev sim cuam tshuam txog tib neeg kab mob. Kev sau cov fecal teeb meem los ntawm AD / MCI cov neeg mob thiab kev tswj hwm kev noj qab haus huv yuav zoo heev rau kev ua qauv nas. Colonization ntawm cov nas tsis muaj kab mob nrog AD / MCI tus neeg mob fecal microbiomes tuaj yeem pab cov kws tshawb fawb zoo dua tus qauv tib neeg GMB hloov hauv AD. Tsis tas li ntawd, cov ntaub ntawv ntxiv, xws li lub hlwb scan / ntshav-raws li biomarker cov ntaub ntawv ua ke nrog qhov no tseem yuav pab tau GMB / AD cov kev tshawb fawb. Peb pom zoo kom txhua qhov kev sim tshuaj AD sau thiab khaws cov qauv fecal los ntawm cov neeg koom nrog rau kev siv hauv GMB cov kev tshawb fawb. Tsis tas li ntawd, nws yuav txaus siab kom nkag siab txog qhov hloov pauv ntawm GMB li cas, xws li kev noj zaub mov, thaj chaw, kev sib deev, kev laus, kev tawm dag zog, thiab pw tsaug zog, tuaj yeem cuam tshuam kev siv zog rau kev kho mob rau GMB. Ib lo lus nug tseem ceeb los teb rau kev txhais lus yog seb GMB-raws li kev kho mob rau AD tuaj yeem ua tau dav dav lossis seb lawv puas yuav tsum tau ua tus kheej rau tus neeg mob. Txhawm rau teb cov lus nug no kom txaus yuav tsum muaj kev tiv thaiv tib neeg mus sij hawm ntev thiab kev sim kho mob siv GMB-raws li kev kho mob. Hauv cov ntsiab lus, txawm hais tias kev tshawb fawb qhia txog kev sib txuas ntawm GMB thiab AD tau tuaj deb dhau lub sijhawm luv luv, kev siv cov cuab yeej tshiab thiab cov txheej txheem yuav nrawm rau txoj kev tshawb fawb kom nkag siab txog qhov kawg thiab kho qhov kev sib txuas no.
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