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Ma granules a Ban-Lan-Gen amachepetsa matenda a dextran sodium sulfate omwe amayambitsidwa ndi matenda obwerezabwereza m'makoswe mwa kusintha ma microbiota am'mimba ndikubwezeretsa kupanga kwa SCFA Derived-GLP-1 m'matumbo.
Jiao Peng,1-3,*Li Xi,4,*Zheng Lin,3,5 Duan Lifang,1 Gao Zhengxian,2,5 Diehu,1 Li Jie,6 Li Xiaofeng,6 Shen Xiangchun,5 Xiao Haitao21Peking University Shenzhen Hospital Dipatimenti ya Mankhwala, Shenzhen, People's Republic of China; 2Shenzhen University Health Science Center School of Pharmacy School of Pharmacy, Shenzhen, People's Republic of China; 3Guizhou Medical University Engineering Technology Research Center of Ethnic Medicine and Traditional Chinese Medicine Development and Application Ministry of Education, Guizhou Provincial Key Laboratory of Pharmacy, Guizhou Medical University, Guiyang, People's Republic of China; 4 Dipatimenti ya Gastroenterology, Peking University Shenzhen Hospital, Shenzhen, People's Republic of China; 5 Sukulu ya Mankhwala, Guizhou Medical University, State Key Laboratory of Medicinal Plant Function and Application, Guiyang; 6 Dipatimenti ya Zamankhwala a Laboratory, Peking University Shenzhen Hospital, Shenzhen, China [email protected] Shen Xiangchun, Sukulu ya Mankhwala, Guizhou Medical University, Guizhou, People's Republic of China, 550004, Imelo [email protected] Cholinga: Chithandizo chochokera ku GLP-1 ndi njira yatsopano yothandizira matenda otupa m'matumbo. Ma granules a Ban-Lan-Gen (BLG) ndi njira yodziwika bwino ya TCM yoletsa kutupa yomwe imasonyeza mphamvu yoletsa kutupa pochiza matenda osiyanasiyana otupa. Komabe, mphamvu yake yoletsa kutupa pa matenda a m'matumbo ndi momwe imagwirira ntchito sizikudziwikabe. NJIRA: Kukhazikitsa matenda obwerezabwereza a m'matumbo omwe amabwera chifukwa cha dextran sodium sulfate (DSS) m'makoswe. Zizindikiro za matenda, zizindikiro za kuvulala, ndi kuchuluka kwa cytokine yotupa zinachitidwa kuti ziwunikire mphamvu yoteteza ya BLG. Zotsatira za BLG pa m'matumbo ndi m'matumbo zinadziwika ndi milingo ya GLP-1 m'magazi ndi Gcg ya m'matumbo, GPR41, ndi GRP43, kapangidwe ka m'matumbo, ndowe Kuchuluka kwa ma SCFA, ndi kutulutsidwa kwa GLP-1 kuchokera ku maselo oyambira a epithelial a mbewa zopangidwa ndi SCFA kupanga GLP-1. Zotsatira: Chithandizo cha BLG chachepetsa kwambiri kuchepa kwa thupi, DAI, kufupikitsa matumbo, kuwonongeka kwa minofu ya m'matumbo, ndi kuchuluka kwa cytokine yotupa ya TNF-α, IL-1β, ndi IL-6 m'matumbo a m'matumbo. Kuphatikiza apo, chithandizo cha BLG chingabwezeretse kwambiri kuchuluka kwa Gcg, GPR41 ndi GRP43 m'matumbo a m'matumbo ndi milingo ya GLP-1 m'magazi a mbewa za colitis, komanso powonjezera mabakiteriya opanga SCFA monga Akkermansia ndi Prevotellaceae_UCG-001, ndikuchepetsa kuchuluka kwa mabakiteriya monga Eubacterium_xylanophilum_group, Ruminococcaceae_UCG-014, Intestinimonas ndi Oscillibacter. Kuphatikiza apo, chithandizo cha BLG chingawonjezere kwambiri kuchuluka kwa ma SCFA m'chimbudzi cha mbewa za colitis. Nthawi yomweyo, zoyeserera za mu vitro zinawonetsanso kuti chotsitsa cha ndowe cha mbewa zothandizidwa ndi BLG chingalimbikitse kwambiri maselo ang'onoang'ono a Murine colonic epithelial omwe amatulutsa GLP-1. Zomaliza: Zomwe zapezekazi zikusonyeza kuti BLG ili ndi mphamvu yotsutsana ndi colitis. BLG ili ndi kuthekera kopangidwa ngati chithandizo, makamaka mwa kusintha ma microbiota am'mimba ndikubwezeretsa kupanga kwa GLP-1 kochokera ku matumbo Mankhwala olonjeza a colitis yobwerezabwereza. Mawu osakira: colitis, Ban-Lan-Gen granules, gut microbiota, short-chain fatty acids, GLP-1
Ulcerative colitis (UC) ndi matenda otupa a m'matumbo ndi m'matumbo omwe amadziwika ndi kutsegula m'mimba mobwerezabwereza, kupweteka m'mimba, kuchepa thupi, ndi ndowe zamagazi.1 Posachedwapa, kufalikira kwa UC kwakhala kukuchulukirachulukira m'maiko omwe kale anali ndi matenda ochepa, kuphatikizapo China, ndi kutchuka kwakukulu kwa moyo wa Kumadzulo.2 Kuwonjezeka kumeneku kumabweretsa mavuto akulu pa thanzi la anthu ndipo kumakhudza kwambiri luso la odwala kugwira ntchito komanso moyo wabwino. Chodziwika bwino n'chakuti, matenda a UC sakudziwika bwino, koma ambiri amavomereza kuti majini, zinthu zachilengedwe, tizilombo toyambitsa matenda m'matumbo, ndi chitetezo chamthupi zonse zimathandiza pakukula kwa UC.3 Ngakhale pano, palibe mankhwala a UC, ndipo cholinga cha chithandizo ndikuwongolera zizindikiro zachipatala, kuyambitsa ndikusunga kuchira, kulimbikitsa kuchira kwa mucosal, ndikuchepetsa kubwereranso. Mankhwala akale akuphatikizapo aminosalicylates, corticosteroids, immunosuppressants, ndi biologics. Komabe, mankhwalawa sangakwaniritse zotsatira zomwe akufuna chifukwa cha zotsatira zake zosiyanasiyana.4 Posachedwapa, kafukufuku wambiri wasonyeza kuti mankhwala achikhalidwe achi China (TCM) awonetsa kuthekera kwakukulu pothandiza kuchepetsa UC yokhala ndi poizoni wochepa, zomwe zikusonyeza kuti kupanga njira zatsopano zochiritsira za TCM ndi njira yabwino yochiritsira ya UC.5-7​​
Banlangen Granules (BLG) ndi mankhwala achi China opangidwa kuchokera ku madzi ochokera muzu wa Banlangen.8 Kuwonjezera pa mphamvu yake yoletsa mavairasi, BLG imasonyeza mphamvu yoletsa kutupa pochiza matenda osiyanasiyana otupa.9,10 Kuphatikiza apo, ma glucosinolates (R,S-goitrin, progoitrin, epiprorubin ndi glucoside apezeka ndikupezeka kuchokera ku zotulutsa zamadzi za Radix isatidis) ndi nucleosides (hypoxanthine, adenosine, uridine ndi guanosine) ndi indigo alkaloids monga indigo ndi indirubin.11,12 Kafukufuku wakale wasonyeza bwino kuti mankhwala a adenosine, uridine ndi indirubin amasonyeza mphamvu zotsutsana ndi colitis m'mitundu yosiyanasiyana ya nyama ya colitis.13-17 Komabe, palibe maphunziro ozikidwa pa umboni omwe achitika kuti awone momwe BLG imagwirira ntchito mu colitis. Mu kafukufukuyu, tafufuza momwe BLG imatetezera matenda a colitis omwe amayambitsidwa ndi dextran sodium sulfate (DSS) mu colitis. Mbewa za C57BL/6 zinapeza kuti kupereka BLG pakamwa kunachepetsa kwambiri matumbo obwerezabwereza omwe amabwera chifukwa cha DSS m'makoswe. Kutupa, njira zake zowongolera zimagwirizana ndi kusintha kwa microbiota ya m'matumbo ndi kubwezeretsa kupanga kwa glucagon-like peptide-1 (GLP-1) yochokera m'matumbo.
Ma granules a BLG (opanda shuga, Z11020357 yovomerezedwa ndi NMPA; Beijing Tongrentang Technology Development Co., Ltd., Beijing, China; nambala ya batch: 20110966) adagulidwa kuchokera ku ma pharmacies. DSS (Kulemera kwa Molecular: 36,000–50,000 Daltons) idagulidwa kuchokera ku MP Biologicals (Santa Ana, USA). Sulfasalazine (SASP) (≥ 98% purity), hematoxylin ndi eosin zidagulidwa kuchokera ku Sigma-Aldrich (St. Louis, MO, USA). Ma Mouse TNF-α, IL-1β ndi IL-6 luminex Elisa assay kits adagulidwa kuchokera ku R&D systems (Minneapolis, MN, USA). Acetic acid, propionic acid, ndi butyric acid zidagulidwa kuchokera ku Aladdin Industries (Shanghai, China). 2-Ethylbutyric acid idagulidwa kuchokera ku Merck KGaA (Darmstadt, Germany).
Mbewa zazimuna za C57BL/6 za masabata 6-8 (kulemera thupi 18-22 g) zinagulidwa ku Beijing Wetahe Laboratory Animal Technology Co., Ltd. (Beijing, China) ndipo zinasungidwa pamalo otentha a 22 ± 2 °C ndi maola 12 kuwala/mdima. Mbewa zinadyetsedwa zakudya zokhazikika za makoswe ndi madzi akumwa kwaulere kwa sabata imodzi kuti zizolowere malo atsopano. Kenako makoswe anagawidwa mwachisawawa m'magulu anayi: gulu lolamulira, gulu la DSS model, gulu lochiritsidwa ndi SASP (200 mg/kg, pakamwa) ndi gulu lochiritsidwa ndi BLG (1 g/kg, pakamwa). Monga momwe zasonyezedwera pa Chithunzi 1A, malinga ndi kafukufuku wathu wakale, matenda obwerezabwereza a colitis oyesera adayambitsidwa m'makoswe ndi magawo atatu a 1.8% DSS kwa masiku 5, kutsatiridwa ndi madzi osungunuka kwa masiku 7, malinga ndi kafukufuku wathu wakale.18 Mbewa m'magulu ochiritsidwa ndi SASP ndi BLG zinathandizidwa ndi SASP ndi BLG, motsatana, tsiku lililonse kuyambira tsiku 0. Malinga ndi kafukufuku woyamba, Mlingo wa BLG unayikidwa pa 1 g/kg. Pakadali pano, mlingo wa SASP unayikidwa pa 200 mg/Kg malinga ndi mabuku.4 Magulu olamulira ndi a DSS analandira madzi ofanana panthawi yonse yoyesera.
Chithunzi 1 BLG imalimbikitsa matenda a m'matumbo obwerezabwereza omwe amabwera chifukwa cha DSS m'makoswe. (A) Kapangidwe koyesera ka matenda a m'matumbo obwerezabwereza komanso chithandizo, (B) kusintha kwa kulemera kwa thupi, (C) chiwerengero cha matenda (DAI), (D) kutalika kwa m'matumbo, (E) chithunzi choyimira cha m'matumbo, (F) kupendekera kwa H&E m'matumbo (kukula, ×100) ndi (G) chiwerengero cha histological. Deta imaperekedwa ngati apakati ± SEM (n = 6).##p < 0.01 kapena ###p < 0.001 vs gulu lolamulira (Con); *p < 0.05 kapena **p < 0.01 kapena ***p < 0.001 vs gulu la DSS.
Kulemera kwa thupi, kukhazikika kwa ndowe, ndi kutuluka magazi m'matumbo zinalembedwa tsiku lililonse. Chizindikiro cha zochita za matenda (DAI) chinadziwika mwa kuphatikiza kulemera kwa thupi, kukhazikika kwa ndowe, ndi kutuluka magazi m'matumbo monga tafotokozera kale.19 Pamapeto pa kuyesera, mbewa zonse zinaphedwa ndipo magazi, ndowe ndi m'matumbo zinasonkhanitsidwa kuti zikayesedwenso.
Minofu ya m'matumbo inakonzedwa kuti ikhale yokhazikika ndipo inayikidwa mu paraffin. Zigawo za 5-micron zinapangidwa ndi kupakidwa ndi hematoxylin-eosin (H&E), kenako zinachotsedwa khungu ndi kuikidwa m'magawo monga momwe tafotokozera kale.19
RNA yonse ya minofu ya m'matumbo inachotsedwa ndi Trizol reagent (Invitrogen, Carlsbad, CA), kutsatiridwa ndi cDNA extraction ndi reverse transcriptase (TaKaRa, Kusatsu, Shiga, Japan). Kuchuluka kwa PCR kunachitika pogwiritsa ntchito njira yeniyeni ya PCR ndi SYBR Green Master (Roche, Basel, Switzerland). Kulemba kwa majini omwe adayikidwa kunasinthidwa kukhala β-actin ndipo deta idasanthulidwa pogwiritsa ntchito njira ya 2-ΔΔCT. Ma primer sequences a majini akuwonetsedwa mu Table 1.
Kupatula maselo a epithelial a mbewa ndi kukulitsa kunachitidwa monga momwe tafotokozera kale.20 Mwachidule, matumbo a mbewa za masabata 6-8 adachotsedwa koyamba ataphedwa ndi kusokonekera kwa chiberekero, kenako adatsegulidwa kwa nthawi yayitali, kuchiritsidwa ndi Hanks Balanced Salt Solution (HBSS, yopanda calcium ndi magnesium) ndikudulidwa mu zidutswa zazing'ono za 0.5-1 mm. Pambuyo pake, minofu idagayidwa ndi 0.4 mg/mL collagenase XI (Sigma, Poole, UK) mu free DMEM medium ndikuyikidwa centrifuge pa 300 xg kwa mphindi 5 kutentha kwa chipinda. Bwezeraninso pellet mu DMEM medium (yowonjezeredwa ndi 10% fetal bovine serum, 100 Units/mL penicillin, ndi 100 µg/mL streptomycin) pa 37 °C ndikudutsa mu nylon mesh (kukula kwa pore ~250 µm). Ma quots a colonic epithelial cells adayikidwa m'mbale zagalasi pansi ndipo adayikidwa ndi acetic acid, propionic acid, asidi wa butyric, ndi zotulutsa za ndowe za mbewa kwa maola awiri pa kutentha kwa 37°C, 5% CO2.
Minofu ya m'matumbo inasinthidwa kukhala yofanana ndi PBS, ndipo milingo ya ma cytokines IL-6, TNF-α ndi IL-1β m'matumbo a m'matumbo inapezeka pogwiritsa ntchito zida zoyesera za luminex ELISA (machitidwe a R&D, Minneapolis, MN, USA). Momwemonso, milingo ya GLP-1 mu seramu ndi malo osungiramo zinthu za maselo oyambira a epithelial a murine colonic anatsimikiziridwa ndi zida za ELISA (Bioswamp, Wuhan, China) malinga ndi malangizo a wopanga.
DNA yonse kuchokera m'ndowe inachotsedwa pogwiritsa ntchito chida chochotsera DNA (Tiangen, China). Ubwino ndi kuchuluka kwa DNA kunayesedwa pa chiŵerengero cha 260 nm/280 nm ndi 260 nm/230 nm, motsatana. Pambuyo pake, pogwiritsa ntchito DNA iliyonse yochotsedwa ngati template, ma primer enieni 338F (ACTCCTACGGGAGGCAGCAG) ndi 806R (GGACTACHVGGGTWTCTAAT) adagwiritsidwa ntchito kukulitsa madera a V3-V4 a jini ya 16S rRNA m'madera osiyanasiyana. Zogulitsa za PCR zinayeretsedwa pogwiritsa ntchito QIAquick Gel Extraction Kit (QIAGEN, Germany), zomwe zinayesedwa ndi PCR yeniyeni, ndikutsatiridwa pogwiritsa ntchito nsanja ya IlluminaMiseq PE300 sequencing (Illumina Inc., CA, USA). Pa kusanthula kwa bioinformatics, kukonza deta kunachitika potsatira ma protocol omwe adanenedwa kale.21,22 Mwachidule, gwiritsani ntchito Cutadapt (V1.9.1) kusefa mafayilo osaphika otulutsa. Ma OTU adayikidwa m'magulu. pogwiritsa ntchito UPARSE (mtundu 7.0.1001) yokhala ndi malire ofanana a 97%, ndipo UCHIME idagwiritsidwa ntchito kuchotsa ma chimeric sequences. Kusanthula kapangidwe ka anthu ammudzi ndi kugawa kunachitika pogwiritsa ntchito RDP classifier (http://rdp.cme.msu.edu/) kutengera SILVA ribosomal RNA gene database.
Milingo ya ma asidi amafuta afupiafupi (acetic acid, propionic acid, ndi butyric acid) inayesedwa monga momwe Tao et al. adafotokozera kale, ndi zosintha zina.23 Mwachidule, 100 mg ya ndowe idayikidwa koyamba mu 0.4 mL ya madzi oyeretsedwa, kutsatiridwa ndi 0.1 mL ya 50% sulfuric acid ndi 0.5 mL ya 2-ethylbutyric acid (muyezo wamkati), kenako idasinthidwa ndikutenthedwa pa 4°C. Kuyeza mphamvu ya centrifuge pa 12,000 rpm kwa mphindi 15 pa C. Supernatant inachotsedwa ndi 0.5 mL ya ether ndikuyiyika mu GC kuti iwunikenso. Pa kusanthula kwa gas chromatography (GC), zitsanzo zinawunikidwa pogwiritsa ntchito GC-2010 Plus gas chromatograph (Shimadzu, Inc.) yokhala ndi chowunikira cha flame ionization (FID). Kulekanitsidwa kunachitika pogwiritsa ntchito ZKAT-624 column, 30 m × 0.53 mm × 0.3 μm (Lanzhou Zhongke Antai Analytical Technology Co., Ltd., China). Deta inapezedwa pogwiritsa ntchito pulogalamu ya GC solution (Shimadzu, Inc.). Chiŵerengero cha kugawanika chinali 10:1, mpweya wonyamula unali nayitrogeni, ndipo kuchuluka kwa madzi kunali 6 mL/min. Kuchuluka kwa jakisoni kunali 1 μL. Kutentha kwa jekeseni ndi chowunikira kunali 300°C. Kutentha kwa uvuni kunasungidwa pa 140°C kwa mphindi 13.5, kenako kunawonjezeka kufika pa 250°C pa kutentha kwa 120°C/min; kutentha kunasungidwa kwa mphindi 5.
Deta imaperekedwa ngati mean ± standard error ya mean (SEM). Kufunika kwa deta kunayesedwa ndi njira imodzi ya ANOVA kutsatiridwa ndi mayeso a Duncan a multiple range. Pulogalamu ya GraphPad Prism 5.0 (GraphPad Software Inc., San Diego, CA, USA) idagwiritsidwa ntchito powerengera zonse ndipo p < 0.05 idawonedwa ngati yofunika kwambiri pa ziwerengero.
Ndizodziwika bwino kuti UC ndi matenda osatha a colitis omwe amabwereranso m'mimba omwe ali ndi ululu waukulu m'mimba, kutsegula m'mimba komanso kutuluka magazi. Chifukwa chake, matenda osatha a colitis omwe amayambitsidwa ndi DSS m'makoswe adakhazikitsidwa kuti awone momwe BLG imagwirira ntchito polimbana ndi colitis (Chithunzi 1A). Poyerekeza ndi gulu lowongolera, mbewa zomwe zili mu gulu la DSS model zidachepetsa kwambiri kulemera kwa thupi komanso DAI yokwera, ndipo kusinthaku kudasinthidwa kwambiri pambuyo pa masiku 24 a chithandizo cha BLG (Chithunzi 1B ndi C). Kufupikitsa colon ndi chizindikiro chofunikira cha UC. Monga momwe zasonyezedwera mu Zithunzi 1D ndi E, kutalika kwa colon kwa mbewa zomwe zidalandira DSS kudafupikitsidwa kwambiri, koma zidachepetsedwa ndi chithandizo cha BLG. Pambuyo pake, kusanthula kwa histopathological kunachitika kuti awone kutupa kwa colon. Zithunzi zodetsedwa za H&E ndi ziwerengero za pathological zidawonetsa kuti kuperekedwa kwa DSS kudasokoneza kwambiri kapangidwe ka colonic ndipo kudapangitsa kuti crypt iwonongeke, pomwe chithandizo cha BLG chidachepetsa kwambiri kuwonongeka kwa crypt ndi ziwerengero za pathological (Chithunzi 1F ndi G). Chodziwika bwino, mphamvu yoteteza ya BLG pa mlingo wa 1 g/Kg inali yofanana ndi ya SASP pa mlingo wa 200 mg/Kg. Zonsezi zikusonyeza kuti BLG ndi yothandiza kuchepetsa kuopsa kwa matenda a m'mimba obwerezabwereza omwe amayambitsidwa ndi DSS m'makoswe.
TNF-α, IL-1β ndi IL-6 ndi zizindikiro zofunika kwambiri za kutupa kwa matumbo. Monga momwe zasonyezedwera pa Chithunzi 2A, DSS idapangitsa kuwonjezeka kwakukulu kwa kufotokozera kwa majini a TNF-α, IL-1β ndi IL-6 m'matumbo poyerekeza ndi gulu lolamulira. Kuyang'anira BLG kumatha kusintha kwambiri kusintha kumeneku komwe kumachitika chifukwa cha DSS. Kenako, tidagwiritsa ntchito ELISA kuti tidziwe kuchuluka kwa ma cytokines otupa a TNF-α, IL-1β, ndi IL-6 m'matumbo a m'mimba. Zotsatira zake zidawonetsanso kuti kuchuluka kwa TNF-α, IL-1β, ndi IL-6 m'matumbo a m'mimba kunawonjezeka kwambiri m'makoswe omwe adalandira DSS, pomwe chithandizo cha BLG chidachepetsa kuwonjezeka kumeneku (Chithunzi 2B).
Chithunzi 2 BLG imaletsa kufalikira kwa majini ndi kupanga ma cytokines oyambitsa kutupa a TNF-α, IL-1β ndi IL-6 m'matumbo a mbewa zomwe zimalandira chithandizo cha DSS.(A) Kufalikira kwa majini a TNF-α, IL-1β ndi IL-6 m'matumbo a mbewa zomwe zimalandira chithandizo cha DSS.(A) Kufalikira kwa majini a TNF-α, IL-1β ndi IL-6 m'matumbo; (B) kuchuluka kwa mapuloteni a TNF-α, IL-1β ndi IL-6 m'matumbo. Deta imaperekedwa ngati apakati ± SEM (n = 4–6).#p < 0.05 kapena ##p < 0.01 kapena ###p < 0.001 vs gulu lolamulira (Con); *p < 0.05 kapena **p < 0.01 vs gulu la DSS.
Dysbiosis ya m'mimba ndi yofunika kwambiri pa matenda a UC.24 Kuti afufuze ngati BLG imasintha ma microbiota a m'matumbo a mbewa zothandizidwa ndi DSS, kusanthula kwa 16S rRNA kunachitika kuti kufufuze gulu la mabakiteriya omwe ali m'matumbo. Chithunzi cha Venn chikuwonetsa kuti magulu atatuwa ali ndi ma OTU 385. Nthawi yomweyo, gulu lililonse linali ndi ma OTU apadera (Chithunzi 3A). Kuphatikiza apo, index ya Chao1 ndi index ya Shannon zomwe zawonetsedwa pa Chithunzi 3B ndi C zawonetsa kuti kusiyanasiyana kwa ma microbiota am'matumbo kunachepa mu mbewa zothandizidwa ndi BLG, chifukwa index ya Shannon idachepa kwambiri mu gulu lothandizidwa ndi BLG. Kusanthula kwa zigawo zazikulu (PCA) ndi kusanthula kwakukulu kwa coordinate (PCoA) zidagwiritsidwa ntchito kudziwa mapangidwe a magulu pakati pa magulu atatuwa ndipo zidawonetsa kuti kapangidwe ka mbewa zothandizidwa ndi DSS kanalekanitsidwa bwino pambuyo pa chithandizo cha BLG (Chithunzi 3D ndi E). Deta iyi ikuwonetsa kuti chithandizo cha BLG chinakhudza kwambiri kapangidwe ka mbewa zomwe zili ndi matenda a m'matumbo omwe amayambitsa matenda a m'matumbo a DSS.
Chithunzi 3 BLG imasintha kusiyanasiyana kwa ma microbiota a m'matumbo mwa mbewa zomwe zili ndi matenda a m'mimba otchedwa DSS-induced colitis.(A) Chithunzi cha Venn cha OTU, (B) Chao1 index, (C) Shannon's richness index, (D) Principal Component Analysis (PCA) score plot ya OTU, (E) OTU Principal Coordinate Analysis (PCoA) score Chithunzi. Deta yaperekedwa ngati mean ± SEM (n = 6).**p < 0.01 vs gulu la DSS.
Kuti tiwone kusintha kwina kwa tizilombo toyambitsa matenda m'matumbo, tinasanthula kapangidwe ka tizilombo toyambitsa matenda m'matumbo pamlingo uliwonse wa taxonomic. Monga momwe zasonyezedwera pa Chithunzi 4A, phyla yayikulu m'magulu onse inali Firmicutes ndi Bacteroidetes, kutsatiridwa ndi Verrucomicrobia. Kuchuluka kwa Firmicutes ndi Firmicutes/Bacteroidetes kunawonjezeka kwambiri m'magulu a tizilombo toyambitsa matenda m'matumbo a mbewa zothandizidwa ndi DSS poyerekeza ndi mbewa zowongolera, ndipo kusinthaku kunasinthidwa kwambiri pambuyo pa chithandizo cha BLG. Makamaka, chithandizo cha BLG chinawonjezera kwambiri kuchuluka kwa Verrucobacterium m'chimbudzi cha mbewa zomwe zili ndi matenda a DSS-induced colitis. Pabanja, madera a tizilombo toyambitsa matenda m'matumbo anali okhala ndi Lachnospiriaceae, Muribaculaceae, Akkermansiaceae, Ruminococcaceae ndi Prevotellaceae (Chithunzi 4B). Poyerekeza ndi gulu la DSS, kuchepa kwa BLG kunawonjezera kuchuluka kwa Akkermansiaceae, koma kunachepetsa kuchuluka kwa Lachnospiraceae ndi Ruminococcaceae. Makamaka, pa mtundu wa Pa mlingo, tizilombo toyambitsa matenda ta ntchentche tinali ndi Lachnospira_NK4A136_group, Akkermansia ndi Prevotellaceae_UCG-001 (Chithunzi 4C). Kupeza kumeneku kunawonetsanso kuti chithandizo cha BLG chinathetsa kusalingana kwa tizilombo toyambitsa matenda poyankha vuto la DSS, lomwe limadziwika ndi kuchepa kwa Eubacterium_xylanophilum_group, Ruminococcaceae_UCG-014, Intestinimonas ndi Oscillibacter, komanso kuwonjezeka kwa Akkermansia ndi Prevotellaceae_UCG-001.
Chithunzi 4 BLG imasintha kuchuluka kwa tizilombo toyambitsa matenda m'matumbo mwa mbewa za DSS-induced colitis.(A) Kuchuluka kwa tizilombo toyambitsa matenda m'matumbo pamlingo wa phylum; (B) Kuchuluka kwa tizilombo toyambitsa matenda m'matumbo pamlingo wa banja; (C) Kuchuluka kwa tizilombo toyambitsa matenda m'matumbo pamlingo wa genus. Deta imaperekedwa ngati mean ± SEM (n = 6).#p < 0.05 kapena ###p < 0.001 vs gulu lolamulira (Con); *p < 0.05 kapena **p < 0.01 kapena ***p < 0.001 vs gulu la DSS.
Poganizira kuti ma asidi amafuta afupiafupi (SCFAs) ndiye ma metabolites akuluakulu a Akkermansia ndi Prevotellaceae_UCG-001, pomwe acetate, propionate ndi butyrate ndi ma SCFA ambiri mu intestine lumen, 25-27 tidakali mu kafukufuku wathu. Monga momwe zasonyezedwera mu Chithunzi 5, kuchuluka kwa fecal acetate, propionate, ndi butyrate kunachepetsedwa kwambiri mu gulu lomwe linalandira DSS, pomwe chithandizo cha BLG chingathe kuletsa kuchepa kumeneku.
Chithunzi 5. BLG imawonjezera kuchuluka kwa ma SCFA m'chimbudzi cha mbewa zomwe zili ndi matenda a m'mimba otchedwa DSS-induced colitis.(A) Kuchuluka kwa asidi wa acetic m'chimbudzi; (B) kuchuluka kwa asidi wa propionic m'chimbudzi; (C) kuchuluka kwa asidi wa butyric m'chimbudzi. Deta imaperekedwa ngati apakati ± SEM (n = 6).#p < 0.05 kapena ##p < 0.01 vs gulu lolamulira (Con); *p < 0.05 kapena **p < 0.01 vs gulu la DSS.
Tinawerengeranso mgwirizano wa Pearson pakati pa kusiyana kwa genus-level SCFA ndi fecal microbiota. Monga momwe zasonyezedwera pa Chithunzi 6, Akkermansia inali yogwirizana bwino ndi kupanga propionic acid (Pearson = 0.4866) ndi butyric acid (Pearson = 0.6192). Mosiyana ndi zimenezi, Enteromonas ndi Oscillobacter zonse zinali zosagwirizana ndi kupanga acetate, ndi Pearson coefficients ya 0.4709 ndi 0.5104, motsatana. Mofananamo, Ruminococcaceae_UCG-014 inali yogwirizana kwambiri ndi kupanga propionic acid (Pearson = 0.4508) ndi butyric acid (Pearson = 0.5842), motsatana.
Chithunzi 6 Kusanthula kwa mgwirizano wa Pearson pakati pa ma SCFA osiyana ndi tizilombo toyambitsa matenda a m'matumbo.(A) Enteromonas yokhala ndi acetic acid; (B) Concussion bacillus yokhala ndi acetic acid; (C) Akkermansia motsutsana ndi propionic acid; (D) Ruminococcus_UCG-014 yokhala ndi propionic acid; (E) Akkermansia yokhala ndi butyric acid; (F) ) Ruminococcus _UCG-014 yokhala ndi butyric acid.
Peptide-like peptide-1 (GLP-1) ndi chinthu cha mtundu wa cell chomwe chimachokera ku proglucagon (Gcg) chomwe chili ndi mphamvu zotsutsana ndi kutupa.28 Monga momwe zasonyezedwera pa Chithunzi 7, DSS idachepetsa kwambiri kufotokozedwa kwa Gcg mRNA. Chithandizo cha Colon ndi BLG chingathe kusintha kwambiri kuchepetsedwa kwa Gcg komwe kumabwera chifukwa cha DSS poyerekeza ndi gulu lolamulira (Chithunzi 7A). Nthawi yomweyo, kuchuluka kwa GLP-1 mu seramu kunachepa kwambiri m'gulu lomwe linalandira DSS, ndipo chithandizo cha BLG chingathe kuletsa kuchepa kumeneku (Chithunzi 7B). Popeza ma asidi amafuta afupiafupi amatha kuyambitsa kutulutsa kwa GLP-1 kudzera mu G-protein-coupled receptor 43 (GRP43) ndi G-protein-coupled receptor 41 (GRP41), tidayang'ananso GPR41 ndi GRP43 m'matumbo a mbewa za colitis ndipo tidapeza kuti kufotokozedwa kwa mRNA ya colonic ya GRP43 ndi GPR41 kunachepa kwambiri pambuyo pa DSS, ndipo chithandizo cha BLG chingathe kupulumutsa kuchepa kumeneku (Chithunzi 7B). 7C ndi D).
Chithunzi 7 BLG imawonjezera kuchuluka kwa GLP-1 m'magazi ndi kufotokozera kwa mRNA ya colonic Gcg, GPR41 ndi GRP43 m'matumbo mwa mbewa zomwe zathandizidwa ndi DSS.(A) Kufotokozera kwa mRNA ya Gcg m'matumbo; (B) Kuchuluka kwa GLP-1 m'magazi; (C) Kufotokozera kwa mRNA ya GPR41 m'matumbo; (D) Kufotokozera kwa mRNA ya GPR43 m'matumbo. Deta imaperekedwa ngati apakati ± SEM (n = 5–6).#p < 0.05 kapena ##p < 0.01 vs gulu lolamulira (Con); *p < 0.05 vs gulu la DSS.
Popeza chithandizo cha BLG chingathe kuwonjezera kuchuluka kwa GLP-1 m'magazi, kufalikira kwa Gcg mRNA m'matumbo, ndi kuchuluka kwa SCFA m'matumbo mwa mbewa zomwe zalandira DSS, tinapitiliza kufufuza acetate, propionate, ndi butyrate komanso kuchokera ku control (F-Con), DSS colitis (F-Con) -DSS) ndi BLG-treated colitis (F-BLG) mbewa zomwe zalandira GLP-1 kuchokera ku maselo oyambira a murine colonic epithelial. Monga momwe zasonyezedwera pa Chithunzi 8A, maselo oyambira a mbewa omwe amalandira GLP-1 kuchokera ku maselo oyambira a murine colonic epithelial. Monga momwe zasonyezedwera pa Chithunzi 8A, maselo oyambira a mbewa omwe amalandira GLP-1 mM acetic acid, propionic acid, ndi butyric acid, motsatana, adalimbikitsa kwambiri kutulutsidwa kwa GLP-1, mogwirizana ndi maphunziro am'mbuyomu.29,30 Momwemonso, F-Con, F-DSS, ndi F-BLG zonse (zofanana ndi 0.25 g ya ndowe) zidalimbikitsa kwambiri kutulutsidwa kwa GLP-1 kuchokera ku maselo oyambira a murine colonic epithelial. Chodziwika bwino ndi chakuti, kuchuluka kwa GLP-1 komwe kumatulutsidwa ndi maselo oyambira a mbewa omwe amalandira F-DSS kunali kotsika kwambiri kuposa komweko. za maselo a epithelial a mbewa oyambilira omwe amathandizidwa ndi F-Con ndi F-BLG. (Chithunzi 8B). Deta iyi ikusonyeza kuti chithandizo cha BLG chinabwezeretsa kwambiri kupanga kwa GLP-1 m'matumbo komwe kumachokera ku SCFA.
Chithunzi 8 SCFA yochokera ku BLG imalimbikitsa kutulutsidwa kwa GLP-1 kuchokera ku maselo oyambira a epithelial a murine colonic.(A) Acetic acid, propionic acid, ndi butyric acid zinalimbikitsa kutulutsidwa kwa GLP-1 kuchokera ku maselo oyambira a epithelial a murine colonic; (B) zotulutsa m'matumbo F-Con, F-DSS ndi F-BLG zoyambitsa maselo oyambira a epithelial a murine colonic Kuchuluka kwa GLP-1 kunatulutsidwa. Ma quot a maselo oyambira a colonic epithelial anaikidwa m'mbale za petri zomwe zili pansi pa galasi ndipo anachiritsidwa ndi 2 mM acetic acid, propionic acid, butyric acid, ndi zotulutsa m'matumbo F-Con, F-DSS, ndi F-BLG (zofanana ndi ndowe za 0.25 g), motsatana. Maola awiri pa 37°C, 5% CO2, motsatana. Kuchuluka kwa GLP-1 komwe kumatulutsidwa kuchokera ku maselo a primary murine colonic epithelial kunapezeka ndi ELISA. Deta imawonetsedwa ngati apakati ± SEM (n = 3).#p < 0.05 kapena ##p < 0.01 vs. blank kapena F-Con; *p < 0.05 vs. F-DSS.
Mafupikitsidwe: Ace, acetic acid; Pro, propionic acid; komabe, butyric acid; F-Con, chotsitsa cha ndowe kuchokera ku mbewa zowongolera; F-DSS, chotsitsa cha ndowe kuchokera ku mbewa za colitis; F-BLG, kuchokera ku matumbo otupa omwe amachiritsidwa ndi BLG.
Bungwe la World Health Organization lalemba kuti ndi matenda osachiritsika, ndipo UC ikukhala ngozi padziko lonse lapansi; Komabe, njira zothandiza zodziwira, kupewa, ndi kuchiza matendawa zikadali zochepa. Chifukwa chake, pakufunika kufufuza mwachangu ndikupanga njira zatsopano zotetezeka komanso zothandiza zochiritsira za UC. Mankhwala achikhalidwe aku China ndi njira yabwino chifukwa mankhwala ambiri achikhalidwe aku China awonetsedwa kuti ndi othandiza pochiza UC mwa anthu aku China kwa zaka mazana ambiri, ndipo onse ndi zinthu zachilengedwe komanso zachilengedwe zomwe sizivulaza anthu ndi nyama.31,32 Kafukufukuyu cholinga chake chinali kufunafuna mankhwala achikhalidwe aku China otetezeka komanso ogwira mtima pochiza UC ndikuwunika momwe imagwirira ntchito.BLG ndi njira yodziwika bwino yochizira matenda a chimfine ku China.8,33 Ntchito mu labotale yathu ndi zina zawonetsa kuti indigo, mankhwala achikhalidwe aku China okonzedwa kuchokera kuzinthu zomwezo monga BLG, ikuwonetsa bwino kwambiri pochiza UC mwa anthu ndi nyama.4,34 Komabe, zotsatira za BLG zotsutsana ndi colitis ndi zotsatira zake Njirayi sizikudziwika bwino. Mu kafukufukuyu wapano, zotsatira zathu zikuwonetsa kuti BLG imachepetsa bwino kutupa kwa m'matumbo komwe kumabwera chifukwa cha DSS, komwe kumakhudzana ndi kusintha kwa m'mimba. microbiota ndi kubwezeretsa kupanga kwa GLP-1 komwe kumachokera m'matumbo.
Ndizodziwika bwino kuti UC imadziwika ndi nthawi zobwereranso zomwe zimakhala ndi zizindikiro za matenda, monga kuchepa thupi, kutsegula m'mimba, kutuluka magazi m'matumbo, komanso kuwonongeka kwakukulu kwa mucosal ya m'matumbo.35 Chifukwa chake, matenda a colitis osatha adaperekedwa popereka magawo atatu a 1.8% DSS kwa masiku asanu, kutsatiridwa ndi masiku asanu ndi awiri akumwa madzi. Monga momwe zasonyezedwera pa Chithunzi 1B, kuchepa thupi kosasinthasintha ndi zigoli za DAI zidawonetsa kuyambitsa bwino kwa matenda a colitis osatha. Mbewa zomwe zidathandizidwa ndi BLG zidawonetsa kuchira kwabwino kuyambira tsiku la 8, zomwe zinali zosiyana kwambiri ndi tsiku la 24. Kusintha komweku kudawonedwanso mu zigoli za DAI, zomwe zikusonyeza kusintha kwa kusintha kwa matenda a colitis. Ponena za kuvulala kwa m'matumbo ndi momwe kutupa kumakhalira, kutalika kwa m'matumbo, kuwonongeka kwa minofu ya m'matumbo, komanso mawonekedwe a majini ndi kupanga ma cytokines oyambitsa kutupa a TNF-α, IL-1β, ndi IL-6 m'matumbo a m'matumbo nawonso adakula kwambiri atalandira chithandizo cha BLG. Zonsezi zikuwonetsa bwino kuti BLG ndi yothandiza pochiza matenda a colitis osatha m'makoswe.
Kodi BLG imagwira ntchito bwanji ndi mankhwala? Kafukufuku wambiri wakale wasonyeza kuti tizilombo toyambitsa matenda m'matumbo timagwira ntchito yofunika kwambiri pa matenda a UC, ndipo mankhwala ochiritsira matenda a microbiome ndi microbiome aonekera ngati njira yokongola kwambiri yochizira UC. Mu kafukufukuyu, tawonetsa kuti chithandizo cha BLG chinapangitsa kusintha kwakukulu kwa kapangidwe ka tizilombo toyambitsa matenda m'matumbo, zomwe zikusonyeza kuti chitetezo cha BLG ku matenda a m'matumbo omwe amabwera chifukwa cha DSS chikugwirizana ndi kusintha kwa tizilombo toyambitsa matenda m'matumbo. Izi zikugwirizana ndi lingaliro lakuti kukonzanso homeostasis ya tizilombo toyambitsa matenda m'matumbo ndi njira yofunika kwambiri yomvetsetsa mphamvu ya mankhwala a TCM.36,37 Chodziwika bwino n'chakuti, Akkermansia ndi bakiteriya wopanda Gram komanso wopanda anaerobic womwe umakhala mu mucus layer ya m'matumbo, womwe umawononga mucins, umapanga propionic acid, umalimbikitsa kusiyana kwa maselo a goblet, ndikusunga mucous. ntchito ya chitetezo cha zotchinga.26 Deta zambiri zachipatala ndi zinyama zikusonyeza kuti Akkermansia imagwirizana kwambiri ndi mucosa wathanzi,38 ndi kumwa Akkermansia spp. zingawongolere kwambiri kutupa kwa mucosal.39 Deta yathu yamakono ikusonyeza kuti kuchuluka kwa Akkermansia kumawonjezeka kwambiri pambuyo pa chithandizo cha BLG. Kuphatikiza apo, Prevotellaceae_UCG-001 ndi bacterium yotulutsa SCFA.27 Kafukufuku wambiri wasonyeza kuti Prevotellaceae_UCG-001 idapezeka yochuluka pang'ono m'chimbudzi cha nyama zomwe zili ndi matenda a m'matumbo.40,41 Deta yathu yamakono ikuwonetsanso kuti chithandizo cha BLG chingawonjeze kwambiri kuchuluka kwa Prevotellaceae_UCG-001 m'matumbo a mbewa zomwe zachiritsidwa ndi DSS. Mosiyana ndi zimenezi, Oscillibacter ndi bacterium yokonda mesophilic, yomwe imakhala ndi anaerobic.42 inanena kuti kuchuluka kwa Oscillibacter kunawonjezeka kwambiri m'mbewa za UC ndipo kunali kogwirizana kwambiri ndi milingo ya IL-6 ndi IL-1β komanso ziwerengero za matenda.43,44 Chodziwika bwino, chithandizo cha BLG chinachepetsa kwambiri kuchuluka kwa Oscillibacter m'chimbudzi cha mbewa zomwe zachiritsidwa ndi DSS. Chodziwika bwino ndi chakuti, mabakiteriya osinthidwa ndi BLG awa anali opanga kwambiri SCFA. Mabakiteriya. Kafukufuku wambiri wakale wasonyeza zotsatira zabwino za ma SCFA pa kutupa kwa m'matumbo ndi kuteteza umphumphu wa epithelial m'matumbo.45,46 Deta yathu yapano yawonanso kuti kuchuluka kwa SCFA acetate, propionate, ndi butyrate mu ndowe zothandizidwa ndi DSS kunawonjezeka kwambiri mu mbewa zothandizidwa ndi BLG. Ponseponse, zomwe zapezekazi zikuwonetsa momveka bwino kuti chithandizo cha BLG chingalimbikitse bwino mabakiteriya opanga SCFA oyambitsidwa ndi DSS m'mbewa zomwe zili ndi matenda a colitis osatha.
GLP-1 ndi incretin yomwe imapangidwa makamaka mu ileum ndi m'matumbo ndipo imagwira ntchito yofunika kwambiri pochedwetsa kutuluka kwa m'mimba ndikuchepetsa shuga m'magazi pambuyo pa kudya.47 Umboni ukusonyeza kuti dipeptidyl peptidase (DPP)-4, GLP-1 receptor agonist, ndi GLP-1 nanomedicine zimatha kuchepetsa kutupa m'matumbo mwa mbewa.48-51 Monga momwe zanenedwera m'maphunziro am'mbuyomu, kuchuluka kwa SCFA kwakukulu kunalumikizidwa ndi kuchuluka kwa GLP-1 m'magazi mwa anthu ndi mbewa. 52 Deta yathu yamakono ikuwonetsa kuti pambuyo pa chithandizo cha BLG, kuchuluka kwa GLP-1 m'magazi ndi kufotokozedwa kwa Gcg mRNA kunawonjezeka kwambiri. Momwemonso, kutulutsa kwa GLP-1 kunawonjezeka kwambiri m'makolo pambuyo polimbikitsidwa ndi zotulutsa za ndowe kuchokera ku mbewa zodwala matenda a colitis zomwe zinachiritsidwa ndi BLG poyerekeza ndi kulimbikitsidwa ndi zotulutsa za ndowe kuchokera ku mbewa zodwala matenda a colitis zomwe zinachiritsidwa ndi DSS. Kodi ma SCFA amakhudza bwanji kutulutsidwa kwa GLP-1? Gwen Tolhurst et al. Zanenedwa kuti SCFA ikhoza kuyambitsa kutulutsa kwa GLP-1 kudzera mu GRP43 ndi GPR41.29 Deta yathu yomwe ilipo ikuwonetsanso kuti chithandizo cha BLG chimawonjezera kwambiri kufotokozedwa kwa mRNA kwa GRP43 ndi GPR41 m'matumbo a mbewa zomwe zalandira DSS. Deta iyi ikusonyeza kuti chithandizo cha BLG chingabwezeretse kupanga kwa GLP-1 komwe kumalimbikitsidwa ndi SCFA mwa kuyambitsa GRP43 ndi GPR41.
BLG ndi mankhwala ogulitsidwa kwa nthawi yayitali (OTC) ku China. Mlingo waukulu kwambiri wa BLG womwe umaloledwa m'makoswe a ku Kunming ndi 80g/Kg, ndipo palibe poizoni woopsa womwe wapezeka.53 Pakadali pano, mlingo woyenera wa BLG (wopanda shuga) mwa anthu ndi 9-15 g/tsiku (katatu patsiku). Kafukufuku wathu adawonetsa kuti BLG pa 1g/Kg idachepetsa matenda a m'mimba obwera chifukwa cha DSS m'makoswe. Mlingowu uli pafupi ndi mlingo wa BLG womwe umagwiritsidwa ntchito kuchipatala. Kafukufuku wathu adapezanso kuti njira yake yogwirira ntchito imayang'aniridwa, pang'ono pang'ono, ndi kusintha kwa ma microbiota m'matumbo, makamaka mabakiteriya opanga SCFA, monga Akkermansia ndi Prevotellaceae_UCG-001, kuti abwezeretse kupanga kwa GLP-1 komwe kumachokera m'matumbo. Zomwe zapezekazi zikusonyeza kuti BLG iyenera kuganiziridwanso ngati mankhwala ochiritsira matenda a m'matumbo. Komabe, njira yeniyeni yomwe imasinthira ma microbiota m'matumbo ikuyenera kutsimikiziridwa ndi mbewa zomwe zili ndi microbiota yosowa komanso kuyika mabakiteriya m'chimbudzi.
Ace, acetic acid; koma, butyric acid; BLG, pandan; DSS, dextran sodium sulfate; DAI, index ya matenda; DPP, dipeptidyl peptidase; FID, chowunikira ionization ya malawi; F-Con, kuwongolera Zotulutsa za Fecal za mbewa; F-DSS, zotulutsa za fecal za mbewa za DSS colitis; F-BLG, zotulutsa za fecal za mbewa zochiritsidwa ndi BLG; GLP-1, glucagon-like peptide-1; Gcg, glucagon; gas chromatography, gas chromatography; GRP43, G protein-coupled receptor 43; GRP41, G protein-coupled receptor 41; H&E, hematoxylin-eosin; HBSS, Hanks' Balanced Salt Solution; OTC, OTC; PCA, kusanthula kwa zigawo zazikulu; PCoA, kusanthula kwakukulu kwa coordinate; Pro, propionic acid; SASP, sulfasalazine; SCFA, short-chain fatty acids; Mankhwala achi China, mankhwala achi China; UC, matenda a zilonda zam'mimba.
Ma protocol onse oyesera adavomerezedwa ndi Animal Ethics Committee ya Peking University Shenzhen-Hong Kong University of Science and Technology Medical Center (Shenzhen, China) malinga ndi Institutional Guidelines and Animal Regulations (ma ethics number A2020157).
Olemba onse adapereka chithandizo chofunikira pakupanga ndi kupanga, kupeza deta, kapena kusanthula deta ndi kutanthauzira; adatenga nawo gawo polemba nkhaniyi kapena kusinthanso mfundo zofunika zamaganizo; adavomereza kutumiza zolembazo ku magazini yamakono; pomaliza adavomereza kuti zifalitsidwe; anali ndi udindo pa mbali zonse za ntchito.
Ntchitoyi inathandizidwa ndi National Natural Science Foundation of China (81560676 ndi 81660479), pulojekiti yoyamba ya Shenzhen University (86000000210), Shenzhen Science and Technology Innovation Committee Fund (JCYJ20210324093810026), ndi Guangdong Provincial Medical Science and Technology Research Fund (A2020157 ndi A2020272), Guizhou Medical University Pharmacy Guizhou Province Funded by Key Laboratory (YWZJ2020-01) ndi Peking University Shenzhen Hospital (JCYJ2018009).
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