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Udukoko twa Ban-Lan-Gen tugabanya indwara ya colitis idakira iterwa na dextran sodium sulfate mu mbeba binyuze mu guhindura mikorobe zo mu mara no kugarura umusaruro wa SCFA Derived-GLP-1 mu mara.
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 Haitao21 Ibitaro bya Kaminuza ya Peking Shenzhen Ishami rya Farumasi, Shenzhen, Repubulika y'Abaturage b'Ubushinwa; 2Ikigo cy'Ubumenyi bw'Ubuzima cya Kaminuza ya Shenzhen, Ishuri rya Farumasi, Shenzhen, Repubulika y'Abaturage b'Ubushinwa; 3 Ikigo cy'Ubushakashatsi ku Ikoranabuhanga rya Kaminuza y'Ubuvuzi ya Guizhou mu Buvuzi bw'Amahanga n'Imiti gakondo y'Abashinwa Minisiteri y'Uburezi, Laboratwari y'ingenzi ya Farumasi yo mu Ntara ya Guizhou, Kaminuza y'Ubuganga ya Guizhou, Guiyang, Repubulika y'Abaturage b'Ubushinwa; 4 Ishami rya Gastroenterology, Ibitaro bya Kaminuza ya Peking Shenzhen, Shenzhen, Repubulika y'Abaturage b'Ubushinwa; 5 Ishuri rya Farumasi, Kaminuza y'Ubuganga ya Guizhou, Laboratwari y'ingenzi ya Leta mu Mikorere n'Imikoreshereze y'Ibimera by'Imiti, Guiyang; 6 Ishami ry’Ubuvuzi bwa Laboratwari, Ibitaro bya Peking University Shenzhen, Shenzhen, Ubushinwa [email protected] Shen Xiangchun, Ishuri rya Farumasi, Kaminuza y’Ubuvuzi ya Guizhou, Guizhou, Repubulika y’Abaturage b’Ubushinwa, 550004, Imeri [email protected] Intego: Ubuvuzi bushingiye kuri GLP-1 ni uburyo bushya bwo kuvura indwara y’amara abyimbye. Uduce twa Ban-Lan-Gen (BLG) ni umuti uzwi wa TCM urwanya virusi ugaragaza ubushobozi bwo kurwanya indwara mu kuvura indwara zitandukanye zibyimbye. Ariko, ingaruka zayo zo kurwanya indwara y’amara abyimbye n’uburyo ikora ntibirasobanuka neza. UBURYO: Kugira ngo hamenyekane indwara y’amara abyimbye idakira iterwa na dextran sodium sulfate (DSS) mu mbeba. Ibipimo by’indwara, ibimenyetso by’imvune, n’urugero rwa cytokine rutera ububyimbirwe byakozwe kugira ngo hamenyekane ingaruka zo kurinda za BLG. Ingaruka za BLG ku mikorobe y’amara n’amara zaranzwe n’urugero rwa GLP-1 mu mara n’imyitwarire ya Gcg y’inkondo y’umura, GPR41, na GRP43, imiterere ya mikorobe y’amara, umwanda Urugero rwa SCFA, no kurekurwa kwa GLP-1 mu turemangingo tw’ibanze tw’imbeba zikora mu mara, umusaruro wa GLP-1 ukomoka kuri SCFA. Ibisubizo: Ubuvuzi bwa BLG bwagabanyije cyane kugabanuka k'ibiro by'umubiri, DAI, kugabanuka kw'amara, kwangirika kw'uturemangingo tw'amara, n'urugero rwa TNF-α, IL-1β, na IL-6 mu mara. Byongeye kandi, ubuvuzi bwa BLG bushobora kugarura cyane urugero rwa Gcg, GPR41 na GRP43 mu mara no mu mara, mu mbeba zikora mu mara, no kongera bagiteri zikora muri SCFA nka Akkermansia na Prevotellaceae_UCG-001, no kugabanya ubwinshi bwa bagiteri nka Eubacterium_xylanophilum_group, Ruminococcaceae_UCG-014, Intestinimonas na Oscillibacter. Byongeye kandi, ubuvuzi bwa BLG bushobora kongera cyane urugero rwa SCFA mu mwanda w'imbeba zikora mu mara. Muri icyo gihe, igerageza ryakozwe muri vitro ryagaragaje ko umwanda w’imbeba zavuwe na BLG ushobora gukurura cyane uturemangingo duto tw’ibanze twa Murine colonic epithelial secretions dusohora GLP-1. Umwanzuro: Ibi byavumbuwe bigaragaza ko BLG ifite ingaruka zo kurwanya colitis. BLG ifite ubushobozi bwo guterwa nk'ubuvuzi, nibura igice kimwe binyuze mu guhindura microbiota mu mara no kugarura umusaruro wa GLP-1 ikomoka kuri SCFA mu mara. Imiti yizewe yo kuvura colitis idakira. Amagambo ahinnye: colitis, Ban-Lan-Gen granules, intestine microbiota, aside fatty acids ngufi, GLP-1
Ulcerative colitis (UC) ni indwara y’ububyimbirwe bw’igihe kirekire mu mara no mu nda irangwa no gucibwamo kenshi, kubabara mu nda, kugabanya ibiro, no kwituma amaraso mu nda.1 Vuba aha, ikwirakwira rya UC ryakomeje kwiyongera mu bihugu byari bisanzwe bitagira ubwiyongere bw’indwara, harimo n’Ubushinwa, aho imibereho yo mu Burengerazuba bw’isi ikomeje kwiyongera.2 Uku kwiyongera guteye ibibazo bikomeye ku buzima rusange kandi bigira ingaruka zikomeye ku bushobozi bw’abarwayi bwo gukora no ku mibereho myiza. Cyane cyane, impamvu za UC ntabwo zirasobanuka neza, ariko muri rusange byemewe ko imiterere y’uturemangingo, ibintu bidukikije, mikorobe zo mu nda, n’ubudahangarwa bw’umubiri byose bigira uruhare mu iterambere rya UC.3 Ndetse na n’ubu, nta muti wa UC uraboneka, kandi intego yo kuvura ni ukugenzura ibimenyetso by’uburwayi, gutera no gukomeza koroherwa, guteza imbere gukira kw’uturemangingo, no kugabanya kongera kugaruka kwabyo. Uburyo bwo kuvura bwa kera burimo aminosalicylates, corticosteroids, imiti igabanya ubudahangarwa bw’umubiri, na biologics. Ariko, iyi miti ntishobora kugera ku ngaruka yifuza bitewe n’ingaruka zayo zitandukanye.4 Vuba aha, ubushakashatsi bwinshi bwagaragaje ko ubuvuzi gakondo bw’Abashinwa (TCM) bwagaragaje ubushobozi bukomeye mu gufasha kugabanya UC ifite uburozi buke, bigaragaza ko iterambere ry'ubuvuzi bushya bwa TCM ari ingamba nziza zo kuvura UC.5-7
Banlangen Granules (BLG) ni umuti gakondo w’Abashinwa ukozwe mu mazi ava mu muzi wa Banlangen.8 Uretse ubushobozi bwayo bwo kurwanya indwara ziterwa n’imiti, BLG igaragaza ubushobozi bwo kurwanya indwara ziterwa n’imiti mu kuvura indwara zitandukanye ziterwa n’imiti.9,10 Byongeye kandi, glucosinolates (R,S-goitrin, progoitrin, epiprorubin na glucoside byatoranijwe kandi byagaragaye mu bivange by’amazi bya Radix isatidis) na nucleosides (hypoxanthine, adenosine, uridine na guanosine) na indigo alkaloids nka indigo na indirubin.11,12 Ubushakashatsi bwabanje bwagaragaje neza ko ibinyabutabire bya adenosine, uridine na indirubin bigaragaza ingaruka zikomeye zo kurwanya indwara ya colitis mu nyamaswa zitandukanye za colitis.13-17 Ariko, nta bushakashatsi bushingiye ku bimenyetso bwakozwe kugira ngo harebwe akamaro ka BLG mu ndwara ya colitis. Muri ubu bushakashatsi, twasuzumye ingaruka zo kurinda za BLG ku ndwara ya colitis idakira iterwa na dextran sodium sulfate (DSS) muri Imbeba za C57BL/6 kandi zasanze gutanga BLG mu kanwa byagabanyije cyane uburyo bwo kugabanya amara ahora asubira inyuma buterwa na DSS mu mbeba. Uburyo bwo kuyirwanya bujyana no guhindura mikorobe zo mu mara no kugarura umusaruro wa peptide-1 (GLP-1) ikomoka mu mara.
Ibinyabutabire bya BLG (bidafite isukari, byemejwe na NMPA na Z11020357; Beijing Tongrentang Technology Development Co., Ltd., Beijing, Ubushinwa; nimero ya batch: 20110966) byaguzwe muri farumasi. DSS (Uburemere bwa Molecular: 36,000–50,000 Daltons) yaguzwe muri MP Biologicals (Santa Ana, Amerika). Sulfasalazine (SASP) (≥ 98% ubuziranenge), hematoxylin na eosin byaguzwe muri Sigma-Aldrich (St. Louis, MO, Amerika). Ifu ya TNF-α, IL-1β na IL-6 luminex Elisa assay yaguzwe muri sisitemu zo gusesengura no guteza imbere ubushakashatsi (Minneapolis, MN, Amerika). Aside asetiki, aside propionic, na aside butyric byaguzwe muri Aladdin Industries (Shanghai, Ubushinwa). 2-Aside ethylbutyric yaguzwe muri Merck KGaA (Darmstadt, Ubudage).
Imbeba z'abagabo zifite ibyumweru 6-8 C57BL/6 (zifite uburemere bw'umubiri 18-22 g) zaguzwe muri Beijing Wetahe Laboratory Animal Technology Co., Ltd. (Beijing, Ubushinwa) zicumbikirwa ahantu hari ubushyuhe bwa 22 ± 2 °C hamwe n'amasaha 12 y'urumuri/umwijima. Imbeba zahawe indyo isanzwe y'imbeba hamwe n'amazi yo kunywa ku buntu mu gihe cy'icyumweru kimwe kugira ngo zimenyere ibidukikije bishya. Hanyuma imbeba zagabanyijwemo amatsinda ane mu buryo butunguranye: itsinda ryo kugenzura, itsinda rya DSS, itsinda ryavuwe na SASP (200 mg/kg, mu kanwa) n'itsinda ryavuwe na BLG (1 g/kg, mu kanwa). Nkuko bigaragara ku Ishusho ya 1A, nk'uko ubushakashatsi bwacu bwa mbere bwabigaragaje, indwara ya colitis idakira yakoreshejwe mu igerageza yatewe n'imbeba mu byiciro bitatu bya 1.8% DSS mu minsi 5, hagakurikiraho amazi yaciwe mu minsi 7, nk'uko ubushakashatsi bwacu bwa mbere bwabigaragaje.18 Imbeba zo mu matsinda yavuwe na SASP na BLG zavuwe na SASP na BLG, buri munsi uhereye ku munsi wa 0. Dukurikije igerageza ry'ibanze, Igipimo cya BLG cyashyizwe kuri 1 g/kg. Hagati aho, igipimo cya SASP cyashyizwe kuri 200 mg/Kg nk'uko inyandiko zibivuga.4 Amatsinda y’icyitegererezo n’ay’icyitegererezo cya DSS yabonye ingano imwe y’amazi mu gihe cyose cy’igerageza.
Ishusho ya 1 BLG yoroshya indwara ya colitis idakira iterwa na DSS mu mbeba. (A) Igerageza ry'indwara ya colitis idakira isubira inyuma n'uburyo ivurwa, (B) impinduka z'uburemere bw'umubiri, (C) amanota y'indwara (DAI), (D) uburebure bw'amara, (E) ishusho igaragaza amara, (F) H&E irangi rya Colon (magnification, ×100) na (G) amanota y'impinduka mu mara. Amakuru agaragazwa nk'ikigereranyo ± SEM (n = 6). ##p < 0.01 cyangwa ###p < 0.001 vs itsinda ryo kugenzura (Con); *p < 0.05 cyangwa **p < 0.01 cyangwa ***p < 0.001 vs itsinda rya DSS.
Uburemere bw'umubiri, imiterere y'umwanda, n'amaraso ava mu maraso byafatwaga buri munsi. Igipimo cy'ibikorwa by'indwara (DAI) cyagenwe hahujwe amanota y'uburemere bw'umubiri, imiterere y'umwanda, n'amaraso ava mu maraso nk'uko byasobanuwe mbere.19 Mu mpera z'igerageza, imbeba zose zaraciwe maze amaraso, amase n'amara bikusanywa kugira ngo bikorerwe andi magerageza.
Uduce tw’amarangi twashyizweho formaline hanyuma dushyirwa muri parafini. Ibice bya mikoroni 5 byakozwe kandi bisiga irangi rya hematoxylin-eosin (H&E), hanyuma bihuma amaso kandi bishyirwa mu madosiye nk'uko byasobanuwe mbere.19
RNA yose y'uturemangingo tw'amara yakuwemo hakoreshejwe reagent ya Trizol (Invitrogen, Carlsbad, CA), hagakurikiraho gukuramo cDNA hakoreshejwe reverse transcriptase (TaKaRa, Kusatsu, Shiga, Ubuyapani). PCR y'ingano yakozwe hakoreshejwe sisitemu ya PCR y'igihe nyacyo hamwe na SYBR Green Master (Roche, Basel, Ubusuwisi). Inyandiko za gene zigamije zahinduwe β-actin kandi amakuru yasesenguwe hakoreshejwe uburyo bwa 2-ΔΔCT. Urutonde rw'uturemangingo twa gene rugaragara muri Table 1.
Gutandukanya uturemangingo tw’imbere tw’imbeba no kuzivura byakozwe nk'uko byasobanuwe mbere.20 Muri make, utunyangingo tw’imbeba dufite ibyumweru 6-8 twabanje gucibwa nyuma yo gucibwa n’inkondo y’umura, hanyuma tugafungurwa mu buryo burambuye, tugavurwa na Hanks Balanced Salt Solution (HBSS, nta calcium na manyeziyumu) ​​hanyuma tugacibwamo uduce duto twa mm 0.5-1. Nyuma yaho, uturemangingo twashyizwemo 0.4 mg/mL ya collagenase XI (Sigma, Poole, UK) mu buryo bwa DMEM budafite imiterere maze dushyirwa kuri 300 xg mu gihe cy'iminota 5 ku bushyuhe bw'icyumba. Ongera ushyiremo agace k’imbeba mu buryo bwa DMEM (kongerwamo 10% by’amaraso y’inka yo mu nda, penicilline 100/mL, na streptomycin 100 µg/mL) kuri 37 °C hanyuma unyure mu muyoboro wa nylon (ingano y’umuyoboro ~ 250 µm). Uduce tw’utunyangingo tw’imbere tw’imbeba twashyizwe mu masahani yo hasi y’ikirahure hanyuma dushyirwamo aside asetiki, aside propionic, aside butyric, n'ibikomoka ku mwanda w'imbeba mu gihe cy'amasaha 2 kuri 37°C, 5% bya CO2.
Uduce tw’inkondo y’umura twahinduwe kimwe na PBS, kandi urugero rwa cytokines IL-6, TNF-α na IL-1β mu duce tw’inkondo y’umura rwabonetse hakoreshejwe ibikoresho bya luminex ELISA assay (systems za R&D, Minneapolis, MN, USA). Mu buryo nk’ubwo, urugero rwa GLP-1 mu maraso n’uburyo bwo gupima uturemangingo tw’inkondo y’umura rwapimwe hakoreshejwe ibikoresho bya ELISA (Bioswamp, Wuhan, Ubushinwa) hakurikijwe amabwiriza y’uruganda.
ADN yose yakuwe mu mwanda hakoreshejwe agakoresho ko gukuramo ADN (Tiangen, Ubushinwa). Ubwiza n'ingano ya ADN byapimwe ku gipimo cya 260 nm/280 nm na 260 nm/230 nm, uko bikurikirana. Nyuma yaho, hakoreshejwe buri ADN yakuwemo nk'icyitegererezo, primers zihariye 338F (ACTCCTACGGGAGGCAGCAG) na 806R (GGACTACHVGGGTWTCTAAT) zakoreshejwe mu kongera uturere twa V3-V4 twa gene ya 16S rRNA mu turere dutandukanye. Ibicuruzwa bya PCR byatunganyijwe hakoreshejwe QIAquick Gel Extraction Kit (QIAGEN, Ubudage), byapimwe hakoreshejwe PCR y'igihe nyacyo, kandi bikurikiranywa hakoreshejwe urubuga rwa IlluminaMiseq PE300 sequencing (Illumina Inc., CA, USA). Ku isesengura rya bioinformatics, gutunganya amakuru byakozwe hakurikijwe protocole zavuzwe mbere.21,22 Muri make, koresha Cutadapt (V1.9.1) kugira ngo uyungurure dosiye za express zitari nziza. OTU zashyizwe mu matsinda. hakoreshejwe UPARSE (verisiyo ya 7.0.1001) ifite ikigereranyo cy’ibisa cya 97%, kandi UCHIME yakoreshejwe mu gukuraho uruhererekane rwa chimeric. Isesengura ry’imiterere y’umuryango n’ishyirwa mu byiciro byakozwe hakoreshejwe uburyo bwa RDP classifier (http://rdp.cme.msu.edu/) bushingiye ku bubiko bwa SILVA ribosomal RNA gene database.
Ingano ya aside irike y’uruhererekane rugufi (aside asetiki, aside propiyoni, na aside butyric) yapimwe nk'uko byasobanuwe mbere na Tao et al., hamwe n'impinduka zimwe na zimwe.23 Muri make, miligarama 100 z'imyanda zabanje gushyirwa mu mazi ya 0.4 mL, hagakurikiraho 0.1 mL ya aside sulfurike 50% na 0.5 mL ya aside 2-ethylbutyric (isanzwe imbere), hanyuma zigahindurwa zigashyuha kuri dogere selisiyusi 4. Centrifuge ku muvuduko wa 12.000 rpm mu minota 15 kuri C. Supernatant yakuwemo 0.5 mL ya ether hanyuma ishyirwa muri GC kugira ngo ikoreshwe. Ku isesengura rya gaz chromatography (GC), ingero zasesenguwe hakoreshejwe GC-2010 Plus gaz chromatography (Shimadzu, Inc.) ifite icyuma gipima umuriro (FID). Gutandukanya byakozwe hakoreshejwe inkingi ya ZKAT-624, 30 m × 0.53 mm × 0.3 μm (Lanzhou Zhongke Antai Analytical Technology Co., Ltd., mu Bushinwa). Amakuru yabonetse hakoreshejwe porogaramu ya GC solution (Shimadzu, Inc.). Igipimo cyo gutandukanya cyari 10: 1, gaz itwara yari azote, kandi umuvuduko w'amazi wari 6 mL / min. Ingano y'ishyirwamo yari 1 μL. Ubushyuhe bw'injector n'imashini ipima bwari 300 ° C. Ubushyuhe bw'ifuru bwagumye kuri 140 ° C mu minota 13.5, hanyuma bwongerwaho 250 ° C kuri igipimo cya 120°C/minota; ubushyuhe bwagumyeho iminota 5.
Amakuru agaragazwa nk'ikosa risanzwe rya ± ikosa risanzwe ry'ikigereranyo (SEM). Uburemere bw'amakuru bwapimwe hakoreshejwe ANOVA y'inzira imwe hagakurikiraho ikizamini cya Duncan cy'uburyo bwinshi. Porogaramu ya GraphPad Prism 5.0 (GraphPad Software Inc., San Diego, CA, USA) yakoreshejwe mu mibare yose naho p < 0.05 yafatwaga nk'ifite agaciro mu mibare.
Birazwi neza ko UC ari indwara idakira ya colitis isubira inyuma ifite ububabare bukomeye mu nda, impiswi no kuva amaraso. Kubwibyo, colitis idakira isubira inyuma iterwa na DSS mu mbeba yashyizweho kugira ngo hasuzumwe ubushobozi bwa BLG bwo kurwanya colitis (Ishusho ya 1A). Ugereranije n'itsinda ryagenzuwe, imbeba zo mu itsinda ry'icyitegererezo rya DSS zagabanutse cyane ibiro by'umubiri ndetse na DAI iri hejuru, kandi izi mpinduka zahindutse cyane nyuma y'iminsi 24 yo kuvurwa na BLG (Ishusho ya 1B na C). Kugabanya amara ni ikimenyetso cy'ingenzi cya UC. Nkuko bigaragara ku Ishusho ya 1D na E, uburebure bw'amara y'imbeba zakiriye DSS bwagabanutse cyane, ariko zagabanutse kubera kuvurwa na BLG. Nyuma yaho, isesengura ry'imyakura ryakozwe kugira ngo hasuzumwe ububyimbirwe bw'amara y'inkondo y'umura. Amashusho ya H&E yanduye n'amanota y'indwara byagaragaje ko gutanga DSS byahungabanyije cyane imiterere y'amara y'inkondo y'umura kandi byatumye habaho kwangirika kw'amamara y'inkondo y'umura, mu gihe kuvurwa na BLG byagabanyije cyane kwangirika kw'amamara y'inkondo y'umura n'amanota y'indwara (Ishusho ya 1F na G). Ikigaragara ni uko ingaruka zo kurinda za BLG ku gipimo cya 1 g/Kg zari zimeze nk'iza SASP ku gipimo cya 200 mg/Kg. Muri rusange, ibi byavumbuwe bigaragaza ko BLG ifite akamaro mu kugabanya ubukana bwa colitis idakira iterwa na DSS mu mbeba.
TNF-α, IL-1β na IL-6 ni ibimenyetso by'ingenzi by'ububyimbirwe bw'ububyimbirwe bw'inkondo y'umura. Nkuko bigaragara ku Ishusho ya 2A, DSS yatumye habaho ukwiyongera gukomeye mu mikorere ya TNF-α, IL-1β na IL-6 mu mara ugereranije n'itsinda ryigenzura. Gukoresha BLG bishobora guhindura cyane izi mpinduka ziterwa na DSS. Hanyuma, twakoresheje ELISA kugira ngo tumenye urugero rwa cytokines zitera ububyimbirwe TNF-α, IL-1β, na IL-6 mu mara. Ibisubizo byagaragaje kandi ko urugero rwa TNF-α, IL-1β, na IL-6 mu mara rwiyongereye cyane mu mbeba zavuwe na DSS, mu gihe ubuvuzi bwa BLG bwagabanyije uku kwiyongera (Ishusho ya 2B).
Ishusho ya 2 BLG ibuza imiterere ya gene no gukora cytokines zitera ububabare TNF-α, IL-1β na IL-6 mu mara y'imbeba zavuwe na DSS. (A) Imiterere ya gene ya colonic ya TNF-α, IL-1β na IL-6; (B) urugero rwa poroteyine ya colonic ya TNF-α, IL-1β na IL-6. Amakuru agaragazwa nk'ikigereranyo ± SEM (n = 4–6).#p < 0.05 cyangwa ##p < 0.01 cyangwa ###p < 0.001 vs itsinda ryo kugenzura (Con); *p < 0.05 cyangwa **p < 0.01 vs itsinda rya DSS.
Dysbiosis yo mu mara ni ingenzi mu ndwara ya UC.24 Kugira ngo hamenyekane niba BLG ihindura mikorobe yo mu mara y'imbeba zavuwe na DSS, hakozwe sequencing ya 16S rRNA kugira ngo hasesengurwe itsinda rya bagiteri ry’ibiri mu mara. Ishusho ya Venn igaragaza ko amatsinda atatu asangiye OTU 385. Muri icyo gihe, buri tsinda ryari rifite OTU zihariye (Ishusho ya 3A). Byongeye kandi, index ya Chao1 n'index ya Shannon bigaragazwa ku Ishusho ya 3B na C byagaragaje ko ubwinshi bw'uturemangingo tw'uturemangingo tw'uturemangingo tw'uturemangingo tw'uturemangingo bwagabanutse mu mbeba zavuwe na BLG, kuko index ya Shannon yagabanutse cyane mu itsinda ryavuwe na BLG. Isesengura ry'ibice by'ingenzi (PCA) n'isesengura ry'ibanze (PCoA) byakoreshejwe kugira ngo hamenyekane imiterere y'amatsinda atatu kandi byagaragaje ko imiterere y'umuryango w'imbeba zavuwe na DSS yatandukanye neza nyuma yo kuvurwa na BLG (Ishusho ya 3D na E). Aya makuru agaragaza ko kuvurwa na BLG byagize ingaruka zikomeye ku miterere y'umuryango w'imbeba zavuwe na DSS.
Ishusho ya 3 BLG ihindura ubwinshi bwa mikorobe zo mu nda mu mbeba zirwaye indwara ya DSS-induced colitis. (A) Ishusho ya Venn ya OTU, (B) Ikimenyetso cya Chao1, (C) Ikimenyetso cya Shannon cy'ubukire, (D) Igishushanyo cy'amanota ya Principal Component Analysis (PCA) ya OTU, (E) Ikimenyetso cya OTU Principal Coordinate Analysis (PCoA) Ishusho. Amakuru agaragazwa nk'ikigereranyo ± SEM (n = 6).**p < 0.01 vs itsinda rya DSS.
Kugira ngo dusuzume impinduka zihariye mu mikorobe y’amafi, twasesenguye imiterere ya mikorobe y’amafi mu mara ku rwego rwose rw’uturemangingo. Nkuko bigaragara ku Ishusho ya 4A, phyla nyamukuru mu matsinda yose yari Firmicutes na Bacteroidetes, hagakurikiraho Verrucomicrobia. Ubwinshi bwa Firmicutes na Firmicutes/Bacteroidetes bwiyongereye cyane mu matsinda y’udukoko two mu mafi y’imbeba zavuwe na DSS ugereranije n’imbeba zigenzura, kandi izi mpinduka zahindutse cyane nyuma yo kuvurwa na BLG. By’umwihariko, kuvurwa na BLG biyongereye cyane ubwinshi bwa Verrucobacterium mu mwanda w’imbeba zarwaye indwara ya DSS-induced colitis. Ku rwego rw’ingo, amatsinda y’udukoko two mu mafi yari yiganjemo Lachnospiriaceae, Muribaculaceae, Akkermansiaceae, Ruminococcaceae na Prevotellaceae (Ishusho ya 4B). Ugereranije n’itsinda rya DSS, kugabanuka kwa BLG byongera ubwinshi bwa Akkermansiaceae, ariko bigabanya ubwinshi bwa Lachnospiraceae na Ruminococcaceae. Cyane cyane, ku bwoko bwa ku rwego rwo hejuru, mikorobe y’umwanda yari yiganjemo Lachnospira_NK4A136_group, Akkermansia na Prevotellaceae_UCG-001 (Ishusho ya 4C). Iki cyavumbuwe cyanagaragaje ko uburyo bwo kuvura bwa BLG bwasubije inyuma ubusumbane bwa mikorobe mu gusubiza ikibazo cya DSS, cyaranzwe no kugabanuka kwa Eubacterium_xylanophilum_group, Ruminococcaceae_UCG-014, Intestinimonas na Oscillibacter, ndetse n’ubwiyongere bwa Akkermansia na Prevotellaceae_UCG-001.
Ishusho ya 4 BLG ihindura ubwinshi bwa mikorobe zo mu mara mu mbeba ziterwa na DSS. (A) Ubwinshi bwa mikorobe zo mu mara ku rwego rwa phylum; (B) Ubwinshi bwa mikorobe zo mu mara ku rwego rw'umuryango; (C) Ubwinshi bwa mikorobe zo mu mara ku rwego rwa genus. Amakuru agaragazwa nk'ikigereranyo ± SEM (n = 6).#p < 0.05 cyangwa ###p < 0.001 vs itsinda ryo kugenzura (Con); *p < 0.05 cyangwa **p < 0.01 cyangwa ***p < 0.001 vs itsinda rya DSS.
Dukurikije ko aside fatty zifata imiyoboro migufi (SCFAs) ari zo zigize metabolites nini za Akkermansia na Prevotellaceae_UCG-001, mu gihe acetate, propionate na butyrate ari zo SCFA nyinshi cyane mu mara, 25-27 turacyari mu bushakashatsi bwacu. Nkuko bigaragara ku Ishusho ya 5, igipimo cya acetate y'amafi, propionate, na butyrate cyagabanutse cyane mu itsinda ryavuwe na DSS, mu gihe uburyo bwo kuvura bwa BLG bwashoboraga gukumira uku kugabanuka.
Ishusho ya 5. BLG yongera urugero rwa SCFA mu mwanda w'imbeba zifite indwara ya DSS-induced colitis. (A) Ingano ya aside asetiki mu mwanda; (B) Ingano ya aside propionic mu mwanda; (C) Ingano ya aside butyric mu mwanda. Amakuru agaragazwa nk'ikigereranyo ± SEM (n = 6). #p < 0.05 cyangwa ##p < 0.01 vs itsinda ryo kugenzura (Con); *p < 0.05 cyangwa **p < 0.01 vs itsinda rya DSS.
Twakomeje kubara igipimo cya Pearson hagati ya SCFA y’ubwoko bw’ibinyabuzima n’udukoko twa microbiota. Nkuko bigaragara ku Ishusho ya 6, Akkermansia yari ifite isano nziza n’ikorwa rya aside propionic (Pearson = 0.4866) na aside butyric (Pearson = 0.6192). Mu buryo bunyuranye, Enteromonas na Oscillobacter byombi byari bifite isano mbi n’ikorwa rya acetate, hamwe na coefficients za Pearson za 0.4709 na 0.5104, uko bikurikirana. Mu buryo nk’ubwo, Ruminococcaceae_UCG-014 yari ifite isano mbi n’ikorwa rya aside propionic (Pearson = 0.4508) na aside butyric (Pearson = 0.5842), uko bikurikirana.
Ishusho ya 6 Isesengura rya Pearson hagati ya SCFA zitandukanye na mikorobe zo mu maraso. (A) Enteromonas hamwe na aside asetiki; (B) Bacillus yo mu bwonko hamwe na aside asetiki; (C) Akkermansia ugereranije na aside propionic; (D) Ruminococcus_UCG-014 hamwe na aside propionic; (E) Akkermansia hamwe na aside butyric; (F) ) Ruminococcus _UCG-014 hamwe na aside butyric.
Peptide-1 isa na Glucagon (GLP-1) ni umusaruro w’uturemangingo twa proglucagon (Gcg) ufite ubushobozi bwo kurwanya ububyimbirwe.28 Nkuko bigaragara ku Ishusho ya 7, DSS yagabanyije cyane igaragara rya Gcg mRNA. Ubuvuzi bwa Colon na BLG bushobora gusubiza inyuma cyane igabanuka rya Gcg riterwa na DSS ugereranije n’itsinda rigenzura (Ishusho ya 7A). Muri icyo gihe, urwego rwa GLP-1 mu maraso rwagabanutse cyane mu itsinda ryavuwe na DSS, kandi ubuvuzi bwa BLG bushobora gukumira iri gabanuka (Ishusho ya 7B). Kubera ko aside fatty y’uruhererekane rugufi ishobora gukurura ikorwa rya GLP-1 binyuze muri receptor ya G-protein-coupled 43 (GRP43) na receptor ya G-protein-coupled 41 (GRP41), twanasuzumye GPR41 na GRP43 mu mara y’imbeba za colitis maze dusanga igaragara rya mRNA ya colonic ya GRP43 na GPR41 ryagabanutse cyane nyuma yo guhura na DSS, kandi ubuvuzi bwa BLG bushobora gukiza neza uku kugabanuka (Ishusho ya 7C na D).
Ishusho ya 7 BLG yongera urugero rwa GLP-1 mu maraso n'igaragara rya mRNA ya Gcg, GPR41 na GRP43 mu mbeba zavuwe na DSS. (A) Igaragara rya mRNA ya Gcg mu maraso; (B) Urugero rwa GLP-1 mu maraso; (C) Igaragara rya mRNA ya GPR41 mu maraso; (D) Igaragara rya mRNA ya GPR43 mu maraso. Amakuru agaragazwa nk'ikigereranyo ± SEM (n = 5–6). #p < 0.05 cyangwa ##p < 0.01 vs itsinda ryo kugenzura (Con); *p < 0.05 vs itsinda rya DSS.
Kubera ko uburyo bwo kuvura BLG bushobora kongera urugero rwa GLP-1 mu maraso, ubwiyongere bwa Gcg mRNA mu maraso, hamwe n'urugero rwa SCFA mu imbeba zavuwe na DSS, twakomeje gusuzuma acetate, propionate, na butyrate ndetse no mu igenzura (F-Con), DSS colitis (F-Con) -DSS) na BLG-treated colitis (F-BLG) ku irekurwa rya GLP-1 mu tunyangingo tw’ibanze twa murine colonic. Nkuko bigaragara ku Ishusho ya 8A, uturemangingo tw’ibanze twa murine colonic epithelial twavuwe na aside asetiki ya 2 mM, aside propionic, na aside butyric, uko bikurikirana, twashishikarije cyane irekurwa rya GLP-1, hakurikijwe ubushakashatsi bwabanje.29,30 Mu buryo nk'ubwo, F-Con, F-DSS, na F-BLG zose (zingana na 0.25 g y'imyanda) zashishikarije cyane irekurwa rya GLP-1 mu tunyangingo tw’ibanze twa murine colonic epithelial. Ikigaragara ni uko ingano ya GLP-1 yarekuwe n'utunyangingo tw’ibanze twa murine colonic epithelial twavuwe na F-DSS yari hasi cyane ugereranyije n’iyo y'uturemangingo tw'imbere tw'imbeba twavuwe na F-BLG. (Ishusho ya 8B). Aya makuru agaragaza ko uburyo bwo kuvura BLG bwasubije cyane umusaruro wa GLP-1 ikomoka ku mara ikomoka kuri SCFA.
Ishusho ya 8 SCFA ikomoka kuri BLG itera irekurwa rya GLP-1 mu turemangingo tw’imbere tw’umurangi. (A) Aside asetiki, aside propionic, na aside butyric byateye irekurwa rya GLP-1 mu turemangingo tw’imbere tw’umurangi; (B) ibikomoka ku mwenda F-Con, F-DSS na F-BLG byateye irekurwa ry’uturemangingo tw’imbere tw’umurangi Umubare wa GLP-1 yasohotse. Utunyangingo tw’imbere tw’umurangi twashyizwe mu masahani ya petri yo hasi mu kirahure maze duterwa aside asetiki ya 2 mM, aside propionic, aside butyric, n’ibikomoka ku mwenda F-Con, F-DSS, na F-BLG (bingana na 0.25 g by’imyanda). Amasaha 2 kuri 37°C, 5% CO2, uko bikurikirana. Ingano ya GLP-1 yasohotse mu turemangingo tw’imbere tw’umura yabonetse na ELISA. Amakuru agaragazwa nk'ikigereranyo ± SEM (n = 3).#p < 0.05 cyangwa ##p < 0.01 ugereranije n'ubusa cyangwa F-Con; *p < 0.05 ugereranije na F-DSS.
Incamake: Ace, aside asetiki; Pro, aside propionic; icyakora, aside butyric; F-Con, imvange y'amase ikomoka ku mbeba zigenzura; F-DSS, imvange y'amase ikomoka ku mbeba zirwaye indwara ya colitis; F-BLG, ikomoka ku mara avuwe na BLG. Imvange y'amase ikomoka ku mbeba zibyimba.
Indwara ya UC, yashyizwe ku rutonde rw'indwara iterwa n'ingufu, ikaba ikomeje kuba akaga ku isi; icyakora, uburyo bwiza bwo kumenya, gukumira, no kuvura iyi ndwara buracyari buke. Kubwibyo, hakenewe cyane gushakisha no guteza imbere ingamba nshya zizewe kandi zinoze zo kuvura UC. Imiti gakondo y’Abashinwa ni amahitamo meza kuko imiti myinshi gakondo y’Abashinwa yagaragaye ko ifite akamaro mu kuvura UC mu baturage b’Abashinwa mu binyejana byinshi, kandi yose ni ibinyabuzima by’umwimerere n’ibikoresho karemano bitagira ingaruka mbi ku bantu n’inyamaswa.31,32 Ubu bushakashatsi bwari bugamije gushaka uburyo gakondo bw’imiti gakondo y’Abashinwa bwo kuvura UC no gusuzuma uburyo ikora.BLG ni formula izwi cyane y’ibimera by’Abashinwa ikoreshwa mu kuvura ibicurane.8,33 Imirimo muri laboratwari yacu n’izindi yagaragaje ko indigo, umuti gakondo w’Abashinwa watunganyijwe uva mu bikoresho bimwe na BLG, igaragaza akamaro kanini mu kuvura UC ku bantu no ku nyamaswa.4,34 Ariko, ingaruka za BLG zo kurwanya colitis n’ingaruka zayo Uburyo bwo kuyivura ntibusobanutse neza. Mu bushakashatsi buriho ubu, ibyavuye mu bushakashatsi bwacu bigaragaza ko BLG igabanya neza ububyimbirwe bw’amara buterwa na DSS, bujyana no guhindura amara. mikorobe no kugarura umusaruro wa GLP-1 ukomoka mu mara.
Birazwi neza ko UC irangwa no gusubira inyuma kw'igihe hamwe n'ibimenyetso bisanzwe by'uburwayi, nko kugabanya ibiro, impiswi, kuva amaraso mu mara, no kwangirika cyane kw'uturemangingo tw'amara.35 Bityo, indwara ya colitis idakira yatanzwe hakoreshejwe 1.8% DSS mu minsi itanu, hagakurikiraho iminsi irindwi yo kunywa amazi. Nkuko bigaragara ku Ishusho ya 1B, kugabanuka kw'ibiro n'amanota ya DAI byagaragaje ko indwara ya colitis idakira yavutse neza. Imbeba zo mu itsinda ryavuwe na BLG zagaragaje ko zisubira inyuma kuva ku munsi wa 8, bitandukanye cyane n'umunsi wa 24. Impinduka zimwe na zimwe zagaragaye mu manota ya DAI, bigaragaza ko indwara ya colitis yazamutse. Ku bijyanye n'imvune z'amara n'imiterere y'ububyimbirwe, uburebure bw'amara, kwangirika kw'uturemangingo tw'amara, n'igaragara ry'uturemangingo tw'uturemangingo (genes) hamwe n'ikorwa rya cytokines zitera ububyimbirwe TNF-α, IL-1β, na IL-6 mu mara nabyo byararushijeho kuba byiza nyuma yo kuvurwa na BLG. Muri rusange, ibi bisubizo bigaragaza neza ko BLG ifite akamaro mu kuvura indwara ya colitis idakira yavutse mu mbeba.
Ni gute BLG igira ingaruka zayo mu buvuzi? Ubushakashatsi bwinshi bwakozwe mbere bwagaragaje ko mikorobe zo mu nda zigira uruhare runini mu gutera indwara ya UC, kandi uburyo bwo kuvura bushingiye kuri mikorobe n’imikorobe bwagaragaye nk'ingamba nziza cyane zo kuvura UC. Muri ubu bushakashatsi, twerekanye ko kuvura BLG byagize impinduka zikomeye mu miterere ya mikorobe zo mu nda, bigaragaza ko ingaruka zo kurinda BLG kuri colitis iterwa na DSS zifitanye isano no guhindura mikorobe zo mu nda. Iki gitekerezo gihuye n'igitekerezo cy'uko kongera gushyiraho homeostasis ya mikorobe zo mu nda ari uburyo bw'ingenzi bwo gusobanukirwa akamaro k'imiti ya TCM.36,37 By'umwihariko, Akkermansia ni bagiteri itera Gram-negative kandi idakora aerobic iba mu gice cy'ururenda rw'amara, ikangiza mucins, igakora aside propionic, ikangura itandukanyirizo ry'uturemangingo tw'imisemburo, kandi ikabungabunga mucosa. imikorere y’ubuziranenge bw’imbogamizi.26 Amakuru menshi yerekeye ubuvuzi n’inyamaswa agaragaza ko Akkermansia ifitanye isano rikomeye n’uturemangingo tw’umubiri tuzima,38 no guhabwa Akkermansia spp mu kanwa. bishobora kunoza cyane ububyimbirwe bw'uturemangingo tw'amaraso.39 Amakuru yacu ubu agaragaza ko ubwinshi bwa Akkermansia bwiyongera cyane nyuma yo kuvurwa na BLG. Byongeye kandi, Prevotellaceae_UCG-001 ni bagiteri ikora SCFA.27 Ubushakashatsi bwinshi bwagaragaje ko Prevotellaceae_UCG-001 yabonetse mu bwinshi buke mu mwanda w'inyamaswa zirwaye indwara ya colitis.40,41 Amakuru yacu ubu agaragaza kandi ko kuvurwa na BLG bishobora kongera cyane ubwinshi bwa Prevotellaceae_UCG-001 mu mara y'imbeba zavuwe na DSS. Ibinyuranye n'ibyo, Oscillibacter ni bagiteri ikunda kugaragara, idakunda kugaragara cyane.42 yavuze ko ubwinshi bwa Oscillibacter bwiyongereye cyane mu mbeba za UC kandi bwari bufite isano ryiza n'urugero rwa IL-6 na IL-1β hamwe n'amanota y'indwara.43,44 Ikigaragara ni uko kuvurwa na BLG byagabanyije cyane ubwinshi bwa Oscillibacter mu mwanda w'imbeba zavuwe na DSS. Ikigaragara ni uko izi bagiteri zahinduwe na BLG ari zo zikora cyane SCFA. Bagiteri. Ubushakashatsi bwinshi bwakozwe mbere bwagaragaje ingaruka nziza zishobora guterwa na SCFA ku kubyimba kw'amara no kurinda ubusugire bw'amara.45,46 Amakuru yacu ya none yagaragaje ko ubwinshi bwa SCFA acetate, propionate, na butyrate mu mwanda wavuwe na DSS bwiyongereye cyane mu mbeba zavuwe na BLG. Ibyo byose hamwe bigaragaza neza ko ubuvuzi bwa BLG bushobora kongera neza bagiteri zikora SCFA ziterwa na DSS mu mbeba zifite indwara idakira yo kurwara indwara ya colitis.
GLP-1 ni incretin ikorerwa cyane cyane muri ileum no mu mara kandi igira uruhare runini mu gutinda gusohora igifu no kugabanya isukari mu maraso nyuma yo kurya.47 Ibimenyetso bigaragaza ko dipeptidyl peptidase (DPP)-4, agonist ya GLP-1 receptor, hamwe na nanomedicine ya GLP-1 bishobora kugabanya kubyimba mu mara mu mbeba.48-51 Nkuko byatangajwe mu bushakashatsi bwabanje, ubwinshi bwa SCFA bwinshi bwahujwe n'urugero rwa GLP-1 mu maraso mu bantu no mu mbeba.52 Amakuru yacu y'ubu agaragaza ko nyuma yo kuvurwa na BLG, urugero rwa GLP-1 mu maraso n'igaragara rya Gcg mRNA byiyongereye cyane. Mu buryo nk'ubwo, gusohora GLP-1 byiyongereye cyane mu mikurire y'inkondo y'umura nyuma yo gukururwa n'ibikomoka ku matungo y'imbeba zavuwe na BLG ugereranije no gukururwa n'ibikomoka ku matungo y'imbeba zavuwe na DSS. Ni gute SCFA zigira ingaruka ku irekurwa rya GLP-1? Gwen Tolhurst et al. byatangaje ko SCFA ishobora gukurura isohoka rya GLP-1 binyuze muri GRP43 na GPR41.29. Amakuru yacu y’ubu agaragaza kandi ko uburyo bwo kuvura BLG bwongera cyane uburyo GRP43 na GPR41 zigaragara mu mara y’imbeba zavuwe na DSS. Aya makuru agaragaza ko uburyo bwo kuvura BLG bushobora kugarura umusaruro wa GLP-1 watewe inkunga na SCFA binyuze mu gukoresha GRP43 na GPR41.
BLG ni umuti ukoreshwa mu gihe kirekire mu Bushinwa ugurishwa mu mabwiriza ya OTC. Igipimo ntarengwa cya BLG cyihanganirwa mu mbeba za Kunming ni 80g/Kg, kandi nta burozi bukabije bwagaragaye.53 Kuri ubu, igipimo cya BLG (kidafite isukari) gisabwa ku bantu ni 9-15 g/umunsi (inshuro 3 ku munsi). Ubushakashatsi bwacu bwagaragaje ko BLG kuri 1g/Kg yongereye indwara ya DSS idakira iterwa na DSS mu mbeba. Iki gipimo kiri hafi y’igipimo cya BLG gikoreshwa mu buvuzi. Ubushakashatsi bwacu bwagaragaje kandi ko imikorere yayo iterwa, nibura igice, n’impinduka muri mikorobiyota yo mu mara, cyane cyane bagiteri zikora SCFA, nka Akkermansia na Prevotellaceae_UCG-001, kugira ngo yongere umusaruro wa GLP-1 ikomoka mu mara. Ibi byavumbuwe bigaragaza ko BLG ikwiye kwitabwaho cyane nk’umuti ushobora kuvura indwara ya colitis. Ariko, uburyo nyabwo bwo guhindura mikorobiyota yo mu mara buracyagomba kwemezwa n’imbeba zidafite mikorobiyota no gutera bagiteri mu mwanda.
Ace, aside asetiki; ariko, aside butyrike; BLG, pandan; DSS, dextran sodium sulfate; DAI, igipimo cy'ibikorwa by'indwara; DPP, dipeptidyl peptidase; FID, icyuma gipima ionization y'umuriro; F-Con, kugenzura ibikomoka ku matungo y'imbeba; F-DSS, ibikomoka ku matungo y'imbeba za DSS; F-BLG, ibikomoka ku matungo y'imbeba zavuwe na BLG; GLP-1, peptide imeze nka glucagon-1; Gcg, glucagon; chromatography ya gaz, chromatography ya gaz; GRP43, receptor ya G protein-coupled 43; GRP41, receptor ya G protein-coupled 41; H&E, hematoxylin-eosin; HBSS, Hanks' Balanced Salt Solution; OTC, OTC; PCA, isesengura ry'ibice by'ingenzi; PCoA, isesengura ry'ibanze; Pro, aside propionic; SASP, sulfasalazine; SCFA, aside fatty y'uruhererekane rugufi; Ubuvuzi bw'Abashinwa, ubuvuzi gakondo bw'Abashinwa; UC, indwara ya kanseri y'ibisebe.
Amabwiriza yose y’igerageza yemejwe na Komite Ishinzwe Imyitwarire y’inyamaswa ya Kaminuza ya Peking Shenzhen-Hong Kong University of Science and Technology Medical Center (Shenzhen, Ubushinwa) hakurikijwe amabwiriza y’ikigo n’amabwiriza agenga inyamaswa (nomero y’amahame A2020157).
Abanditsi bose bagize uruhare runini mu gushushanya no gushushanya, gushaka amakuru, cyangwa gusesengura no gusobanura amakuru; bagize uruhare mu kwandika iyo nkuru cyangwa kuvugurura ibikubiye mu bwenge by'ingenzi mu buryo bwimbitse; bemeye kohereza inyandiko mu kinyamakuru gishya; amaherezo bemeye verisiyo kugira ngo isohoke; Bashinzwe ibintu byose bijyanye n'akazi.
Iki gikorwa cyatewe inkunga n'Ikigo cy'Igihugu cy'Ubumenyi bw'Inyamaswa cy'Ubushinwa (81560676 na 81660479), umushinga w'icyiciro cya mbere cya Kaminuza ya Shenzhen (86000000210), Ikigega cya Komite Ishinzwe Ubumenyi n'Ikoranabuhanga ya Shenzhen (JCYJ20210324093810026), n'Ikigega cy'Ubushakashatsi ku Buvuzi n'Ikoranabuhanga mu Ntara ya Guangdong (A2020157 na A2020272), Farumasi ya Kaminuza y'Ubuganga ya Guizhou Intara ya Guizhou yatewe inkunga na Laboratwari y'ingenzi (YWZJ2020-01) n'Ibitaro bya Kaminuza ya Peking Shenzhen (JCYJ2018009).
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