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Saray Ban-Lan-Gen granules et mamalemew ed dextran sodium sulfate-induced chronic relapsing colitis ed saray ayep diad panamegley na pangi-modulate ed gut microbiota tan pangipawil na intestinal SCFA Derived-GLP-1 production
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 Department of Pharmacy, Shenzhen, Republics of China; 2Shenzhen University Health Science Center 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 Department of Gastroenterology, Peking University Shenzhen Hospital, Shenzhen, People's Republic of China; 5 School of Pharmacy, Guizhou Medical University, State Key Laboratory of Medicinal Plant Function and Application, Guiyang; 6 Department of Laboratory Medicine, Peking University Shenzhen Hospital, Shenzhen, China [email protected] Shen Xiangchun, School of Pharmacy, Guizhou Medical University, Guizhou, People's Republic of China, 550004, Email [email protected] Objective: Say GLP-1-based ya therapy et sakey a balon opsyon ed panagtambal parad inflammatory bowel disease parad LGB-LG. Say (BLG) granules et sakey a kabkabat ya antiviral TCM formulation ya mangipapatnag na potensyal ya anti-inflammatory ya aktibidad ed panagtambal na nanduruman inflammatory conditions. Balet, say anti-inflammatory ya epekto to ed colitis tan say mekanismo na kiwas to et agni malinew.METHODS: Pian naestablisa so dextran sodium sulfate (DSS)-induced chronic colpsing activity ed sakit na ulpo. saray indeks, histological markers na injury, tan proinflammatory cytokine levels so ginawa pian naseguro so proteksion na BLG. Say epekto na BLG ed gut microbiota tan bituka et nabidbir ed serum GLP-1 levels tan colonic Gcg, GPR41, tan GRP43 expression, gut microbiota composition, fecal SC levels, tan primary GLP-release manlapud mouse colonic epithelial cells SCFA-derived GLP-1 production.Resulta: Say panagtambal na BLG et makabkabaliksan ya amawala na belat na laman, DAI, panpaabeba na bituka, pakaderal na tisyu na bituka, tan say proinflammatory cytokine levels na TNF-α, IL-1β, tan IL-6 ed tisyu na bituka. Niarum ni, say panagtambal na BLG et makagunggona ya makapawil ed GPR14. tan say GRP43 expression tan serum GLP-1 levels ed saray colitis mice, tan diad pamarakep na SCFA-producing bacteria a singa say Akkermansia tan Prevotellaceae_UCG-001, tan say pambawas ed karakel na bakterya a singa say Eubacterium_xylanophilum_group, Ruminococcaceae_Gmonantes, 14 Imonantes, tan Icbacteris. Niarum ni, say panagtambal na BLG et makapangipaatagey na SCFAs ed tai na saray colitis ya ayep. Diad saman met a panaon, impanengneng met na saray eksperimento ed vitro ya say fecal extract na saray ayep ya inikdan na BLG et makapangiter na maong ed manunan melag iran Murine colonic epithelial cells ya mangisekreto na GLP-1. Konklusyon: Ipapanengneng na sarayan naromog ya say BLG et walay epekto to ed colitis. Say BLG et walay potensyal ton nagawa bilang sakey a therapy, anggan panon et diad panamegley na pangi-modulate ed gut microbiota tan pangipawil ed intestinal SCFA-derived GLP-1 production Promising drugs for chronic relapsing colitis. Keywords: colitis, Ban-Lan-Gen granules, gut microbiota, short-chain fatty acids, GLP-1
Say ulcerative colitis (UC) et sakey a andukey a panaon ya sakit ed colon tan rectum ya walay paulit-ulit ya panag-ebak, ot-ot na eges, ibabaleg na belat, tan mucopurulent bloody stools.1 Diad kaplesan, say inkalaknab na UC et ondarakel ed saray bansan datin abebay insidente, kaiba lay China, ya ondarakel so popularidad na saray estilo na panagbilay ed Mamasagur. mangiiter na angkabaleg iran problema ed bunigas na publiko tan walaan na seryoson implikasyon ed abilidad na saray pasyente ya mantrabaho tan kalidad na bilay. Makatantanda, say pathogenesis na UC et ag ni malinew, balet ta aawaten na karaklan ya say genetics, saray environmental factors, say gut microbiota, tan say immune system et makatulong ed itatatken na UC.3 Anggad natan, anggapo ni tambal parad UC, tan say panagtambal na UC et onla ed klinikal a panangontrol ed saray sintomas mamawala tan mamasiansia na remission, mamaaligwas ed panpaabig na mucosal, tan mamawas ed ipawil na sakit. Saray klasikal a panagtambal et kaiba iray aminosalicylates, corticosteroids, immunosuppressants, tan biologics. Balet, sarayan tambal et agmakadampot na labay ya epekto lapud nanduruman epekto ra.4 Diad kaplesan, dakel a kaso so mangipapanengneng ya say tradisyonal a tambal na China (MTC) et walaan na baleg a potensyal ya ontulong pian naekal so UC ya abeba so toxicity to, ya mangisusuheri ya say panggawa na balon TCM therapies et sakey a maabig ya estratehiya ed panagtambal parad UC.5-7�
Say Banlangen Granules (BLG) et sakey a tradisyonal ya preparasyon na tambal na Tsina ya ginawa manlapud danum ya inala ed lamot na Banlangen.8 Nilikud ed inkaepektibo to ed antiviral, say BLG et walaan na potensyal ya anti-inflammatory ya aktibidad ed panagtambal na nanduruman kondisyon na pamamaga.9,10 Niarum ni, saray glucosinolates (R,S-goitrin, progoitrin, tan glucobin tan glucoside et na-isolate naimano manlapud saray aqueous extracts na Radix isatidis) tan nucleosides (hypoxanthine, adenosine, uridine tan guanosine) tan indigo alkaloids a singa say indigo tan indirubin.11,12 Saray akaunan impanaral so akadokumento a maong a saray compound ya adenosine, uridine tan indirubin so mangipapatnag na mabiskeg ya epekto ed anti-colitis ed nanduruman modelo na ayayep. Balet, anggapoy ginawan impanaral ya base ed ebidensya pian naseguro so inkaepektibo na BLG ed colitis. Diad sayan impanaral, inimbestigaan mi so proteksion ya epekto na BLG ed dextran sodium sulfate (DSS)-induced chronic relapsing colitis ed C57BL/6 ya ayep tan aromog mi ya say oral ya pangiter na BLG et makabkabaliksan ya mamatunda ed DSS-induced chronic relapsing colitis Say inflammation, say regulatory mechanisms to et misiglaotan ed modulation na gut microbiota tan say kipawil na gut-derived glucagon-like peptide-1 (GLP-1) production.
Saray BLG granules (anggapoy asukar, NMPA-approved Z11020357; Beijing Tongrentang Technology Development Co., Ltd., Beijing, China; batch number: 20110966) et sinaliw ed saray botika. MP Biologicals (Santa Ana, USA). Say Sulfasalazine (SASP) (≥ 98% purity), hematoxylin tan eosin et sinaliw ed Sigma-Aldrich (St. Louis, MO, USA). Saray mouse TNF-α, IL-1β tan IL-6 luminex Elisa assay kits et sinaliw ed R&D system (Minetic, MNacetic, USA). say propionic acid, tan butyric acid et sinaliw ed Aladdin Industries (Shanghai, China).2-Ethylbutyric acid et sinaliw ed Merck KGaA (Darmstadt, Germany).
Say 6-8-simba ya laki ya C57BL/6 ya ayep (18-22 g so belat na laman to) et sinaliw ed Beijing Wetahe Laboratory Animal Technology Co., Ltd. (Beijing, China) tan inyan ed kaliberliber ya 22 ± 2 °C ya walay 12 oras ya liwawa/ ambilunget ya siklo et pinakan da so sakey ya ayep ya libren nainum na sakey ya ayep. simba pian makaadapta ed balon kaliberliber. Saray ayep et random ya inapag ed apatiran grupo: control group, DSS model group, SASP-treated group (200 mg/kg, oral) tan BLG-treated group (1 g/kg, oral). Singa nipanengneng ed Figure 1A, unong ed akaunan impanaral mi, say eksperimental ya chronic relapsing colitis et nanlapud taloran cycle na DSS parad 18% na DSS. 5 ya agew, ya tinumbokan na distilled water ed loob na 7 ya agew, unong ed akaunan impanaral mi.18 Saray ayep ed saray grupon tinambal na SASP tan BLG et inikdan na SASP tan BLG, unong ed inagew-agew ya manlapud agew 0. Unong ed saray inmunan eksperimento, say dosis na BLG et inletneg ed 1 g/kg. Kaleganan na satan, say dosis na SASP et inletneg ed 20/kg say literatura.4 Say control tan DSS model groups et akaawat na parehon karakel na danum legan na eksperimento.
Say Figure 1 Say BLG et mamaabig ed DSS-induced chronic relapsing colitis ed saray ayep. (A) Eksperimental a desinyo na chronic recurrent colitis tan panagtambal, (B) pananguman na belat na laman, (C) disease activity index (DAI) score, (D) karukey na colon, (E) representative image na colon, (F) H&E staining Colon (1 × 10) (G) score.Say datos et nipresenta bilang mean ± SEM (n = 6).##p < 0.01 odino ###p < 0.001 vs control (Con) group; *p < 0.05 odino **p < 0.01 odino ***p < 0.001 no ikompara ed grupo na DSS.
Say belat na laman, inkapara na dutak, tan panagdugo ed eges et inagew-agew ya inrekord. Say disease activity index (DAI) et nadetermina diad pangitipon na saray iskor na belat na laman, inkapara na dutak, tan panagdugo ed eges a singa adeskribe la.19 Diad sampot na eksperimento, amin ya ayep so pinatey tan say dala, tai tan bituka so inala parad kaaruman iran eksperimento.
Say tisyu na bituka et inyan ed formalin tan inyan ed paraffin. Saray 5-micron ya seksion so ginawa tan inmantsa na hematoxylin-eosin (H&E), insan binulag tan inmarka unong ed akauna lan indeskribe.19
Say dagup na RNA na tisyu na bituka et inala panamegley na Trizol reagent (Invitrogen, Carlsbad, CA), insan inala so cDNA panamegley na reverse transcriptase (TaKaRa, Kusatsu, Shiga, Japan). Say quantitative PCR et ginawa ya inusar so real-time PCR system ya walay SYBR Green Master (Roche, Basel, Switzerland, Switzerland, Switzerland et in-transcript-in normalized genes pian na-normalize so β). saray datos et inanalisa ya inusar so 2-ΔΔCT a paraan. Saray gene primer sequences et nanengneng ed Table 1.
Say primary mouse colonic epithelial cell isolation tan culture et ginawa unong ed akauna lan indeskribe.20 Diad antikey, saray colon na 6-8 simba ya ayep so inmuna ya inekal kayari na panagsakripisyo panamegley na cervical dislocation, insan inlukas ed andukey, ya inikdan na Hanks Balanced Salt Solution (HBSS, ya anggapoy calcium tan magne) tan melag a cut. piraso. Kayari to, saray tisyu et tinunaw na 0.4 mg/mL collagenase XI (Sigma, Poole, UK) ed libren DMEM medium tan in-centrifuge ed 300 xg ed loob na 5 min ed temperatura na kuarto. I-resuspend so pellet ed DMEM medium (ya indagdag na 10% fetal bovinenic serum, 100/00 units, tan peillin 100 μg/mL streptomycin) ed 37 °C tan ondalan ed nylon mesh (pore size ~250 μm). Saray aliquot na colonic epithelial cells et inyan ed saray pinggan ya walay salming ed dalem to tan inkulongan na acetic acid, propionic acid, butyric acid, tan fecal extract ed loob na 37 °C ed loob na 37 °C 5% CO2.
Say tisyu na bituka et in-homogenize ed PBS, tan say lebel na cytokines IL-6, TNF-α tan IL-1β ed tisyu na bituka et adiskobre ya inusar so luminex ELISA assay kits (R&D systems, Minneapolis, MN, USA). Ontan met, say lebel na GLP-1 ed serum tan culture medium na manunan epithelinic cells et nadetermina ELISA kit (Bioswamp, Wuhan, China) unong ed instruksion na manggagawa.
Say amin ya DNA manlapud saray tae et inala ya inusar so DNA extraction kit (Tiangen, China). Say kalidad tan karakel na DNA et sinukat ed ratio ya 260 nm/280 nm tan 260 nm/230 nm, unong ed inkauksoy da. Kayari to, inusar so kada inala ya DNA bilang template, saray espisipikon primer 338F (ACCCG) GAGCAGA GCAGGAG806 (GGACTACHVGGGTWTCTAAT) so inusar pian napalaknab so V3-V4 iran rehyon na 16S rRNA gene ed nanduruman rehyon. Saray produkto na PCR et inlinisan ya inusar so QIAquick Gel Extraction Kit (QIAGEN, Germany), ya in-quantify panamegley na real-time PCR, tan in-sequence ya inusar so IlluminaMiseq PE300 sequence platform (Illumina Miseq Incluminacing Inclumina, USA, USA). bioinformatics analysis, data processing et ginawa unong ed saray akaunan nireport ya protocol.21,22 Diad antikey, usaren so Cutadapt (V1.9.1) pian na-filter iray raw express files.Saray OTU et in-cluster ya inusar so UPARSE (version 7.0.1001) ya walay similarity cutoff ya 97%, tan say UCHIME so inusar pian naekal so chimer sequence classification tan community analysis. ginawa ya inusar so RDP classifier (http://rdp.cme.msu.edu/) base ed SILVA ribosomal RNA gene database.
Say lebel na short-chain fatty acids (acetic acid, propionic acid, tan butyric acid) et sinukat unong ed akauna lan indeskribe nen Tao et al., ya walay pigaran pananguman.23 Diad antikey, 100 mg na tae so inmuna ya insuspinde ed 0.4 mL na deionized water, insan 0.1 mL na 0.1 mL na 0.0 mL na acid tan sulfuric 50%. 2-ethylbutyric acid (internal standard), insan in-homogenize tan pinainit ed 4°C. I-centrifuge ed 12,000 rpm ed loob na 15 minutos ed C. Say supernatant et inala ed 0.5 mL na ether tan in-inject ed GC parad panagsukimat. Parad gas chromatography (GC) ya panagsukimat, saray sample so inanalisa ya inusar so GC-2010 Plus gas chromatograph (Shimadzu, Inc) ya walaan na flameon detector. (FID). Say inkaapag-apag et agawaan ya inusar so ZKAT-624 ya kolum, 30 m × 0.53 mm × 0.3 μm (Lanzhou Zhongke Antai Analytical Technology Co., Ltd., China). Saray datos et naala ya inusar so GC solution software (Shimadzu, Inc.). Say ratio na inkaapag-apag et 10:10, say carrier et nitrogen, tan say nitroheno, tan say carrier et gas, tan say carrier et 10, tan say carrier et gas, tan say carrier et 10. say flow rate et 6 mL/min. Say injection volume et 1 μL. Say temperatura na injector tan detector et 300°C. Say temperatura na oven et inyan ed 140°C ed loob na 13.5 minutos, insan inmatagey ed 250°C diad rate ya 120°C/min; say temperatura et nansiansia ed loob na 5 minuto.
Say datos et nipresenta bilang mean ± standard error of the mean (SEM). Say kabaliksan na datos et inusisa panamegley na one-way ANOVA ya tinumbokan na Duncan's multiple range test. Say GraphPad Prism 5.0 software (GraphPad Software Inc., San Diego, CA, USA) so inusar ed amin a kalkulasyon tan say p < 0.05 so inkonsidera ya statistically significant.
Kabkabat ya say UC et sakey a chronic relapsing colitis disease ya walay graben ot-ot na eges, panag-ebak tan panag-bleeding. Kanian, say DSS-induced chronic relapsing colitis ed saray ayep so inletneg pian nasuri so anti-colitis efficacy na BLG (Fig. 1A). No ikompara ed control group, saray ayep ed DSS model et walaan na mas atagey a belat na laman tan mas atagey so belat na laman da DAI, tan sarayan pananguman et signipikantin inuman kayari na 24 ya agew na BLG ya panagtambal (Figure 1B tan C). Say panpaabeba na colon et sakey ya importantin pakabidbiran na UC. Singa nanengneng ed Figures 1D tan E, say karukey na colon na saray ayep ya akaawat na DSS et signipikantin inmawet, balet ta nainawaan lapud BLG ya panagtambal. Kayari to, ginawa so patolohikon panagsukimat pian nasuri inflammation.Impanengneng na H&E stained images tan pathological scores ya say pangiter na DSS et makaderal ed colonic architecture tan nanresulta ed inkaderal na crypt, bangbalet say BLG ya panagtambal et makabkabaliksan ya amawala na crypt destruction tan pathological scores (Figure 1F tan G). Say proteksion ya epekto na BLG ed dosis ya 1 g/Kg et mipara ed dosis na SASP20 mg/Kg. Diad pankakasakey, sarayan naromog et mangisusuheri ya say BLG et epektibo ed pambawas ed inkagrabe na DSS-induced chronic relapsing colitis ed saray ayep.
Say TNF-α, IL-1β tan IL-6 et importantin inflammatory markers na colon inflammation. Singa nanengneng ed Figure 2A, say DSS so angitonton na signipikantin indakel na gene expression na TNF-α, IL-1β tan IL-6 ed colon no ikompara ed control group. Say pangiter na BLG et makabkabaliksan ya mamasimbalo ed sarayan DSS-mediated ya pananguman, inusar mi pian nadetermina so lebel na ELISA. saray inflammatory cytokines TNF-α, IL-1β, tan IL-6 ed tisyu na bituka. Impanengneng met na resulta ya say lebel na TNF-α, IL-1β, tan IL-6 ed bituka et signipikantin inmatagey ed saray utot ya inikdan na DSS, bangbalet say panagtambal na BLG et amalemew ed sarayan indakel (Figure 2B).
Figure 2 Say BLG et mangaamper ed gene expression tan produksyon na proinflammatory cytokines TNF-α, IL-1β tan IL-6 ed colon na saray DSS-treated mice.(A) Colonic gene expression na TNF-α, IL-1β tan IL-6; (B) saray lebel na protina na bituka na TNF-α, IL-1β tan IL-6. Say datos et nipresenta bilang mean ± SEM (n = 4–6).#p < 0.05 odino ##p < 0.01 odino ###p < 0.001 vs control (Con) group; *p < 0.05 odino **p < 0.01 sumpad DSS ya grupo.
Say intestinal dysbiosis et kritikal ed pathogenesis na UC.24 Pian nausisa no kasin say BLG et man-modulate ed gut microbiota na saray DSS-treated mice, ginawa so 16S rRNA sequencing pian na-analisa so komunidad na bakterya ed saray karga na bituka. Ipapanengneng na Venn diagram ya say taloran grupo et walaan na 385 OTUs. Diad parehon panaon, kada grupo et walaan na nikadkaduman panaon (Figs. OTU). 3A). Niarum ni, say Chao1 index tan Shannon index ya nanengneng ed Figure 3B tan C so angipatnag ya say pandurumaan na komunidad na gut microbiota et abawasan ed saray BLG-treated mice, lapud say Shannon index et signipikantin inmabeba ed BLG-treated ya grupo. Say Principal component analysis (PCA) tan principal coordinate analysis (PCA) so inusar pian nadetermina so taloran cluster patter grupo tan impanengneng to ya say istruktura na komunidad na saray ayep ya atambalan na DSS et malinew ya insian kayari na panagtambal na BLG (Figure 3D tan E). Ipapanengneng na sarayan datos ya say panagtambal na BLG et makabkabaliksan ya apektado so istruktura na komunidad na saray ayep ya walay DSS-induced colitis.
Say Figure 3 Say BLG et manguuman ed pandurumaan na gut microbiota ed saray ayep ya walay DSS-induced colitis. (A) Venn diagram na OTU, (B) Chao1 index, (C) Shannon's richness index, (D) Principal Component Analysis (PCA) score plot na OTU, (E) OTU Principal Coordinate Analysis score (PCA) Figure. Saray datos et nipresenta bilang mean ± SEM (n = 6).**p < 0.01 vs DSS group.
Pian naseguro so espisipikon pananguman ed fecal microbiota, inaral mi so komposisyon na gut microbiota ed amin a taxonomic levels. Singa nanengneng ed Figure 4A, say manunan phyla ed amin a grupo et Firmicutes tan Bacteroidetes, ya tinumbokan na Verrucomicrobia. Say relatibon karakel na Firmicutes tan Firmicutes/Bacteroidetes et signipikantin dinmaak ed saray fecal feo saray komunidad na mikrobyo na saray ayep ya inikdan na DSS no ikompara ed saray ayep ya kontrolado, tan sarayan pananguman so signipikantin inuman kayari na panagtambal na BLG. Diad partikular, say panagtambal na BLG so signipikantin amabaleg ed relatibon karakel na Verrucobacterium ed saray tae na saray ayep ya walay DSS-induced colitis. Diad sankaabungan, saray komunidad na mikrobyo ed tae so inokupaan na Lachnoaspire, Muribaculaceae, Akkermansiaceae, Ruminococcaceae tan Prevotellaceae (Fig. 4B). No ikompara ed grupo na DSS, say inkaandi na BLG et amabaleg ed karakel na Akkermansiaceae, balet ta binawasan toy karakel na Lachnospiraceae tan Ruminococcaceae. Notan, diad lebel na feo et mikrobyo, et mikrobyo so feota. okupado na Lachnospira_NK4A136_group, Akkermansia tan Prevotellaceae_UCG-001 (Fig. 4C). Impanengneng met na sayan adiskobre ya say panagtambal na BLG et epektibon amasimbalo ed ag-inkabalanse na microbiota bilang ebat ed DSS challenge, ya nanengneng ed ibabawas na Eubacterium_xylalanophilum_group, Ruminococcaceae_UCG-014, Intestinimonas tan Oscillibacter, tan say idakel na Akkermansia tan Prevotellaceae_UCG-001.
Figure 4 Say BLG et manguuman ed karakel na gut microbiota ed DSS-induced colitis mice.(A) Dakel na gut microbiota ed lebel na phylum; (B) Dakel na gut microbiota ed pamilya; (C) Dakel na gut microbiota ed lebel na genus. Saray datos et nipresenta bilang mean ± SEM (n = 6).#p < 0.05 odino ###p < 0.001 vs control (Con) group; *p < 0.05 odino **p < 0.01 odino ***p < 0.001 no ikompara ed grupo na DSS.
No ikonsidera ya saray short-chain fatty acids (SCFAs) so manunan metabolites na Akkermansia tan Prevotellaceae_UCG-001, bangta say acetate, propionate tan butyrate so sankarakelan ya SCFAs ed intestinal lumen, 25-27 wala kami ni ed panagaral mi. Singa nanengneng ed Figure 5, saray konsentrasyon na fecal fecate, propiorate, tan propiorate so signipikantin nabawasan ed grupon tinambalan na DSS, bangta say panagtambal na BLG so nayarin mamatunda ed sayan ibawas.
Pigura 5. Say BLG et mamaaligwas ed lebel na SCFAs ed tai na saray ayep ya walay DSS-induced colitis.(A) Say acetic acid content ed tai; (B) say lugan na propionic acid ed tai; (C) butyric acid content ed tai. Say datos et nipresenta bilang mean ± SEM (n = 6).#p < 0.05 odino ##p < 0.01 vs control (Con) group; *p < 0.05 odino **p < 0.01 sumpad DSS ya grupo.
Kinalkula mi met so Pearson correlation coefficient ed baetan na genus-level differential SCFA tan fecal microbiota. Singa nanengneng ed Figure 6, say Akkermansia et positibon mikonektaan ed produksyon na propionic acid (Pearson = 0.4866) tan butyric acid (Pearson = 0.6192 Diad pidumaan, parehon negatibo so Enteromonas tan Ocillocters). ya misiglaotan ed produksyon na acetate, ya walay Pearson coefficients ya 0.4709 tan 0.5104, unong ed inkauksoy da. Ontan met, say Ruminococcaceae_UCG-014 et negatibon mikonektaan ed produksyon na propionic acid (Pearson = 0.4508) tan butyric acid (Pearson = 0.4508), unong ed inkauksoy da.
Figure 6 Pearson correlation analysis ed baetan na differential SCFAs tan colonic microbes.(A) Enteromonas ya walay acetic acid; (B) Concussion bacillus ya walay acetic acid to; (C) Akkermansia vs propionic acid; (D) Ruminococcus_UCG-014 ya walay propionic acid to; (E) Akkermansia ya walay butyric acid to; (F) ) Ruminococcus _UCG-014 ya walay butyric acid to.
Say Glucagon-like peptide-1 (GLP-1) et sakey a cell-type-specific post-translational product na proglucagon (Gcg) ya walaan na anti-inflammatory properties.28 Singa nanengneng ed Figure 7, say DSS so angitarok na signipikantin ibawas ed Gcg mRNA expression. Say colon tan BLG ya panagtambal et makabkabaliksan a mamasimbalo ed DSS-induction Ggcc no ikompara ed control group (Fig. 7A).Diad saman met a panaon, say lebel na GLP-1 ed serum et signipikantin inmabeba ed grupon tinambal na DSS, tan say panagtambal na BLG et makaamper ed sayan ibawas (Fig. 7B). Lapud saray short-chain fatty acids et makapangiter na GLP-1 secretion panamegley na G-protein-coupled receptor 43 (GRP43) tan GRP-protein receptor 43 (GRP43) activation, ineksamin mi met so GPR41 tan GRP43 ed colon na saray colitis mice tan aromog mi ya say colonic mRNA expression na GRP43 tan GPR41 et signipikantin inmabeba kayari na DSS challenge, tan say BLG ya panagtambal et epektibon makaresalba ed sarayan inmabeba (Figure 7C tan D).
Figure 7 BLG et mamaaligwas ed serum GLP-1 levels tan colonic Gcg, GPR41 tan GRP43 mRNA expression ed DSS-treated mice.(A) Gcg mRNA expression ed colon tissue; (B) GLP-1 ya lebel ed dala; (C) GPR41 mRNA expression ed colon tissue; (D) GPR43 mRNA expression ed colon tissue. Saray datos et nipresenta bilang mean ± SEM (n = 5-6).#p < 0.05 odino ##p < 0.01 vs control (Con) group; *p < 0.05 vs DSS group.
Lapud say BLG ya panagtambal et makapangipaatagey na serum GLP-1 levels, colonic Gcg mRNA expression, tan fecal SCFA levels ed saray DSS-treated mice, ineksamin mi ni so acetate, propionate, tan butyrate ontan met ed control (F-Con), DSS colitis (F-Con) -DSS) tan BLG-treated colitis (F-Con) ya impaway na GLP-1 manlapud saray manunan murine colonic epithelial cells. Unong ed nanengneng ed Figure 8A, saray manunan mouse colonic epithelial cells ya inikdan na 2 mM acetic acid, propionic acid, tan butyric acid, unong ed inkauksoy da, so makatantandan amakiwas ed GLP-1 ya ipaway, a mipara ed saray akaunan impanaral.29,30 Ontan met, amin ya FDS-on, F-SBL, tan F-SG-equivalent ( 0.25 g na tai) so amabiskeg a maong ed pangibulos na GLP-1 manlapud manunan murine colonic epithelial cells. Makatantanda, say karakel na GLP-1 ya impaway na F-DSS-treated primary mouse colonic epithelial cells et mas abeba nen say F-Con tan F-BLG-treated primary mouse epithelial cells (Isusuheri na Pigura 8 B). Say panagtambal na BLG et makabkabaliksan ya amapawil ed intestinal SCFA-derived GLP-1 production.
Figure 8 Say BLG-derived SCFA et mamapakiwas ed GLP-1 ya ompaway ed manunan murine colonic epithelial cells. (A) Say acetic acid, propionic acid, tan butyric acid so mamapakiwas ed ompaway na GLP-1 manlapud manunan murine colonic epithelial cells; (B) fecal extracts F-Con, F-DSS tan F-BLG ya pinakiwas na manunan murine colonic epithelial cells Say karakel na GLP-1 ya nibulos. Saray aliquots na colonic epithelial cells et inyan ed glass-bottom petri dishes tan inikdan na 2 mM acetic acid, propionic acid, propioric acid, balet fecal extract, tan F-Con F-DSS, tan F-BLG (mipara ed 0.25 g ya tai), unong ed inkauksoy da. 2 oras ed 37°C, 5% CO2, unong ed inkauksoy da. Say karakel na GLP-1 ya impaway manlapud manunan murine colonic epithelial cells et adiskobre panamegley na ELISA. Say datos et nipresenta bilang mean ± SEM (n = 3).#p < 0.05 odino ##p < 0.01 vs. blank o F-C; *p < 0.05 vs. F-DSS.
Abbreviations: Ace, acetic acid; Pro, propionic acid; balet, butyric acid; F-Con, fecal extract manlapud saray kontrol ya ayep; F-DSS, fecal extract manlapud colitis ya ayep; F-BLG, manlapud BLG-treated colon Fecal extracts na inflammatory mice.
Say UC ya inlista na World Health Organization bilang sakey a sakit ya ag-onsaew, et magmamaliw lan sankamundoan a kapeligroan; balet, limitado ni ray epektibon paraan pian naisip, naprebentaan, tan natambal so sakit. Kanian, kaukolan ya mansukimat tan manggawa na balon ligtas tan epektibon estratehiya ed panagtambal parad UC. Saray tradisyonal ya panagparaan na tambal na Tsina et sakey a promising ya opsyon lapud dakel ya tradisyonal ya panagparaan na tambal na Tsina so apaneknekan ya epektibo ed panagtambal na UC ed loob na nilasus a taon tan amin da et biolohikon organiko tan natural iran materyales ya maslak et agmakaderal ed totoo tan ayayep.31,32 Say gagala na sayan impanaral et pian anapen so ligtas tan epektibon tradisyonal a panagtambal na Chinese parad panagtambal na UC tan pian nasukimat so mekanismo na kiwas to.Say BLG et sakey a kabkabat a Chinese herbal formula ya uusaren pian tambalen so trangkaso. say tradisyonal ya produkto na tambal na Tsina ya nanlapud parehon hilaw a materyales a singa say BLG, et mangipapanengneng na signipikantin inkaepektibo ed panagtambal na UC ed totoo tan ayayep.4,34 Balet, say anti-colitis ya epekto na BLG tan saray epekto to Say mekanismo et agmalinew. Diad kaplesan ya impanaral, ipapanengneng na saray resulta mi ya say BLG et epektibon mamalemew ed DSS-induced colonic inflammation ya misiglaotan ed modulation na bituka microbiota tan say pangipawil na produksyon na GLP-1 ya nanlapud bituka.
Kabkabat ya say UC et nabidbir ed saray panaon ya ompawil a walaan na saray tipikal a klinikal a nengneng, a singa say ibawas na belat, panag-atake, panagdugo ed pueg, tan malaknab a pakaderal na colonic mucosal.35 Kanian, say chronic relapsing colitis et inter diad pangiter na taloran siklo na 1.8% DSS ed loob na limaran agew, ya tumbokan na pitoran agew ya iyinum na danum ed saray FigureAs. 1B, say manguuman-uman ya belat tan DAI scores so mangipapanengneng na matalonan induction na chronic relapsing colitis. Saray ayep ed grupon tinambal na BLG et angipatnag na upshift recovery manlapud agew 8, ya signipikantin midumaan ed agew 24. Saray parehon pananguman so naobserbaan met ed DAI score, ya mangisusuheri na inyaligwas ed klinikal ya inyaligwas na kipapasen na colitis tan inflammatory terms. say karukey na bituka, say inkaderal na tisyu na bituka, tan say gene expression tan say produksyon na proinflammatory cytokines TNF-α, IL-1β, tan IL-6 ed tisyu na bituka so inmaligwas met a maong kayari na panagtambal na BLG. No pankasakeyen, sarayan resulta so malinew ya mangipapanengneng ya say BLG et epektibo ed panagtambal na chronic relapsing colitis ed saray ayep.
Panon ya ipapanengneng na BLG so epekto to ed parmakolohiya? Dakel ya akaunan impanaral so angipatnag ya say gut microbiota so walaan na manunan betang ed pathogenesis na UC, tan saray microbiome-based tan microbiome-targeted therapies so pinmatnag bilang makapasagyat ya estratehiya parad panagtambal na UC. Diad sayan impanaral, impanengneng mi ya say panagtambal na BLG et nanresulta ed signipikantin pananguman ed komposisyon na gut microbio say proteksion ya epekto na BLG sumpad DSS-induced colitis et misiglaotan ed modulasyon na gut microbiota. Sayan obserbasyon et mitunosan ed kanonotan ya say pangi-reprogram ed homeostasis na gut microbiota et sakey ya importantin paraan pian natalosan so inkaepektibo na saray preparasyon na TCM.36,37 Makatantanda, say Akkermansia et sakey a Gram-negatibo tan estrikton anaerobicus ya manbibilay ed layer na layer na baccrium say bituka, ya mamapawala na mucins, mamapawala na propionic acid, mamapawala na goblet cell differentiation, tan mamasiansia ed mucosa. say kimey na integridad na babeng.26 Say dakel a datos ed klinika tan ayep so mangisusuheri ya say Akkermansia et walay koneksion tod mabunigas a mucosa,38 tan say oral ya pangiter na Akkermansia spp. nayarin mamaaligwas ed mucosal inflammation.39 Say kaplesan ya datos tayo et mangisusuheri ya say relatibon karakel na Akkermansia et makatantandan dinmaak kayari na panagtambal na BLG. Niarum ni, say Prevotellaceae_UCG-001 et sakey a bakterya ya manggagawa na SCFA.27 Impanengneng na dakel ya impanaral ya say Prevotellaceae_UCG-001 et aromog ed relatibon karakel na tai na ayayep colitis.40,41 Ipapanengneng met na kaplesan ya datos tayo ya say panagtambal na BLG et makapangiter na baleg ya karakel na Prevotellaceae_UCG-001 ed colon na saray ayep ya inikdan na DSS. Diad pidumaan, say Oscillibacter et sakey a mesophilic, estrikton anaerobic ya bakterya.42 inreport dan say karakel na Ocillibacter ed UCClibacter et makatantandan dinmaak mice tan positibon mikonektaan ed IL-6 tan IL-1β levels tan pathological scores.43,44 Makatantanda, say panagtambal na BLG et makatantandan amawala na relatibon karakel na Oscillibacter ed saray tai na DSS-treated mice. Makatantanda, sarayan BLG-altered bacteria so sanka-SCFA-producer ya makagunggona iran epekto na akaunan impanaral. Saray SCFA ed impeksion na bituka tan proteksion na integridad na intestinal epithelial.45,46 Naobserbaan met na kaplesan ya datos tayo ya say konsentrasyon na SCFA acetate, propionate, tan butyrate ed saray tai ya inikdan na DSS et dinmaak a maong ed saray ayep ya inikdan na BLG. No pankasakeyen, sarayan naromog et malinew ya mangipapanengneng ya say BLG ya panagtambal et epektibon mamaaligwas ed DSS SCFA-producing bacteria ed saray ayep ya walay chronic relapsing colitis.
Say GLP-1 et sakey ya incretin ya manunan napapawala ed ileum tan colon tan walay importantin betang to ed pangitunda ed pan-empty na eges tan pangibaba na glucose ed dala kayari na panangan.47 Ipapanengneng na ebidensya ya say dipeptidyl peptidase (DPP)-4, sakey a GLP-1 receptor agonist, tan sakey a GLP-1 nanomedicine et epektibon mamalemew ed intestinal inflammace diad As-as-185. inreport ed saray akaunan impanaral, say atagey ya konsentrasyon na SCFA et walay koneksion to ed plasma GLP-1 levels na totoo tan ayep. 52 Ipapanengneng na kaplesan ya datos tayo ya kayari na BLG treatment, say serum GLP-1 levels tan Gcg mRNA expression et signipikantin inmatagey. Ontan met, say GLP-1 secretion et signipikantin inmatagey ed saray colonic culture kayari na stimulation na fecal extracts manlapud BLG-treated colitis mice no ikompara ed stimulation na fecal extracts manlapud DSS-treated colitis mice. pangibulos na GLP-1? Gwen Tolhurst et al. inreport ya say SCFA et makapangiter na GLP-1 secretion panamegley na GRP43 tan GPR41.29 Ipapanengneng met na kaplesan ya datos tayo ya say BLG ya panagtambal et makabkabaliksan ya mamaaligwas ed mRNA expression na GRP43 tan GPR41 diad colon na saray DSS-treated mice. Isusuheri na sarayan datos ya say BLG ya panagtambal et makapangipawil na SCFA-promoted GLP-1 production diad panamegley na GRP43 tan GPR41441.
Say BLG et sakey a tambal ya ag-onkukurang ed reseta (OTC) ed China. Say sankatageyan ya dosis na BLG ed saray Kunming mice et 80g/Kg, tan anggapoy naobserbaan ya acute toxicity.53 Diad kaplesan, say nirekomenda ya dosis na BLG (ya anggapoy asukar) ed totoo et 9-15 g/agew (3 beses ed sanagew). Impanengneng na impanaral mi ya say BLG ed 1g/DSS et mamaabig ed saray chronic-colp ed saray ayep. Sayan dosis et asingger ed dosis na BLG ya uusaren ed klinika. Nalmoan met na impanaral mi ya say mekanismo na kiwas to et napapaarap, anggan panon et diad saray pananguman ed gut microbiota, partikular ed SCFA-producing bacteria, a singa say Akkermansia tan Prevotellaceae_UCG-001, pian nipawil so produksyon na gut-derived GLP. kaaruman ya konsiderasyon bilang posiblin therapeutic agent parad panagtambal na clinical colitis. Balet, say eksakton mekanismo no panon ton i-modulate so gut microbiota et agni nakumpirma na saray microbiota-deficient ya ayep tan fecal bacterial transplantation.
Ace, acetic acid; balet, butyric acid; BLG, pandan; DSS, dextran sodium sulfate; DAI, indeks na aktibidad na sakit; DPP, dipeptidyl peptidase; FID, flame ionization detector; F-Con, control Fecal extracts na saray ayep; F-DSS, fecal extracts na DSS colitis ya ayep; F-BLG, fecal extracts na BLG-treated colitis mice; 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, manunan kabiangan na panagsukimat; PCoA, manunan panagsukimat na koordinasyon; Pro, propionic acid; SASP, sulfasalazine; SCFA, short-chain fatty acids; tambal na Tsina, tradisyonal a tambal na Tsina; UC, ulcerative colitis.
Amin ya eksperimenton protocol et inaprobaan na Animal Ethics Committee na Peking University Shenzhen-Hong Kong University of Science and Technology Medical Center (Shenzhen, China) unong ed Institutional Guidelines and Animal Regulations (ethics number A2020157).
Amin ya autor et walaan na baleg a kontribusyon ed konsepto tan desinyo, panag-ala na datos, odino panagsukimat tan pangipatalos na datos; akibiang ed impanggawa na artikulo odino kritikal ya inuman so importantin intelektual a lugan; inmabobon ya iter so manuskrito ed kaplesan ya dyurnal; diad kaunoran et inaprobaan so bersion parad publikasyon; Responsabilidad ed amin ya aspekto na trabaho.
Sayan kimey et sinuportaan na National Natural Science Foundation of China (81560676 tan 81660479), say sankaunaan ya proyekto na Shenzhen University (86000000210), say Shenzhen Science and Technology Innovation Committee Fund (JCYJ2021032409381020), tan say Guangdong Science and Medical Science Research Fund (A2020157 tan A2020272), Guizhou Medical University Pharmacy Guizhou Province ya Pinondoan na Key Laboratory (YWZJ2020-01) tan Peking University Shenzhen Hospital (JCYJ2018009).
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