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Ban-Lan-Gen granules hian mice-ah dextran sodium sulfate-induced chronic relapsing colitis a tiziaawm a, gut microbiota a modulate a, intestinal SCFA Derived-GLP-1 production a siam tha leh bawk
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, People’s Republic of China 2Shenzhen University Health Science Center School of Pharmacy, Shenzhen, China ram chhunga awmte chu an zirchiang a; 3Guizhou Medical University Engineering Technology Research Center of Ethnic Medicine leh Traditional Chinese Medicine hmasawnna leh hman dan 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, China ram chhunga awm te; 5 School of Pharmacy, Guizhou Medical University-a State Key Laboratory of Medicinal Plant hnathawh leh hman dan, Guiyang-a awm; 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] Tum: GLP-1 hmanga enkawlna hi inflammatory bowel disease enkawlna thar a ni.Ban-Lan-Gen (BLG) granules hi antiviral TCM formulation hriat lar tak a ni a, inflammatory condition hrang hrang enkawlnaah anti-inflammatory activity a lantir thei a ni.Amaherawhchu, colitis-a a anti-inflammatory effect leh a hnathawh dan erawh a la chiang lo.METHODS: Mice-a dextran sodium sulfate (DSS)-induced chronic relapsing colitis din turin.Disease activity indices, histological markers of injury, leh proinflammatory cytokine levels te chu BLG venhimna a nih dan tehna atan an ti a. BLG hian gut microbiota leh gut a nghawng dan chu serum GLP-1 level leh colonic Gcg, GPR41, leh GRP43 expression, gut microbiota composition, fecal SCFAs level, leh primary mouse colonic epithelial atanga GLP-1 release te a ni cells SCFA-derived GLP-1 production.Results: BLG hmanga enkawlna hian taksa rihna tlahniam, DAI, colon tawi, colon tissue tihchhiat, leh colon tissue-a TNF-α, IL-1β, leh IL-6 proinflammatory cytokine levels nasa takin a tihhniam a ni.Chu bakah, BLG enkawlna hian colonic Gcg, GPR41 leh GRP43 expression leh serum GLP-1 levels in colitis mice te, leh SCFA siamtu bacteria Akkermansia leh Prevotellaceae_UCG-001 te tihpun te, leh Eubacterium_xylanophilum_group, Ruminococcaceae_UCG-014, Intestinimonas leh Oscillibacter te bacteria tamna tihtlem te a ni. Hei bakah hian BLG hmanga enkawlna hian colitis mice-te ek a SCFAs level nasa takin a tisang thei bawk. Chutih rual chuan in vitro experiment-ah pawh BLG hmanga enkawl mice-te fecal extract hian primary small Murine colonic epithelial cells secrete GLP-1 chu nasa takin a tichak thei tih hmuhchhuah a ni bawk. Thutlukna: Heng thil hmuhchhuah te hian BLG hian anti-colitis effect a nei tih a tilang. BLG hian therapy anga siam chhuah theihna a nei a, a tlem berah chuan gut microbiota modulate leh intestinal SCFA-derived GLP-1 production siam that lehna hmangin Chronic relapsing colitis tan damdawi beisei awm tak a ni. Thumal pawimawh tak tak: colitis, Ban-Lan-Gen granules, gut microbiota, short-chain fatty acids, GLP-1 te hi a awm a
Ulcerative colitis (UC) hi hun rei tak chhunga colon leh rectum-a inflammatory disease a ni a, a natna chu ril\am leh ril, pum na, taksa rihna tlahniam, leh mucopurulent bloody stools te a ni.1 Tun hnaiah chuan UC vei hi a hmaa a vei tlem ber ramteah a pung chho zel a, China pawh a tel a, khawthlang lam nunphung a lar chho zel a ni.2 Hetianga pung hian mipui tan harsatna lian tak a siam a ni health and has serious implications for patients’ ability to work and quality of life.Hriat tur pawimawh tak chu UC pathogenesis hi a tam zawkah chuan a chiang lo hle a, mahse genetics, environmental factors, gut microbiota, leh immune system te hian UC lo awm theihna tura puitu zawng zawng hi pawm tlangpui a ni.3 Tunah pawh hian UC damdawi a la awm lo a, enkawlna tum ber chu clinically-a clinical symptoms control, induce leh maintain a ni remission, promote mucosal healing, and reduce recurrence.Classical treatment-ah chuan aminosalicylates , corticosteroids, immunosuppressants, leh biologics te a tel.Amaherawhchu, heng damdawi te hian an side effect hrang hrang avang hian duhthusam chu an nei thei lo.4 Tun hnaiah case study tam takah chuan traditional Chinese medicine (TCM) hian toxicity hniam tak nei UC tihziaawmna kawngah theihna nasa tak a nei tih a tarlang a, hei hian a tilang TCM therapies thar siam chhuah hi UC.5-7 tan enkawlna kawng beisei awm tak a nih thu a sawi
Banlangen Granules (BLG) hi Chinese damdawi siam dan phung pangngai Banlangen zung atanga siam a ni.8 A antiviral efficacy bakah hian BLG hian inflammatory condition hrang hrang enkawlnaah anti-inflammatory activity a lantir thei bawk.9,10 Chu bakah, glucosinolates (R,S-goitrin, progoitrin, epiprorubin leh glucoside te chu isolated leh identified a ni bawk aqueous extracts of Radix isatidis) leh nucleosides (hypoxanthine, adenosine, uridine leh guanosine) leh indigo alkaloids indigo leh indirubin te.11,12 Tun hmaa zirchianna hrang hrangah chuan compound adenosine, uridine leh indirubin te hian colitis rannung model hrang hrangah anti-colitis effect chak tak an nei tih an lo ziak tawh a ni.13-17 Mahse, no evidence-based study te chu colitis-a BLG hman tangkai dan tehna atan an nei tawh a ni.Tun zirchiannaah hian C57BL/6 mice-a dextran sodium sulfate (DSS)-induced chronic relapsing colitis-a BLG-in a venghim dan kan zirchiang a, BLG oral administration hian mice-a DSS-induced chronic relapsing colon chu nasa takin a ti tlahniam tih kan hmuchhuak a ni Inflammation, a regulatory mechanisms te hi gut microbiota modulation leh gut atanga chhuak glucagon-like peptide-1 (GLP-1) siam that lehna nen a inzawm a ni.
BLG granules (sugar tel lo, NMPA-in a pawmpui Z11020357; Beijing Tongrentang Technology Development Co., Ltd., Beijing, China; batch number: 20110966) chu damdawi dawr a\angin lei a ni.DSS (Molecular Weight: 36,000–50,000 Daltons) hi MP Biologicals (Santa Ana, 50,000) a\angin lei a ni. USA).Sulfasalazine (SASP) (≥ 98% thianghlimna), hematoxylin leh eosin te chu Sigma-Aldrich (St. Louis, MO, USA) atangin lei a ni.Mouse TNF-α, IL-1β leh IL-6 luminex Elisa assay kit te hi R&D system (Minneapolis, MN, USA) atanga lei a ni.Acetic acid, propionic acid, leh butyric acid te chu Aladdin atanga lei a ni Industries (Shanghai, China).2-Ethylbutyric acid hi Merck KGaA (Darmstadt, Germany) atangin lei a ni.
Kar 6-8 mipa C57BL/6 mice (taksa rih zawng 18-22 g) chu Beijing Wetahe Laboratory Animal Technology Co., Ltd. (Beijing, China) atangin lei niin, 22 ± 2 °C-a 12 h light/ dark cycle neia dah an ni.Mice te chu boruak thara an insiamrem theih nan standard rodent diet pek an ni a, kar khat chhung chu tui in tur zalen takin an pe a ni.The mice te chu randomly in group paliah then an ni a, chungte chu control group, DSS model group, SASP-treated group (200 mg/kg, oral) leh BLG-treated group (1 g/kg, oral) te an ni.Figure 1A a kan hmuh angin kan zirchianna hmasaah khan experimental chronic relapsing colitis chu mice ah 1.8% DSS cycle thum hmangin ni 5 chhung kan induced a, chu chu distilled water hmangin ni 7 chhung kan induce a ni days, according to our previous study.18 SASP leh BLG enkawl group-a mice te chu ni 0 atanga tan nitin SASP leh BLG hmanga enkawl an ni.Experiment hmasa danah chuan BLG dose chu 1 g/kg-ah dah a ni.Hetih lai hian SASP dose chu literature-a tarlan danin 200 mg/Kg-ah dah a ni.4 Control leh DSS model group-te pawhin an dawng ve ve bawk experiment chhung zawnga tui volume a awm.
Figure 1 BLG hian mice-ah DSS-induced chronic relapsing colitis a ti \ha a ni.(A) Chronic recurrent colitis leh enkawlna experimental design, (B) taksa rih zawng inthlak danglamna, (C) disease activity index (DAI) score, (D) colon sei zawng, (E) colon aiawhtu image, (F) H&E staining Colon (magnification, ×100) leh (G) histological score.Data chu mean ± SEM (n = 6) anga tarlan a ni.##p < 0.01 emaw ###p < 0.001 vs control (Con) group; *p < 0.05 emaw **p < 0.01 emaw ***p < 0.001 emaw DSS group nen an inthlau hle.
Taksa rih zawng, bawlhhlawh inmil dan, leh rectal bleeding te chu nitin record a ni.Disease activity index (DAI) chu a hmaa kan sawi tawh angin taksa rih zawng, stool consistency leh rectal bleeding score te inzawmkhawmin an chhut a ni.19 Experiment tawp lamah chuan mice zawng zawng chu euthanized vek an ni a, thisen, ek leh colon te chu experiment dang neih belh turin an la khawm a ni.
Colon tissue chu formalin-fixed niin paraffin-ah embedded a ni.5-micron section siamin hematoxylin-eosin (H&E) hmangin stain a ni a, chutah chuan blinded a ni a, a hmaa kan sawi tawh angin score a ni
Colon tissue zawng zawng RNA chu Trizol reagent (Invitrogen, Carlsbad, CA) hmangin lakchhuah a ni a, chumi hnuah reverse transcriptase (TaKaRa, Kusatsu, Shiga, Japan) hmangin cDNA lakchhuah a ni.Quantitative PCR chu real-time PCR system hmangin SYBR Green Master (Roche, Basel, Switzerland) hmangin kan ti a.Target gene transcripts chu β-actin-ah normalized a ni a, data chu analyze a ni 2-ΔΔCT method hmangin.Gene primer sequence te chu Table 1-ah hian tarlan a ni.
Primary mouse colonic epithelial cell isolation leh culture chu a hmaa kan sawi tawh ang khan an ti a.20 A tawi zawngin, kar 6-8 mi mice-te colon chu an inthawi hnuah cervical dislocation hmangin an la chhuak hmasa a, chutah chuan longitudinally-in an hawng a, Hanks Balanced Salt Solution (HBSS, calcium leh magnesium tel lo) hmangin an enkawl a, 0.5-1 mm-ah an cut a pieces.Chu hnuah tissue te chu free DMEM medium-ah 0.4 mg/mL collagenase XI (Sigma, Poole, UK) hmangin digested a ni a, 300 xg-ah room temperature-ah min 5 chhung centrifuged a ni.Pellet chu DMEM medium-ah (10% fetal bovine serum, 100 Units/mL penicillin, leh 100 μg/mL streptomycin) 37 °C-ah dahin nylon mesh (pore size ~250 μm) a paltlang a ni.Colonic epithelial cells aliquots chu glass-bottom dish-ah dahin acetic acid, propionic acid, butyric acid, leh mouse fecal extracts te nen darkar 2 chhung 37°C, 5% CO2-ah incubate a ni.
Colon tissue chu PBS hmangin homogenized a ni a, colon tissue-a cytokines IL-6, TNF-α leh IL-1β level chu luminex ELISA assay kit (R&D systems, Minneapolis, MN, USA) hmangin an hmuchhuak a ni.Chutiang bawkin primary murine colonic epithelial cells serum leh culture medium-a GLP-1 level chu ELISA kit hmangin an chhut bawk (Bioswamp, Wuhan, China) ah chuan a siamtu thupek angin a awm ang.
Feces atanga DNA zawng zawng chu DNA extraction kit (Tiangen, China) hmangin lakchhuah a ni.DNA quality leh quantity chu 260 nm/280 nm leh 260 nm/230 nm ratio-ah teh a ni.Hemi hnuah DNA lakchhuah pakhat zel chu template atan hmangin, specific primers 338F (ACTCCTACGGGGAGGCAGCAG) leh 806R (GGACTACHVGGGTWTCTAAT) hmangin 16S rRNA gene-a V3-V4 regions te chu region hrang hrangah amplify a ni.PCR products te chu QIAquick Gel Extraction Kit (QIAGEN, Germany) hmangin tihthianghlim a ni a, real-time PCR hmangin quantified a ni a, IlluminaMiseq PE300 sequencing platform (Illumina Inc., CA, USA) hmangin sequenced a ni bawk.For bioinformatics, data processing chu a hmaa report tawh protocol zawmin tih a ni.21,22 A tawi zawngin, Raw express files filter nan Cutadapt (V1.9.1) hmang rawh.OTU te chu UPARSE (version 7.0.1001) hmangin clustered niin similarity cutoff 97% a awm a, UCHIME hmangin chimeric sequences te paih chhuah a ni bawk.Community composition analysis leh classification chu RDP classifier hmangin an ti a ni (http://rdp.cme.msu.edu/) chu SILVA ribosomal RNA gene database hmanga siam a ni.
Short-chain fatty acids (acetic acid, propionic acid, leh butyric acid) level chu Tao leh a thawhpuiten an sawi tawh angin an teh a, siamthatna engemaw zat an nei bawk.23 A tawi zawngin, bawlhhlawh 100 mg chu deionized water 0.4 mL-ah dah hmasak a ni a, chu chu 50% sulfuric acid 0.1 mL leh 0.5 mL-ah dah a ni 2-ethylbutyric acid (internal standard) a ni a, chu chu homogenized niin 4°C-ah tihlum a ni. C-ah minute 15 chhung 12,000 rpm-ah centrifuge rawh.Supernatant chu ether 0.5 mL hmangin lakchhuah a ni a, GC-ah inject a ni a, analysis atan.Gas chromatography (GC) analysis atan chuan sample te chu GC-2010 Plus gas chromatograph (Shimadzu, Inc.) flame ionization detector (FID) hmanga thuam hmangin an zirchiang a.Separation chu a thleng thei a ni ZKAT-624 column hmangin 30 m × 0.53 mm × 0.3 μm (Lanzhou Zhongke Antai Analytical Technology Co., Ltd., China) a ni.GC solution software (Shimadzu, Inc.) hmangin data an la a ni.Split ratio chu 10:1 a ni a, carrier gas chu nitrogen a ni a, flow rate chu 6 mL/min a ni.Injection volume chu 1 a ni μL.Injector leh detector temperature chu 300°C a ni.Oven temperature chu 140°C-ah minute 13.5 chhung dah a ni a, chutah chuan 250°C-ah 120°C/min rate-in tihsan a ni a; temperature chu minute 5 chhung an dah a.
Data chu mean ± standard error of the mean (SEM) anga tarlan a ni.Data significance chu one-way ANOVA hmanga teh a ni a, chumi hnuah Duncan’s multiple range test hmangin an zirchiang a ni.GraphPad Prism 5.0 software (GraphPad Software Inc., San Diego, CA, USA) chu chhut zawng zawngah hman a ni a, p < 0.05 chu statistically significant anga ngaih a ni.
UC hi chronic relapsing colitis disease a ni tih chu hriat lar tak a ni a, pum na tak, riltam leh thisen chhuak a ni.Chuvangin, BLG anti-colitis efficacy tehna atan mice-ah DSS-induced chronic relapsing colitis hi din a ni (Fig. 1A).Control group nen khaikhin chuan DSS model group-a mice-te chuan taksa rihna leh higher DAI, and these changes were significantly reversed after 24 days of BLG treatment (Figure 1B and C).Colon shortening hi UC hallmark pawimawh tak a ni.Figure 1D leh E-a kan hmuh angin DSS dawngtu mice-te colon sei zawng chu nasa takin a tawi a, mahse BLG treatment hmangin a reh a ni.Chumi hnuah chuan histopathological analysis chu assess colonic-ah an ti a inflammation.H&E stained images leh pathological score-ah chuan DSS pek hian colonic architecture nasa takin a tibuai a, crypt tihchhiatna a thlen a, chutih laiin BLG enkawlna chuan crypt tihchhiat leh pathological score nasa takin a tihhniam thung (Figure 1F leh G).Hriat tur pawimawh tak chu BLG dose 1 g/Kg-a venhimna effect chu SASP dose 200-a pek nen khaikhin theih a ni mg/Kg.A pum puia kan hmuh dan chuan BLG hian mice-a DSS-induced chronic relapsing colitis natna a tihziaawmna kawngah a thawk tha hle tih a tilang.
TNF-α, IL-1β leh IL-6 te hi colonic inflammation inflammatory marker pawimawh tak an ni.Figure 2A a kan hmuh angin DSS hian control group nena khaikhin chuan colon-ah TNF-α, IL-1β leh IL-6 gene expression nasa takin a tipung a ni.BLG pek hian heng DSS-mediated changes te hi nasa takin a tidanglam thei a ni.A dawtah chuan ELISA hmangin inflammatory levels te chu kan chhut a ni cytokines TNF-α, IL-1β, leh IL-6 in colon tissue.Results atanga a lan dan chuan DSS hmanga enkawl mice-ah TNF-α, IL-1β, leh IL-6 te chu colonic level-ah nasa takin a sang a, BLG hmanga enkawlna erawh chuan heng a punna hi a tiziaawm thung (Figure 2B).
Figure 2 BLG hian DSS hmanga enkawl mice-te colon-a proinflammatory cytokines TNF-α, IL-1β leh IL-6 te gene expression leh siamchhuahna a titawp a ni.(A) TNF-α, IL-1β leh IL-6 te colonic gene expression (B) TNF-α, IL-1β leh IL-6-te colonic protein level.Data chu mean ± SEM (n = 4–6) anga tarlan a ni.#p < 0.05 emaw ##p < 0.01 emaw ###p < 0.001 vs control (Con) group *p < 0.05 emaw **p < 0.01 emaw a ni a, DSS group nen a inthlau hle.
Intestinal dysbiosis hi UC pathogenesis-ah a pawimawh hle.24 DSS hmanga enkawl mice-te gut microbiota BLG hian a modulate em tih zirchian nan 16S rRNA sequencing hmangin gut contents-a bacterial community an zirchiang a.Venn diagram-ah chuan group pathumte hian OTU 385 an nei tih a tarlang a.At the same time, group each had unique OTUs (Fig. 3A).Chubakah, Figure 3B leh C-a kan hmuh Chao1 index leh Shannon index te hian BLG hmanga enkawl mice-ah hian gut microbiota community diversity a tlahniam tih a tarlang a, hei hi BLG hmanga enkawl group-ah Shannon index a tlahniam nasa hle a ni.Group pathumte leh group pathumte inkara clustering pattern hriat nan principal component analysis (PCA) leh principal coordinate analysis (PCoA) te hman a ni BLG hmanga enkawl mice te community structure chu BLG treatment hnuah chiang takin a inthen tih an hmuchhuak (Figure 3D leh E).Heng data te hian BLG treatment hian DSS-induced colitis vei mice te community structure nasa takin a nghawng tih a tarlang.
Figure 3 BLG hian DSS-induced colitis vei mice-a gut microbiota chi hrang hrang a tidanglam a ni.(A) OTU-a Venn diagram, (B) Chao1 index, (C) Shannon-a richness index, (D) OTU-a Principal Component Analysis (PCA) score plot, (E) OTU Principal Coordinate Analysis (PCoA) score Figure. Data chu mean ± SEM (n = 6) anga tarlan a ni.**p < 0.01 vs DSS group.
Fecal microbiota-a inthlak danglamna bik tehna atan taxonomic level zawng zawngah gut microbiota composition kan zirchiang a.Figure 4A-a kan hmuh angin group zawng zawnga phyla ber chu Firmicutes leh Bacteroidetes an ni a, a dawttu chu Verrucomicrobia an ni.The relative abundances of Firmicutes and Firmicutes/Bacteroidetes ratios were significantly increased in the Fecal microbial communities of DSS-treated mice compared with control mice, and these changes were significantly reversed after BLG treatment .A bik takin, BLG hmanga enkawl hian DSS-induced colitis vei mice-te ek-a Verrucobacterium relative abundance chu nasa takin a tipung a ni.In chhung level-ah chuan fecal microbial communities chu Lachnospiriaceae, Muribaculaceae, Akkermansiaceae, Ruminococcaceae leh Prevotellaceae (Fig. 4B).DSS group nen khaikhin chuan BLG tlakchhamna hian Akkermansiaceae tamna a tipung a, mahse Lachnospiraceae leh Ruminococcaceae tamna a ti tlem thung.Hriat tur pawimawh tak chu genus level-ah chuan fecal microbiota chu a luah a ni by Lachnospira_NK4A136_group, Akkermansia and Prevotellaceae_UCG-001 (Fig. 4C).He thil hmuhchhuah hian BLG enkawlna hian DSS challenge chhanna atana microbiota imbalance chu nasa takin a tidanglam tih a tilang bawk a, hei hi Eubacterium_xylanophilum_group, Ruminococcaceae_UCG-014, Intestinimonas leh Oscillibacter, leh Akkermansia leh Prevotellaceae_UCG-001 te a pung bawk.
Figure 4 BLG hian DSS-induced colitis mice-a gut microbiota tamna a tidanglam a ni.(A) Phylum level-a gut microbiota tamna; (B) Chhungkaw level-a gut microbiota tamna; (C) Genus level-a gut microbiota tamna.Data chu mean ± SEM (n = 6) anga tarlan a ni.#p < 0.05 emaw ###p < 0.001 vs control (Con) group *p < 0.05 emaw **p < 0.01 emaw ***p < 0.001 emaw DSS group nen an inthlau hle.
Short-chain fatty acids (SCFAs) hi Akkermansia leh Prevotellaceae_UCG-001 metabolite lian ber a nih thu ngaihtuah chuan, acetate, propionate leh butyrate te hi intestinal lumen-a SCFA tam ber an nih laiin, 25-27 kan zirchiannaah hian kan la awm reng a ni.Figure 5-a kan hmuh angin fecal acetate, propionate, leh butyrate concentration te chu a ni DSS hmanga enkawl group-ah chuan nasa takin a tlahniam a, BLG enkawlna erawh chuan he tlahniam hi nasa takin a titawp thei thung.
Figure 5. BLG hian DSS-induced colitis vei mice-te ek-ah SCFAs level a tisang a ni.(A) Feces-a acetic acid awm zat; (B) bawlhhlawh chhunga propionic acid awm zat; (C) bawlhhlawh chhunga butyric acid awm zat.Data chu mean ± SEM (n = 6) anga tarlan a ni.#p < 0.05 emaw ##p < 0.01 vs control (Con) group; *p < 0.05 emaw **p < 0.01 emaw a ni a, DSS group nen a inthlau hle.
Genus-level differential SCFA leh fecal microbiota inkara Pearson correlation coefficient kan chhut belh leh a.Figure 6-a kan hmuh angin Akkermansia hi propionic acid (Pearson = 0.4866) leh butyric acid (Pearson = 0.6192) siamna nen a inzawm tha hle a ni.Chutiang bawkin Enteromonas leh Oscillobacter te hi acetate nen hian inzawmna tha lo tak an nei a ni production, with Pearson coefficients of 0.4709 and 0.5104, respectively.Chutiang bawkin Ruminococcaceae_UCG-014 pawh hi propionic acid (Pearson = 0.4508) leh butyric acid (Pearson = 0.5842) siam chhuahna nen a inzawm tha lo hle.
Figure 6 Pearson-a’n differential SCFA leh colonic microbes inkara inzawmna thlirletna.(A) Enteromonas with acetic acid; (B) Concussion bacillus chu acetic acid nen a inzawm a; (C) Akkermansia leh propionic acid te hi an inthlau hle a; (D) Ruminococcus_UCG-014 chu propionic acid hmanga siam a ni a; (E) Akkermansia chu butyric acid nen a inzawm a; (F) ) Ruminococcus _UCG-014 chu butyric acid hmanga siam a ni.
Glucagon-like peptide-1 (GLP-1) hi proglucagon (Gcg) atanga cell-type-specific post-translational product a ni a, anti-inflammatory properties a nei a ni.28 Figure 7-a kan hmuh angin DSS hian Gcg mRNA expression nasa takin a tihhniam a ni.Colon leh BLG treatment hian control group nena khaikhin chuan DSS-induced Gcg reduction chu nasa takin a tidanglam thei a ni (Fig. 7A).Chutih rual chuan DSS hmanga enkawl group-ah serum-a GLP-1 level chu nasa takin a tlahniam a, BLG hmanga enkawlna hian he tihtlem hi nasa takin a veng thei a ni (Fig. 7B).Short-chain fatty acids hian G-protein-coupled receptor 43 (GRP43) leh G-protein-coupled receptor 41 (GRP41) activation hmangin GLP-1 secretion a tichak thei a, kan colitis mice-te colon-a GPR41 leh GRP43 te pawh an enfiah a, DSS challenge hnuah GRP43 leh GPR41-te colonic mRNA expression chu nasa takin a tlahniam tih an hmuchhuak a, BLG hmanga enkawlna hian heng tlahniamte hi a chhanchhuak thei a ni (Figure 7C leh D).
Figure 7 BLG hian DSS hmanga enkawl mice-ah serum GLP-1 level leh colonic Gcg, GPR41 leh GRP43 mRNA expression a tisang a ni.(A) Colon tissue-a Gcg mRNA expression (B) Serum-a GLP-1 level; (C) GPR41 mRNA expression chu colon tissue-ah a awm a; (D) Colon tissue-a GPR43 mRNA expression.Data chu mean ± SEM (n = 5–6) anga tarlan a ni.#p < 0.05 emaw ##p < 0.01 vs control (Con) group *p < 0.05 leh DSS group nen an inthlau.
BLG hmanga enkawlna hian DSS hmanga enkawl mice-ah serum GLP-1 level, colonic Gcg mRNA expression, leh fecal SCFA level a tihsan theih avangin, primary murine atanga GLP-1 chhuah a nih veleh control (F-Con), DSS colitis (F-Con) -DSS) leh BLG-treated colitis (F-BLG) mice atanga acetate, propionate, leh butyrate te kan enfiah belh leh a ni colonic epithelial cells.Figure 8A-a kan hmuh angin, primary mouse colonic epithelial cells 2 mM acetic acid, propionic acid leh butyric acid hmanga enkawl te chuan GLP-1 release nasa takin a tichak a, hei hi zirchianna hmasa nen a inmil hle.29,30 Chutiang bawkin F-Con, F-DSS, leh F-BLG zawng zawng (feces 0.25 g tlukpui) te pawh a ni. greatly stimulated the release of GLP-1 from primary murine colonic epithelial cells.Hriat tur pawimawh tak chu F-DSS hmanga enkawl primary mouse colonic epithelial cells atanga GLP-1 chhuah zat chu F-Con leh F-BLG hmanga enkawl primary mouse colonic epithelial cells te aiin a hniam zawk hle.(Figure 8B).He data hian BLG enkawlna hian nasa takin a siam tha leh tih a tilang intestinal SCFA atanga siam GLP-1 siam chhuah a ni.
Figure 8 BLG atanga chhuak SCFA hian primary murine colonic epithelial cells atanga GLP-1 release a tichak a.(A) Acetic acid, propionic acid leh butyric acid te hian primary murine colonic epithelial cells atanga GLP-1 release a tichak a (B) fecal extracts F-Con, F-DSS leh F-BLG te hian primary murine colonic epithelial cells a tichak a GLP-1 released zat.Colonic epithelial cells aliquots te chu glass-bottom petri dish-ah dahin 2 mM acetic acid, propionic acid, butyric acid, leh fecal extracts F-Con, F-DSS, leh F-BLG (0.25 g feces tlukpui), a hnuaia mi ang hian. 37°C-ah darkar 2, 5% CO2, a hnuaia mi ang hian.Primary murine colonic epithelial cells atanga GLP-1 chhuak zat chu ELISA hmangin an hmuchhuak a.Data chu mean ± SEM (n = 3) anga tarlan a ni.#p < 0.05 or ##p < 0.01 vs. blank or F-Con *p < 0.05 a ni a, F-DSS nen a inthlau.
A tawi zawngin: Ace, acetic acid; Pro, propionic acid tih a ni a; mahse, butyric acid a ni a; F-Con, control mice atanga bawlhhlawh lakchhuah; F-DSS, colitis mice atanga bawlhhlawh lakchhuah; F-BLG, BLG hmanga enkawl colon Fecal extract atanga inflammatory mice atanga lak chhuah.
World Health Organization-in natna refractory disease anga a dah, UC hi khawvel pum huapa hlauhawm tak a ni chho mek a; mahse, natna sawi lawk, venna leh enkawlna atana hmanraw tangkai tak takte chu a la tlem hle.Chuvangin, UC tana enkawlna kawng thar him leh tangkai tak zawn leh siam chhuah a ngai nghal vat a ngai a ni.Traditional Chinese medicine preparations hi duhthlan tur beisei awm tak a ni a, a chhan chu traditional Chinese medicine preparation tam tak chu kum zabi tam tak chhung chu Chinese population-a UC enkawlnaah a tangkai hle tih hmuhchhuah a ni tawh a, an vai hian biological organic leh natural material an ni vek a ni that are mostly harmless to humans and animals.31,32 He zirchianna hian UC enkawlna atana traditional Chinese medicine inbuatsaihna him leh tangkai tak zawng a, a hnathawh dan chhui chhuah a tum a ni.BLG hi Chinese herbal formula hriat hlawh tak, flu enkawlna atana hman thin a ni.8,33 Kan laboratory leh midangte hnathawhnaah chuan indigo, BLG nen raw material inang atanga processed traditional Chinese medicine product, exhibits significant efficacy in the treatment of UC in humans and animals.4,34 Mahse, BLG-in anti-colitis a nghawng dan leh a nghawng dan A mechanism hi a chiang lo.Tun zirchiannaah hian kan result-ah hian BLG hian DSS-induced colonic inflammation chu a tichak hle tih a tarlang a, hei hi gut microbiota modulation leh gut-derived GLP-1 siam tharna nen a inzawm a ni.
UC hi clinical features tlangpui neia period relapsing a ni tih chu hriat lar tak a ni. fluctuating weight loss leh DAI score-te chuan chronic relapsing colitis induction hlawhtling tak a lantir a ni.BLG hmanga enkawl group-a mice-te chuan ni 8 aṭang khan upshift recovery an nei a, hei hi ni 24 aiin a danglam hle.DAI score-ah pawh hetiang chiah hian danglamna hmuh a ni a, hei hian colitis clinical improvement-ah hmasawnna a awm tih a tilang.Colon injury leh inflammatory status chungchangah chuan, length, colon tissue chhiatna, leh gene expression leh colon tissue-a proinflammatory cytokines TNF-α, IL-1β, leh IL-6 siamchhuah te pawh BLG enkawl hnuah nasa takin a tha chho bawk.A pum puia thlir chuan heng result te hian BLG hi mice-a chronic relapsing colitis enkawlnaah a tangkai tih chiang takin a tarlang a ni.
Engtin nge BLG hian a pharmacological effects a neih?Tun hmaa zirchianna tam takah chuan UC natna thlentuah hian gut microbiota hian hmun pawimawh tak a chang tih hmuhchhuah a ni a, microbiome-based leh microbiome-targeted therapies te chu UC enkawlna atana strategy ngaihnawm tak angin a lo chhuak ta a ni.Tun zirchiannaah hian BLG enkawlna hian gut microbiota composition-ah danglamna nasa tak a thlen tih kan hmuchhuak a, hei hian a tilang a ni protective effect of BLG against DSS-induced colitis is related to modulation of gut microbiota.He thil hmuhchhuah hi gut microbiota homeostasis reprogramming hi TCM siam thatna hriatthiamna atana hmanraw pawimawh tak a ni tih ngaihdan nen a inmil a ni.36,37 Hriat tur pawimawh tak chu Akkermansia hi Gram-negative leh strictly anaerobic bacterium a ni a, mucus-ah a cheng a ni layer of the gut, chu chuan mucins a tichhe a, propionic acid a siam a, goblet cell differentiation a tichak a, mucosa a vawng reng bawk. function of barrier integrity.26 Clinical leh animal data tam tak atanga a lan dan chuan Akkermansia hi mucosa hrisel,38 leh Akkermansia spp. can significantly improve mucosal inflammation.39 Tuna kan data atanga kan hmuh dan chuan BLG enkawlna hnuah Akkermansia relative abundance hi nasa takin a pung a ni.Chu bakah, Prevotellaceae_UCG-001 hi SCFA siamtu bacterium a ni.27 Zirna tam takah chuan Prevotellaceae_UCG-001 hi ran vun natna (feces)-ah relative abundance hniam takah hmuh a ni tih hmuhchhuah a ni colitis.40,41 Tuna kan data hian BLG hmanga enkawlna hian DSS hmanga enkawl mice-te colon-ah Prevotellaceae_UCG-001 relative abundance nasa takin a tipung thei tih a tarlang bawk.Chu danglamna chu Oscillibacter hi mesophilic, strictly anaerobic bacterium a ni.42 chuan UC mice-ah Oscillibacter relative abundance chu nasa takin a pung tih an sawi a, a nasa hle bawk positively correlated with IL-6 and IL-1β levels and pathological scores.43,44 Hriat tur pawimawh tak chu BLG enkawlna hian DSS hmanga enkawl mice-te ek-a Oscillibacter awm zat chu nasa takin a tihtlem a ni.Hriat tur pawimawh tak chu heng BLG-a inthlak danglam bacteria te hi SCFA siamtu bacteria tam ber an ni.Tun hmaa zirchianna tam takah chuan SCFAs hian colonic-a nghawng tha tak a neih theih dan an tarlang tawh a ni inflammation and protection of intestinal epithelial integrity.45,46 Tuna kan data kan hmuh hian DSS hmanga enkawl mice-a SCFA acetate, propionate, leh butyrate concentration chu BLG hmanga enkawl mice-ah nasa takin a pung tih kan hmu bawk.Heng thil hmuhchhuah zawng zawng hi khaikhawm ila, BLG hmanga enkawlna hian chronic nei mice-ah DSS-induced SCFA-producing bacteria chu nasa takin a tichak thei tih a tilang chiang hle colitis natna lo lang leh thei.
GLP-1 hi ileum leh colon-a siam chhuah incretin a ni a, gastric emptying tihkhawtlai leh ei hnua thisen glucose tihhniamna kawngah hmun pawimawh tak a chang a ni.47 Evidence atanga a lan dan chuan dipeptidyl peptidase (DPP)-4, GLP-1 receptor agonist leh GLP-1 nanomedicine te hian mice-a intestinal inflammation chu tha takin a tiziaawm thei a ni. SCFA concentration sang chu mihring leh mice-a plasma GLP-1 level nen a inzawm tih hmuhchhuah a ni. 52 Our current data show that after BLG treatment, serum GLP-1 levels and Gcg mRNA expression was significantly increased.Likewise, GLP-1 secretion was significantly increased in colonic cultures following stimulation with fecal extracts from BLG-treated colitis mice compared to stimulation with fecal extracts from DSS-treated colitis mice.How do SCFAs affect the release of GLP-1?Gwen Tolhurst leh a thawhpui te chuan. reported that SCFA can stimulate GLP-1 secretion through GRP43 and GPR41.29 Kan data hman mek hian BLG enkawlna hian DSS hmanga enkawl mice-te colon-a GRP43 leh GPR41 mRNA expression nasa takin a tipung tih a tarlang bawk.Heng data hian BLG enkawlna hian GRP43 leh GPR41 activate-in SCFA-promoted GLP-1 production a siam ṭha leh thei tih a tilang.
BLG hi China ramah chuan hun rei tak chhunga over-the-counter (OTC) damdawi a ni. Kunming mice-a BLG tolerated dose sang ber chu 80g/Kg a ni a, acute toxicity hmuh tur a awm lo.53 Tunah hian mihringah BLG (sugar tel lo) dose rawt chu 9-15 g/day (ni khatah vawi 3) a ni.Kan zirchiannaah chuan BLG at 1g/Kg hian DSS-induced chronic relapsing colitis in mice.He dose hi clinically-a hman BLG dose nen a inhnaih hle a ni.Kan zirchiannaah hian a hnathawh dan hi a tlem berah chuan gut microbiota, a bik takin SCFA siamtu bacteria, Akkermansia leh Prevotellaceae_UCG-001 te, gut-derived GLP-1 production siam that lehna tur a inthlak danglamna avanga mediated a ni tih kan hmu bawk.Heng thil hmuhchhuah te hian BLG hian a belhchhah a phu tih a tilang bawk consideration as a potential therapeutic agent for clinical colitis treatment.Amaherawhchu, gut microbiota a modulate dan dik tak chu microbiota tlachham mice leh fecal bacterial transplantation hmangin finfiah a la ni lo.
Ace, acetic acid hmanga siam a ni a; mahse, butyric acid hmanga siam a ni a; BLG, pandan tih te; DSS, dextran sodium sulfate hmanga siam a ni a; DAI, natna hnathawh dan tehna; DPP, dipeptidyl peptidase tih a ni a; FID, meialh ionization hriat theihna; F-Con, control Mice atanga Fecal extracts te; F-DSS, DSS colitis mice-a bawlhhlawh paih chhuah; F-BLG, BLG hmanga enkawl colitis mice-a fecal extract; GLP-1, glucagon ang chi peptide-1; Gcg, glucagon tih a ni a; gas chromatography, gas chromatography hmanga thil tih te; GRP43, G protein nena inzawm receptor 43; GRP41, G protein nena inzawm receptor 41; H&E, hematoxylin-eosin tih te hi a ni a; HBSS, Hanks-a Salt Solution inthlau tak ; OTC, OTC hmanga tih a ni a; PCA, thil pawimawh ber berte thlirletna; PCoA, principal coordinate hmanga zirchianna; Pro, propionic acid tih a ni a; SASP, sulfasalazine tih te hi a awm a; SCFA, chain tawi nei thau acids te; Chinese damdawi, Chinese damdawi hmanlai; UC, natna hrik (ulcerative colitis) a ni.
Experimental protocol zawng zawng hi Peking University Shenzhen-Hong Kong University of Science and Technology Medical Center (Shenzhen, China)-a Animal Ethics Committee chuan Institutional Guidelines leh Animal Regulations (ethics number A2020157) angin a pawm vek a ni.
Lehkhabu ziaktu zawng zawngte hian conception leh design-ah te, data lakkhawmnaah te, emaw data thlirletna leh hrilhfiahnaah te thawhhlawk tak an nei a; article siamnaah emaw, intellectual content pawimawh tak takte critically revising-ah emaw a tel a; manuscript chu tuna journal-a thehluh a remti a; a tawpah chuan version chu chhuah turin a pawm ta a; Hnathawh kawng tinrenga mawhphurtu.
He hna hi National Natural Science Foundation of China (81560676 leh 81660479), Shenzhen University-a first-class project (86000000210), Shenzhen Science and Technology Innovation Committee Fund (JCYJ20210324093810026), leh Guangdong Provincial Medical Science and Technology Research Fund te chuan an pui a ni (A2020157 leh A2020272), Guizhou Medical University Pharmacy Guizhou Province-a Key Laboratory (YWZJ2020-01) leh Peking University Shenzhen Hospital (JCYJ2018009) te sum hmanga siam a ni.
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