Anti-tumor necrosis factor α therapy associates to type 17 helper T lymphocytes immunological shift and significant microbial changes in dextran sodium sulphate colitis
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摘要
BACKGROUND Anti-tumor necrosis factor α(TNFα) represents the best therapeutic option to induce mucosal healing and clinical remission in patients with moderate-severe ulcerative colitis. On the other side gut microbiota plays a crucial role in pathogenesis of ulcerative colitis but few information exists on how microbiota changes following anti-TNFα therapy and on microbiota role in mucosal healing.AIM To elucidate whether gut microbiota and immune system changes appear following anti TNFα therapy during dextran sulfate sodium(DSS) colitis.METHODS Eighty C57 BL/6 mice were divided into four groups: "No DSS", "No DSS + antiTNFα", "DSS" and "DSS + anti-TNFα". "DSS" and "DSS + anti-TNFα" were treated for 5 d with 3% DSS. At day 3, mice whithin "No DSS+anti-TNFα" and"DSS+anti-TNFα" group received 5 mg/kg of an anti-TNFα agent. Forty mice were sacrificed at day 5, forty at day 12, after one week of recovery post DSS. The severity of colitis was assessed by a clinical score(Disease Activity Index), colon length and histology. Bacteria such as Bacteroides, Clostridiaceae, Enterococcaceae and Fecalibacterium prausnitzii(F. prausnitzii) were evaluated by quantitative PCR.Type 1 helper T lymphocytes(Th1), type 17 helper T lymphocytes(Th17) and CD4+ regulatory T lymphocytes(Treg) distributions in the mesenteric lymph node(MLN) were studied by flow cytometry.RESULTS Bacteria associated with a healthy state(i.e., such as Bacteroides, Clostridiaceae and F. prausnitzii) decreased during colitis and increased in course of anti-TNFαtreatment. Conversely, microorganisms belonging to Enterococcaceae genera,which are linked to inflammatory processes, showed an opposite trend.Furthermore, in colitic mice treated with anti-TNFα microbial changes were associated with an initial increase(day 5 of the colitis) in Treg cells and a consequent decrease(day 12 post DSS) in Th1 and Th17 frequency cells. Healthy mice treated with anti-TNFα showed the same histological, microbial and immune features of untreated colitic mice. "No DSS + anti-TNFα" group showed a lymphomononuclear infiltrate both at 5 th and 12 th d at hematoxylin and eosin staining, an increase of in Th1 and Th17 frequency at day 12, an increase of Enterococcaceae at day 5, a decrease of Bacteroides and Clostridiaceae at day 12.CONCLUSION Anti-TNFα treatment in experimental model of colitis improves disease activity but it is associated to an increase in Th17 pathway together with gut microbiota alteration.
BACKGROUND Anti-tumor necrosis factor α(TNFα) represents the best therapeutic option to induce mucosal healing and clinical remission in patients with moderate-severe ulcerative colitis. On the other side gut microbiota plays a crucial role in pathogenesis of ulcerative colitis but few information exists on how microbiota changes following anti-TNFα therapy and on microbiota role in mucosal healing.AIM To elucidate whether gut microbiota and immune system changes appear following anti TNFα therapy during dextran sulfate sodium(DSS) colitis.METHODS Eighty C57 BL/6 mice were divided into four groups: "No DSS", "No DSS + antiTNFα", "DSS" and "DSS + anti-TNFα". "DSS" and "DSS + anti-TNFα" were treated for 5 d with 3% DSS. At day 3, mice whithin "No DSS+anti-TNFα" and"DSS+anti-TNFα" group received 5 mg/kg of an anti-TNFα agent. Forty mice were sacrificed at day 5, forty at day 12, after one week of recovery post DSS. The severity of colitis was assessed by a clinical score(Disease Activity Index), colon length and histology. Bacteria such as Bacteroides, Clostridiaceae, Enterococcaceae and Fecalibacterium prausnitzii(F. prausnitzii) were evaluated by quantitative PCR.Type 1 helper T lymphocytes(Th1), type 17 helper T lymphocytes(Th17) and CD4+ regulatory T lymphocytes(Treg) distributions in the mesenteric lymph node(MLN) were studied by flow cytometry.RESULTS Bacteria associated with a healthy state(i.e., such as Bacteroides, Clostridiaceae and F. prausnitzii) decreased during colitis and increased in course of anti-TNFαtreatment. Conversely, microorganisms belonging to Enterococcaceae genera,which are linked to inflammatory processes, showed an opposite trend.Furthermore, in colitic mice treated with anti-TNFα microbial changes were associated with an initial increase(day 5 of the colitis) in Treg cells and a consequent decrease(day 12 post DSS) in Th1 and Th17 frequency cells. Healthy mice treated with anti-TNFα showed the same histological, microbial and immune features of untreated colitic mice. "No DSS + anti-TNFα" group showed a lymphomononuclear infiltrate both at 5 th and 12 th d at hematoxylin and eosin staining, an increase of in Th1 and Th17 frequency at day 12, an increase of Enterococcaceae at day 5, a decrease of Bacteroides and Clostridiaceae at day 12.CONCLUSION Anti-TNFα treatment in experimental model of colitis improves disease activity but it is associated to an increase in Th17 pathway together with gut microbiota alteration.
BACKGROUND Anti-tumor necrosis factor α(TNFα) represents the best therapeutic option to induce mucosal healing and clinical remission in patients with moderate-severe ulcerative colitis. On the other side gut microbiota plays a crucial role in pathogenesis of ulcerative colitis but few information exists on how microbiota changes following anti-TNFα therapy and on microbiota role in mucosal healing.AIM To elucidate whether gut microbiota and immune system changes appear following anti TNFα therapy during dextran sulfate sodium(DSS) colitis.METHODS Eighty C57 BL/6 mice were divided into four groups: "No DSS", "No DSS + antiTNFα", "DSS" and "DSS + anti-TNFα". "DSS" and "DSS + anti-TNFα" were treated for 5 d with 3% DSS. At day 3, mice whithin "No DSS+anti-TNFα" and"DSS+anti-TNFα" group received 5 mg/kg of an anti-TNFα agent. Forty mice were sacrificed at day 5, forty at day 12, after one week of recovery post DSS. The severity of colitis was assessed by a clinical score(Disease Activity Index), colon length and histology. Bacteria such as Bacteroides, Clostridiaceae, Enterococcaceae and Fecalibacterium prausnitzii(F. prausnitzii) were evaluated by quantitative PCR.Type 1 helper T lymphocytes(Th1), type 17 helper T lymphocytes(Th17) and CD4+ regulatory T lymphocytes(Treg) distributions in the mesenteric lymph node(MLN) were studied by flow cytometry.RESULTS Bacteria associated with a healthy state(i.e., such as Bacteroides, Clostridiaceae and F. prausnitzii) decreased during colitis and increased in course of anti-TNFαtreatment. Conversely, microorganisms belonging to Enterococcaceae genera,which are linked to inflammatory processes, showed an opposite trend.Furthermore, in colitic mice treated with anti-TNFα microbial changes were associated with an initial increase(day 5 of the colitis) in Treg cells and a consequent decrease(day 12 post DSS) in Th1 and Th17 frequency cells. Healthy mice treated with anti-TNFα showed the same histological, microbial and immune features of untreated colitic mice. "No DSS + anti-TNFα" group showed a lymphomononuclear infiltrate both at 5 th and 12 th d at hematoxylin and eosin staining, an increase of in Th1 and Th17 frequency at day 12, an increase of Enterococcaceae at day 5, a decrease of Bacteroides and Clostridiaceae at day 12.CONCLUSION Anti-TNFα treatment in experimental model of colitis improves disease activity but it is associated to an increase in Th17 pathway together with gut microbiota alteration.
引文
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2 Scaldaferri F,Fiocchi C.Inflammatory bowel disease:progress and current concepts of etiopathogenesis.J Dig Dis 2007;8:171-178[PMID:17970872 DOI:10.1111/j.1751-2980.2007.00310.x]
3 Benchimol EI,Fortinsky KJ,Gozdyra P,Van den Heuvel M,Van Limbergen J,Griffiths AM.Epidemiology of pediatric inflammatory bowel disease:a systematic review of international trends.Inflamm Bowel Dis 2011;17:423-439[PMID:20564651 DOI:10.1002/ibd.21349]
4 Mir-Madjlessi SH,Michener WM,Farmer RG.Course and prognosis of idiopathic ulcerative proctosigmoiditis in young patients.J Pediatr Gastroenterol Nutr 1986;5:571-575[PMID:2874204]
5 Molodecky NA,Soon IS,Rabi DM,Ghali WA,Ferris M,Chernoff G,Benchimol EI,Panaccione R,Ghosh S,Barkema HW,Kaplan GG.Increasing incidence and prevalence of the inflammatory bowel diseases with time,based on systematic review.Gastroenterology 2012;142:46-54.e42;quiz e30[PMID:22001864 DOI:10.1053/j.gastro.2011.10.001]
6 Ye Y,Pang Z,Chen W,Ju S,Zhou C.The epidemiology and risk factors of inflammatory bowel disease.Int J Clin Exp Med 2015;8:22529-22542[PMID:26885239]
7 Ng SC,Shi HY,Hamidi N,Underwood FE,Tang W,Benchimol EI,Panaccione R,Ghosh S,Wu JCY,Chan FKL,Sung JJY,Kaplan GG.Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century:a systematic review of population-based studies.Lancet 2018;390:2769-2778[PMID:29050646 DOI:10.1016/S0140-6736(17)32448-0]
8 Yang L,Liu C,Zhao W,He C,Ding J,Dai R,Xu K,Xiao L,Luo L,Liu S,Li W,Meng H.Impaired Autophagy in Intestinal Epithelial Cells Alters Gut Microbiota and Host Immune Responses.Appl Environ Microbiol 2018;84[PMID:30006408 DOI:10.1128/AEM.00880-18]
9 Nicholson JK,Holmes E,Kinross J,Burcelin R,Gibson G,Jia W,Pettersson S.Host-gut microbiota metabolic interactions.Science 2012;336:1262-1267[PMID:22674330 DOI:10.1126/science.1223813]
10 Jostins L,Ripke S,Weersma RK,Duerr RH,McGovern DP,Hui KY,Lee JC,Schumm LP,Sharma Y,Anderson CA,Essers J,Mitrovic M,Ning K,Cleynen I,Theatre E,Spain SL,Raychaudhuri S,Goyette P,Wei Z,Abraham C,Achkar JP,Ahmad T,Amininejad L,Ananthakrishnan AN,Andersen V,Andrews JM,Baidoo L,Balschun T,Bampton PA,Bitton A,Boucher G,Brand S,Büning C,Cohain A,Cichon S,D'Amato M,De Jong D,Devaney KL,Dubinsky M,Edwards C,Ellinghaus D,Ferguson LR,Franchimont D,Fransen K,Gearry R,Georges M,Gieger C,Glas J,Haritunians T,Hart A,Hawkey C,Hedl M,Hu X,Karlsen TH,Kupcinskas L,Kugathasan S,Latiano A,Laukens D,Lawrance IC,Lees CW,Louis E,Mahy G,Mansfield J,Morgan AR,Mowat C,Newman W,Palmieri O,Ponsioen CY,Potocnik U,Prescott NJ,Regueiro M,Rotter JI,Russell RK,Sanderson JD,Sans M,Satsangi J,Schreiber S,Simms LA,Sventoraityte J,Targan SR,Taylor KD,Tremelling M,Verspaget HW,De Vos M,Wijmenga C,Wilson DC,Winkelmann J,Xavier RJ,Zeissig S,Zhang B,Zhang CK,Zhao H,Silverberg MS,Annese V,Hakonarson H,Brant SR,Radford-Smith G,Mathew CG,Rioux JD,Schadt EE,Daly MJ,Franke A,Parkes M,Vermeire S,Barrett JC,Cho JH;International IBD Genetics Consortium(IIBDGC).Hostmicrobe interactions have shaped the genetic architecture of inflammatory bowel disease.Nature 2012;491:119-124[PMID:23128233 DOI:10.1038/nature11582]
11 Neurath MF.Cytokines in inflammatory bowel disease.Nat Rev Immunol 2014;14:329-342[PMID:24751956 DOI:10.1038/nri3661]
12 Jones-Hall YL,Nakatsu CH.The Intersection of TNF,IBD and the Microbiome.Gut Microbes 2016;7:58-62[PMID:26939853 DOI:10.1080/19490976.2015.1121364]
13 Himmel ME,Yao Y,Orban PC,Steiner TS,Levings MK.Regulatory T-cell therapy for inflammatory bowel disease:more questions than answers.Immunology 2012;136:115-122[PMID:22348589 DOI:10.1111/j.1365-2567.2012.03572.x]
14 Eckburg PB,Bik EM,Bernstein CN,Purdom E,Dethlefsen L,Sargent M,Gill SR,Nelson KE,Relman DA.Diversity of the human intestinal microbial flora.Science 2005;308:1635-1638[PMID:15831718DOI:10.1126/science.1110591]
15 Sokol H,Seksik P,Furet JP,Firmesse O,Nion-Larmurier I,Beaugerie L,Cosnes J,Corthier G,Marteau P,DoréJ.Low counts of Faecalibacterium prausnitzii in colitis microbiota.Inflamm Bowel Dis 2009;15:1183-1189[PMID:19235886 DOI:10.1002/ibd.20903]
16 Bernstein CN,Forbes JD.Gut Microbiome in Inflammatory Bowel Disease and Other Chronic ImmuneMediated Inflammatory Diseases.Inflamm Intest Dis 2017;2:116-123[PMID:30018962 DOI:10.1159/000481401]
17 Sartor RB,Wu GD.Roles for Intestinal Bacteria,Viruses,and Fungi in Pathogenesis of Inflammatory Bowel Diseases and Therapeutic Approaches.Gastroenterology 2017;152:327-339.e4[PMID:27769810DOI:10.1053/j.gastro.2016.10.012]
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