Anti-tumor necrosis factor α therapy associates to type 17 helper T lymphocytes immunological shift and significant microbial changes in dextran sodium sulphate colitis

作     者：Valentina Petito Cristina Graziani Loris R Lopetuso Marco Fossati Alessandra Battaglia Vincenzo Arena Domenico Scannone Gianluca Quaranta Andrea Quagliariello Federica Del Chierico Lorenza Putignani Luca Masucci Maurizio Sanguinetti Alessandro Sgambato Antonio Gasbarrini Franco Scaldaferri 

作者机构：Istituto di Patologia Speciale Medica Università Cattolica del Sacro Cuore UOC di Medicina Interna e Gastroenterologia Area di Gastroenterologia e Oncologia Medica Dipartimento di Scienze Gastroenterologiche Endocrino-Metaboliche e Nefro-Urologiche Fondazione Policlinico Universitario "A. Gemelli" IRCCS Dipartimento delle Scienze della Salute della Donna e del Bambino Fondazione Policlinico Universitario "A. Gemelli" IRCCS Istituto di Clinica Ostetrica e Ginecologica Università Cattolica del Sacro Cuore U.O.S.A. Gineco-Patologia e Patologia Mammaria Fondazione Policlinico Universitario "A. Gemelli" IRCCS Istituto di Anatomia Patologica Università Cattolica del Sacro Cuore Dipartimento di Anatomia Patologica e Istologia Fondazione Policlinico Universitario "A. Gemelli" IRCCS Dipartimento di MicrobiologiaFondazione Policlinico Universitario "A. Gemelli" IRCCS Istituto di Microbiologia Università Cattolica del Sacro Cuore Unità di Microbioma UmanoOspedale Pediatrico Bambino Gesù IRCCS Unità di Parassitologia Ospedale Pediatrico Bambino Gesù IRCCS Istituto di Patologia Generale Università Cattolica del Sacro Cuore 

出 版 物：《World Journal of Gastroenterology》 (世界胃肠病学杂志（英文版）)

年 卷 期：2019年第25卷第12期

页      面：1465-1477页

核心收录：

学科分类：1002[医学-临床医学] 10[医学] 

主　　题：Gut microbiota Dextran sodium sulphate colitis Immune system T cells Mesenchymal lymphnode Tumor necrosis factor α 

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 andDSS+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.