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

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

Research output: Contribution to journalArticle

Abstract

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 C57BL/6 mice were divided into four groups: "No DSS", "No DSS + anti-TNFα", "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-TNFα treatment. 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 5th and 12th 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.

Original languageEnglish
Pages (from-to)1465-1477
Number of pages13
JournalWorld Journal of Gastroenterology
Volume25
Issue number12
DOIs
Publication statusPublished - Mar 28 2019

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Dextran Sulfate
Colitis
Helper-Inducer T-Lymphocytes
Tumor Necrosis Factor-alpha
Enterococcaceae
Therapeutics
Bacteroides
Microbiota
Regulatory T-Lymphocytes
Ulcerative Colitis
Bacteria
Th17 Cells
Hematoxylin
Eosine Yellowish-(YS)
Inbred C57BL Mouse

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Anti-tumor necrosis factor α therapy associates to type 17 helper T lymphocytes immunological shift and significant microbial changes in dextran sodium sulphate colitis. / Petito, Valentina; Graziani, Cristina; Lopetuso, Loris R; Fossati, Marco; Battaglia, Alessandra; Arena, Vincenzo; Scannone, Domenico; Quaranta, Gianluca; Quagliariello, Andrea; Del Chierico, Federica; Putignani, Lorenza; Masucci, Luca; Sanguinetti, Maurizio; Sgambato, Alessandro; Gasbarrini, Antonio; Scaldaferri, Franco.

In: World Journal of Gastroenterology, Vol. 25, No. 12, 28.03.2019, p. 1465-1477.

Research output: Contribution to journalArticle

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abstract = "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 C57BL/6 mice were divided into four groups: {"}No DSS{"}, {"}No DSS + anti-TNFα{"}, {"}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-TNFα treatment. 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 5th and 12th 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.",
author = "Valentina Petito and Cristina Graziani and Lopetuso, {Loris R} and Marco Fossati and Alessandra Battaglia and Vincenzo Arena and Domenico Scannone and Gianluca Quaranta and Andrea Quagliariello and {Del Chierico}, Federica and Lorenza Putignani and Luca Masucci and Maurizio Sanguinetti and Alessandro Sgambato and Antonio Gasbarrini and Franco Scaldaferri",
year = "2019",
month = "3",
day = "28",
doi = "10.3748/wjg.v25.i12.1465",
language = "English",
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TY - JOUR

T1 - Anti-tumor necrosis factor α therapy associates to type 17 helper T lymphocytes immunological shift and significant microbial changes in dextran sodium sulphate colitis

AU - Petito, Valentina

AU - Graziani, Cristina

AU - Lopetuso, Loris R

AU - Fossati, Marco

AU - Battaglia, Alessandra

AU - Arena, Vincenzo

AU - Scannone, Domenico

AU - Quaranta, Gianluca

AU - Quagliariello, Andrea

AU - Del Chierico, Federica

AU - Putignani, Lorenza

AU - Masucci, Luca

AU - Sanguinetti, Maurizio

AU - Sgambato, Alessandro

AU - Gasbarrini, Antonio

AU - Scaldaferri, Franco

PY - 2019/3/28

Y1 - 2019/3/28

N2 - 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 C57BL/6 mice were divided into four groups: "No DSS", "No DSS + anti-TNFα", "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-TNFα treatment. 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 5th and 12th 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.

AB - 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 C57BL/6 mice were divided into four groups: "No DSS", "No DSS + anti-TNFα", "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-TNFα treatment. 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 5th and 12th 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.

U2 - 10.3748/wjg.v25.i12.1465

DO - 10.3748/wjg.v25.i12.1465

M3 - Article

C2 - 30948910

VL - 25

SP - 1465

EP - 1477

JO - World Journal of Gastroenterology

JF - World Journal of Gastroenterology

SN - 1007-9327

IS - 12

ER -