Published online Mar 28, 2019. doi: 10.3748/wjg.v25.i12.1465
Peer-review started: November 14, 2018
First decision: January 6, 2019
Revised: February 15, 2019
Accepted: February 22, 2019
Article in press: February 23, 2019
Published online: March 28, 2019
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.
To elucidate whether gut microbiota and immune system changes appear following anti TNFα therapy during dextran sulfate sodium (DSS) colitis.
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.
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.
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.
Core tip: The effect of the gut microbiota on the immune responses is not limited to the gut. On the other hand, autoimmune diseases, such as inflammatory bowel disease, are associated to different degree of dysbiosis involving different bacterial genera. Using a colitic mouse model, we aimed to evaluate the impact of anti-tumor necrosis factor α (TNFα) therapy on the intestinal immune system and gut microbiota concurrently. Healthy mice treated with anti-TNFα showed similar histological, microbial and immune features of untreated colitic mice, a lymphomononuclear infiltrate both at day 5 and 12 at hematoxylin and eosin staining, an increase of type 1 helper T lymphocytes and type 17 helper T lymphocytes at day 12, and finally increase of Enterococcaceae at day 5, a decrease of Bacteroides and Clostridiaceae at day 12.