Abstract
Inflammatory bowel disease (IBD) is associated with prolonged, excess secretions of Tumor Necrosis Factor (TNF). Many patients with IBD have successful management of IBD symptoms by blocking TNF secretion or signaling. However, some patients are non-responsive to this therapy, eventually become refractory to therapy, or Alterations in the microbiota that are associated with the lack of TNF could be a contributing cause of this therapeutic insufficiency seen in some patients. Here we use wildtype (WT) and mice lacking Tnf (Tnf -/-) in an acute TNBS colitis model to investigate the role of TNF in colitis and how its presence or absence affects the colonic microbiota. As expected, Tnf -/- had less severe inflammation than WT mice. Microbiome analysis revealed significant Tnf dependent-differences in alpha and beta diversity. There were also notable differences in many species that were also primarily Tnf dependent. Taken together, our data indicates that TNF contributes significantly to the inflammation and microbiotal alterations in that occur in IBD.
Highlights
Inflammatory bowel disease (IBD) consists of two inflammatory disorders, Crohn’s disease (CD) and Ulcerative Colitis (UC), both of which are characterized by lifelong and repeated bouts of inflammation and healing in the gastrointestinal (GI) tract [1]
When severity of inflammation was evaluated as a sole criterion, we found that there was significantly more severe inflammation in the trinotrobenzene sulfonic acid (TNBS) treated WT mice than Tnf-/- mice (Fig 1F)
To further evaluate the role of Tumor Necrosis Factor (TNF) in driving inflammation in this model, we analyzed the microbiota of both genotypes of mice, before and after TNBS and shaved area. Control mice (SHAM) treatment to determine if specific microbes or microbial communities contribute to the disease seen in WT mice
Summary
Inflammatory bowel disease (IBD) consists of two inflammatory disorders, Crohn’s disease (CD) and Ulcerative Colitis (UC), both of which are characterized by lifelong and repeated bouts of inflammation and healing in the gastrointestinal (GI) tract [1] The pathogenesis of these diseases has not been fully elucidated, it is generally accepted that disease develops in genetically susceptible individuals that have hyper-immune responsiveness to their intestinal microbiota [2,3,4,5]. The mucin layer covering the intestinal epithelia is the first line of defense in preventing the attachment and invasion of luminal bacteria to the intestinal epithelia [6,7]. IBD patients have deficient or aberrant mucin [8], which likely leads to displacement of luminal bacteria to the submucosal compartment and the initiation of inflammation [9].
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