Ethanol-induced colitis prevents oral tolerance induction in mice

Abstract

The gut mucosa is a major site of contact with antigens from food and microbiota. Usually, these daily contacts with natural antigens do not result in inflammatory reactions; instead they result in a state of systemic hyporesponsiveness named oral tolerance. Inflammatory bowel diseases (IBD) are associated with the breakdown of the immunoregulatory mechanisms that maintain oral tolerance. Several animal models of IBD/colitis are available. In mice, these include targeted disruptions of the genes encoding cytokines, T cell subsets or signaling proteins. Colitis can also be induced by intrarectal administration of chemical substances such as 2,4,6-trinitrobenzene sulfonic acid in 50% ethanol. We report here a novel model of colitis induced by intrarectal administration of 50% ethanol alone. Ethanol-treated mice develop an inflammatory reaction in the colon characterized by an intense inflammatory infiltrate in the mucosa and submucosa of the large intestine. They also present up-regulation of both interferon gamma (IFN-γ) and interleukin-4 (IL-4) production by cecal lymph node and splenic cells. These results suggest a mixed type of inflammation as the substrate of the colitis. Interestingly, cells from mesenteric lymph nodes of ethanol-treated mice present an increase in IFN-γ production and a decrease in IL-4 production indicating that the cytokine balance is altered throughout the gut mucosa. Moreover, induction of oral tolerance to ovalbumin is abolished in these animals, strongly suggesting that ethanol-induced colitis interferes with immunoregulatory mechanisms in the intestinal mucosa. This novel model of colitis resembles human IBD. It is easy to reproduce and may help us to understand the mechanisms involved in IBD pathogenesis.

Diarrhoea is not the only symptom that needs to be treated in patients with microscopic colitis

“…Findings support the hypothesis that the cytoskeleton may be a major target for injury in damaged intestinal epithelium [34]. In accordance, ethanol can be used in mice to develop an inflammatory reaction in the colon characterized by an intense inflammatory infiltrate in the mucosa and submucosa [35].…”

Critical Role for Mast Cells in the Pathogenesis of 2,4-Dinitrobenzene-Induced Murine Colonic Hypersensitivity Reaction

“…An explanation for these conflicting results can be found in the use of 50% ethanol, used as vehicle in the TNBS-colitis model to break the mucosal barrier. As mentioned before, 50% ethanol is capable of inducing an inflammation by itself (31). This damage-induced inflammation by ethanol is mast cell-independent and most likely masks the haptenspecific response induced by TNBS.…”

“…Ethanol is known to cause local irritation. Although often used in the TNBS-colitis model as vehicle, it was recently shown that 50% ethanol can induce colitis by itself and prevent oral tolerance (31). In our model, 10% ethanol is used as a mucosal barrier breaker.…”

“…4. Also the number of CAE-positive mast cells was increased after DNFB sensitization and DNS challenge compared with vehiclesensitized and DNS-challenged mice (mast cell number per colon: vehicle/DNS 16 (6 -22), DNFB/DNS 28 (22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36); results are expressed as median (range); p Ͻ 0.05, n ϭ 6). TNF-␣ is one of the major cytokines released upon mast cell activation.…”

Induction of an antigen specific gut inflammatory reaction in mice and rats: a model for human Inflammatory Bowel Disease

“…In the gut, special sets of T and B cells co-exist, which suggests the existence of a special immunological reactivity, prepared for constant contacts of the immune system and the environment. On the contrary, Inflammatory Bowel Disease (IBD) is associated with classical Th1 and Th2 responses, which are characterized by the breakdown of the immunoregulatory mechanisms that maintain oral tolerance (Andrade et al, 2003). Crohn's disease and Ulcerative colitis both are IBD's with distinct immunoregulatory characteristics and clinical manifestations.…”