Abstract
BackgroundMelanin-concentrating hormone (MCH), an evolutionarily conserved appetite-regulating neuropeptide, has been recently implicated in the pathogenesis of inflammatory bowel disease (IBD). Expression of MCH is upregulated in inflamed intestinal mucosa in humans with colitis and MCH-deficient mice treated with trinitrobenzene-sulfonic acid (TNBS) develop an attenuated form of colitis compared to wild type animals. Zebrafish have emerged as a new animal model of IBD, although the majority of the reported studies concern zebrafish larvae. Regulation MCH expression in the adult zebrafish intestine remains unknown.MethodsIn the present study we induced enterocolitis in adult zebrafish by intrarectal administration of TNBS. Follow-up included survival analysis, histological assessment of changes in intestinal architecture, and assessment of intestinal infiltration by myeloperoxidase positive cells and cytokine transcript levels. ResultsTreatment with TNBS dose-dependently reduced fish survival. This response required the presence of an intact microbiome, since fish pre-treated with vancomycin developed less severe enterocolitis. At 6 hours post-challenge, we detected a significant influx of myeloperoxidase positive cells in the intestine and upregulation of both proinflammatory and anti-inflammatory cytokines. Most importantly, and in analogy to human IBD and TNBS-induced mouse experimental colitis, we found increased intestinal expression of MCH and its receptor in TNBS-treated zebrafish. ConclusionsTaken together these findings not only establish a model of chemically-induced experimental enterocolitis in adult zebrafish, but point to effects of MCH in intestinal inflammation that are conserved across species.
Highlights
Melanin-concentrating hormone (MCH) was initially purified from salmon pituitaries and as its name indicates, it induces fish skin pallor in response to environmental cues by segregating the pigment-containing granules in melanocytes [1]
In order to make direct comparisons as they relate to regulation of MCH between the current and our previous studies in mice with trinitrobenzenesulfonic acid (TNBS)-induced colitis, we developed a TNBS-induced model of experimental enterocolitis
We used this model to demonstrate upregulation of MCH in the inflamed intestine of adult zebrafish as we have previously shown in mice with experimental colitis and in patients with inflammatory bowel disease (IBD) [12]
Summary
Melanin-concentrating hormone (MCH) was initially purified from salmon pituitaries and as its name indicates, it induces fish skin pallor in response to environmental cues by segregating the pigment-containing granules in melanocytes [1]. Acute administration of MCH in the rat brain increases food intake while chronic administration results in excessive weight gain and insulin resistance [3] Consistent with these observations, transgenic mice overexpressing MCH were hyperphagic and obese [4]; MCH-deficient mice exhibit a lean phenotype and are resistant to diet-induced obesity [5,6]. Expression of MCH is upregulated in inflamed intestinal mucosa in humans with colitis and MCH-deficient mice treated with trinitrobenzenesulfonic acid (TNBS) develop an attenuated form of colitis compared to wild type animals. Results: Treatment with TNBS dose-dependently reduced fish survival This response required the presence of an intact microbiome, since fish pre-treated with vancomycin developed less severe enterocolitis. In analogy to human IBD and TNBS-induced mouse experimental colitis, we found increased intestinal expression of MCH and its receptor in TNBS-treated zebrafish. Conclusions: Taken together these findings establish a model of chemically-induced experimental enterocolitis in adult zebrafish, but point to effects of MCH in intestinal inflammation that are conserved across species
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