Treatment with Obestatin—A Ghrelin Gene-Encoded Peptide—Reduces the Severity of Experimental Colitis Evoked by Trinitrobenzene Sulfonic Acid

Abstract

Obestatin is a 23-amino acid peptide derived from proghrelin, a common prohormone for ghrelin and obestatin. Previous studies showed that obestatin exhibited some protective and therapeutic effects in the gut. The aim of our presented study was to examine the effect of treatment with obestatin on trinitrobenzene sulfonic acid (TNBS)-induced colitis. In rats anesthetized with ketamine, colitis was induced through intrarectal administration of 25 mg of 2,4,6-trinitrobenzene sulfonic acid (TNBS). Obestatin was administered intraperitoneally at doses of 4, 8, or 16 nmol/kg, twice per day for four consecutive days. The first dose of obestatin was given one day before the induction of colitis, and the last one was given two days after administration of TNBS. Fourteen days after the induction of colitis, rats were anesthetized again with ketamine, and the severity of colitis was determined. The administration of obestatin had no effect on the parameters tested in rats without the induction of colitis. In rats with colitis, administration of obestatin at doses of 8 or 16 nmol/kg reduced the area of colonic damage, and improved mucosal blood flow in the colon. These effects were accompanied by a reduction in the colitis-evoked increase in the level of blood leukocytes, and mucosal concentration of pro-inflammatory interleukin-1β. Moreover, obestatin administered at doses of 8 or 16 nmol/kg reduced histological signs of colonic damage. The administration of obestatin at a dose of 4 nmol/kg failed to significantly affect the parameters tested. Overall, treatment with obestatin reduced the severity of TNBS-induced colitis in rats. This effect was associated with an improvement in mucosal blood flow in the colon, and a decrease in local and systemic inflammatory processes.

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“…Ghrelin administered to animals with dextran sulfate sodium -induced colitis restored both the DNA synthesis, and normal blood flow contributing to the preventive effect against progression of DSS-induced colitis [ 73 ]. Similar results were obtained for obestatin in the case of aceticacid-induced colitis [ 74 ] and trinitrobenzene sulfonic acid (TNBS)-induced colitis [ 75 ]. PPIs were recognized as important dysbiotic medicines increasing susceptibility to Clostridium difficile infection [ 76 ] as well as small intestinal bacterial overgrowth, bacterial peritonitis, and poor outcomes in inflammatory bowel disease [ 77 ].…”

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“…Meanwhile, obestatin, similarly to grelin, exhibited some protective and therapeutic effects in the stomach ulcers and duodenum colitis. With reference to gastric cancer, the obestatin stimulates mitogenesis of gastric cancer cells [ 59 , 60 , 61 , 62 ]. Therefore, further studies utilizing more neuronal markers (especially sensory markers), have to be carried out, in order to elucidate the relevance of different subpopulation of neurons innervating the stomach wall [ 63 , 64 ].…”

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“…The protective or therapeutic effect of obestatin has been observed in the heart [291,292,293], kidney [294] and skeletal muscle [295]. In the gut, animal studies have shown that obestatin accelerates the healing of chronic gastric ulcer evoked by acetic acid [296] (Figure 3), attenuates mesenteric ischemia/reperfusion-induced oxidative injury of the ileum and lung [297], inhibits the development of acetic acid-induced colitis [298], reduces the severity of experimental colitis evoked by trinitrobenzene sulfonic acid [299] and accelerates the healing of acetic acid-induced colitis in rats [300]. In the pancreas, obestatin promotes the survival of pancreatic beta-cells and human islets and induces the expression of genes involved in the regulation of beta-cell mass and function [282], as well as enhances the in vitro generation of pancreatic islets through the regulation of developmental pathways [301].…”

“…Previous studies have shown that pretreatment with obestatin inhibits the development of dextran sulfate sodium-induced colitis [226] and acetic acid-induced colitis in rats [298]. The therapeutic effect of obestatin has been found in experimental colitis evoked by acetic acid [300] or trinitrobenzene sulfonic acid [299]. The beneficial effect of obestatin has been also found in the liver, where it exhibits a protective effect against ischemia/reperfusion-induced hepatic injury [306], as well as inhibits and reverses the development of nonalcoholic fatty liver disease [307].…”