Title

 

Authors

R. Russo¹, G. D’Agostino¹, G. Mattace Raso¹, G. La Rana¹, R. Meli¹, R. Berni Canani², and A. Calignano<sup>1

1</sup>Dipartimento di Farmacologia Sperimentale, ²Dipartimento di Pediatria, Università degli Studi di Napoli “Federico II”; Napoli.

 

Abstract

Among the main luminal factors endogenously produced in the colon and known to modulate gut functions are short chain fatty acids. They are generated in the large intestine as a result of bacterial fermentation of dietary fibres and resistant starch is considered the main source of butyrate Butyrate has an important role in regulating colonic mucosa homeostasis (1). In particular, butyrate is the primary energy source for the colonic epithelium, it has trophic effects, and reduces oxidative stress by increasing glutathione concentrations and is involved in electrolytes resumption (2). Several studies have shown that butyrate has anti-carcinogenic and anti-inflammatory effects (3). In vitro, butyrate has been shown to reduce inflammation by inhibition of NFκB activation (4) and upregulation of PPARγ(5). In vivo, several studies have demonstrated a decrease in inflammation due to rectal administration of butyrate or mixtures of SCFA in patients with active ulcerative colitis (6,7) and diversion colitis,(8,9) although not all studies were able to show significant effects (9).  We have tested the effects of a synthetic butyrate derivative able to release butyrate at intestinal level in comparison to equimolecular doses of sodium butyrate (BuNa) in intestinal mice transit, castor oil-induced diarrhoea, and dextran sulfate sodium (DSS)-induced colitis. Sodium butyrate (10-100 mg/kg) or N-(1-carbamoyl-2-phenyl-ethyl) butyramide (BuToRo) (21,2-212 mg/kg) have been orally administered 30 min before the charcoal meal. Thirty minutes after the mice were sacrificed and the length travelled by the charcoal meal measured. Both acute or repeated treatment of BuNa or BuToRo were equally able to reduce in a dose dependent manner the length travelled by the charcoal meal. In castor oil–induced diarrhoea, BuToRo resulted more effective in reducing castor-oil-induced transit than equimolecular doses BuNa (75 % vs 27% highest doses n=12 p<001). In experimental colitis, the treatment with BuNa (20 mg/kg/die per os) or BuToRo (42.5 mg/kg/die per os), started ten days before DSS challenge and continued for all experimental period, reduced colonic damage evidenced by intestine length and histological analysis with a significant decrease in inflammatory parameters, such as myeloperoxidase content, iNOS and COX-2 expression. Our results indicate that in the regular peristalsis BuNa and BuToRo are equally active, whereas the local intraluminal release of butyrate, due to BuToRo, is a key point to obtain a strong effect in controlling non physiological peristalsis. We conclude that during pathological states in which luminal secretion is increased, the intraluminal release of butyrate plays an important role in controlling secretion, diarrhoea, and inflammation.

References
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