Enhanced Ghrelin Levels and Hypothalamic Orexigenic AgRP and NPY Neuropeptide Expression in Models of Jejuno-Colonic Short Bowel Syndrome.

Laura Gillard,Jean-Noël Freund,Lara Ribeiro-Parenti,Johanne Le Beyec,Muriel Thomas,Jean-Baptiste Cavin,Anne-Charlotte Jarry,Françoise Cluzeaud,Jean-Marc Lacorte,André Bado,Maude Le Gall,Camille Mayeur,Bogdan Stan-Iuga,Lore Billiauws,Francisca Joly

doi:10.1038/srep28345

Abstract

Short bowel syndrome (SBS) patients developing hyperphagia have a better outcome. Gastrointestinal endocrine adaptations help to improve intestinal functions and food behaviour. We investigated neuroendocrine adaptations in SBS patients and rat models with jejuno-ileal (IR-JI) or jejuno-colonic (IR-JC) anastomosis with and without parenteral nutrition. Circulating levels of ghrelin, PYY, GLP-1, and GLP-2 were determined in SBS rat models and patients. Levels of mRNA for proglucagon, PYY and for hypothalamic neuropeptides were quantified by qRT-PCR in SBS rat models. Histology and immunostaining for Ki67, GLP-1 and PYY were performed in SBS rats. IR-JC rats, but not IR-JI, exhibited significantly higher crypt depths and number of Ki67-positive cells than sham. Fasting and/or postprandial plasma ghrelin and PYY concentrations were higher, or tend to be higher, in IR-JC rats and SBS-JC patients than in controls. Proglucagon and Pyy mRNA levels were significantly enhanced in IR-JC rats. Levels of mRNA coding hypothalamic orexigenic NPY and AgRP peptides were significantly higher in IR-JC than in sham rats. We demonstrate an increase of plasma ghrelin concentrations, major changes in hypothalamic neuropeptides levels and greater induction of PYY in SBS-JC rats and patients suggesting that jejuno-colonic continuity creates a peculiar environment promoting further gut-brain adaptations.

Highlights

Gut hormones are key factors in this spontaneous intestinal adaptation[10]
These peripheral gastrointestinal signals are integrated into the hypothalamus, which contains two populations of neurons: orexigenic neurons co-expressing neuropeptide Y (NPY) and agouti-related peptide (AgRP) and anorexigenic neurons co-expressing pro-opiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART)[14,23] Ghrelin increases food intake through the activation of hypothalamic orexigenic neurons[24]
All rats were on oral nutrition with free access to food, but a group of IR jejuno-colonic (IR-JC) rats received PN to partially compensate for their malabsorption

Summary

Introduction

Gut hormones are key factors in this spontaneous intestinal adaptation[10]. Increased secretions of glucagon-like peptide-1 (GLP-1) and glucagon-like peptide-2 (GLP-2) have been reported in preclinical models[11,12] and in SBS patients with the colon in continuity[3], but not in SBS patients with jejunostomy (i.e. with no colon and no ileum)[4,13] These hormones are secreted, together with Peptide YY (PYY), by the enteroendocrine L cells of the ileum and colon, in response to nutrient stimulation[14]. The molecular and physiological mechanisms underlying the development of this compensatory overeating in SBS patients remain unknown In addition to their gastro-intestinal effects, gut hormones (such as CCK, PYY, GLP-1 and ghrelin) participate in the regulation of appetite and food intake[14]. To address the colonic cellular and molecular mechanisms of adaptive hormonal secretions, we set up two rat models of extensive intestinal resection with colon in continuity and with or without a resected ileum We use these models to analyze food intake, hypothalamic neuropeptides expression and to evaluate gastro-intestinal production and secretion of gut hormones (ghrelin, PYY, GLP-1 and GLP-2) in comparison with sham-operated animals. We further analyzed the clinical relevance of hormonal adaptation in relation to food intake (fasting and post-prandial gut hormone secretion) in jejuno-colonic and jejuno-ileal SBS patients

Methods

Results

Conclusion