Publications (322) View all
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Article: The hypersensitivity to colonic distension of IBS patients can be transferred to rats through their fecal microbiota.
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ABSTRACT: BACKGROUND: Alterations of intestinal microbiota and hypersensitivity to colonic distension are two features of the irritable bowel syndrome (IBS). However, the role of intestinal microbiota in visceral hypersensitivity of IBS patients is far to be established. The aim of our study was to determine whether the intestinal microbiota is involved in the visceral hypersensitivity in IBS. METHODS: The painful response to colorectal distension and colonic mucosal parameters were assessed in gnotobiotic rats. Germfree (GF) rats were inoculated with the fecal microbiota from IBS patients characterized by hypersensitivity to colorectal distension (IBS HMA rats) or from non-hypersensitive healthy volunteers (Healthy HMA rats). Conventional rats were studied as normosensitivity control. Fecal microbial analyses were carried out in human and HMA rats fecal samples using cultural and molecular approaches. KEY RESULTS: The microbial dysbiosis of the IBS gut microbiota (more sulfate-reducing bacteria and Enterobacteriaceae and less bifidobacteria) could be maintained in gnotobiotic rats. The number of abdominal contractions in response to colorectal distensions was significantly higher in IBS HMA rats than in healthy HMA rats. No difference was observed between healthy HMA and conventional rats. Colorectal compliance, epithelial paracellular permeability, and density of colonic mucosal mast cells were similar in the three groups of rats. CONCLUSIONS & INFERENCES: We herein showed that sensitivity to colonic distension of IBS patients can be transferred to rats by the fecal microbiota. Mucosal alterations associated with microbiota transfer are not involved in this hypersensitivity. The altered IBS microbiota may have important role in the hypersensitivity characterizing IBS patients through specific bacterial metabolites.Neurogastroenterology and Motility 02/2013; · 3.41 Impact Factor -
Article: Effects of octreotide on jejunal hypersensitivity triggered by Cryptosporidium parvum intestinal infection in an immunocompetent suckling rat model.
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ABSTRACT: Similar to other bacterial or protozoan infections, human cryptosporidiosis may trigger postinfectious irritable bowel syndrome (IBS)-like symptoms, a condition in which enhanced visceral perception of pain during intestinal distension plays a pivotal role. In an immunocompetent suckling rat model which mimicks features of postinfectious IBS, Cryptosporidium parvum infection induces long-lasting jejunal hypersensitivity to distension in association with intestinal activated mast cell accumulation. The aim of the present study was to explore in this model whether octreotide, a somatostatin agonist analog, could prevent the development of jejunal hypersensitivity and intestinal mast cell/nerve fiber accumulation. Five-day-old Sprague-Dawley rats were infected with C. parvum and treated 10 days later with octreotide (50 g kg(-1) day(-1), i.p.) for 7 days. Compared with untreated infected rats, octreotide treatment of infected rats resulted in increased weight gain [day 23 postinfection (PI)], decreased food intake (day 16 PI), and a reduction in jejunal villus alterations (day 14 PI), CD3(+) IEL (day 37 PI) and mast cell (days 37 and 50 PI) accumulations, nerve fiber densities (day 50 PI), and hypersensitivity to distension (day 120 PI). In uninfected rats, the effects of octreotide treatment were limited to higher weight gain (days 16 and 23 PI) and decreased food intake (day 23 PI) compared with uninfected-untreated rats. Data confirms the relevance of the present rat model to postinfectious IBS studies and prompt further investigation of somatostatin-dependent regulatory interactions in cryptosporidiosis.Neurogastroenterology and Motility 02/2011; 23(11):1043-50, e499. · 3.41 Impact Factor -
Article: Maternal deprivation alters epithelial secretory cell lineages in rat duodenum: role of CRF-related peptides.
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ABSTRACT: Chronic psychological stress is associated with development of intestinal barrier dysfunction and impairs host defence mechanisms. The intestinal epithelium, consisting of enterocytes, endocrine cells, goblet cells and Paneth cells, is an important component of this barrier. In the present study, the impact of maternal deprivation (MD) on secretory lineages of duodenal epithelium and the involvement of the peripheral corticotropin-releasing factor (CRF) pathway were investigated. Rat pups were deprived of their dam for 3 h/day (days 5-20). Non-deprived pups served as controls. On days 8, 13, 20, 24, 34, 44 and 84, duodenal tissues were collected for quantitative real-time PCR and immunohistochemistry studies. MD induced a sustained decrease in the number of Paneth and goblet cells but hyperplasia of endocrine cells. These alterations were associated with a duodenal increase of CRF, urocortin 2 and CRF receptor subtype 2 (CRFR(2)) mRNA, whereas CRFR(1) expression was decreased. The effects of MD on intestinal epithelium were inhibited by the CRFR(1)/R(2) antagonist astressin injected daily before MD. Studies using specific receptor antagonists in rats subjected to MD revealed that CRFR(1) was involved in the hyperplasia of endocrine cells and CRFR(2) in the depletion of Paneth cells. Conversely, daily injection of CRF and of the CRFR(2) agonist urocortin 2 in control rats resulted in changes in epithelial differentiation similar to MD. The activation of CRFR(1) and CRFR(2) induced by MD markedly altered the quantitative distribution of secretory cells of the intestinal epithelium. These alterations, in particular the depletion of Paneth and goblet cells, may create conditions leading to the development of an epithelial barrier defect.Gut 06/2010; 59(6):744-51. · 10.11 Impact Factor -
Article: Guanylate cyclase C-mediated antinociceptive effects of linaclotide in rodent models of visceral pain.
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ABSTRACT: BACKGROUND Linaclotide is a novel, orally administered investigational drug currently in clinical development for the treatment of constipation-predominant irritable bowel syndrome (IBS-C) and chronic idiopathic constipation. Visceral hyperalgesia is a major pathophysiological mechanism in IBS-C. Therefore, we investigated the anti-nociceptive properties of linaclotide in rodent models of inflammatory and non-inflammatory visceral pain and determined whether these pharmacological effects are linked to the activation of guanylate cyclase C (GC-C). METHODS Orally administered linaclotide was evaluated in non-inflammatory acute partial restraint stress (PRS) and acute water avoidance stress (WAS) models in Wistar rats, and in a trinitrobenzene sulfonic acid (TNBS)-induced inflammatory model in Wistar rats and GC-C null mice. KEY RESULTS In TNBS-induced colonic allodynia, linaclotide significantly decreased the number of abdominal contractions in response to colorectal distension without affecting the colonic wall elasticity change in response to distending pressures after TNBS. However, linaclotide had no effect on visceral sensitivity under basal conditions. In addition, linaclotide significantly decreased colonic hypersensitivity in the PRS and WAS models. In wild type (wt) and GC-C null mice, the instillation of TNBS induced similar hyperalgesia and allodynia. However, in post-inflammatory conditions linaclotide significantly reduced hypersensitivity only in wt mice, but not in GC-C null mice. CONCLUSIONS & INFERENCES These findings indicate that linaclotide has potent anti-nociceptive effects in several mechanistically different rodent models of visceral hypersensitivity and that these pharmacological properties of linaclotide are exerted through the activation of the GC-C receptor. Therefore, linaclotide may be capable of decreasing abdominal pain in patients suffering from IBS-C.Neurogastroenterology and Motility 09/2009; 22(3):312-e84. · 3.41 Impact Factor -
Article: Lactobacillus farciminis treatment attenuates stress-induced overexpression of Fos protein in spinal and supraspinal sites after colorectal distension in rats.
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ABSTRACT: Abstract Irritable bowel syndrome (IBS), frequently associated with psychological distress, is characterized by hypersensitivity to gut wall distension. Some probiotics are able to alleviate IBS symptoms and reduce visceromotor response to mechanical stimuli in animals. Moreover, we have previously shown that Lactobacillus farciminis treatment abolished the hyperalgesia to colorectal distension (CRD) induced by acute stress. The aims of the present study were to determine whether (i) stress-induced visceral hyperalgesia modifies the expression of Fos, a marker of general neuronal activation, induced by CRD, (ii) this activation can be modulated by L. farciminis treatment. Female rats were treated by L. farciminis and CRD was performed after partial restraint stress (PRS) or sham-PRS. The expression of Fos protein was measured by immunohistochemistry. After CRD or PRS, Fos expression was increased in spinal cord section (S1), nucleus tractus solitarius (NTS), paraventricular nucleus (PVN) of the hypothalamus, and in the medial nucleus of the amygdala (MeA). The combination of both stimuli, PRS and CRD, markedly increased this Fos overexpression in the sacral spinal cord section, PVN and MeA, but not in NTS. By contrast, a pretreatment with L. farciminis significantly reduced the number of Fos positive cells in these area. This study shows that PRS enhances Fos protein expression induced by CRD at the spinal and supraspinal levels in rats. Lactobacillus farciminis treatment inhibited this enhancing effect, suggesting that the antinociceptive effect of this probiotic strain results from a decrease of the stress-induced activation/sensitization of sensory neurons at the spinal and supraspinal level.Neurogastroenterology and Motility 03/2009; 21(5):567-73, e18-9. · 3.41 Impact Factor
