This study illustrates that a probiotic food containing B. lactis CNCM I-2494 strain reduces visceral hypersensitivity associated with acute stress by normalizing intestinal epithelial barrier via a synergistic interplay with the different probiotic strains and/or metabolites contained in this product.

Background and purpose:Vgf gene expression has been detected in various endocrine and neuronal cells in the gastrointestinal tract. In this study we investigated the pharmacological activity of different VGF-derived peptides. Among these, TLQP-21, corresponding to the 556-576 fragment of the protein was the unique active peptide, and its pharmacological profile was further studied. Experimental approach: The effects of TLQP-21 were examined in vitro by smooth muscle contraction in isolated preparations from the rat gastrointestinal tract and, in vivo, by assessing gastric emptying in rats. Rat stomach tissues were also processed for immunohistochemical and biochemical characterization. Key results: In rat longitudinal forestomach strips, TLQP-21 (100 nmol·L -1 -10 mmol·L -1 ) concentration-dependently induced muscle contraction (in female rats, EC50 = 0.47 mmol·L -1 , Emax: 85.7 Ϯ 7.9 and in male rats, 0.87 mmol·L -1 , Emax: 33.4 Ϯ 5.3; n = 8), by release of prostaglandin (PG)E2 and PGF2a from the mucosal layer. This effect was significantly antagonized by indomethacin and selective inhibitors of either cyclooxygenase-1 (S560) or cyclooxygenase-2 (NS398). Immunostaining and biochemical studies confirmed the presence of VGF in the gastric neuronal cells. TLQP-21, injected i.c.v. (2-32 nmol per rat), significantly decreased gastric emptying by about 40%. This effect was significantly (P < 0.05) blocked by i.c.v. injection of indomethacin, suggesting that, also in vivo, this peptide acts in the brain stimulating PG release. Conclusions and implications:The present results demonstrate that this VGF-derived peptide plays a central and local role in the regulation of rat gastric motor functions.

The last ten years' wide progress in the gut microbiota phylogenetic and functional characterization has been made evidencing dysbiosis in several gastrointestinal diseases including inflammatory bowel diseases and irritable bowel syndrome (IBS). IBS is a functional gut disease with high prevalence and negative impact on patient's quality of life characterized mainly by visceral pain and/or discomfort, representing a good paradigm of chronic gut hypersensitivity. The IBS features are strongly regulated by bidirectional gut-brain interactions and there is increasing evidence for the involvement of gut bacteria and/or their metabolites in these features, including visceral pain. Further, gut microbiota modulation by antibiotics or probiotics has been promising in IBS. Mechanistic data provided mainly by animal studies highlight that commensals or probiotics may exert a direct action through bacterial metabolites on sensitive nerve endings in the gut mucosa, or indirect pathways targeting the intestinal epithelial barrier, the mucosal and/or systemic immune activation, and subsequent neuronal sensitization and/or activation.

Nociceptin/orphanin FQ (N/OFQ) and its NOP receptors are present in the central nervous system and in the periphery playing important roles in the modulation of gastrointestinal functions and pain. The aim of this study was to investigate the role of central and peripheral N/OFQ-NOP receptor system in the nociceptive response to colorectal distension (CRD) in basal condition and in two models of gut hypersensitivity triggered by both inflammation and stress. Male Wistar rats were tested in basal and in post-inflammatory conditions, i.e., 5 days after IC TNBS instillation (80 mg/Kg) and received N/OFQ (2 nmol/Kg IP), UFP-101 (a selective NOP receptor antagonist, 10 nmol/Kg IP), N/OFQ+UFP-101, N/OFQ (0.5 nmol/rat ICV) or vehicle. Female rats were tested in basal and after partial restraint stress receiving the same pharmacological treatment. CRD was performed using barostat and abdominal contractions were recorded by electromyography. In basal condition, N/OFQ, ICV and IP injected, did not modify basal visceral sensitivity. Both in TNBS and stress-induced hyperalgesia, IP but not ICV injection of N/OFQ significantly decreased the number of abdominal contractions. Peripheral injection of UFP-101 antagonized N/OFQ effect. Moreover, in post-inflammatory colitis, UFP-101, injected alone, exacerbated visceral hyperalgesia to CRD compared with vehicle. These findings indicate that in rats, N/OFQ, only peripherally injected, reduces visceral hypersensitivity triggered by inflammation or stress without affecting basal sensitivity. N/OFQ visceral anti-hyperalgesic effect involves peripheral NOP receptors. In a post-inflammatory, but not in an acute stress colitis model, N/OFQergic system is endogenously activated.

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These findings provide new evidence showing that the pancreatic CB1-r/CB2-r system modulates pro-inflammatory factor levels in rat exocrine pancreatic acinar cells. The dual, time-dependent WIN55,212-induced changes in the development and course of acute pancreatitis support the idea that the role of the endogenous CB receptor system differs according to the local inflammatory status.

In this study, seeking further information on the role of the nociceptin/orphanin FQ (N/OFQ)-ergic system in normal and disturbed colonic motor function in rats, we compared the colonic effects of UFP-112, a novel highly potent agonist, with those of N/OFQ. When injected intracerebroventricularly (i.c.v.) and intraperitoneally (i.p.), UFP-112 and N/OFQ increased bead expulsion time in a statistically significant and dose-related manner and reduced the percentage of rats with castor oil-induced diarrhoea. UFP-112 showed greater efficacy, higher potency and longer-lasting inhibitory effects than N/OFQ, and pretreatment with UFP-101, a selective antagonist, blocked the N/OFQ analogue-induced responses in both tests. When injected i.c.v., UFP-112 and N/OFQ inhibited corticotrophin releasing factor- and restrain stress-stimulated faecal pellet excretion significantly and in a dose-related manner. Conversely, when injected peripherally both peptides significantly inhibited colonic propulsive motility but did so in a non-dose-related manner. In conclusion, these findings indicate that, in the rat, the central and peripheral N/OFQ systems have an inhibitory role in modulating distal colonic propulsive motility under physiological and pathological conditions. UFP-112 therefore promises to be a useful pharmacological tool for investigating the role of the N/OFQ system in motor functions in the distal colonic tract under physiological and pathological conditions.