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Background & Aims Acute infectious gastroenteritis increases the risk for irritable bowel syndrome (IBS) and functional dyspepsia (FD). Children are particularly vulnerable to gastroenteritis because of the immaturity of their intestinal barrier, enteric nervous system, and immune response to pathogens. We investigated whether acute gastroenteritis in early life increases the risk of IBS and FD throughout adulthood. Methods In 1994, we identified and monitored a single culture-proven foodborne Salmonella enteritidis outbreak that involved 1811 patients (mostly pediatric) in Bologna, Italy. Clinical data were collected and a prospective, controlled, cohort study was designed. Long-term effects were assessed by mailing a questionnaire to 757 subjects 16 years after the outbreak (when all of the children were adults). We randomly selected a cohort of 250 adults exposed to Salmonella as children, all 127 individuals exposed as adults, and a cohort of nonexposed participants matched for number, age, sex, and area of residence (controls). Results Among 198 exposed participants, 64 reported FD (32.3%), compared with 51 of 188 controls (27.1%; P = .268). Among 204 exposed participants, 75 reported having IBS (36.8%) compared with 44 of 189 controls (23.3%; P = .004). The odds ratio for IBS among people exposed to the Salmonella was 1.92 (95% confidence interval: 1.23–2.98). The prevalence of IBS was higher in individuals exposed Salmonella as children than in controls (35.3% vs 20.5%; P = .008), but not in individuals exposed as adults, compared with controls. After multivariate logistic regression, post-infectious IBS was independently associated with anxiety and FD. Conclusions Based on data collected from a single culture-proven foodborne Salmonella enteritidis outbreak in 1994, Salmonella -induced gastroenteritis during childhood (but not adulthood) is a risk factor for IBS.

Background & Aims There has not been a broad analysis of the combined effects of altered activities of microRNAs (miRNAs) in pancreatic ductal adenocarcinoma (PDAC) cells, and it is unclear how these might affect tumor progression or patient outcomes. Methods We combined data from miRNA and messenger RNA (mRNA) expression profiles and bioinformatic analyses to identify an miRNA−mRNA regulatory network in PDAC cell lines (PANC-1 and MIA PaCa-2) and in PDAC samples from patients. We used this information to identify miRNAs that contribute most to tumorigenesis. Results We identified 3 miRNAs (MIR21, MIR23A, and MIR27A) that acted as cooperative repressors of a network of tumor suppressor genes that included PDCD4, BTG2, and NEDD4L. Inhibition of MIR21, MIR23A, and MIR27A had synergistic effects in reducing proliferation of PDAC cells in culture and growth of xenograft tumors in mice. The level of inhibition was greater than that of inhibition of MIR21 alone. In 91 PDAC samples from patients, high levels of a combination of MIR21, MIR23A, and MIR27A were associated with shorter survival times after surgical resection. Conclusions In an integrated data analysis, we identified functional miRNA−mRNA interactions that contribute to growth of PDACs. These findings indicate that miRNAs act together to promote tumor progression; therapeutic strategies might require inhibition of several miRNAs.

BACKGROUND & AIMS: Intestinal mast cell infiltration may participate to abdominal pain in irritable bowel syndrome (IBS) patients. However, the underlying mechanisms remain unknown. We assessed the effect of mast cell mediators released from the colonic mucosa of IBS patients on the activation of rat sensory neurons in vitro. METHODS: Colonic mast cell infiltration and mediator release were assessed with quantitative immunofluorescence and immunoenzymatic assays. The effect of mucosal mediators was tested on mesenteric sensory nerve firing and Ca(2+) mobilization in dorsal root ganglia in rats. RESULTS: Mediators from IBS patients, but not controls, markedly enhanced the firing of mesenteric nerves (14.7 +/- 3.2 imp/sec vs 2.8 +/- 1.5 imp/sec; P < .05) and stimulated mobilization of Ca(2+) in dorsal root ganglia neurons (29% +/- 4% vs 11% +/- 4%; P < .05). On average, 64% of dorsal root ganglia responsive to mediators were capsaicin-sensitive, known to mediate nociception. Histamine and tryptase were mainly localized to mucosal mast cells. IBS-dependent nerve firing and Ca(2+) mobilization were correlated with the area of the colonic lamina propria occupied by mast cells (r = 0.74; P < .01, and r = 0.78; P < .01, respectively). IBS-dependent excitation of dorsal root ganglia was inhibited by histamine H(1) receptor blockade and serine protease inactivation (inhibition of 51.7%; P < .05 and 74.5%; P < .05; respectively). CONCLUSIONS: Mucosal mast cell mediators from IBS patients excite rat nociceptive visceral sensory nerves. These results provide new insights into the mechanism underlying visceral hypersensitivity in IBS.

Background & Aims: Hydrogen sulfide (H2S) has been suggested as a novel gasomediator. We explored its unknown neuromodulatory role in human and guinea-pig colon. Methods: We used immunohistochemistry to detect H2S-producing enzymes cystathionine γ-lyase (CSE) and cystathionine β-synthase (CBS) in enteric neurons, Ussing chambers to measure mucosal ion secretion, and neuroimaging with voltage- and Ca++-sensitive dyes to record H2S effects on guinea-pig and human enteric neurons. Results: More than 90% of guinea-pig and human submucous and myenteric neurons were colabeled for CSE and CBS. Myenteric interstitial cells of Cajal were CSE-immunoreactive. The exogenous H2S donor NaHS (0.2–2.5 mmol/L) concentration-dependently increased chloride secretion in human and guinea-pig submucosa/mucosa preparations, but not in the colonic epithelial cell line T84. The secretory response was reduced significantly by tetrodotoxin (0.5 μmol/L), capsaicin desensitization (10 μmol/L), and the transient receptor potentials vanilloid receptor 1 antagonist capsazepine (10 μmol/L). The endogenous H2S donor L-cysteine also induced secretion that was diminished significantly by capsaicin desensitization, the CBS inhibitor amino-oxyacetic acid, and the CSE inhibitor propargylglycine. NaHS increased spike discharge in 23% of guinea-pig and 36% of human submucous neurons, but had no effect on Ca++ mobilization in cultured guinea-pig enteric neurons. This excitatory response was reduced significantly by capsaicin desensitization and capsazepine, but not by glibenclamide (10 μmol/L). Conclusions: The presence of H2S-producing enzymes in human and guinea-pig enteric neurons, the excitatory action on enteric neurons, and the prosecretory effects of NaHS suggest H2S as a novel gut-signaling molecule. Its action mainly involves transient receptor potentials vanilloid receptor 1 receptors on extrinsic afferent terminals, which in turn activate enteric neurons.

Inflammatory neuropathy of the enteric nervous system is emerging as an important topic in the field of neurogastroenterology. Enteric ganglionitis can be either primary or secondary to a wide array of diseases (i.e., paraneoplastic, infectious, and neurological disorders) and is characterized by a dense infiltrate of inflammatory/immune cells mainly confined to the neural microenvironment. The clinical picture reflects the involved segment of the gastrointestinal tract (achalasia, gastroparesis, pseudo-obstruction, and megacolon). In these settings, symptoms may develop either acutely (frequently after a flulike episode in otherwise previously healthy individuals) or more slowly (e.g., in paraneoplastic syndromes). The inflammatory/immune response in enteric ganglionitis leads to neuronal dysfunction and degeneration over time and sometimes results in a complete loss of enteric neurons. The diagnosis of enteric ganglionitis is supported by detection of circulating antineuronal antibodies against select molecular targets, including Hu and Yo proteins, neurotransmitter receptors, and ion channels. Potential mechanisms involved in neuronal dysfunction include viral antigen expression in the enteric neural environment, molecular mimicry (onconeural antigens), and the role exerted by cellular and humoral autoimmunity. A short course of steroid or other immunosuppressive therapy has been shown to be helpful in the treatment of these conditions. This feature reinforces the concept of a cause/effect relationship of the immune-mediated insult damaging the enteric innervation. An increased awareness of the clinical features and the immunologic and neurodegenerative mechanisms of these forms of peripheral neuropathy is important to correctly diagnose this problem during the early stages of the disease process and to provide appropriate immunosuppressive therapies.