Francesca Galeazzi

Cigarette smoke aggravates experimental colitis in rats

BACKGROUND & AIMS Tobacco smoking has a complex effect on intestinal inflammation, being protective in ulcerative colitis, whereas it aggravates Crohns disease. The beneficial effect of smoking has been attributed to nicotine, but the mechanisms underlying the adverse effect are still under investigation. The aim of this study was to examine the effect of cigarette smoking on experimental colitis in rats and to investigate the underlying mechanism. METHODS Rats were exposed daily to cigarette smoke by means of a specialized smoking chamber. Control rats were placed in the same chamber without introducing smoke. In parallel experiments, rats received the ganglionic blocker hexamethonium before smoke exposure. After 2 weeks, colitis was induced by dinitrobenzenesulfonic acid (DNBS), and inflammation was assessed 3 days later. RESULTS Exposure to cigarette smoke significantly increased macroscopic and histological damages as well as myeloperoxidase activity compared with sham-treated controls. Treatment with hexamethonium before smoking reversed the effect of the smoke on the colitis, improving all parameters. CONCLUSIONS Exposure to cigarette smoke aggravates DNBS-induced colitis in the rat. This effect is reversed by hexamethonium, suggesting that a neural pathway is involved.

Role of M-CSF-dependent macrophages in colitis is driven by the nature of the inflammatory stimulus

Although macrophages are considered a critical factor in determining the severity of acute inflammatory responses in the gut, recent evidence has indicated that macrophages may also play a counterinflammatory role. In this study, we examined the role of a macrophage subset in two models of colitis. Macrophage colony-stimulating factor (M-CSF)-deficient osteopetrotic mice (op/op) and M-CSF-expressing heterozygote (+/?) mice were studied following the induction of colitis by either dinitrobenzene sulfonic acid (DNBS) or dextran sulfate sodium (DSS). DNBS induced a severe colitis in M-CSF-deficient op/op mice compared with +/? mice. This was associated with increased mortality and more severe macroscopic and microscopic injury. Colonic tissue myeloperoxidase (MPO) activity as well as concentrations of TNF-alpha, IL-1beta, and IL-6 were higher and IL-10 lower in op/op mice with DNBS colitis. The severity of inflammation and mortality was attenuated in op/op mice that had received human recombinant M-CSF prior to the induction of colitis. In contrast, op/op mice appeared less vulnerable to colitis induced by DSS. Macroscopic damage, microscopic injury, MPO activity, and tissue concentrations of TNF-alpha, IL-1beta, and IL-6 were all lower in op/op mice compared with +/? mice with DSS colitis, and no changes were seen in IL-10. Macrophage inflammatory protein-1alpha concentrations were increased in op/op but not +/? mice following colitis induced by DNBS but not DSS. These results indicate that M-CSF-dependent macrophages may play either a pro- or counterinflammatory role in acute experimental colitis, depending on the stimulus used to induce colitis.

Esophagogastric junction morphology is associated with a positive impedance-pH monitoring in patients with GERD

High‐resolution manometry (HRM) provides information on esophagogastric junction (EGJ) morphology, distinguishing three different subtypes. Data on the correlation between EGJ subtypes and impedance‐pH detected reflux patterns are lacking. We aimed to correlate the EGJ subtypes with impedance‐pH findings in patients with reflux symptoms.

13C-octanoic acid breath test (OBT) with a new test meal (EXPIROGer®): Toward standardization for testing gastric emptying of solids

BACKGROUND Standardization of the (13)C-octanoic acid breath test is still lacking. AIM To evaluate the accuracy of the (13)C-octanoic acid breath test using a new standardized ready-to-eat, gluten-, glucose-, and lactose-free muffin. METHODS Healthy subjects were recruited and sorted by sex and age. Patients with diabetic gastroparesis and untreated celiac disease with known gastric motility disorders were also tested with the new labelled muffin. Expired breath (13)CO(2) was analysed and t(1/2) was calculated. RESULTS Overall, 131 healthy subjects were enrolled. The reference range of t(1/2) was 88+/-29min with the value of 146min as the upper limit of normal range. No significant difference in t(1/2) was found among subjects sorted by sex or age. The within-subject variability of t(1/2) was 17%. Mean (+/-standard deviation) t(1/2) values were 179+/-50min in patients with diabetic gastroparesis (n=8) and 151+/-20min in those with untreated celiac disease (n=11) (p<or=0.001 vs controls). CONCLUSIONS A new standardized test meal simplifies the execution of the (13)C-octanoic acid breath test, is not influenced by sex or age, has low intra-individual variability, is palatable, does not cause side effects, and is able to evaluate gastric emptying in both patients and healthy controls. Moreover, it can be used in subjects with lactose intolerance, diabetes, and celiac disease.

Functional variants in the sucrase-isomaltase gene associate with increased risk of irritable bowel syndrome

Objective IBS is a common gut disorder of uncertain pathogenesis. Among other factors, genetics and certain foods are proposed to contribute. Congenital sucrase–isomaltase deficiency (CSID) is a rare genetic form of disaccharide malabsorption characterised by diarrhoea, abdominal pain and bloating, which are features common to IBS. We tested sucrase–isomaltase (SI) gene variants for their potential relevance in IBS. Design We sequenced SI exons in seven familial cases, and screened four CSID mutations (p.Val557Gly, p.Gly1073Asp, p.Arg1124Ter and p.Phe1745Cys) and a common SI coding polymorphism (p.Val15Phe) in a multicentre cohort of 1887 cases and controls. We studied the effect of the 15Val to 15Phe substitution on SI function in vitro. We analysed p.Val15Phe genotype in relation to IBS status, stool frequency and faecal microbiota composition in 250 individuals from the general population. Results CSID mutations were more common in patients than asymptomatic controls (p=0.074; OR=1.84) and Exome Aggregation Consortium reference sequenced individuals (p=0.020; OR=1.57). 15Phe was detected in 6/7 sequenced familial cases, and increased IBS risk in case–control and population-based cohorts, with best evidence for diarrhoea phenotypes (combined p=0.00012; OR=1.36). In the population-based sample, 15Phe allele dosage correlated with stool frequency (p=0.026) and Parabacteroides faecal microbiota abundance (p=0.0024). The SI protein with 15Phe exhibited 35% reduced enzymatic activity in vitro compared with 15Val (p<0.05). Conclusions SI gene variants coding for disaccharidases with defective or reduced enzymatic activity predispose to IBS. This may help the identification of individuals at risk, and contribute to personalising treatment options in a subset of patients.

The GerdQ questionnaire and high resolution manometry support the hypothesis that proton pump inhibitor-responsive oesophageal eosinophilia is a GERD-related phenomenon.

Little is known about the relationship between proton pump inhibitor‐responsive oesophageal eosinophilia (PPI‐REE), eosinophilic esophagitis (EoE) and gastro‐oesophageal reflux disease (GERD).

Esophageal hyperalgesia in patients with ulcerative colitis: role of experimental stress

OBJECTIVES:Intestinal inflammation is associated with enteric nervous system alterations, at both inflamed and noninflamed sites. The perception of stimuli from the GI tract is enhanced during inflammatory conditions, but it is unknown whether visceral hypersensitivity is limited to the inflamed area or diffuse throughout the entire GI tract. Moreover, although stress can reactivate inflammatory processes in the gut, it is unknown if this can alter perception from the GI tract. Our aim was to determine if patients with ulcerative colitis (UC) have increased esophageal sensitivity to distention and whether this is modified by experimental stress.METHODS:Ten UC patients and 12 healthy volunteers (HVs) underwent gradual balloon distension of the esophagus to assess their visceral sensitivity. Perceptive and pain thresholds were evaluated in basal conditions and after induction of experimental stress (cold water pressure test) while blood pressure and heart rate were monitored.RESULTS:Patients with UC had perceptive thresholds to distension similar to HVs (14.8 ± 2.0 ml of air vs 14.5 ± 3.0 ml); in contrast, the volume increment needed to evoke pain was significantly lower in UC patients than in HVs (58.9% vs 149.9%, p < 0.05). Physical stress caused a similar decrease in perceptive thresholds in HVs (−29.1 ± 8.4%) and patients (−17.7 ± 9.1%), but pain thresholds were significantly decreased only in HVs (−28.3 ± 7.1% vs− 11.5 ± 12.3%).CONCLUSIONS:UC is characterized by increased esophageal sensitivity, indicating the existence of diffuse hyperalgesia during intestinal inflammatory processes. This increased sensitivity may account for the frequent upper GI symptoms these patients complain of when in clinical remission.

Diagnosis and treatment of faecal incontinence: Consensus statement of the Italian Society of Colorectal Surgery and the Italian Association of Hospital Gastroenterologists.

Faecal incontinence is a common and disturbing condition, which leads to impaired quality of life and huge social and economic costs. Although recent studies have identified novel diagnostic modalities and therapeutic options, the best diagnostic and therapeutic approach is not yet completely known and shared among experts in this field. The Italian Society of Colorectal Surgery and the Italian Association of Hospital Gastroenterologists selected a pool of experts to constitute a joint committee on the basis of their experience in treating pelvic floor disorders. The aim was to develop a position paper on the diagnostic and therapeutic aspects of faecal incontinence, to provide practical recommendations for a cost-effective diagnostic work-up and a tailored treatment strategy. The recommendations were defined and graded on the basis of levels of evidence in accordance with the criteria of the Oxford Centre for Evidence-Based Medicine, and were based on currently published scientific evidence. Each statement was drafted through constant communication and evaluation conducted both online and during face-to-face working meetings. A brief recommendation at the end of each paragraph allows clinicians to find concise responses to each diagnostic and therapeutic issue.

Clinical, endoscopic, histological and radiological characteristics of Italian patients with eosinophilic oesophagitis

BACKGROUND Limited data are available on eosinophilic oesophagitis in Italy. AIM To evaluate typical features of eosinophilic oesophagitis patients in a tertiary centre. METHODS 973 consecutive patients with dysphagia and/or bolus impaction were prospectively enrolled and underwent upper endoscopy for eosinophilic oesophagitis (≥15 eosinophils in at least one high-power field [hpf] and no response to acid suppressants). Demographic and multiple clinical factors were collected. RESULTS 45 patients (80% males, mean age 35±16) with incident eosinophilic oesophagitis (mean eosinophil peak count 57.2±40.6/hpf) were enrolled. 32 patients complained of solids dysphagia (71%), and 29 of bolus impaction (64%). Endoscopy found rings in 20 (44%), furrows in 9 (20%), whitish exudates/plaques in 12 (27%), crêpe paper in 7 (13%) and normal findings in 14 patients (31%). Endoscopic and radiologic stenosis occurred in 20 (44%) and 23 (51%), respectively. Ten patients had proton pump inhibitor-oesophageal eosinophilia (22%). Topic fluticasone was effective in 28 of the remaining cases (62%), while 7 required additional treatments (16%). CONCLUSION Eosinophilic oesophagitis prevalence was 12% in patients with dysphagia and/or bolus impaction, emphasizing the importance of this disease in Italy. Despite different environmental factors and dietary habits, Italian patients with eosinophilic oesophagitis present similar characteristics to those of other Western counties.

Increased Prevalence of Rare Sucrase-isomaltase (SI) Pathogenic Variants in Irritable Bowel Syndrome Patients

&NA; Patients with irritable bowel syndrome (IBS) often associate their symptoms to certain foods. In congenital sucrase‐isomaltase deficiency (CSID), recessive mutations in the SI gene (coding for the disaccharidase digesting sucrose and 60% of dietary starch)1 cause clinical features of IBS through colonic accumulation of undigested carbohydrates, triggering bowel symptoms.2 Hence, in a previous study,3 we hypothesized that CSID variants reducing SI enzymatic activity may contribute to development of IBS symptoms. We detected association with increased risk of IBS for 4 rare loss‐of‐function variants typically found in (homozygous) CSID patients, because carriers (heterozygous) of these rare variants were more common in patients than in controls.1,4 Through a 2‐step computational and experimental strategy, the present study aimed to determine whether other (dys‐)functional SI variants are associated with risk of IBS in addition to known CSID mutations. We first aimed to identify all SI rare pathogenic variants (SI‐RPVs) on the basis of integrated Mendelian Clinically Applicable Pathogenicity (M‐CAP) and Combined Annotation Dependent Depletion (CADD) predictive (clinically relevant) scores; next, we inspected genotype data currently available for 2207 IBS patients from a large ongoing project to compare SI‐RPV case frequencies with ethnically matched population frequencies from the Exome Aggregation Consortium (ExAC).