Site and duration of abdominal pain discriminate symptomatic uncomplicated diverticular disease from previous diverticulitis patients.

Abdominal pain in patients with diverticular disease (DD) can be challenging in clinical practice. Patients with symptomatic uncomplicated diverticular disease (SUDD) and patients with a previous acute diverticulitis (PD) may share a similar clinical pattern, difficult to differentiate from irritable bowel syndrome (IBS). We used standardized questionnaires for DD (short and long lasting abdominal pain) and IBS (following Rome III Criteria) to assess clinical features of abdominal pain, in terms of presence, severity and length, in SUDD and PD patients. One hundred and forty-eight SUDD and 118 PD patients completed all questionnaires. Short-lasting pain was more frequent in SUDD than PD patients (p = 0.007). Number of long-lasting pain episodes was higher in SUDD (6.6 ± 11.9) compared to PD patients (3.4 ± 6.9) (p < 0.001). PD patients reported long-lasting pain more frequently in the lower left abdomen (p < 0.001), while in SUDD it was more frequently diffuse (p = 0.002) or localized in the lower right quadrant (p = 0.009). Features associated with long-lasting pain (fever, confinement to bed, consultations, antibiotic therapy, hospitalization) were more often reported in PD patients. IBS criteria were reported in 28.2% of patients and were more frequent in SUDD than PD patients (37.2% vs 17.1%, p < 0.001). SUDD and PD patients presented different pattern of abdominal pain (length, number of long lasting episodes, site and associated features), with a third reporting overlap with IBS. Further observational studies are needed to better characterize abdominal symptoms in DD patients, especially in those not fulfilling IBS criteria.Trial registration: The REMAD Registry is registered as an observational study in ClinicalTrial.gov (ID: NCT03325829).

Patients with Diverticular Disease Have Different Dietary Habits Compared to Control Subjects: Results from an Observational Italian Study.

The role of dietary habits as risk factor for the development of diverticular complications has strongly emerged in the last years. We aimed to evaluate possible differences in dietary habits between patients with diverticular disease (DD) and matched controls without diverticula. Dietary habits were obtained from standardized food frequency questionnaires collected at entry to the Diverticular Disease Registry (REMAD). We compared controls (C) (n = 119) with asymptomatic diverticulosis (D) (n = 344), symptomatic uncomplicated diverticular disease (SUDD) (n = 154) and previous diverticulitis (PD) (n = 83) patients, in terms of daily calories, macro and micronutrients and dietary vitamins. Daily kcal intake and lipids, both saturated and unsaturated, were significantly lower in patients with DD than C. Total protein consumption was lower in PD than D, with differing consumption of unprocessed red meat, white meat and eggs between groups. Consumption of fibre, both soluble and insoluble, was lower in patients with PD compared to patients with SUDD, D and C, whereas dietary vitamins A, C, D and E and Oxygen Radical Adsorbance Capacity index were lower in all DD groups compared to C. This observational study showed that DD patients have different dietary habits, mainly in terms of caloric, fat, fibre and vitamin intake, compared to control subjects.

Role of Dietary Habits in the Prevention of Diverticular Disease Complications: A Systematic Review.

Recent evidence showed that dietary habits play a role as risk factors for the development of diverticular complications. This systematic review aims to assess the effect of dietary habits in the prevention of diverticula complications (i.e., acute diverticulitis and diverticula bleeding) in patients with diverticula disease. PubMed and Scopus databases were searched up to 19 January 2021, 330 records were identified, and 8 articles met the eligibility criteria and were subjected to data extraction. The quality of the studies was evaluated by the Newcastle-Ottawa quality assessment form. No study meets the criteria for being a high-quality study. A high intake of fiber was associated to a decreased risk of diverticulitis or hospitalization due to diverticular disease, with a protective effect for fruits and cereal fiber, but not for vegetable fiber; whereas, a high red meat consumption and a generally Western dietary pattern were associated with an increased risk of diverticulitis. Alcohol use seemed to be associated to diverticular bleeding, but not to recurrent diverticulitis or diverticular complications. Further high-quality studies are needed to better define these associations. It is mandatory to ascertain the role of dietary habits for the development of recurrent acute diverticulitis and diverticular bleeding.

Distinguishing features between patients with acute diverticulitis and diverticular bleeding: Results from the REMAD registry.

BACKGROUND: Pathogenesis of acute diverticulitis and diverticular bleeding remains poorly defined, and few data compare directly risk factors for these complications. AIMS: to assess differences in clinical features, lifestyles factors and concurrent drug use in patients with acute diverticulitis and those with diverticular bleeding. METHODS: Data were obtained from the REMAD Registry, an ongoing 5-year prospective, observational, multicenter, cohort study conducted on 1,217 patients. Patient- and clinical- related factors were compared among patients with uncomplicated diverticular disease, patients with previous acute diverticulitis, and patients with previous diverticular bleeding. RESULTS: Age was significantly lower (OR 0.48, 95% CI: 0.34-0.67) and family history of diverticular disease was significantly higher (OR 1.60, 95% CI: 1.11-2.31) in patients with previous diverticulitis than in patients with uncomplicated diverticular disease, respectively. Chronic obstructive pulmonary disease was significantly higher in patients with previous diverticular bleeding as compared with both uncomplicated diverticular disease (OR 8.37, 95% CI: 2.60-27.0) and diverticulitis (OR 4.23, 95% CI: 1.11-16.1). CONCLUSION: This ancillary study from a nationwide Registry showed that some distinctive features identify patients with acute diverticulitis and diverticular bleeding. These information might improve the assessment of risk factors for diverticular complications.

The Trends of Complicated Acute Colonic Diverticulitis-A Systematic Review of the National Administrative Databases.

Background and Objectives: The diverticular disease includes a broad spectrum of different "clinical situations" from diverticulosis to acute diverticulitis (AD), with a full spectrum of severity ranging from self-limiting infection to abscess or fistula formation to free perforation. The present work aimed to assess the burden of complicated diverticulitis through a comparative analysis of the hospitalizations based on the national administrative databases. Materials and Methods: A review of the international and national administrative databases concerning admissions for complicated AD was performed. Results: Ten studies met the inclusion criteria and were included in the analysis. No definition of acute complicated diverticulitis was reported in any study. Complicated AD accounted for approximately 42% and 79% of the hospitalizations. The reported rates of abscess varied between 1% and 10% from all admissions for AD and 5-29% of the cases with complicated AD. An increasing temporal trend was found in one study-from 6% to 10%. The rates of diffuse peritonitis ranged from 1.6% to 10.2% of all hospitalizations and 11% and 47% of the complicated cases and were stable in the time. Conclusions: The available data precluded definitive conclusions because of the significant discrepancy between the included studies. The leading cause was the presence of heterogeneity due to coding inaccuracies in all databases, absence of ICD codes to distinguish the different type of complications, and the lack of coding data about some general conditions such as sepsis, shock, malnutrition, steroid therapy, diabetes, pulmonary, and heart failure.

Italian nationwide survey of pharmacologic treatments in diverticular disease: Results from the REMAD registry.

Background: Although diverticular disease is a common condition, its effective treatment is challenging in clinical practice. Objective: The objective of this article is to assess pharmacological management in different clinical settings of diverticular disease and factors associated with treatment using the Italian registry Registro Malattia Diverticolare (REMAD). Methods: At study enrolment, patients were categorised into subgroups: diverticulosis, symptomatic uncomplicated diverticular disease and previous diverticulitis. We registered demographic, clinical and lifestyle factors, quality of life and the use of treatments for diverticular disease in the last year. Logistic regression analysis assessed the association between clinical factors and treatment consumption. Results: A total of 500 of the 1206 individuals included had had at least one treatment for diverticular disease in the last year: 23.6% (166/702) of patients with diverticulosis, 55.9% (165/295) of patients with symptomatic diverticular disease, and 80.9% (169/209) of patients with previous diverticulitis (p < 0.001). In multivariate analysis, the following factors were significantly associated with treatment use: female gender, family history of colonic diverticula, organic digestive comorbidity and impaired physical quality of life components. Conclusion: Individuals with diverticular disease take medications based on the different clinical settings of disease. We identified different features associated with treatment use in the distinct clinical entities of diverticular disease.ClinicalTrial.gov Identifier: NCT03325829.

Surgical treatment of acute complicated diverticulitis in the elderly.

Although the true prevalence is unknown, colonic diverticulosis is one of the most common disease of the digestive tract in Western countries. Based on administrative data of hospitalized patients, the incidence of diverticulitis has been increasing in last decades. In general, elderly patients undergo less frequently an elective colonic resection; but a substantial part of emergency surgeries is performed in elderly patients. In these older patients the choice of any clinical and surgical option is to be correlated not only to the severity of diverticulitis, but also to general status and the co-existing comorbidities. In this regard, it is mandatory that all patients undergo a multidimensional, comprehensive geriatric assessment to correctly identify those who are fit, vulnerable or frail. The analysis of data currently available highlights three relevant elements: type and severity of peritoneal contamination, hemodynamic conditions (stable or unstable), and concomitant comorbidities (fit or frail status). There is no single ideal surgical treatment that can be considered as gold standard for all clinical presentations; the final clinical decision-making should always be based on patient's general health status, severity of peritonitis and of sepsis. In a septic elderly patient who is hemodynamically unstable, treatment should be as prompt as possible independent of the Hinchey's stage, and could include either a Mickulicz stoma or a DCS strategy. In an elderly patient who is fit and hemodynamically stable, the surgical options are similar to those in a younger patient. If a patient is frail but hemodynamically stable, he should be treated with a Hartmann's procedures.

Mild dehydration in dyspeptic athletes is able to increase gastrointestinal symptoms: Protective effects of an appropriate hydration.

BACKGROUND: Water balance influences gastrointestinal (GI) activity. Our aim was to evaluate how dehydration and rehydration with different types of water are able to affect GI activity in healthy and dyspeptic athletes. METHODS: Twenty non-competitive athletes, respectively 10 healthy and 10 dyspeptic subjects, were enrolled. All subjects underwent three test sessions (0, A, B) of 6 hours. Dehydration was achieved with a walking/jogging exercise test on a treadmill. After exercising, 500 mL of calcium-bicarbonate (Test A) or soft water (Test B) were administered, while no rehydration was provided during Test 0; thereafter, all subjects consumed a light lunch. GI symptoms were evaluated during each test and an electrocardiogram (ECG) Holter recording was performed at the end of the exercise. KEY RESULTS: Dyspeptic subjects exhibited higher overall symptoms during Test 0 (VAS: 30.8 ± 0.8 mm) compared to Test A (18.4 ± 1.1, P < 0.001) and Test B (24.4 ± 1.3, P < 0.001). However, analyzing GI symptoms, only subjects receiving calcium-bicarbonate water (Test A) showed significantly lower symptomatic scores compared to Test 0 or Test B. Moreover, heart rate variability analyses revealed that only in Test A dyspeptic patients exhibit a trend to a decrease in the post-prandial low/high frequency (LF/HF) ratio, similarly to healthy subjects, while in Test 0 and Test B, post-prandial LF/HF ratio was increased compared to the pre-prandial phase. CONCLUSIONS AND INFERENCES: Our results show that mild dehydration in dyspeptic athletes is able to increase GI symptoms but an adequate rehydration, with calcium-bicarbonate water, is able to improve post-exercise disturbances restoring sympathovagal imbalance.

Treatment of diverticular disease, targeting symptoms or underlying mechanisms.

Diverticular disease (DD) is a highly prevalent disease in western industrialized countries that encompasses a complex set of disorders. Because of its complexity and heterogeneity, both from a pathogenic and a clinical point of view, the management of this disease represent a challenge in clinical practice. This review aims to analyze and summarize the most recent evidence on the medical strategies for DD, considering separately the different stages of the disease, from prevention of diverticula formation to treatment of acute diverticulitis and prevention of recurrences. Based on some evidence, dietary fiber is useful to prevent diverticula formation and in diverticulosis, with no pharmacological treatment in these settings. Treatment of symptomatic uncomplicated diverticular disease as well as primary prevention of acute diverticulitis is based on probiotics, fibres, mesalazine and rifaximin, individually or as combination therapy, although a standard approach has not yet been defined. On the contrary, in acute diverticulitis (AD) recent acquisitions have clarified and standardized the role of systemic antibiotics, reserving its use only to complicated forms and in selected cases of uncomplicated disease. Secondary prevention of AD is essentially based on mesalazine and rifaximin but, despite promising results, no strong evidence have been produced. To date, grey areas remain in the medical management of DD.

Increasing trend in admission rates and costs for acute diverticulitis during 2005-2015: real-life data from the Abruzzo Region.

BACKGROUND: Scarce data are available on the epidemiological trend of diverticulitis and its financial burden in Italy. The aim of this work was to explore a potential variation in the rate and costs of hospital admissions for uncomplicated and complicated diverticulitis over the last decade. METHODS: We selected all hospitalizations for diverticulitis of residents in the Abruzzo Region, Italy between 2005 and 2015. Age-standardized hospitalization rates (HRs) per 100,000 inhabitants for overall, uncomplicated and complicated diverticulitis were calculated. A linear model on the log of the age-standardized rates was used to calculate annual percentage changes (APC). Costs were derived from the official DRG tariff. RESULTS: From 2005 to 2015, the HR for acute diverticulitis increased from 38.9 to 45.2 per 100,000 inhabitants (APC + 1.9%). The HR for complicated diverticulitis increased from 5.9 to 13.3 (APC + 7.6%), whereas it remained stable for uncomplicated diverticulitis. The mean hospital cost was 1.8-times higher for complicated diverticulitis compared with that for uncomplicated disease and 3.5-times higher for patients with a surgery stay compared with that for patients with a medical stay. CONCLUSION: During the last decade, in the Abruzzo Region, the HRs for diverticulitis and their costs increased significantly, mainly due to disease complications. Further studies are needed to explore strategies to prevent complications and to realise cost-saving policies.

Demographic and clinical features distinguish subgroups of diverticular disease patients: Results from an Italian nationwide registry.

BACKGROUND: Clinical features and lifestyle factors associated with diverticulosis compared to diverticular disease (DD), either symptomatic uncomplicated diverticular disease (SUDD) or in patients who have had previous diverticulitis (PD), are unclear. OBJECTIVE: The objective of this article is to compare cross-sectionally demographic and clinical features and quality of life (QoL) in diverticulosis, SUDD and PD patients. METHODS: The REMAD Registry is a prospective, observational, multicentre, cohort study. Patients were categorised according to: diverticulosis; SUDD (recurrent abdominal symptoms attributed to diverticula in absence of overt inflammation) and PD (≥1 previous diverticulitis). RESULTS: A total of 1217 patients (57.9% diverticulosis, 24.7% SUDD and 17.4% PD) were included. Compared to diverticulosis, female gender was associated to SUDD (OR 1.94; 95% CI: 1.43-2.62) and PD (OR 1.79; 95% CI: 1.24-2.56); age ≤ 60 years was associated to PD (OR 2.10; 95% CI: 1.42-3.08 vs diverticulosis, OR 1.57; 95% CI: 1.01-2.45 vs SUDD). PD patients showed an association with past bleeding (OR 29.29; 95% CI: 8.17-104.98 vs diverticulosis, OR 16.84; 95% CI: 3.77-75.25 vs SUDD). Compared to diverticulosis, family history for diverticula was associated to PD (OR 1.88; 95% CI: 1.27-2.78). Patients with diverticulosis showed higher QoL scores, both physical (p = 0.0001 and 0.0257) and mental (p < 0.0001 and 0.0038), in comparison to SUDD and PD. CONCLUSION: Family history for diverticula and history of bleeding distinguish diverticulosis from DD. These clinical features should be kept in mind in the management of DD.

Dietary Interventions to Modulate the Gut Microbiome-How Far Away Are We From Precision Medicine.

The importance of the gut microbiome in human health and disease is fully acknowledged. A perturbation in the equilibrium among the different microbial populations living in the gut (dysbiosis) has been associated with the development of several types of diseases. Modulation of the gut microbiome through dietary intervention is an emerging therapeutic and preventive strategy for many conditions. Nevertheless, interpersonal differences in response to therapeutic treatments or dietary regimens are often observed during clinical trials, and recent research has suggested that subject-specific features of the gut microbiota may be responsible. In this review, we summarize recent findings in personalized nutrition, highlighting how individualized characterization of the microbiome may assist in designing ad hoc tailored dietary intervention for disease treatment and prevention. Moreover, we discuss the limitations and challenges encountered in integrating patient-specific microbial data into clinical practice.

Female-Specific Association Between Variants on Chromosome 9 and Self-Reported Diagnosis of Irritable Bowel Syndrome.

BACKGROUND & AIMS: Genetic factors are believed to affect risk for irritable bowel syndrome (IBS), but there have been no sufficiently powered and adequately sized studies. To identify DNA variants associated with IBS risk, we performed a genome-wide association study (GWAS) of the large UK Biobank population-based cohort, which includes genotype and health data from 500,000 participants. METHODS: We studied 7,287,191 high-quality single nucleotide polymorphisms in individuals who self-reported a doctor's diagnosis of IBS (cases; n = 9576) compared to the remainder of the cohort (controls; n = 336,499) (mean age of study subjects, 40-69 years). Genome-wide significant findings were further investigated in 2045 patients with IBS from tertiary centers and 7955 population controls from Europe and the United States, and a small general population sample from Sweden (n = 249). Functional annotation of GWAS results was carried out by integrating data from multiple biorepositories to obtain biological insights from the observed associations. RESULTS: We identified a genome-wide significant association on chromosome 9q31.2 (single nucleotide polymorphism rs10512344; P = 3.57 × 10-8) in a region previously linked to age at menarche, and 13 additional loci of suggestive significance (P < 5.0×10-6). Sex-stratified analyses revealed that the variants at 9q31.2 affect risk of IBS in women only (P = 4.29 × 10-10 in UK Biobank) and also associate with constipation-predominant IBS in women (P = .015 in the tertiary cohort) and harder stools in women (P = .0012 in the population-based sample). Functional annotation of the 9q31.2 locus identified 8 candidate genes, including the elongator complex protein 1 gene (ELP1 or IKBKAP), which is mutated in patients with familial dysautonomia. CONCLUSIONS: In a sufficiently powered GWAS of IBS, we associated variants at the locus 9q31.2 with risk of IBS in women. This observation may provide additional rationale for investigating the role of sex hormones and autonomic dysfunction in IBS.

HIV-1 Tat-induced diarrhea is improved by the PPARalpha agonist, palmitoylethanolamide, by suppressing the activation of enteric glia.

BACKGROUND: Diarrhea is a severe complication in HIV-1-infected patients with Trans-activator of transcription (HIV-1 Tat) protein being recognized as a major underlying cause. Beside its direct enterotoxic effects, Tat protein has been recently shown to affect enteric glial cell (EGC) activity. EGCs regulate intestinal inflammatory responses by secreting pro-inflammatory molecules; nonetheless, they might also release immune-regulatory factors, as palmytoilethanolamide (PEA), which exerts anti-inflammatory effects by activating PPARα receptors. We aimed at clarifying whether EGCs are involved in HIV-1 Tat-induced diarrhea and if PEA exerts antidiarrheal activity. METHODS: Diarrhea was induced by intracolonic administration of HIV-1 Tat protein in rats at day 1. PEA alone or in the presence of peroxisome proliferator-activated receptor (PPAR) antagonists was given intraperitoneally from day 2 to day 7. S100B, iNOS, NF-kappaB, TLR4 and GFAP expression were evaluated in submucosal plexi, while S100B and NO levels were measured in EGC submucosal plexi lysates, respectively. To verify whether PEA effects were PPARα-mediated, PPARα-/- mice were also used. After 7 days from diarrhea induction, endogenous PEA levels were measured in submucosal plexi homogenates deriving from rats and PPARα-/- mice. RESULTS: HIV-1 Tat protein induced rapid onset diarrhea alongside with a significant activation of EGCs. Tat administration significantly increased all hallmarks of neuroinflammation by triggering TLR4 and NF-kappaB activation and S100B and iNOS expression. Endogenous PEA levels were increased following HIV-1 Tat exposure in both wildtype and knockout animals. In PPARα-/- mice, PEA displayed no effects. In wildtype rats, PEA, via PPARα-dependent mechanism, resulted in a significant antidiarrheal activity in parallel with marked reduction of EGC-sustained neuroinflammation. CONCLUSIONS: EGCs mediate HIV-1 Tat-induced diarrhea by sustaining the intestinal neuroinflammatory response. These effects are regulated by PEA through a selective PPARα-dependent mechanism. PEA might be considered as an adjuvant therapy in HIV-1-induced diarrhea.

Postprandial Gastrointestinal Function Differs after Acute Administration of Sourdough Compared with Brewer's Yeast Bakery Products in Healthy Adults.

Background: Europeans consume large quantities of bakery products, although these are known as one of the food categories that potentially leads to postprandial symptoms (such as fullness and bloating). Objective: The aim of this study was to evaluate the effects of sourdough baked goods on gastric emptying and gastrointestinal fermentation and symptoms in healthy people. Methods: In a double-blind, randomized crossover study, 2 sourdough croissants (SCs) or 2 brewer's yeast croissants (BCs) were served as single meals to 17 healthy adults [9 women; age range: 18-40 y; body mass index range (in kg/m2): 18-24]. Gastric volume (GV) was evaluated by magnetic resonance to calculate gastric-emptying rate in the 3-h interval after croissant ingestion. A hydrogen breath test was performed to measure hydrogen production after SC and BC ingestion. Palatability and postprandial gastrointestinal symptoms (discomfort, nausea, fullness, and bloating) over a 4-h period after the meal were evaluated. The area under the curve (AUC) was used to evaluate the overall effects on all variables tested. Results: The total GV AUC was reduced by 11% during the 3 h after the consumption of SCs compared with BCs (P = 0.02). Hydrogen production during the 4-h interval after ingestion of SCs was 30% lower than after BCs (P = 0.03). SCs were rated as being >2 times as palatable as BCs (P < 0.001). The overall severity of postprandial symptoms was 36% lower during the 4 h after intake of SCs compared with BCs (P = 0.05). Conclusion: Sourdough bakery products could promote better postprandial gastrointestinal function in healthy adults and be more acceptable than those prepared with brewer's yeast. This trial was registered at www.clinicaltrials.gov as NCT03207516.

Increased Prevalence of Rare Sucrase-isomaltase Pathogenic Variants in Irritable Bowel Syndrome Patients.

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).

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.

Endocannabinoid-related compounds in gastrointestinal diseases.

The endocannabinoid system (ECS) is an endogenous signalling pathway involved in the control of several gastrointestinal (GI) functions at both peripheral and central levels. In recent years, it has become apparent that the ECS is pivotal in the regulation of GI motility, secretion and sensitivity, but endocannabinoids (ECs) are also involved in the regulation of intestinal inflammation and mucosal barrier permeability, suggesting their role in the pathophysiology of both functional and organic GI disorders. Genetic studies in patients with irritable bowel syndrome (IBS) or inflammatory bowel disease have indeed shown significant associations with polymorphisms or mutation in genes encoding for cannabinoid receptor or enzyme responsible for their catabolism, respectively. Furthermore, ongoing clinical trials are testing EC agonists/antagonists in the achievement of symptomatic relief from a number of GI symptoms. Despite this evidence, there is a lack of supportive RCTs and relevant data in human beings, and hence, the possible therapeutic application of these compounds is raising ethical, political and economic concerns. More recently, the identification of several EC-like compounds able to modulate ECS function without the typical central side effects of cannabino-mimetics has paved the way for emerging peripherally acting drugs. This review summarizes the possible mechanisms linking the ECS to GI disorders and describes the most recent advances in the manipulation of the ECS in the treatment of GI diseases.

Cannabidiol restores intestinal barrier dysfunction and inhibits the apoptotic process induced by Clostridium difficile toxin A in Caco-2 cells.

BACKGROUND: Clostridium difficile toxin A is responsible for colonic damage observed in infected patients. Drugs able to restore Clostridium difficile toxin A-induced toxicity have the potential to improve the recovery of infected patients. Cannabidiol is a non-psychotropic component of Cannabis sativa, which has been demonstrated to protect enterocytes against chemical and/or inflammatory damage and to restore intestinal mucosa integrity. OBJECTIVE: The purpose of this study was to evaluate (a) the anti-apoptotic effect and (b) the mechanisms by which cannabidiol protects mucosal integrity in Caco-2 cells exposed to Clostridium difficile toxin A. METHODS: Caco-2 cells were exposed to Clostridium difficile toxin A (30 ng/ml), with or without cannabidiol (10-7-10-9 M), in the presence of the specific antagonist AM251 (10-7 M). Cytotoxicity assay, transepithelial electrical resistence measurements, immunofluorescence analysis and immunoblot analysis were performed in the different experimental conditions. RESULTS: Clostridium difficile toxin A significantly decreased Caco-2 cells' viability and reduced transepithelial electrical resistence values and RhoA guanosine triphosphate (GTP), bax, zonula occludens-1 and occludin protein expression, respectively. All these effects were significantly and concentration-dependently inhibited by cannabidiol, whose effects were completely abolished in the presence of the cannabinoid receptor type 1 (CB1) antagonist, AM251. CONCLUSIONS: Cannabidiol improved Clostridium difficile toxin A-induced damage in Caco-2 cells, by inhibiting the apoptotic process and restoring the intestinal barrier integrity, through the involvement of the CB1 receptor.

Cortical representation of different taste modalities on the gustatory cortex: A pilot study.

BACKGROUND: Right insular cortex is involved in taste discrimination, but its functional organization is still poorly known. In general, sensory cortices represent the spatial prevalence of relevant features for each sensory modality (visual, auditory, somatosensory) in an ordered way across the cortical space. Following this analogy, we hypothesized that primary taste cortex is organized in similar ordered way in response to six tastes with known receptorial mechanisms (sweet, bitter, sour, salt, umami, CO2). DESIGN: Ten normal subjects were enrolled in a pilot study. We used functional magnetic resonance imaging (fMRI), a high resolution cortical registration method, and specialized procedures of feature prevalence localization, to map fMRI responses within the right insular cortex, to water solutions of quinine hydrochloride (bitter), Acesulfamate K (sweet), sodium chloride (salt), mono potassium glutamate + inosine 5' mono phosphate (Umami), citric acid (sour) and carbonated water (CO2). During an fMRI scan delivery of the solutions was applied in pseudo-random order interleaved with cleaning water. RESULTS: Two subjects were discarded due to excessive head movements. In the remaining subjects, statistically significant activations were detected in the fMRI responses to all tastes in the right insular cortex (p<0.05, family-wise corrected for multiple comparisons). Cortical representation of taste prevalence highlighted two spatially segregated clusters, processing two and three tastes coupled together (sweet-bitter and salt-umami-sour), with CO2 in between. CONCLUSIONS: Cortical representation of taste prevalence within the right primary taste cortex appears to follow the ecological purpose of enhancing the discrimination between safe nutrients and harmful substances.