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Persistent Intraepithelial Lymphocytosis in Celiac Patients Adhering to Gluten-Free Diet Is Not Abolished Despite a Gluten Contamination Elimination Diet.
Zanini, B, Marullo, M, Villanacci, V, Salemme, M, Lanzarotto, F, Ricci, C, Lanzini, A
Nutrients. 2016;(9)
Abstract
The gluten-free diet (GFD) is the only validated treatment for celiac disease (CD), but despite strict adherence, complete mucosal recovery is rarely obtained. The aim of our study was to assess whether complete restitutio ad integrum could be achieved by adopting a restrictive diet (Gluten Contamination Elimination Diet, GCED) or may depend on time of exposure to GFD. Two cohorts of CD patients, with persisting Marsh II/Grade A lesion at duodenal biopsy after 12-18 months of GFD (early control) were identified. Patients in Cohort A were re-biopsied after a three-month GCED (GCED control) and patients in Cohort B were re-biopsied after a minimum of two years on a standard GFD subsequent to early control (late control). Ten patients in Cohort A and 19 in Cohort B completed the study protocol. There was no change in the classification of duodenal biopsies in both cohorts. The number of intraepithelial lymphocytes, TCRγδ+ (T-Cell Receptor gamma delta) T cell and eosinophils significantly decreased at GCED control (Cohort A) and at late control (Cohort B), compared to early control. Duodenal intraepithelial lymphocytosis persisting in CD patients during GFD is not eliminated by a GCED and is independent of the length of GFD. [NCT 02711696].
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Ancient pathogen-driven adaptation triggers increased susceptibility to non-celiac wheat sensitivity in present-day European populations.
Sazzini, M, De Fanti, S, Cherubini, A, Quagliariello, A, Profiti, G, Martelli, PL, Casadio, R, Ricci, C, Campieri, M, Lanzini, A, et al
Genes & nutrition. 2016;:15
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BACKGROUND Non-celiac wheat sensitivity is an emerging wheat-related syndrome showing peak prevalence in Western populations. Recent studies hypothesize that new gliadin alleles introduced in the human diet by replacement of ancient wheat with modern varieties can prompt immune responses mediated by the CXCR3-chemokine axis potentially underlying such pathogenic inflammation. This cultural shift may also explain disease epidemiology, having turned European-specific adaptive alleles previously targeted by natural selection into disadvantageous ones. METHODS To explore this evolutionary scenario, we performed ultra-deep sequencing of genes pivotal in the CXCR3-inflammatory pathway on individuals diagnosed for non-celiac wheat sensitivity and we applied anthropological evolutionary genetics methods to sequence data from worldwide populations to investigate the genetic legacy of natural selection on these loci. RESULTS Our results indicate that balancing selection has maintained two divergent CXCL10/CXCL11 haplotypes in Europeans, one responsible for boosting inflammatory reactions and another for encoding moderate chemokine expression. CONCLUSIONS This led to considerably higher occurrence of the former haplotype in Western people than in Africans and East Asians, suggesting that they might be more prone to side effects related to the consumption of modern wheat varieties. Accordingly, this study contributed to shed new light on some of the mechanisms potentially involved in the disease etiology and on the evolutionary bases of its present-day epidemiological patterns. Moreover, overrepresentation of disease homozygotes for the dis-adaptive haplotype plausibly accounts for their even more enhanced CXCR3-axis expression and for their further increase in disease risk, representing a promising finding to be validated by larger follow-up studies.
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Randomised clinical study: gluten challenge induces symptom recurrence in only a minority of patients who meet clinical criteria for non-coeliac gluten sensitivity.
Zanini, B, Baschè, R, Ferraresi, A, Ricci, C, Lanzarotto, F, Marullo, M, Villanacci, V, Hidalgo, A, Lanzini, A
Alimentary pharmacology & therapeutics. 2015;(8):968-76
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BACKGROUND It is unknown whether symptoms in non-coeliac patients (non-CD) meeting clinical diagnostic criteria for noncoeliac gluten sensitivity (NCGS) are specifically triggered by gluten. AIM: To assess gluten sensitivity in patients diagnosed with NCGS. METHODS We studied 35 non-CD subjects (31 females) that were on a gluten-free diet (GFD), in a double-blind challenge study. Participants were randomised to receive either gluten-containing flour or gluten-free flour for 10 days, followed by a 2-week washout period and were then crossed over. The main outcome measure was their ability to identify which flour contained gluten. Secondary outcome measures were based upon Gastrointestinal Symptoms Rating Scale (GSRS) scores. RESULTS The gluten-containing flour was correctly identified by 12 participants (34%), who were classified as having NCGS. Their mean GSRS dimension scores were significantly higher following gluten challenge compared to baseline. The scores were: pain, 1.7 ± 0.8 vs. 2.6 ± 1.0; reflux, 1.6 ± 0.5 vs. 2.2 ± 0.9; indigestion, 1.9 ± 0.7 vs. 3.2 ± 1.1; diarrhoea, 1.6 ± 0.7 vs. 2.9 ± 1.5 and constipation, 1.9 ± 0.9 vs. 2.9 ± 1.3. Seventeen participants (49%) erroneously considered the gluten-free flour to contain gluten. Their mean GSRS dimension scores were significantly higher following gluten-free flour challenge compared to baseline. The scores were: pain, 1.6 ± 0.9 vs. 3.0 ± 0.9; reflux, 1.4 ± 0.5 vs. 2.3 ± 1.1; indigestion, 2.0 ± 1.1 vs. 3.7 ± 1.1; diarrhoea, 1.6 ± 0.7 vs. 3.0 ± 1.2 and constipation, 1.6 ± 0.9 vs. 2.6 ± 1.3. The other six participants (17%) were unable to distinguish between the flours. CONCLUSION Double-blind gluten challenge induces symptom recurrence in just one-third of patients fulfilling the clinical diagnostic criteria for non-coeliac gluten sensitivity.
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Triticum monococcum in patients with celiac disease: a phase II open study on safety of prolonged daily administration.
Zanini, B, Villanacci, V, De Leo, L, Lanzini, A
European journal of nutrition. 2015;(6):1027-9
Abstract
BACKGROUND AND AIMS To assess safety of prolonged daily administration of Triticum monococcum (Tm) using clinical, serological and histological criteria. Tm is an ancient wheat suitable for production of palatable baked goods that contains gluten devoid of strongly immunostimulatory epitopes and potentially safe for celiac disease (CD) patients as suggested by in vitro and ex vivo studies. METHODS Protocol involved 60-day administration of 100 g/day Tm water biscuits to CD patients in remission on gluten-free diet. Symptoms Gastrointestinal Symptom Rating Scale questionnaire (GSRS) and CD-related serology were assessed at time (T) 0, T30 and T60 days, and duodenal biopsy was obtained at T0 and T60. RESULTS Eight patients (F/M: 6/2, median age 26) were enrolled. One patient was excluded at T0 because of positive serology, and two patients dropped out because of symptoms recurrence. In the five patients completing the study, there was no difference in GSRS score at T0 to T60. All patients had Marsh II lesion at T0, four had Marsh III and one had recurrence of dermatitis herpetiformis at T60. CD-related antibodies converted from negative to positive at T60 in three patients. CONCLUSIONS Our study shows that Tm is toxic for CD patients as judged on histological and serological criteria, but it was well tolerated by the majority of patients, suggesting that Tm is not a safe cereal for celiacs, but that it may be of value for patients with gluten sensitivity or for prevention of CD.
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Search for atoxic cereals: a single blind, cross-over study on the safety of a single dose of Triticum monococcum, in patients with celiac disease.
Zanini, B, Petroboni, B, Not, T, Di Toro, N, Villanacci, V, Lanzarotto, F, Pogna, N, Ricci, C, Lanzini, A
BMC gastroenterology. 2013;13:92
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Plain language summary
The only current treatment for coeliac disease (CD) is lifelong adherence to a gluten free diet (GFD). As many CD patients report this to be difficult, alternatives for a baking-quality wheat that does not contain gluten are sought. Triticum monococcum (TM) is an ancient wheat that has shown potential to be a non-toxic gluten alternative for patients with CD. The aim of this study was to assess the safety of TM administration in patients with CD. 12 CD patients who have followed a gluten free diet for at least one year and were challenged with rice, gluten or TM, and followed for four weeks. The findings of this study showed that the safety of TM administration is inconclusive, though well tolerated by all patients. The authors encourage further investigation on this cereal as a harmless gluten alternative for CD patients.
Abstract
BACKGROUND Cereals of baking quality with absent or reduced toxicity are actively sought as alternative therapy to a gluten-free diet (GFD) for patients with coeliac disease (CD). Triticum monococcum, an ancient wheat, is a potential candidate having no toxicity in in-vitro and ex-vivo studies. The aim of our study was to investigate on the safety of administration of a single dose of gluten of Tm in patients with CD on GFD. METHODS We performed a single blind, cross-over study involving 12 CD patients who had been on a GFD for at least 12 months, challenged on day 0, 14 and 28 with a single fixed dose of 2.5 grams of the following (random order): Tm, rice (as reference atoxic protein) and Amygluten (as reference toxic protein) dispersed in a gluten-free pudding. The primary end-point of the study was the change in intestinal permeability, as assessed by changes in the urinary lactulose/rhamnose ratio (L/R ratio) measured by High Pressure Liquid Chromatography. We also assessed the occurrence of adverse gastrointestinal events, graded for intensity and duration according to the WHO scale. Variables were expressed as mean ± SD; paired t-test and χ² test were used as appropriate. RESULTS The urinary L/R ratio did not change significantly upon challenge with the 3 cereals, and was 0.055 ± 0.026 for Tm Vs 0.058 ± 0.035 for rice (p = 0.6736) and Vs 0.063 ± 0.054 with Amygluten (p = 0.6071). Adverse gastrointestinal events were 8 for Tm, Vs 11 for rice (p = 0.6321) and Vs 31 for Amygluten p = 0.0016), and, in all cases events were graded as "mild" or "moderate" with TM and rice, and as "severe" or "disabling" in 4 cases during Amygluten. CONCLUSIONS No definite conclusion can be drawn on the safety of Tm, based on no change in urinary L/R because even Amygluten, a toxic wheat protein, did not cause a significant change in urinary L/R indicating low sensitivity of this methodology in studies on acute toxicity. Tm was, however, well tolerated by all patients providing the rationale for further investigation on the safety of this cereal for CD patients. TRIAL REGISTRATION EudraCT-AIFA n2008-000697-20.
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Abnormal anandamide metabolism in celiac disease.
Battista, N, Di Sabatino, A, Di Tommaso, M, Biancheri, P, Rapino, C, Vidali, F, Papadia, C, Montana, C, Pasini, A, Lanzini, A, et al
The Journal of nutritional biochemistry. 2012;(10):1245-8
Abstract
The endocannabinoid system has been extensively investigated in experimental colitis and inflammatory bowel disease, but not in celiac disease, where only a single study showed increased levels of the major endocannabinoid anandamide in the atrophic mucosa. On this basis, we aimed to investigate anandamide metabolism in celiac disease by analyzing transcript levels (through quantitative real-time reverse transcriptase-polymerase chain reaction), protein concentration (through immunoblotting) and activity (through radioassays) of enzymes responsible for anandamide synthesis (N-acylphosphatidyl-ethanolamine specific phospholipase D, NAPE-PLD) and degradation (fatty acid amide hydrolase, FAAH) in the duodenal mucosa of untreated celiac patients, celiac patients on a gluten-free diet for at least 12 months and control subjects. Also, treated celiac biopsies cultured ex vivo with peptic-tryptic digest of gliadin were investigated. Our in vivo experiments showed that mucosal NAPE-PLD expression and activity are higher in untreated celiac patients than treated celiac patients and controls, with no significant difference between the latter two groups. In keeping with the in vivo data, the ex vivo activity of NAPE-PLD was significantly enhanced by incubation of peptic-tryptic digest of gliadin with treated celiac biopsies. On the contrary, in vivo mucosal FAAH expression and activity did not change in the three groups of patients, and accordingly, mucosal FAAH activity was not influenced by treatment with peptic-tryptic digest of gliadin. In conclusion, our findings provide a possible pathophysiological explanation for the increased anandamide concentration previously shown in active celiac mucosa.
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Slow gallbladder emptying reverts to normal but small intestinal transit of a physiological meal remains slow in celiac patients during gluten-free diet.
Benini, F, Mora, A, Turini, D, Bertolazzi, S, Lanzarotto, F, Ricci, C, Villanacci, V, Barbara, G, Stanghellini, V, Lanzini, A
Neurogastroenterology and motility. 2012;(2):100-7, e79-80
Abstract
BACKGROUND Alterations of small intestinal transit and gallbladder (GB) motility have been reported in celiac disease (CD) in studies involving, in most cases, non-physiological experimental conditions and artificial stimuli to motility. Our aims were to quantitate non-invasively small intestinal transit time and GB emptying during administration of a physiological and palatable solid meal, and to assess the effect of gluten-free diet (GFD). METHODS We simultaneously measured mouth-to-cecum transit time (MCTT) using a validated H(2) breath test, and GB motility using ultrasonography. We studied CD patients before (n = 19) and during (n = 14) GFD, and healthy volunteers (n = 24) following administration of a physiological solid meal (Kcal 539). KEY RESULTS Mouth-to-cecum transit time was more prolonged in CD (mean ± SEM: 235 ± 96 min) than in controls (169 ± 65 min, P = 0.0039). The GB fasting volume and postprandial residual volume were significantly higher in CD than in controls, and GB emptying constant was slower in CD than in controls. During GFD, GB emptying reverted to normal, but MCTT remained unchanged (229 ± 69 min) and more prolonged in CD than in controls (P = 0.0139). During GFD, duodenal infiltration with lymphocytes and mast cells persisted higher than that in controls, and the number of mast cells lying in proximity of nervous endings did not change. CONCLUSIONS & INFERENCES Slow postprandial MCTT in response to a physiological meal does not revert to normal during GFD, an effect mirroring incomplete histopathologic recovery.
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Gastroesophageal reflux disease and Barrett's esophagus.
Vaira, D, Gatta, L, Ricci, C, Castelli, V, Fiorini, G, Kajo, E, Lanzini, A
Internal and emergency medicine. 2011;(4):299-306
Abstract
Gastroesophageal reflux disease is the most common gastrointestinal diagnosis recorded during visits to outpatient clinics. The spectrum of injury includes esophagitis, stricture, the development of columnar metaplasia in place of the normal squamous epithelium (Barrett's esophagus), and adenocarcinoma. Barrett's esophagus is a premalignant lesion detected in the majority of patients with esophageal and gastroesophageal adenocarcinoma. The incidence of these cancers has been increasing in the United States and they are associated with a low rate of survival (5-year survival rate, 15-20%). When symptoms of gastroesophageal reflux disease are typical and the patient responds to therapy, no diagnostic tests are necessary to verify the diagnosis. Endoscopy is the primary test in patients whose condition is resistant to empirical therapy but its yield in this setting is low because of the poor correlation between symptoms attributed to the condition and endoscopic features of the disease. Clinical experience suggests that lifestyle modifications may be beneficial for gastroesophageal reflux disease although trials of the clinical efficacy of dietary or behavioral changes are lacking. Abundant data from randomized trials show benefits of inhibiting gastric acid secretion and suggest that proton-pump inhibitors are superior to H2-blockers and that both are superior to placebo. In patients with Barrett's esophagus, antireflux interventions are intended to control symptoms of reflux and promote healing of the esophageal mucosa. If a patient has symptoms refractory to proton-pump inhibitors or cannot tolerate such therapy, antireflux surgery, most commonly Nissen fundoplication, may be an alternative management approach. In patients with high-grade dysplasia, endoscopic therapies or surgical resection must be considered.
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Ursodeoxycholic acid does not affect ethinylestradiol bioavailability in women taking oral contraceptives.
Baisini, O, Benini, F, Petraglia, F, Kuhnz, W, Scalia, S, Marschall, HU, Brunetti, G, Tauschel, HD, Lanzini, A
European journal of clinical pharmacology. 2004;(7):481-7
Abstract
OBJECTIVE Contraception is recommended for female patients during ursodeoxycholic acid (UDCA) treatment for the potential teratogenic effect of this bile acid, and the aim of our study was to determine whether this treatment affects the bioavailability of ethinylestradiol (EE2). METHODS In this double-blind, randomised study, we measured EE2 pharmacokinetics in eight healthy volunteers randomly allocated to receive oral contraceptive (30 microg EE2 and 75 microg gestodene) plus either UDCA (8-10 mg/kg per day) or placebo for 21 days during the first of three consecutive menstrual cycles. After a washout period during the second cycle, the subjects received the alternative treatment during the third menstrual cycle. Serum EE2 and UDCA were measured using radioimmunoassay and gas chromatography-mass spectrometry, respectively. RESULTS The profile for serum EE2 concentration was similar during UDCA (mean maximum serum concentration 177 pg/ml, SEM 59) and during placebo treatment (153 pg/ml, SEM 62), and mean area under the curve (AUC) was 1374 pg/h per ml (SEM 580) and 1320 pg/h per ml (SEM 551) during the two regimens, respectively. The point estimates and 90% confidence intervals of UDCA/placebo ratios for EE2 AUC and for maximum serum concentration were 1.1 (0.8-1.5) and 1.2 (1.0-1.4), respectively. Mean serum triglycerides concentration increased from 58.3 mg/dl (SEM 6.8) at enrolment to 91.4 mg/dl (SEM 10.7) during placebo (P < 0.01) and to 88.6 mg/dl (SEM 13.7) during UDCA treatment (P < 0.05). During UDCA treatment, serum enrichment with this bile acid and with the metabolite iso-UDCA was 29% (16%) and 3% (2%), respectively. CONCLUSION Co-administration with UDCA does not affect the bioavailability of EE2 in healthy volunteers, indicating that contraceptive efficacy is not affected.
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Ursodeoxycholic acid alone or with chenodeoxycholic acid for dissolution of cholesterol gallstones: a randomized multicentre trial. The British-Italian Gallstone Study group.
Petroni, ML, Jazrawi, RP, Pazzi, P, Lanzini, A, Zuin, M, Pigozzi, MG, Fracchia, M, Galatola, G, Alvisi, V, Heaton, KW, et al
Alimentary pharmacology & therapeutics. 2001;(1):123-8
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BACKGROUND Combination therapy using ursodeoxycholic acid plus chenodeoxycholic acid has been advocated for dissolution of cholesterol gallstones because the two bile acids have complementary effects on biliary lipid metabolism and cholesterol solubilization. AIM: To compare the clinical efficacy of combination therapy with ursodeoxycholic acid monotherapy. PATIENTS AND METHODS A total of 154 symptomatic patients with radiolucent stones (< or = 15 mm) in functioning gallbladders were enrolled from six centres in England and Italy. They were randomized to either a combination of chenodeoxycholic acid plus ursodeoxycholic acid (5 mg.day/kg each) or to ursodeoxycholic acid alone (10 mg.day/kg). Dissolution was assessed by 6-monthly oral cholecystography and ultrasonography for up to 24 months. RESULTS Both regimens reduced the frequency of biliary pain and there was no significant difference between them in terms of side-effects or dropout rate. Complete gallstone dissolution on an intention-to-treat basis was similar at all time intervals. At 24 months this was 28% with ursodeoxycholic acid alone and 30% with combination therapy. The mean dissolution rates at 6 and 12 months were 47% and 59% with ursodeoxycholic acid, and 44% and 59% with combination therapy, respectively. CONCLUSION There is no substantial difference in the efficacy of combined ursodeoxycholic acid and chenodeoxycholic acid and that of ursodeoxycholic acid alone in terms of gallstone dissolution rate, complete gallstone dissolution, or relief of biliary pain.