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Background: Primary sclerosing cholangitis (PSC) is a progressive bile duct disease associated with inflammatory bowel disease (PSC-IBD)., Aim: To investigate whether patients with PSC-IBD benefit from a gluten-free and amylase trypsin inhibitor (ATI)-free diet (GFD)., Methods: We performed a prospective clinical pilot study administering an eight-week GFD. The primary outcomes were colonic inflammation assessed by proctosigmoidoscopy, and liver stiffness (surrogate for fibrosis, inflammation and cholestasis) measured by transient elastography before and after GFD. Amongst the secondary (exploratory) outcomes were colonic mucosal and serum cytokine/chemokine changes, the intestinal microbiome and transcriptome dynamics, and shifts in serum markers of hepatic fibrogenesis., Results: Fifteen patients with PSC-IBD completed the study. The study did not meet its primary outcome: the endoscopic score and liver stiffness remained unchanged. However, the expression of pro-inflammatory mucosal cytokines and chemokines such as IL6, IL8, CCL2, and TNFα was significantly down-regulated. Two critical markers of liver fibrosis and matrix remodelling, thrombospondin-2 and -4, decreased significantly. The microbiota composition changed slightly, including a decrease in the pathogen Romboutsia ilealis. The intestinal transcriptome indicated a gut barrier improvement. Pruritus, fatigue, overall well-being, faecal calprotectin levels, and serum alkaline phosphatase did not change significantly., Conclusions: This study did not demonstrate a clinical improvement with short-term GFD in patients with PSC-IBD. However, a gluten/ATI-free diet may improve biomarkers of intestinal inflammation and barrier function in these patients with associated changes in the enteric microbiota. Further investigation of the therapeutic potential of the GFD in PSC-IBD is warranted., (© 2022 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

Background: The role of microRNAs (miRNAs) in celiac disease (CD) is unclear., Aims: We evaluated inflammation-related miRNA-146a, miRNA-155, miRNA-21, and miRNA-125b expression in peripheral blood and intestinal mucosa of CD adults., Methods: Thirty patients with CD were included: patients with active CD on a gluten-containing diet (CD-active, n = 10), patients on a gluten-free diet (for at least 1 year), and patients with negative blood antibodies (CD-inactive PE , n = 10). In addition, ten healthy volunteers formed the comparison/control group. MiRNA expression was measured in duodenal biopsies from patients (CD-inactive MU , n = 10) after in vitro exposure to PT gliadin and 33-mer peptide. MiRNAs expression was measured in plasma and in peripheral blood mononuclear cells (PBMCs) and monocytes, before and after in vitro exposure to native gliadin (gliadin N )., Results: Expression levels of miRNA-146a, miRNA-155, and miRNA-21 in PBMCs, miRNA-155 in monocytes and miRNA-155, miRNA-21, and miRNA-125b in plasma were elevated in both groups of celiac patients. After in vitro exposure with gliadin N , miRNA-146a and miRNA-155 expression markedly increased in PBMCs and monocytes, while miRNA-155 and miRNA-21 increased in the CD-active group. MiRNAs expression in intestinal mucosa did not change. MiRNA-146a and miRNA-155 expression showed high sensitivity and specificity for the presence of CD, irrespective of the current dietary treatment., Conclusions: Selected inflammation-related miRNAs expression is elevated in the peripheral blood of celiac. This suggests their participation in the immune processes underlying the pathology. Their similar response in active and inactive CD suggests that they should be further evaluated, as potential diagnostic biomarkers for CD.

We have identified a clinical association between self-reported non-celiac wheat sensitivity (NCWS) and Familial Mediterranean Fever (FMF). Objectives: A) To determine whether a 2-week double-blind placebo-controlled (DBPC) cross-over wheat vs. rice challenge exacerbates the clinical manifestations of FMF; B) to evaluate innate immune responses in NCWS/FMF patients challenged with wheat vs. rice. The study was conducted at the Department of Internal Medicine of the University Hospital of Palermo and the Hospital of Sciacca, Italy. Six female volunteers with FMF/NCWS (mean age 36 ± 6 years) were enrolled, 12 age-matched non-FMF, NCWS females, and 8 sex- and age-matched healthy subjects served as controls. We evaluated: 1. clinical symptoms by the FMF-specific AIDAI (Auto-Inflammatory Diseases Activity Index) score; 2. serum soluble CD14 (sCD14), C-reactive protein (CRP), and serum amyloid A (SSA); 3. circulating CD14 + monocytes expressing interleukin (IL)-1β and tumor necrosis factor (TNF)-α. The AIDAI score significantly increased in FMF patients during DBPC with wheat, but not with rice (19 ± 6.3 vs. 7 ± 1.6; p = 0.028). sCD14 values did not differ in FMF patients before and after the challenge, but were higher in FMF patients than in healthy controls (median values 11357 vs. 8710 pg/ml; p = 0.002). The percentage of circulating CD14 + /IL-1β + and of CD14 + /TNF-α + monocytes increased significantly after DBPC with wheat vs. baseline or rice challenge. Self-reported NCWS can hide an FMF diagnosis. Wheat ingestion exacerbated clinical and immunological features of FMF. Future studies performed on consecutive FMF patients recruited in centers for auto-inflammatory diseases will determine the real frequency and relevance of this association.

Celiac disease (CD) is the most common autoimmune enteropathy worldwide. In CD, dietary gluten triggers a T cell driven small intestinal inflammation in a subset of genetically predisposed subjects, expressing the HLA DQ2 and/or DQ8 genes on their antigen presenting cells. HLA DQ2/DQ8 can bind gluten peptides after their prior modification by the CD autoantigen, tissue transglutaminase (TG2). This process leads to the activation of gluten reactive T cells, small bowel villous atrophy, crypt hyperplasia and intraepithelial lymphocytosis, the histological hallmarks of CD. The clinical picture of CD is extremely heterogeneous including intestinal (especially diarrhea, abdominal pain, bloating) and extraintestinal (especially associated autoimmune diseases, anemia, osteoporosis) manifestations. The prevalence of CD in most parts of the world is estimated at 1:100-1:150 and its diagnosis is based on the presence of circulating autoantibodies (anti-TG2) and the histological detection of villous atrophy. Treatment is a lifelong gluten free diet but adjunctive therapies are in development. Although CD is a well-characterized disease, it is grossly underdiagnosed, despite the severe consequences of long-term gluten ingestion in CD, such as enhanced autoimmunity, refractory CD and intestinal T cell lymphoma. The aim of the presented review is to provide a clinical guide and to summarize the most recent clinical progress in CD research., (Copyright © 2018 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.)

Background: Gliadins are involved in gluten-related disorders and are responsible for the alteration of the cellular redox balance. It is not clear if the gliadin-related oxidative stress can induce DNA damage in enterocytes., Aim: To investigate any possible genotoxicity caused by gliadin and to assess its relationship with oxidative stress in vitro and ex vivo., Methods: Caco-2 cells were exposed for 6-12-24 h to increasing concentrations (250 μg/mL-1000 μg/mL) of digested gliadin. We investigated: cytotoxicity, oxidative balance (reactive oxygen species, ROS), DNA damage (comet assay and γ-H2AX detection), transglutaminase type 2 (TG2) activity and annexin V expression. H2AX and 8-OHG immunohistochemistry has been evaluated on duodenal biopsies of celiac subjects and controls., Results: Gliadin induced a significant increase (+50%) of ROS after 12 h of exposition starting with a 500 μg/mL dose of gliadin. Comet assay and γ-H2AX demonstrated DNA damage, evident at the gliadin concentration of 500 μg/mL after 24 h. TG2 activity increased in chromatin and cytoskeleton cellular compartments at different gliadin doses (250/500/1000 μg/mL). The γ-H2AX and 8-OHG immunohistochemistry was altered in the duodenal biopsies of celiac patients., Conclusions: Gliadin induces cellular oxidative stress, DNA damage and pro-apoptotic stimulation in Caco-2 cells and in the duodenal mucosa of celiac patients., (Copyright © 2018 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Introduction: High levels of reactive oxygen species (ROS) and impaired antioxidant defense systems lead to oxidative stress (OxS) and tissue injury in different intestinal and extra intestinal conditions, including celiac disease (CD). The aim of the present study was to investigate the role and potential use of ROS and other biomarkers of OxS in the clinical management of CD., Methods: We collected duodenal specimens and blood samples from naïve patients (N-CD), patients on a gluten free diet (GFD) including responders (CD-GFD) and non-responders (NRCD). We measured plasmatic ROS production (electron paramagnetic resonance, EPR), lipid peroxidation (thiobarbituric acid-reactive substances, TBARS), protein oxidation (protein carbonyl, PC), total antioxidant capacity (TAC), nitric oxides and glutathione (GSH) in erythrocytes., Results: Fifty-four patients affected by CD were enrolled (17 N-CD, 18 CD-GFD and 19 NRCD; 44 F; age 44 ± 13 years). A significant increase of plasmatic OxS biomarkers (ROS, peroxidated lipids, oxidized proteins, and nitrate concentrations) and decrease of antioxidant species (TAC and GSH levels) were found in NRCD and N-CD compared to CD-GFD. Comparably, a significant direct relationship between the severity of duodenal atrophy, ROS production rates and TBARS was found; conversely, TAC and GSH presented an inverse correlation., Discussion: OxS is involved in CD tissue damage and correlates with the degree of duodenal atrophy. These findings suggest the possible role of OxS biomarkers as indicators of CD activity during the clinical follow-up.

Background: Spinal muscular atrophy (SMA) is an autosomal recessive motor neuron disease caused by mutations in the survival motor neuron gene (SMN1) and the leading genetic cause of infant mortality. Currently, there is no effective treatment other than supportive care., Objective: This article provides a general overview of the main aspects that need to be taken into account to design a more efficient clinical trial and to summarize the most promising molecular trials that are currently in development or are being planned for the treatment of SMA., Methods: A systematic review of the literature was performed, identifying key clinical trials involving novel molecular therapies in SMA. In addition, abstracts presented at the meetings of the Families of Spinal Muscular Atrophy were searched and the Families of Spinal Muscular Atrophy Web site was carefully analyzed. Finally, a selection of SMA clinical trials registered at clinical-trials.gov has been included in the article., Results: The past decade has seen a marked advancement in the understanding of both SMA genetics and molecular mechanisms. New molecules targeting SMN have shown promise in preclinical studies, and various clinical trials have started to test the drugs that were discovered through basic research., Conclusions: Both preclinical and early clinical trial results involving novel molecular therapies suggest that the clinical care paradigm in SMA will soon change., (© 2014 Elsevier HS Journals, Inc. All rights reserved.)