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Transglutaminase 2 (TG2) plays a pivotal role in the pathogenesis of celiac disease (CeD) by deamidating dietary gluten peptides, which facilitates antigenic presentation and a strong anti-gluten T cell response. Here, we elucidate the molecular mechanisms underlying the efficacy of the TG2 inhibitor ZED1227 by performing transcriptional analysis of duodenal biopsies from individuals with CeD on a long-term gluten-free diet before and after a 6-week gluten challenge combined with 100 mg per day ZED1227 or placebo. At the transcriptome level, orally administered ZED1227 effectively prevented gluten-induced intestinal damage and inflammation, providing molecular-level evidence that TG2 inhibition is an effective strategy for treating CeD. ZED1227 treatment preserved transcriptome signatures associated with mucosal morphology, inflammation, cell differentiation and nutrient absorption to the level of the gluten-free diet group. Nearly half of the gluten-induced gene expression changes in CeD were associated with the epithelial interferon-γ response. Moreover, data suggest that deamidated gluten-induced adaptive immunity is a sufficient step to set the stage for CeD pathogenesis. Our results, with the limited sample size, also suggest that individuals with CeD might benefit from an HLA-DQ2 / HLA-DQ8 stratification based on gene doses to maximally eliminate the interferon-γ-induced mucosal damage triggered by gluten. Viiri and colleagues show that an orally administered transglutaminase 2 inhibitor prevented gluten-induced intestinal damage and inflammation at the transcriptional level.

ObjectiveType 1 diabetes (T1D) is characterised by islet autoimmunity and beta cell destruction. A gut microbiota–immunological interplay is involved in the pathophysiology of T1D. We studied microbiota-mediated effects on disease progression in patients with type 1 diabetes using faecal microbiota transplantation (FMT).DesignPatients with recent-onset (<6 weeks) T1D (18–30 years of age) were randomised into two groups to receive three autologous or allogenic (healthy donor) FMTs over a period of 4 months. Our primary endpoint was preservation of stimulated C peptide release assessed by mixed-meal tests during 12 months. Secondary outcome parameters were changes in glycaemic control, fasting plasma metabolites, T cell autoimmunity, small intestinal gene expression profile and intestinal microbiota composition.ResultsStimulated C peptide levels were significantly preserved in the autologous FMT group (n=10 subjects) compared with healthy donor FMT group (n=10 subjects) at 12 months. Small intestinal Prevotella was inversely related to residual beta cell function (r=−0.55, p=0.02), whereas plasma metabolites 1-arachidonoyl-GPC and 1-myristoyl-2-arachidonoyl-GPC levels linearly correlated with residual beta cell preservation (rho=0.56, p=0.01 and rho=0.46, p=0.042, respectively). Finally, baseline CD4 +CXCR3+T cell counts, levels of small intestinal Desulfovibrio piger and CCL22 and CCL5 gene expression in duodenal biopsies predicted preserved beta cell function following FMT irrespective of donor characteristics.ConclusionFMT halts decline in endogenous insulin production in recently diagnosed patients with T1D in 12 months after disease onset. Several microbiota-derived plasma metabolites and bacterial strains were linked to preserved residual beta cell function. This study provides insight into the role of the intestinal gut microbiome in T1D.Trial registration numberNTR3697.

Emerging data increasingly point towards the duodenum as a key region underlying the pathophysiology of functional dyspepsia (FD), one of the most prevalent functional GI disorders. The duodenum plays a major role in the control and coordination of gastroduodenal function. Impaired duodenal mucosal integrity and low-grade inflammation have been associated with altered neuronal signalling and systemic immune activation, and these alterations may ultimately lead to dyspeptic symptoms. Likely luminal candidates inducing the duodenal barrier defect include acid, bile, the microbiota and food antigens although no causal association with symptoms has been convincingly demonstrated. Recognition of duodenal pathology in FD will hopefully lead to the discovery of new biomarkers and therapeutic targets, allowing biologically targeted rather than symptom-based therapy. In this review, we summarise the recent advances in the diagnosis and treatment of FD with a focus on the duodenum.

Background: Intestinal exposure to gliadin leads to zonulin upregulation and consequent disassembly of intercellular tight junctions and increased intestinal permeability. We aimed to study response to gliadin exposure, in terms of barrier function and cytokine secretion, using intestinal biopsies obtained from four groups: celiac patients with active disease (ACD), celiac patients in remission (RCD), non-celiac patients with gluten sensitivity (GS) and non-celiac controls (NC). Methods: Ex-vivo human duodenal biopsies were mounted in microsnapwells and luminally incubated with either gliadin or media alone. Changes in transepithelial electrical resistance were monitored over 120 min. Media was subsequently collected and cytokines quantified. Results: Intestinal explants from all groups (ACD (n = 6), RCD (n = 6), GS (n = 6), and NC (n = 5)) demonstrated a greater increase in permeability when exposed to gliadin vs. media alone. The increase in permeability in the ACD group was greater than in the RCD and NC groups. There was a greater increase in permeability in the GS group compared to the RCD group. There was no difference in permeability between the ACD and GS groups, between the RCD and NC groups, or between the NC and GS groups. IL-10 was significantly greater in the media of the NC group compared to the RCD and GS groups. Conclusions: Increased intestinal permeability after gliadin exposure occurs in all individuals. Following gliadin exposure, both patients with gluten sensitivity and those with active celiac disease demonstrate a greater increase in intestinal permeability than celiacs in disease remission. A higher concentration of IL-10 was measured in the media exposed to control explants compared to celiac disease in remission or gluten sensitivity.

Tissue maintenance and repair depend on the integrated activity of multiple cell types 1 . Whereas the contributions of epithelial 2 , 3 , immune 4 , 5 and stromal cells 6 , 7 in intestinal tissue integrity are well understood, the role of intrinsic neuroglia networks remains largely unknown. Here we uncover important roles of enteric glial cells (EGCs) in intestinal homeostasis, immunity and tissue repair. We demonstrate that infection of mice with Heligmosomoides polygyrus leads to enteric gliosis and the upregulation of an interferon gamma (IFNγ) gene signature. IFNγ-dependent gene modules were also induced in EGCs from patients with inflammatory bowel disease 8 . Single-cell transcriptomics analysis of the tunica muscularis showed that glia-specific abrogation of IFNγ signalling leads to tissue-wide activation of pro-inflammatory transcriptional programs. Furthermore, disruption of the IFNγ–EGC signalling axis enhanced the inflammatory and granulomatous response of the tunica muscularis to helminths. Mechanistically, we show that the upregulation of Cxcl10 is an early immediate response of EGCs to IFNγ signalling and provide evidence that this chemokine and the downstream amplification of IFNγ signalling in the tunica muscularis are required for a measured inflammatory response to helminths and resolution of the granulomatous pathology. Our study demonstrates that IFNγ signalling in enteric glia is central to intestinal homeostasis and reveals critical roles of the IFNγ–EGC–CXCL10 axis in immune response and tissue repair after infectious challenge. Enteric glial cells have tissue-wide immunoregulatory roles through the upregulation of IFNγ-dependent genes both at steady state and after parasite infection, promoting immune homeostasis and CXCL10-mediated tissue repair after pathogen-induced intestinal damage in mice.

The objective of this study was to determine whether constipation-predominant irritable bowel syndrome (IBS-C) is associated with changes in intestinal barrier and secretory function. A total of 19 IBS-C patients and 18 healthy volunteers (all females) underwent saccharide excretion assay (0.1 g C mannitol and 1 g lactulose), measurements of duodenal and colonic mucosal barrier (transmucosal resistance (TMR), macromolecular and Escherichia coli Bio-Particle translocation), mucosal secretion (basal and acetylcholine (Ach)-evoked short-circuit current (Isc)), in vivo duodenal mucosal impedance, circulating endotoxins, and colonic tight junction gene expression. There were no differences in the in vivo measurements of barrier function between IBS-C patients and healthy controls: cumulative excretion of C mannitol (0-2 h mean (s.e.m.); IBS-C: 12.1 (0.9) mg vs. healthy: 13.2 (0.8) mg) and lactulose (8-24 h; IBS-C: 0.9 (0.5) mg vs. healthy: 0.5 (0.2) mg); duodenal impedance IBS-C: 729 (65) Ω vs. healthy: 706 (43) Ω; plasma mean endotoxin activity level IBS-C: 0.36 (0.03) vs. healthy: 0.35 (0.02); and in colonic mRNA expression of occludin, zonula occludens (ZO) 1-3, and claudins 1-12 and 14-19. The ex vivo findings were consistent, with no group differences: duodenal TMR (IBS-C: 28.2 (1.9) Ω cm vs. healthy: 29.8 (1.9) Ω cm ) and colonic TMR (IBS-C: 19.1 (1.1) Ω cm vs. healthy: 17.6 (1.7) Ω cm ); fluorescein isothiocyanate (FITC)-dextran (4 kDa) and E. coli Bio-Particle flux. Colonic basal Isc was similar, but duodenal basal Isc was lower in IBS-C (43.5 (4.5) μA cm ) vs. healthy (56.9 (4.9) μA cm ), P=0.05. Ach-evoked ΔIsc was similar. Females with IBS-C have normal colonic barrier and secretory function. Basal duodenal secretion is decreased in IBS-C.

Aims/hypothesis Metformin lowers postprandial glycaemic excursions in individuals with type 2 diabetes by modulating gastrointestinal function, including the stimulation of glucagon-like peptide-1 (GLP-1). The impact of varying the timing of metformin administration on postprandial glucose metabolism is poorly defined. We evaluated the effects of metformin, administered at different intervals before an intraduodenal glucose infusion, on the subsequent glycaemic, insulinaemic and GLP-1 responses in metformin-treated type 2 diabetes. Methods Sixteen participants with type 2 diabetes that was relatively well-controlled by metformin monotherapy were studied on four separate days in a crossover design. On each day, participants were randomised to receive a bolus infusion of metformin (1000 mg in 50 ml 0.9% saline) via a nasoduodenal catheter at t = −60, −30 or 0 min (and saline at the other timepoints) or saline at all timepoints (control), followed by an intraduodenal glucose infusion of 12.56 kJ/min (3 kcal/min) at t = 0–60 min. The treatments were blinded to both participants and investigators involved in the study procedures. Plasma glucose, insulin and total GLP-1 levels were measured every 30 min between t = −60 min and t = 120 min. Results There was a treatment-by-time interaction for metformin in reducing plasma glucose levels and increasing plasma GLP-1 and insulin levels ( p <0.05 for each). The reduction in plasma glucose levels was greater when metformin was administered at t = −60 or −30 min vs t = 0 min ( p <0.05 for each), and the increases in plasma GLP-1 levels were evident only when metformin was administered at t = −60 or −30 min ( p <0.05 for each). Although metformin did not influence insulin sensitivity, it enhanced glucose-induced insulin secretion ( p <0.05), and the increases in plasma insulin levels were comparable on the 3 days when metformin was given. Conclusions/interpretation In well-controlled metformin-treated type 2 diabetes, glucose-lowering by metformin is greater when it is given before, rather than with, enteral glucose, and this is associated with a greater GLP-1 response. These observations suggest that administration of metformin before meals may optimise its effect in improving postprandial glycaemic control. Trial registration www.anzctr.org.au ACTRN12621000878875 Funding The study was not funded by a specific research grant. Graphical Abstract

ObjectiveThe intestinal immune response could play an important role in obesity-related comorbidities. We aim to study the profile of duodenal cytokines and chemokines in patients with morbid obesity (MO), its relation with insulin resistance (IR) and the intake of metformin, and with the evolution of MO after sleeve gastrectomy (SG).Research design and methodsDuodenal levels of 24 cytokines and 9 chemokines were analyzed in 14 nonobese and in 54 MO who underwent SG: with lower IR (MO-lower-IR), with higher IR (MO-higher-IR), and with type 2 diabetes treated with metformin (MO-metf-T2DM).ResultsMO-lower-IR had higher levels of cytokines related to Th1, Th2, Th9, Th17, Th22, M1 macrophages, and chemokines involved in the recruitment of macrophages and T-lymphocytes (p < 0.05), and total (CD68 expression) and M1 macrophages (ITGAX expression) (p < 0.05) when compared with nonobese patients, but with a decrease in M2 macrophages (MRC1 expression) (p < 0.05). In MO-higher-IR, these chemokines and cytokines decreased and were similar to those found in nonobese patients. In MO-metf-T2DM, only IL-4 (Th2) and IL-22 (Th22) increased their levels with regard to MO-higher-IR (p < 0.05). In MO-higher-IR and MO-metf-T2DM, there was a decrease of CD68 expression (p < 0.05) while ITGAX and MRC1 were similar with regard to MO-lower-IR. We found an association between CXCL8, TNFβ and IL-2 with the evolution of body mass index (BMI) after SG (p < 0.05).ConclusionsThere is an association between a higher IR and a lower duodenal immune response in MO, with a slight increase in those patients with metformin treatment. Intestinal immune response could be involved in the evolution of BMI after SG.

Microbe-host interactions are generally homeostatic, but when dysfunctional, they canincite food sensitivities and chronic diseases. Celiac disease (CeD) is a food sensitivitycharacterized by a breakdown of oral tolerance to gluten proteins in genetically predisposedindividuals, although the underlying mechanisms are incompletely understood. Here weshow that duodenal biopsies from patients with active CeD have increased proteolyticactivity against gluten substrates that correlates with increased Proteobacteria abundance,includingPseudomonas. UsingPseudomonas aeruginosaproducing elastase as a model, weshow gluten-independent, PAR-2 mediated upregulation of inflammatory pathways inC57BL/6 mice without villus blunting. In mice expressing CeD risk genes,P. aeruginosaelastase synergizes with gluten to induce more severe inflammation that is associated withmoderate villus blunting. These results demonstrate that proteases expressed by opportu-nistic pathogens impact host immune responses that are relevant to the development of food sensitivities, independently of the trigger antigen.

In a phase 2 proof-of-concept trial, patients with celiac disease controlled on a gluten-free diet were assigned to one of three dose levels of ZED1227 (a selective transglutaminase 2 inhibitor) or placebo. Patients were challenged with 3 g of gluten daily for 6 weeks. Comparison of duodenal-biopsy samples between baseline and 6 weeks showed that ZED1227 attenuated gluten-induced mucosal damage.