Murray, Joseph A.

ABSTRACTObjectives:Guidelines for diagnosing celiac disease (CD) recommend initial testing with a highly sensitive serologic test for anti–tissue transglutaminase immunoglobulin A antibodies (tTG IgA). When the probability of CD is high, IgA deficiency should be considered. The 2 approaches to address this include measuring “both tTG IgA and tTG IgG” or measuring “total IgA.” We aim to assess the utility of an isolated positive tTG IgG result in diagnosing CD.Methods:We conducted a retrospective review of patients undergoing serologic testing for CD from January 1997 to June 2014. Patients with positive tTG IgG and negative tTG IgA were included. Moreover, all patients who had any other positive CD‐specific serologic findings were excluded. Demographics, clinical presentation, tests, and biopsy results were recorded.Results:The indication for checking celiac serology was gastrointestinal symptoms in 172 of 233 patients, iron deficiency anemia in 12, and high‐risk screening in 48. Small bowel biopsy was performed in 178 patients (77%); 160 had normal results and 18 had histologic changes suggestive of enteropathy. Nine patients had increased intraepithelial lymphocytes, and 9 had partial villous atrophy. Only 6 cases of CD were, however, confirmed. The utility of isolated tTG IgG in diagnosis of CD was low at 3% (6/178).Conclusion:In this cohort of patients, the utility of isolated tTG IgG in diagnosing CD was low at 3%.

SummaryBackgroundRefractory coeliac disease is a severe complication of coeliac disease with heterogeneous outcome.AimTo create a prognostic model to estimate survival of patients with refractory coeliac disease.MethodsWe evaluated predictors of 5‐year mortality using Cox proportional hazards regression on subjects from a multinational registry. Bootstrap resampling was used to internally validate the individual factors and overall model performance. The mean of the estimated regression coefficients from 400 bootstrap models was used to derive a risk score for 5‐year mortality.ResultsThe multinational cohort was composed of 232 patients diagnosed with refractory coeliac disease across seven centres (range of 11–63 cases per centre). The median age was 53 years and 150 (64%) were women. A total of 51 subjects died during a 5‐year follow‐up (cumulative 5‐year all‐cause mortality = 30%). From a multiple variable Cox proportional hazards model, the following variables were significantly associated with 5‐year mortality: age at refractory coeliac disease diagnosis (per 20 year increase, hazard ratio = 2.21; 95% confidence interval, CI: 1.38–3.55), abnormal intraepithelial lymphocytes (hazard ratio = 2.85; 95% CI: 1.22–6.62), and albumin (per 0.5 unit increase, hazard ratio = 0.72; 95% CI: 0.61–0.85). A simple weighted three‐factor risk score was created to estimate 5‐year survival.ConclusionsUsing data from a multinational registry and previously reported risk factors, we create a prognostic model to predict 5‐year mortality among patients with refractory coeliac disease. This new model may help clinicians to guide treatment and follow‐up.

Prior studies in with irritable bowel syndrome with diarrhea (IBS-D) patients showed immune activation, secretion, and barrier dysfunction in jejunal or colorectal mucosa. We measured mRNA expression by RT-PCR of 91 genes reflecting tight junction proteins, chemokines, innate immunity, ion channels, transmitters, housekeeping genes, and controls for DNA contamination and PCR efficiency in small intestinal mucosa from 15 IBS-D and 7 controls (biopsies negative for celiac disease). Fold change was calculated using 2(−ΔΔCT) formula. Nominal P values ( P < 0.05) were interpreted with false detection rate (FDR) correction ( q value). Cluster analysis with Lens for Enrichment and Network Studies (LENS) explored connectivity of mechanisms. Upregulated genes (uncorrected P < 0.05) were related to ion transport (INADL, MAGI1, and SONS1), barrier (TJP1, 2, and 3 and CLDN) or immune functions (TLR3, IL15, and MAPKAPK5), or histamine metabolism (HNMT); downregulated genes were related to immune function (IL-1β, TGF-β1, and CCL20) or antigen detection (TLR1 and 8). The following genes were significantly upregulated ( q < 0.05) in IBS-D: INADL, MAGI1, PPP2R5C, MAPKAPK5, TLR3, and IL-15. Among the 14 nominally upregulated genes, there was clustering of barrier and PDZ domains (TJP1, TJP2, TJP3, CLDN4, INADL, and MAGI1) and clustering of downregulated genes (CCL20, TLR1, IL1B, and TLR8). Protein expression of PPP2R5C in nuclear lysates was greater in patients with IBS-D and controls. There was increase in INADL protein (median 9.4 ng/ml) in patients with IBS-D relative to controls (median 5.8 ng/ml, P > 0.05). In conclusion, altered transcriptome (and to lesser extent protein) expression of ion transport, barrier, immune, and mast cell mechanisms in small bowel may reflect different alterations in function and deserves further study in IBS-D.

Background Environmental enteric dysfunction (EED) is an asymptomatic intestinal disorder affecting populations living in conditions of poor sanitation and hygiene. The study tested intestinal barrier function in infants with EED. Methods We prospectively studied an advanced high-performance liquid chromatography mass spectrometry assay of urine collected after oral intake of the monosaccharide, L-rhamnose and the disaccharide, lactulose, in 112 children from three continents. Findings Compared to the US cohort (n=27), the cohorts of children from Peru (n=19) and Zambia (n=85) were older with evidence of growth impairment. The median (range) of age (months) was 8.0 (2.0 to 13.0), 27.0 (15.0 to 29.0) and 21.0 (12.0 to 36.0), respectively. The median (range) of height for age Z score was −0.1 (−1.8 to 2.4), −1.8 (−3.3 to −0.2) and −2.3 (−8.5 to 1.2), respectively. Among children with valid sugar data (n=22 USA, n=19 Peru, n=73 Zambia), there were no significant differences in the median rhamnose urine concentrations between the three groups. The median (range) lactulose concentration (µg/mL) was 6.78 (0.29 to 31.90), 47.60 (4.23 to 379.00) and 75.40 (0.67 to 873.00) in the US, Peruvian and Zambian cohorts, respectively (p<0.001). The lactulose/rhamnose ratio (LRR) was higher in cohorts from Peru (0.75, 0.15, 5.02) and Zambia (2.26, 0.08, 14.48) compared to the US (0.14, 0.06, 1.00) cohort (p<0.001). In a multivariate effect modification model, higher weight-for-age z scores were associated with lower post-dose lactulose when rhamnose excretion was constant (p=0.003). Conclusions This non-invasive two saccharide permeability protocol measures changes in intestinal permeability in children with EED and permits the identification of individuals for interventional trials.

ObjectiveThe gut microbiome regulates host immune homeostasis. Rheumatoid arthritis (RA) is associated with intestinal dysbiosis. This study was undertaken to test the ability of a human gut‐derived commensal to modulate immune response and treat arthritis in a humanized mouse model.MethodsWe isolated a commensal bacterium, Prevotella histicola, that is native to the human gut and has systemic immune effects when administered enterally. Arthritis‐susceptible HLA–DQ8 mice were immunized with type II collagen and treated with P histicola. Disease incidence, onset, and severity were monitored. Changes in gut epithelial proteins and immune response as well as systemic cellular and humoral immune responses were studied in treated mice.ResultsWhen treated with P histicola in prophylactic or therapeutic protocols, DQ8 mice exhibited significantly decreased incidence and severity of arthritis compared to controls. The microbial mucosal modulation of arthritis was dependent on regulation by CD103+ dendritic cells and myeloid suppressors (CD11b+Gr‐1+ cells) and by generation of Treg cells (CD4+CD25+FoxP3+) in the gut, resulting in suppression of antigen‐specific Th17 responses and increased transcription of interleukin‐10. Treatment with P histicola led to reduced intestinal permeability by increasing expression of enzymes that produce antimicrobial peptides as well as tight junction proteins (zonula occludens 1 and occludin). However, the innate immune response via Toll‐like receptor 4 (TLR‐4) and TLR‐9 was not affected in treated mice.ConclusionOur results demonstrate that enteral exposure to P histicola suppresses arthritis via mucosal regulation. P histicola is a unique commensal that can be explored as a novel therapy for RA and may have few or no side effects.

Summary Background Patients with Crohn's disease ( CD ) have serologic responses to various microbial antigens. Serologic markers are associated with aggressive forms of disease and can be detected before onset of symptoms. Their utility in pre‐clinical disease or prediction of complicated disease course before diagnosis is unclear. Aim To evaluate the pattern of serologic anti‐microbial antibodies long prior to diagnosis and the subsequent risk of complicated Crohn's disease at diagnosis. Methods Sera from 100 US military personnel with Crohn's disease were obtained from the Department of Defense Serum Repository. For each patient, four samples were obtained at different time points before and around diagnosis, and were tested for 6 microbiota‐directed antibodies ( ASCA ‐IgA, ASCA ‐IgG, anti‐OmpC, anti‐ CB ir1, anti‐A4‐Fla2 and anti‐FlaX). Associations between the presence and accumulation of Crohn's disease anti‐microbial antibodies before diagnosis and with the later development of complications were evaluated. Results Overall, 65 patients were positive for at least one Crohn's disease associated anti‐microbial antibody in the earliest available sample, at a median of 6 years before Crohn's disease diagnosis (interquartile range, 5.6–8.2). The number of positive anti‐microbial antibodies increased up to the time of Crohn's disease diagnosis. Complicated disease developed around the time of diagnosis in 24 patients. The proportion of positive antimicrobial antibodies before diagnosis was higher in patients with complicated vs. noncomplicated Crohn's disease. There was an inverse relationship between the time to first complication and the magnitude of serologic response before diagnosis. Conclusion The presence and accumulation of circulating anti‐microbial antibodies years before Crohn's disease diagnosis was associated with complicated Crohn's disease at or shortly after diagnosis.

The process of transition from childhood to adulthood is characterised by physical, mental and psychosocial development. Data on the transition and transfer of care in adolescents/young adults with coeliac disease (CD) are scarce. In this paper, 17 physicians from 10 countries (Sweden, Italy, the USA, Germany, Norway, the Netherlands, Australia, Britain, Israel and Denmark) and two representatives from patient organisations (Association of European Coeliac Societies and the US Celiac Disease Foundation) examined the literature on transition from childhood to adulthood in CD. Medline (Ovid) and EMBASE were searched between 1900 and September 2015. Evidence in retrieved reports was evaluated using the Grading of Recommendation Assessment, Development and Evaluation method. The current consensus report aims to help healthcare personnel manage CD in the adolescent and young adult and provide optimal care and transition into adult healthcare for patients with this disease. In adolescence, patients with CD should gradually assume exclusive responsibility for their care, although parental support is still important. Dietary adherence and consequences of non-adherence should be discussed during transition. In most adolescents and young adults, routine small intestinal biopsy is not needed to reconfirm a childhood diagnosis of CD based on European Society for Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) or North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) criteria, but a biopsy may be considered where paediatric diagnostic criteria have not been fulfilled, such as, in a patient without biopsy at diagnosis, additional serology (endomysium antibody) has not been performed to confirm 10-fold positivity of tissue transglutaminase antibodies or when a no biopsy strategy has been adopted in an asymptomatic child.

Celiac disease (CD) is a common chronic immune disease triggered by gluten. Gliadin peptides pass through the epithelial layers, either paracellularly or transcellularly, to launch a potent adaptive immune response in the lamina propria. This aberrant immune response leads to diverse gastrointestinal and extra-gastrointestinal symptoms. Currently, the only treatment for CD is a strict lifelong adherence to a gluten-free diet (GFD), which can be challenging. An early effect of gluten in CD is an increase in gut permeability. Larazotide acetate, also known as AT-1001, is a synthetic peptide developed as a permeability regulator primarily targeting CD. In vitro studies indicate that larazotide acetate is capable of inhibiting the actin rearrangement caused by gliadin and clinical studies have been conducted using this peptide as a therapy for CD.