Reduced infant rhesus macaque growth rates due to environmental enteric dysfunction and association with histopathology in the large intestine

Environmental enteric dysfunction is associated with malnutrition as well as infant growth stunting and has been classically defined by villous blunting, decreased crypt-to-villus ratio, and inflammation in the small intestine. Here, we characterized environmental enteric dysfunction among infant rhesus macaques that are naturally exposed to enteric pathogens commonly linked to human growth stunting. Remarkably, despite villous atrophy and histological abnormalities observed in the small intestine, poor growth trajectories and low serum tryptophan levels were correlated with increased histopathology in the large intestine. This work provides insight into the mechanisms underlying this disease and indicates that the large intestine may be an important target for therapeutic intervention.

Celiac Disease After Administration of Immune Checkpoint Inhibitors: A Case Report

Immune checkpoint inhibitors (ICI) reinvigorate the immune system to recognize and destroy tumor cells. Because of this biological mechanism, patients might develop autoimmune toxicities, notably in the digestive tract (most frequently, hepatitis or colitis). A 70-year-old man with relapsed mesothelioma was treated with nivolumab in 3rd line. He was hospitalized for watery and foul-smelling diarrhea. He underwent gastrointestinal endoscopy, showing duodenitis and villous atrophy and measurement of serum IgA antibodies to tissue transglutaminase (tTG-IgA+), leading to the diagnosis of ICI-induced celiac disease. He was treated with steroids, proton pump inhibitors, and a gluten-free diet. If ICI-induced celiac disease is rare in the literature, increasing reports suggest that celiac disease might represent an underestimated ICI toxicity. This case highlights the necessity of complementary investigation (including tTG-IgA and endoscopic biopsies) in patients with atypical digestive symptoms during immunotherapy.

Association between Endoscopic Findings Vs. Serology Findings of Patients with Suspected Celiac Disease

Objective: To determine the association between endoscopic findings vs. serology findings of patients with suspected celiac disease Methods: All the suspected cases (based on their clinical manifestations) of celiac disease were initially recruited having age >14 years and <40 years of both gender. Patients who did not willing to participate, patients already taking gluten diet for more than 3 months, patients with other causes of chronic diarrhea and alternate diagnosis like thyrotoxicosis, whipple’s disease, giardiasis, patients with drug induced diarrhea, patients in whom we cannot perform endoscopy, pregnant women, and patients already diagnosed cases of celiac disease were excluded from this study. Celiac disease was confirmed based on positive anti-tTG antibodies. Endoscopic evaluation of duodenum was performed in all positive cases. Results: A total of 50 patients were recruited for final analysis. Diagnostic accuracy of endoscopy was 34.6%. Young population (31.14±6.07 years) with females predominance (72%, n=36) were more common than males. The most common symptoms were presence of chronic diarrhea (74%, n=37) followed by abdominal pain (52%, n=26), nausea & vomiting (34%, n=17), and least common was presence of constipation (2%, n=1). On endoscopic evaluation, out of 50 positive anti-tTG antibodies cases, 24 had normal mucosa while partial villous atrophy observed in 15 (30%) cases and total villous atrophy observed in 11 cases (22%). Conclusions: Celiac disease was more prevalent in young females and patients usually presents with history of chronic diarrhea. Anti-tTG antibodies have more diagnostic value than duodenal endoscopy. Villous atrophy was found in more than 50% of the patients who were diagnosed with celiac disease.

Intestinal Cellular Biomarkers of Mucosal Lesion Progression in Pediatric Celiac Disease

Celiac disease (CD) is a chronic intestinal inflammation caused by gluten ingestion in genetically predisposed individuals. Overt-CD and potential-CD are the two main forms of gluten intolerance in pediatric patients with different grades of intestinal mucosa lesion and clinical management. For overt-CD patients the gluten-free diet is mandatory, while for potential-CD the dietary therapy is recommended only for those subjects becoming clinically symptomatic overtime. To date, specific early biomarkers of evolution to villous atrophy in potential-CD are lacking. We recently observed an expansion of TCRγδ+ T cells and a concomitant disappearance of IL4-producing T cells in the intestinal mucosa of overt-CD patients compared to potential-CD children, suggesting the involvement of these two cells subsets in the transition from potential-CD to overt-CD. In this study, we demonstrated that the intestinal densities of IL4+ T cells inversely correlated with TCRγδ+ T cell expansion (p < 0.005) and with the serum levels of anti-tissue transglutaminase antibodies (p < 0.01). The changes of these two cell subsets strongly correlated with mucosal lesions, according to the histological Marsh classification, as the transition from M0 to M3 lesions was associated with a significant reduction of IL4+ T cells (M0 vs. M1 p < 0.04, M0 vs. M3 p < 0.007) and an increase of TCRγδ+ T cells (M0 vs. M1 p < 0.05, M0 vs. M3 p < 0.0006). These findings strongly suggest that the detection of TCRγδ+ and IL4+ T cells could serve as cellular biomarkers of mucosal lesion and targets of novel immunomodulatory therapies for CD.

The Role of the Gluten-Free Diet in the Management of Seronegative Enteropathy

The differential diagnosis and treatment of seronegative enteropathy, also termed seronegative villous atrophy (SNVA), is a clinical challenge. Although seronegative coeliac disease (CD) is a frequent cause of SNVA, the aetiology can include immune-mediated, inflammatory, infectious, and drug-related forms. As a misdiagnosis of SNVA can result in patients being unnecessarily placed on a lifelong strict gluten-free diet or even given incorrect immunosuppressive therapy, the aim of this paper is to provide an evidence-based and practical approach for the workup and management of SNVA.

May Antitransglutaminase Levels Predict Severity of Duodenal Lesions in Adults with Celiac Disease?

Background and Objective: Pediatric guidelines on celiac disease (CD) state that children with anti-transglutaminase antibodies (TGAs) >×10 upper limit of normal (ULN) may avoid endoscopy and biopsy. We aimed to evaluate whether these criteria may be suitable for villous atrophy diagnosis in CD adults. Materials and Methods: We retrospectively enrolled patients with CD aged >18 years. TGAs were expressed as xULN. Duodenal lesions were classified as atrophic or non-atrophic according to Marsh-Oberhuber. Fisher’s exact and t-test were used for variables comparison. Receiver operating characteristics (ROC) curve analysis was performed with estimation of area under the curve (AUC), sensitivity, specificity, and positive and negative predictive value (PPV/NPV). Results: One hundred and twenty-one patients were recruited. Sixty patients (49.6%) had TGA >×10 ULN, and 93 (76.8%) had villous atrophy. The cut-off of >×10 ULN had sensitivity = 53.7%, specificity = 64.3%, PPV = 83.3%, and NPV = 29.5% to predict atrophy. Therefore, considering pediatric criteria, in 50 (41.3%) patients, biopsy could have been avoided. Patient subgroup with atrophy had higher TGA levels despite being not significant (37.2 ± 15.3 vs. 8.0 ± 1.3 ULN, p = 0.06). In adults, a slightly better diagnostic performance was obtained using a cut-off of TGA >×6.2 ULN (sensitivity = 57.1%, specificity = 65.6%, and AUC = 0.62). Conclusions: Despite our confirmation that villous atrophy is linked to high TGA levels, CD and atrophy diagnosis based only on serology is not reliable in adults.

Enteropathies with villous atrophy but negative coeliac serology in adults: current issues

ObjectiveThe differential diagnosis and management of seronegative enteropathies is challenging due to the rarity of these conditions, the overlap of clinical and histopathological features and the current lack of an international consensus on their nomenclature.DesignThis is a narrative review providing pragmatic guide on the investigation and clinical management of seronegative enteropathies in adults based on the available literature and our clinical experience.ConclusionsSeronegative coeliac disease is the most frequent cause among the heterogeneous group of seronegative enteropathies and its diagnosis is confirmed by the clinical and histological response to a gluten-free diet after the exclusion of other causes of villous atrophy. Correct identification and targeted management of seronegative enteropathies is mandatory because of the variation in terms of clinical outcomes and prognosis.

A Combined mRNA- and miRNA-Sequencing Approach Reveals miRNAs as Potential Regulators of the Small Intestinal Transcriptome in Celiac Disease

Celiac disease (CeD) is triggered by gluten and results in inflammation and villous atrophy of the small intestine. We aimed to explore the role of miRNA-mediated deregulation of the transcriptome in CeD. Duodenal biopsies of CeD patients (n = 33) and control subjects (n = 10) were available for miRNA-sequencing, with RNA-sequencing also available for controls (n = 5) and CeD (n = 6). Differential expression analysis was performed to select CeD-associated miRNAs and genes. MiRNA‒target transcript pairs selected from public databases that also displayed a strong negative expression correlation in the current dataset (R < −0.7) were used to construct a CeD miRNA‒target transcript interaction network. The network includes 2030 miRNA‒target transcript interactions, including 423 experimentally validated pairs. Pathway analysis found that interactions are involved in immune-related pathways (e.g., interferon signaling) and metabolic pathways (e.g., lipid metabolism). The network includes 13 genes previously prioritized to be causally deregulated by CeD-associated genomic variants, including STAT1. CeD-associated miRNAs might play a role in promoting inflammation and decreasing lipid metabolism in the small intestine, thereby contributing unbalanced cell turnover in the intestinal crypt. Some CeD-associated miRNAs deregulate genes that are also affected by genomic CeD-risk variants, adding an additional layer of complexity to the deregulated transcriptome in CeD.

Molecular Detection and Phylogenetic Analysis of Chicken Astrovirus Associated with Poultry Enteritis

Background: Poultry enteritis is an important multifactorial disease. Chicken Astrovirus (CAstV) usually associated with enteritis. The aim of this study was to investigate the occurrence of CAstV in poultry enteritis cases, its molecular characterization, phylogenetic analysis and gross and microscopic examination of intestine and liver specimen affected with CAstV. Methods: Total 604 dead poultry birds from commercial poultry farms affected with enteritis were examined for presence of CAstV. Intestinal samples of four birds were pooled to make one biological sample. CAstV was detected by reverse transcriptase PCR (RT-PCR) using ORF-1b gene specific primers. Molecular characterization was carried out by partial gene sequencing. Result: CAstV was detected in 20.52% (31/151) of samples. Highest prevalence (49.29%) was observed in 0-1 week old chicks. The partial molecular characterization revealed high similarity of the nucleotide sequence from India (97% to 93%) and from USA, Brazil, Poland and Korea (94 to 92%). Further similarity of amino acid sequences of CAstV from India (100% to 98%) and from USA, Brazil, Poland and Korea (98 to 97%) was observed. Histopathological examination revealed villous atrophy, congestion and atrophic cystic glands in sub-mucosa of intestine. Further severe congestion and hemorrhages along with infiltration of inflammatory cells in liver parenchyma was observed.