Microbiome signatures of progression toward celiac disease onset in at-risk children in a longitudinal prospective cohort study.

Other than exposure to gluten and genetic compatibility, the gut microbiome has been suggested to be involved in celiac disease (CD) pathogenesis by mediating interactions between gluten/environmental factors and the host immune system. However, to establish disease progression markers, it is essential to assess alterations in the gut microbiota before disease onset. Here, a prospective metagenomic analysis of the gut microbiota of infants at risk of CD was done to track shifts in the microbiota before CD development. We performed cross-sectional and longitudinal analyses of gut microbiota, functional pathways, and metabolites, starting from 18 mo before CD onset, in 10 infants who developed CD and 10 matched nonaffected infants. Cross-sectional analysis at CD onset identified altered abundance of six microbial strains and several metabolites between cases and controls but no change in microbial species or pathway abundance. Conversely, results of longitudinal analysis revealed several microbial species/strains/pathways/metabolites occurring in increased abundance and detected before CD onset. These had previously been linked to autoimmune and inflammatory conditions (e.g., Dialister invisus, Parabacteroides sp., Lachnospiraceae, tryptophan metabolism, and metabolites serine and threonine). Others occurred in decreased abundance before CD onset and are known to have anti-inflammatory effects (e.g., Streptococcus thermophilus, Faecalibacterium prausnitzii, and Clostridium clostridioforme). Additionally, we uncovered previously unreported microbes/pathways/metabolites (e.g., Porphyromonas sp., high mannose-type N-glycan biosynthesis, and serine) that point to CD-specific biomarkers. Our study establishes a road map for prospective longitudinal study designs to better understand the role of gut microbiota in disease pathogenesis and therapeutic targets to reestablish tolerance and/or prevent autoimmunity.

Pediatric Nonceliac Gluten Sensitivity: A Gluten-related Disorder Treatment Center Experience.

OBJECTIVE: The aim of the study was to identify the prevalence and clinical characteristics of children with nonceliac gluten sensitivity (NCGS) presenting to a tertiary care center specialized for evaluation of gluten-related disorders. METHODS: The medical records of all patients aged 0 to 18 years who presented to our center over a 4-year period (July 2013-June 2018) and consented to participate in our research registry were reviewed. Patients meeting the clinical criteria for NCGS were reviewed in detail. RESULTS: Among 500 pediatric patients who volunteered to participate in the registry during the study period, we identified 26 (5.2%) with NCGS. Both gastrointestinal and extraintestinal symptoms associated with gluten ingestion were common with abdominal pain (57.7%), bloating (53.9%), rash (53.9%), diarrhea/loose stool (42.3%), and emotional/behavioral issues (42.3%) emerging as the predominant complaints. In addition, children with NCGS demonstrated a high personal history (61.5%) and family history (61.5%) of concomitant allergic/atopic disease. CONCLUSIONS: Even within our highly specialized population of patients with a suspected gluten-related disorder, pediatric NCGS is relatively uncommon. The estimated prevalence and clinical features mirror those previously reported in a similarly highly selective population of adults. In the absence of celiac disease, clinical suspicion for NCGS should arise in a child with gastrointestinal and/or extraintestinal complaints alleviated with gluten removal and considered in symptomatic patients with associated allergic/atopic disease. Proper and adequate exclusion of celiac disease and other potential causes of the clinical complaints is essential to justify adoption of the gluten-free diet according to an appropriate stringency and with dietitian supervision to avoid nutritional deficiencies.

Effect of transcutaneous auricular vagus nerve stimulation on impaired glucose tolerance: a pilot randomized study.

BACKGROUND: Impaired glucose tolerance (IGT) is a pre-diabetic state of hyperglycemia that is associated with insulin resistance, increased risk of type II diabetes, and cardiovascular pathology. Recently, investigators hypothesized that decreased vagus nerve activity may be the underlying mechanism of metabolic syndrome including obesity, elevated glucose levels, and high blood pressure. METHODS: In this pilot randomized clinical trial, we compared the efficacy of transcutaneous auricular vagus nerve stimulation (taVNS) and sham taVNS on patients with IGT. 72 participants with IGT were single-blinded and were randomly allocated by computer-generated envelope to either taVNS or sham taVNS treatment groups. In addition, 30 IGT adults were recruited as a control population and not assigned treatment so as to monitor the natural fluctuation of glucose tolerance in IGT patients. All treatments were self-administered by the patients at home after training at the hospital. Patients were instructed to fill in a patient diary booklet each day to describe any side effects after each treatment. The treatment period was 12 weeks in duration. Baseline comparison between treatment and control group showed no difference in weight, BMI, or measures of systolic blood pressure, diastolic blood pressure, fasting plasma glucose (FPG), 2-hour plasma glucose (2hPG), or glycosylated hemoglobin (HbAlc). RESULTS: 100 participants completed the study and were included in data analysis. Two female patients (one in the taVNS group, one in the sham taVNS group) dropped out of the study due to stimulation-evoked dizziness. The symptoms were relieved after stopping treatment. Compared with sham taVNS, taVNS significantly reduced the two-hour glucose tolerance (F(2) = 5.79, p = 0.004). In addition, we found that taVNS significantly decreased (F(1) = 4.21, p = 0.044) systolic blood pressure over time compared with sham taVNS. Compared with the no-treatment control group, patients receiving taVNS significantly differed in measures of FPG (F(2) = 10.62, p < 0.001), 2hPG F(2) = 25.18, p < 0.001) and HbAlc (F(1) = 12.79, p = 0.001) over the course of the 12 week treatment period. CONCLUSIONS: Our study suggests that taVNS is a promising, simple, and cost-effective treatment for IGT/ pre-diabetes with only slight risk of mild side-effects.

An Adolescent with Undiagnosed Ulcerative Colitis Presenting with Toxic Megacolon and Cavitary Pulmonary Nodules.

Toxic megacolon and pulmonary nodules are not seen frequently on diagnosis in pediatric ulcerative colitis patients. This report emphasizes the importance of carefully evaluating and managing complications in pediatric ulcerative colitis cases, especially in the presence of pulmonary nodules.

Pre-clerkship Pediatric Exposure Enhances Understanding of Social Determinants of Health.

The Child and Adolescent Motivation and Enrichment Program (CHAMP), an initiative pairing pre-clerkship medical students with pediatric patients undergoing hemodialysis (HD), provides support to HD patients while also providing medical students with opportunities to increase their comfort in the clinical environment and awareness of social determinants of health (SDH). SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40670-021-01329-4.

A Medical Student Initiative to Enhance the Pediatric Hemodialysis Experience.

BACKGROUND: Children and young adults receiving hemodialysis (HD) face unique challenges including frequent school absenteeism, psychosocial issues, and social isolation, placing them at risk for decreased academic achievement and health literacy. OBJECTIVE: To address this, we implemented the Child and Adolescent Motivation and Enrichment Program (CHAMP) at Holtz Children's Hospital in Miami, FL. The objective of this study is to describe the organizational structure and program design of CHAMP and provide preliminary program opinions. METHODS: Medical students served as longitudinal one-on-one mentors to patients receiving HD. Face-to-face intervention, books, board games, and electronic tablets were used to enhance patients' educational and recreational experience. We surveyed participating patients, medical students, and unit nurses regarding their opinions of CHAMP. KEY RESULTS: Patients responded to a series of questions on a Likert scale scored from 1 to 5 and reported the highest scores on questions pertaining to having fun with mentors (mean = 4.88), enjoying mentor visits (mean = 4.78), and learning during visits (mean = 3.88). Mentors reported the highest level of agreement (mean = 4.82) that CHAMP helped them gain empathy for patients with chronic and/or special health care needs. Nurses scored highly on the point that "overall, the program was useful and helped the patient" (mean = 6.86 of a possible 7). CONCLUSION: CHAMP is an academic and psychosocial enrichment program for children and adolescents receiving HD. The program is regarded highly by participating patients, medical students, and unit nurses. Patients report enjoying and learning from mentor sessions, whereas nurses report improved interactions with patients. Medical students who participate as mentors also gain important exposure to the field of pediatric nephrology. The program design as described herein positions CHAMP for replication at academic medical centers nationwide, allowing for optimization of the health and well-being of the pediatric HD population. [HLRP: Health Literacy Research and Practice. 2021;5(1):e60-e69.] Plain Language Summary: Pediatric patients undergoing hemodialysis (HD) are at risk for decreased academic achievement and health literacy. To address this, we implemented the Child and Adolescent Motivation and Enrichment Program, a longitudinal mentorship program pairing medical students as one-on-one mentors to patients undergoing HD. Preliminary results from this program demonstrate satisfaction and enjoyment by participating patients, medical students, and dialysis unit nurses.

Long-term Persistence of Allosensitization After Islet Allograft Failure.

BACKGROUND: Allosensitization has been reported after discontinuation of immunosuppression following graft failure in islet transplantation (ITx) recipients, though duration of its persistence is unknown. METHODS: We evaluated 35 patients with type 1 diabetes who received ITx, including 17 who developed graft failure (ITx alone, n = 13; ITx plus bone marrow-derived hematopoietic stem cells, n = 4) and 18 with persistent graft function. Panel-reactive antibody (PRA) was measured yearly for the duration of graft function within 1 y after graft failure at enrollment and yearly thereafter. RESULTS: In ITx alone graft failure patients, 61% (8/13) were PRA-positive at 6 y postgraft failure, and 46% (6/13) developed donor-specific anti-HLA antibodies (DSA to 2 ± 1 donors) during follow-up. The degree of sensitization was variable (cPRA ranging between 22% and 100% after graft failure). Allosensitization persisted for 7-15 y. Three subjects (3/13) were not allosensitized. In ITx plus bone marrow-derived hematopoietic stem cell recipients, cPRA-positivity (88%-98%) and DSA positivity persisted for 15 y in 75% (3/4) of subjects. CONCLUSIONS: Allosensitization was minimal while subjects remained on immunosuppression, but after discontinuation of immunosuppressive therapy, the majority of subjects (77%) became allosensitized with persistence of PRA positivity for up to 15 y. Persistence of allosensitization in this patient population is of clinical importance as it may result in longer transplant waiting list times for identification of a suitable donor in the case of requiring a subsequent transplant.

Pediatric Eye Care: We Cannot Lose Sight of Its Importance despite the COVID-19 Pandemic.

Visual impairment affects over 19 million children globally and, if left untreated, can result in significant ocular morbidity. Due to the treatable nature of many childhood visual disturbances, pediatric vision screening is essential for optimization of health and developmental outcomes. The coronavirus disease 2019 (COVID-19) pandemic has inevitably disrupted the provision of routine pediatric health care as evidenced by reduced adherence to vaccination schedules. Further, the home environment, which many children have now become confined to, is known to pose risk for eye trauma which may result in irreversible vision loss. Therefore, it is imperative for pediatricians and pediatric ophthalmologists to focus on eye health and safety, despite the backdrop of a global pandemic.

Telehealth Training Is Essential to Care for Underserved Populations: a Medical Student Perspective.

Telehealth is an area of medicine which has magnified the ability to treat patients remotely. Presently the education of medical professionals pertaining to the value, use, and implementation of telehealth is not adequate to harness the potential of available technologies. Patients engaging in telehealth experience time and cost savings, improved disease management through remote monitoring programs, and high-quality care regardless of geographic location. Despite this, medical education has been slow to evolve. It is therefore imperative that medical curricula incorporate training for this rapidly advancing mode of healthcare delivery to enable students to best care for their future patient population.

Impact of the coronavirus pandemic on pediatric eye-related emergency department services.

Literature describing the trends and utilization of pediatric eye-related emergency department (ED) visits is limited. We performed a retrospective cohort study of 311 pediatric patients visiting Bascom Palmer Eye Institute (BPEI) ED between March and May 2020 to quantify the effect of the coronavirus (COVID-19) on ophthalmology care utilization. In our study, pediatric ED visits declined by half at the onset of the pandemic in March. The number of visits reached the lowest point in early April and increased to 48% of the pre-COVID volume by the end of May. Despite changes in volume, patient demographics and clinical diagnoses were relatively consistent throughout the pandemic.

Multi-omics analysis reveals the influence of genetic and environmental risk factors on developing gut microbiota in infants at risk of celiac disease.

BACKGROUND: Celiac disease (CD) is an autoimmune digestive disorder that occurs in genetically susceptible individuals in response to ingesting gluten, a protein found in wheat, rye, and barley. Research shows that genetic predisposition and exposure to gluten are necessary but not sufficient to trigger the development of CD. This suggests that exposure to other environmental stimuli early in life, e.g., cesarean section delivery and exposure to antibiotics or formula feeding, may also play a key role in CD pathogenesis through yet unknown mechanisms. Here, we use multi-omics analysis to investigate how genetic and early environmental risk factors alter the development of the gut microbiota in infants at risk of CD. RESULTS: Toward this end, we selected 31 infants from a large-scale prospective birth cohort study of infants with a first-degree relative with CD. We then performed rigorous multivariate association, cross-sectional, and longitudinal analyses using metagenomic and metabolomic data collected at birth, 3 months and 6 months of age to explore the impact of genetic predisposition and environmental risk factors on the gut microbiota composition, function, and metabolome prior to the introduction of trigger (gluten). These analyses revealed several microbial species, functional pathways, and metabolites that are associated with each genetic and environmental risk factor or that are differentially abundant between environmentally exposed and non-exposed infants or between time points. Among our significant findings, we found that cesarean section delivery is associated with a decreased abundance of Bacteroides vulgatus and Bacteroides dorei and of folate biosynthesis pathway and with an increased abundance of hydroxyphenylacetic acid, alterations that are implicated in immune system dysfunction and inflammatory conditions. Additionally, longitudinal analysis revealed that, in infants not exposed to any environmental risk factor, the abundances of Bacteroides uniformis and of metabolite 3-3-hydroxyphenylproprionic acid increase over time, while those for lipoic acid and methane metabolism pathways decrease, patterns that are linked to beneficial immunomodulatory and anti-inflammatory effects. CONCLUSIONS: Overall, our study provides unprecedented insights into major taxonomic and functional shifts in the developing gut microbiota of infants at risk of CD linking genetic and environmental risk factors to detrimental immunomodulatory and inflammatory effects. Video Abstract.

Targeted genotyping for the prediction of celiac disease autoimmunity development in patients with type 1 diabetes and their family members.

BACKGROUND: Patients with type 1 diabetes (T1D) and their first-degree relatives (FDRs) have an increased risk of developing celiac disease (CD) compared to the general population. This is largely explained by the shared association with major histocompatibility class II human leukocyte antigen (HLA) DQ2 and/or DQ8 between the two disease states. AIM: To describe the frequency of CD autoimmunity (CDA) and the distribution of HLA and haptoglobin genotypes in patients with T1D and their FDRs. Additionally, we aimed at identifying predictors associated with an increased risk of developing CDA in patients with T1D and their family members. METHODS: We obtained clinical information and blood samples from 1027 participants (302 with T1D and 725 FDRs) over a five-year period. Samples were tested for autoantibodies associated with CD, HLA-DQ alleles, and haptoglobin genotype. We fit univariate and multiple logistic regression models for CDA separately for subjects with T1D and for FDRs of subjects with T1D. RESULTS: Implementation of a screening program increased the frequency of CDA by 2-fold in participants with T1D and 2.8-fold in their FDRs. Multivariate analysis found that, in participants with T1D, having both DR7-DQ2 and DR4-DQ8 was associated with an increased frequency of CDA. In FDRs of T1D patients, reported CD in the family was associated with an increased frequency of CDA during screening. Haptoglobin 2 genotype was not associated with developing CDA in the multivariate analysis. CONCLUSION: Patients with T1D and their FDRs have a high frequency of CDA. Carrying both DR7-DQ2 and DR4-DQ8 was associated with development of CDA in patients with T1D.

RNA sequencing of intestinal mucosa reveals novel pathways functionally linked to celiac disease pathogenesis.

BACKGROUND & AIMS: The early steps in the pathophysiology of celiac disease (CD) leading to loss of tolerance to gluten are poorly described. Our aim was to use RNA sequencing of duodenal biopsies in patients with active CD, CD in remission, and non-CD controls to gain insight into CD pathophysiology, identify additional genetic signatures linked to CD, and possibly uncover targets for future therapeutic agents. METHODS: We performed whole transcriptome shotgun sequencing of intestinal biopsies in subjects with active and remission CD and non-CD controls. We also performed functional pathway analysis of differentially expressed genes to identify statistically significant pathways that are up or down regulated in subjects with active CD compared to remission CD. RESULTS: We identified the upregulation of novel genes including IL12R, ITGAM and IGSF4 involved in the immune response machinery and cell adhesion process in the mucosa of subjects with active CD compared to those in remission. We identified a unique signature of genes, related to innate immunity, perturbed exclusively in CD irrespective of disease status. Finally, we highlight novel pathways of interest that may contribute to the early steps of CD pathogenesis and its comorbidities such as the spliceosome, pathways related to the innate immune response, and pathways related to autoimmunity. CONCLUSIONS: Our study confirmed previous findings based on GWAS and immunological studies pertinent to CD pathogenesis and describes novel genes and pathways that with further validation may be found to contribute to the early steps in the pathogenesis of CD, ongoing inflammation, and comorbidities associated with CD.

[Design of a genomic, environmental, microbial and metabolomic study on celiac disease: an approach to the future of personalized prevention of celiac disease]. / Disegno dello studio genomico, ambientale, microbiomico e metabolomico sulla celiachia: un approccio al futuro della prevenzione personalizzata della celiachia.

Over recent years we have seen rising many clinical and scientific innovations about celiac disease (CE), however the most important innovation that will contribute to change the future of the research and clinic in this field is the natural history of the disease. For many years it has been though that a genetic predisposition and the exposure to gluten were necessary and sufficient to develop CE. Recent studies, however, suggest that the loss of tolerance to gluten may occur in any moment of life upon certain conditions. Furthermore, several environmental factors known to play a role in shaping the intestinal microflora have also been considered related to the development of CE. Delivery mode, the infant diet and the use of antibiotics are included among these factors. To this day no large scale studies have determined if and how the microbiome composition and its metabolomic profile may influence the loss of tolerance to gluten and the consequent development of CE. In this paper we describe a prospective, multi-centric and longitudinal study on infants at risk for CE that will use different techniques to better understand the role of the microbome during the first steps in the development of the autoimmune disease.

Blood-brain barrier and intestinal epithelial barrier alterations in autism spectrum disorders.

BACKGROUND: Autism spectrum disorders (ASD) are complex conditions whose pathogenesis may be attributed to gene-environment interactions. There are no definitive mechanisms explaining how environmental triggers can lead to ASD although the involvement of inflammation and immunity has been suggested. Inappropriate antigen trafficking through an impaired intestinal barrier, followed by passage of these antigens or immune-activated complexes through a permissive blood-brain barrier (BBB), can be part of the chain of events leading to these disorders. Our goal was to investigate whether an altered BBB and gut permeability is part of the pathophysiology of ASD. METHODS: Postmortem cerebral cortex and cerebellum tissues from ASD, schizophrenia (SCZ), and healthy subjects (HC) and duodenal biopsies from ASD and HC were analyzed for gene and protein expression profiles. Tight junctions and other key molecules associated with the neurovascular unit integrity and function and neuroinflammation were investigated. RESULTS: Claudin (CLDN)-5 and -12 were increased in the ASD cortex and cerebellum. CLDN-3, tricellulin, and MMP-9 were higher in the ASD cortex. IL-8, tPA, and IBA-1 were downregulated in SCZ cortex; IL-1b was increased in the SCZ cerebellum. Differences between SCZ and ASD were observed for most of the genes analyzed in both brain areas. CLDN-5 protein was increased in ASD cortex and cerebellum, while CLDN-12 appeared reduced in both ASD and SCZ cortexes. In the intestine, 75% of the ASD samples analyzed had reduced expression of barrier-forming TJ components (CLDN-1, OCLN, TRIC), whereas 66% had increased pore-forming CLDNs (CLDN-2, -10, -15) compared to controls. CONCLUSIONS: In the ASD brain, there is an altered expression of genes associated with BBB integrity coupled with increased neuroinflammation and possibly impaired gut barrier integrity. While these findings seem to be specific for ASD, the possibility of more distinct SCZ subgroups should be explored with additional studies.

Celiac Disease Genomic, Environmental, Microbiome, and Metabolomic (CDGEMM) Study Design: Approach to the Future of Personalized Prevention of Celiac Disease.

In the past it was believed that genetic predisposition and exposure to gluten were necessary and sufficient to develop celiac disease (CD). Recent studies however suggest that loss of gluten tolerance can occur at any time in life as a consequence of other environmental stimuli. Many environmental factors known to influence the composition of the intestinal microbiota are also suggested to play a role in the development of CD. These include birthing delivery mode, infant feeding, and antibiotic use. To date no large-scale longitudinal studies have defined if and how gut microbiota composition and metabolomic profiles may influence the loss of gluten tolerance and subsequent onset of CD in genetically-susceptible individuals. Here we describe a prospective, multicenter, longitudinal study of infants at risk for CD which will employ a blend of basic and applied studies to yield fundamental insights into the role of the gut microbiome as an additional factor that may play a key role in early steps involved in the onset of autoimmune disease.

The Role of Gluten in Celiac Disease and Type 1 Diabetes.

Celiac disease (CD) and type 1 diabetes (T1D) are autoimmune conditions in which dietary gluten has been proven or suggested to play a pathogenic role. In CD; gluten is established as the instigator of autoimmunity; the autoimmune process is halted by removing gluten from the diet; which allows for resolution of celiac autoimmune enteropathy and subsequent normalization of serological markers of the disease. However; an analogous causative agent has not yet been identified for T1D. Nevertheless; the role of dietary gluten in development of T1D and the potentially beneficial effect of removing gluten from the diet of patients with T1D are still debated. In this review; we discuss the comorbid occurrence of CD and T1D and explore current evidences for the specific role of gluten in both conditions; specifically focusing on current evidence on the effect of gluten on the immune system and the gut microbiota.

A longitudinal study of the reliability of acupuncture deqi sensations in knee osteoarthritis.

Deqi is one of the core concepts in acupuncture theory and encompasses a range of sensations. In this study, we used the MGH Acupuncture Sensation Scale (MASS) to measure and assess the reliability of the sensations evoked by acupuncture needle stimulation in a longitudinal clinical trial on knee osteoarthritis (OA) patients. The Knee injury and Osteoarthritis Outcome Score (KOOS) was used as the clinical outcome. Thirty OA patients were randomized into one of three groups (high dose, low dose, and sham acupuncture) for 4 weeks. We found that, compared with sham acupuncture, real acupuncture (combining high and low doses) produced significant improvement in knee pain (P = .025) and function in sport (P = .049). Intraclass correlation analysis showed that patients reliably rated 11 of the 12 acupuncture sensations listed on the MASS and that heaviness was rated most consistently. Overall perceived sensation (MASS Index) (P = .014), ratings of soreness (P = .002), and aching (P = .002) differed significantly across acupuncture groups. Compared to sham acupuncture, real acupuncture reliably evoked stronger deqi sensations and led to better clinical outcomes when measured in a chronic pain population. Our findings highlight the MASS as a useful tool for measuring deqi in acupuncture research.