Recognition of the antigen-presenting molecule MR1 by a Vδ3+ γδ T cell receptor.

Unlike conventional αß T cells, γδ T cells typically recognize nonpeptide ligands independently of major histocompatibility complex (MHC) restriction. Accordingly, the γδ T cell receptor (TCR) can potentially recognize a wide array of ligands; however, few ligands have been described to date. While there is a growing appreciation of the molecular bases underpinning variable (V)δ1+ and Vδ2+ γδ TCR-mediated ligand recognition, the mode of Vδ3+ TCR ligand engagement is unknown. MHC class I-related protein, MR1, presents vitamin B metabolites to αß T cells known as mucosal-associated invariant T cells, diverse MR1-restricted T cells, and a subset of human γδ T cells. Here, we identify Vδ1/2- γδ T cells in the blood and duodenal biopsy specimens of children that showed metabolite-independent binding of MR1 tetramers. Characterization of one Vδ3Vγ8 TCR clone showed MR1 reactivity was independent of the presented antigen. Determination of two Vδ3Vγ8 TCR-MR1-antigen complex structures revealed a recognition mechanism by the Vδ3 TCR chain that mediated specific contacts to the side of the MR1 antigen-binding groove, representing a previously uncharacterized MR1 docking topology. The binding of the Vδ3+ TCR to MR1 did not involve contacts with the presented antigen, providing a basis for understanding its inherent MR1 autoreactivity. We provide molecular insight into antigen-independent recognition of MR1 by a Vδ3+ γδ TCR that strengthens an emerging paradigm of antibody-like ligand engagement by γδ TCRs.

Co-design and Consultation Ensure Consumer Needs Are Met: Building an eHealth Platform for Children with Inflammatory Bowel Disease.

BACKGROUND: Crohn's Colitis Care is an adult inflammatory bowel disease eHealth system. Crohn's Colitis Care required additional pediatric functionality to enable life-long records and mitigate transition inadequacies. AIM: This study describes and evaluates a consensus method developed to ensure consumer needs were met. METHODS: Pediatric-specific functionality and associated resources considered important for inclusion were developed by a clinician consensus group. This group was divided into thematic subgroups and underwent two voting rounds. The content validity index was used to determine items reaching consensus. Children with inflammatory bowel disease and their parents were later shown a descriptive list of non-clinical inclusion topics proposed by the consensus group, and asked to vote on whether topic-related functionality and resources should be included. RESULTS: The consensus process consulted 189 people in total (38 clinicians, 32 children with inflammatory bowel disease and 119 parents). There was agreement across all groups to incorporate functionality and resources pertaining to quality of life, mental health, self-management, and transition readiness; however, divergence was seen for general inflammatory bowel disease facts, your inflammatory bowel disease history, and satisfaction. Cost saw the greatest disparity, being less supported by consumers compared to clinicians. Over 75% of consumers agreed it would be okay for appointments to take longer for survey completion, and > 90% thought Crohn's Colitis Care should allow consumers to ask their treating team questions. CONCLUSIONS: Widespread consumer co-design and consultation were important in unveiling differing perspectives to ensure Crohn's Colitis Care was built to support both consumer and clinician perspectives. Consumers collaborate to create a list of functionality and resources to be included in software (left), influencing the final product build (right).

Isolated positive deamidated gliadin peptide-IgG has limited diagnostic utility in coeliac disease.

AIM: Deamidated gliadin peptide-IgG (DGP-IgG) antibody serology testing is widely utilised in screening for coeliac disease in Australia; however, it is used sparingly in Europe. The aim of this study was to assess the diagnostic value of a positive DGP-IgG in the setting of a negative tissue transglutaminase-IgA (tTG-IgA) for gastrointestinal pathology among paediatric patients. METHODS: We conducted a retrospective cohort study of all children with an elevated DGP-IgG in the setting of a negative tTG-IgA who underwent gastroscopy over a 48-month period (January 2015-December 2018) at a tertiary paediatric centre. They were identified utilising the electronic pathology database and demographic and clinical data were collected from electronic medical records. Patients who had previously been diagnosed with coeliac disease were on a gluten-free diet or over the age of 18 were excluded from the study. RESULTS: Twenty-six patients with an elevated DGP-IgG in the setting of a negative tTG-IgA underwent gastroscopy. Our study yielded a positive predictive value of 1/26 (3.9% CI 95% 0.7%, 18.9%) for the diagnosis of coeliac disease. Overall, there were 25 histopathological diagnoses including 1 diagnosis of coeliac disease among the total 26 patients who were positive DGP-IgG and negative tTG-IgA and underwent gastroscopy. CONCLUSIONS: Our findings suggest that an isolated positive DGP-IgG has a very low diagnostic yield for coeliac disease in children and may be indicative of other gastrointestinal pathology.

Impact of a new young adult inflammatory bowel disease transition clinic on patient satisfaction and clinical outcomes.

AIM: The transition from paediatric to adult care for patients with inflammatory bowel disease (IBD) is associated with an increased risk of treatment non-adherence, hospitalizations and emergency department (ED) use. We established a new young adult IBD clinic (YAC) in Melbourne to capture this at-risk population. We aimed to assess patient satisfaction as well as clinical outcomes. METHODS: All patients who attended the YAC between its inception in November 2016 and November 2018 were recruited to our YAC group, 61 patients in total. A control group was selected from the pre-existing adult clinic (AC) at our service, 34 patients in total. IBD-related ED (IBD-ED) visits were collected for all patients. We compared IBD-ED visits in the 2 years before and after attending the clinic for the first time. Patient satisfaction was assessed using the IBD-Patient Satisfaction Questionnaire. RESULTS: There was an overall decrease in IBD-ED visits between the pre-clinic and post-clinic periods in both the YAC (42.9% reduction) and AC (69.2% reduction) (P < 0.001). Patient satisfaction was high amongst both services with YAC patients indicating higher satisfaction with communication (P = 0.015). CONCLUSION: There was a reduction in IBD-ED visits in both the YAC and the AC, high patient satisfaction, and statistically higher satisfaction with communication in the YAC. We speculate the importance of a YAC is to capture those patients in the peri-transitional period at risk of being lost to follow-up or not previously referred for specialist care.

Decade of the dangers of multiple magnet ingestion in children: A retrospective review.

AIM: Magnet ingestion has become more frequent in children as magnetic toys and jewellery have been popularised, with the potential to cause significant morbidity. Our aim was to describe our experience at a tertiary paediatric surgical centre. METHODS: Retrospective review of patients admitted with multiple magnet ingestion (January 2011-December 2020). Division into an intervention group and conservative group. Comparisons included demographics, number of magnets and clinical outcomes. Data analysis with a Student's t-test and ROC Curve, P value of <0.05 was significant. RESULTS: A total of 23 patients were identified with a total of 150 magnets ingested. The majority required an intervention for magnets retrieval (15/23, 65.2%), 11/15 (73.3%) surgical and 4/15 (26.7%) endoscopic. In the surgery group, 6/11 (54%) presented with an initial perforation and 1/11 (9.1%) an entero-enteric fistula. One patient (9.1%) had a multi-site anastomotic leak post-operatively. The conservative group had a significantly lower median number of ingested magnets (2 (2-6) vs. 7 (2-40), P = 0.03) and median length of stay (1 (1-4) vs. 7 (1-24), P = 0.03). ROC curve analysis revealed ingestion of >3 magnets had a sensitivity of 86.7% (95% CI: 62.1-97.6%) and specificity of 87.5% (95% CI: 53.0-99.4%) for requiring an intervention. CONCLUSION: This series highlights a significant morbidity in children with a higher incidence of intervention following ingestion of more than three magnets. There is a strong requirement for the creation and adherence to new legislature involving industry standards.

The future is now? Clinical and translational aspects of "Omics" technologies.

Big data has become a central part of medical research, as well as modern life generally. "Omics" technologies include genomics, proteomics, microbiomics and increasingly other omics. These have been driven by rapid advances in laboratory techniques and equipment. Crucially, improved information handling capabilities have allowed concepts such as artificial intelligence and machine learning to enter the research world. The COVID-19 pandemic has shown how quickly information can be generated and analyzed using such approaches, but also showed its limitations. This review will look at how "omics" has begun to be translated into clinical practice. While there appears almost limitless potential in using big data for "precision" or "personalized" medicine, the reality is that this remains largely aspirational. Oncology is the only field of medicine that is widely adopting such technologies, and even in this field uptake is irregular. There are practical and ethical reasons for this lack of translation of increasingly affordable techniques into the clinic. Undoubtedly, there will be increasing use of large data sets from traditional (e.g. tumor samples, patient genomics) and nontraditional (e.g. smartphone) sources. It is perhaps the greatest challenge of the health-care sector over the coming decade to integrate these resources in an effective, practical and ethical way.

Emergency Presentations for Gastrostomy Complications Are Similar in Adults and Children.

ABSTRACT: Gastrostomy tube (GT) complications are often managed in the Emergency Department (ED). We aimed to characterize and compare the pattern of ED presentations of GT complications in adults and children. A retrospective chart review of patients with GT complications presenting to 3 Australian EDs in 2 years was undertaken. ED visits for GT complications occurred in 70 GT patients (36 adults, 34 children) with 122 presentations. When comparing adults to children, infections occurred in 21% versus 36%, respectively; P = 0.08, mechanical issues in 48% versus 52%; P = 0.86, vomiting in 23% versus 8%; P = 0.02, and other issues in 7% versus 5%; P = 0.7. Presentation to ED within 28 days of initial GT insertion occurred in 3 (8%) adults and 3 (9%) children, predominantly with tube dislodgement. GT complications seen in ED are predominantly infectious and mechanical in nature, with an increased frequency of vomiting in adults when compared with children.

Histology at diagnostic gastroscopy predicts outcome after intestinal resection in pediatric Crohn's disease.

BACKGROUND AND AIM: Pediatric Crohn's disease (CD) has been shown to have a high recurrence rate following surgical resection. Risk factors for postoperative CD recurrence in children are not well known. The aim of this study was to identify factors influencing postoperative recurrence in pediatric CD. METHODS: Pediatric CD patients who underwent surgical resection with primary anastomosis with a minimum follow up of 2 years were identified from databases at the Royal London Hospital and Massachusetts General Hospital. Patients were subdivided into a recurrence group defined by clinical, endoscopic, histological, radiological and/or surgical outcomes, and a nonrecurrence group. Patient demographics, initial gastroscopy and colonoscopy findings, Paris classification, and preoperative and postoperative pharmacotherapy were analyzed. RESULTS: Ninety-six children who underwent an ileal or ileocolonic resection with primary anastomosis were identified. Fifty-seven children had postoperative recurrence. Recurrence was associated with abnormal initial gastroscopy findings (P = 0.0077), ileocolonic disease location (P = 0.03), and perianal disease involvement (P = 0.04). Patients with abnormal initial gastroscopy had higher rates of relapse (hazard ratio 3.42, 95% confidence interval [CI] [1.86-6.30], P = 0.001). Multivariate analysis demonstrated that abnormal diagnostic gastroscopy histology was a significant independent predictor of postoperative recurrence in this cohort (odds ratio 1.33, 95% CI [1.04-1.70], P = 0.024). The most common histological abnormality was non-Helicobacter gastritis, found in 29/46 (63%). CONCLUSION: This dual-center study has shown that the presence of upper gastrointestinal tract inflammation, especially non-Helicobacter gastritis, at the time of diagnosis, is associated with an increased risk of postoperative recurrence in pediatric CD.

Microbiome in health and disease.

There has been an exponential rise in research into the microbiota of the human gastrointestinal tract, particularly of the genomic content (the microbiome). The vast number of micro-organisms residing in our gut has an integral role in essential processes, including growth and development. Probiotics, live micro-organisms with putative benefits on health have become ubiquitous as treatments for many conditions, despite often limited robust clinical trial data. However, the resurgence of faecal microbial transplantation as an effective treatment modality provides further promise that manipulation of our microbiome can have clinical benefits. This review will present the recent evidence for the role of the microbiome in development and growth, and focus on the evidence for its manipulation in paediatric diseases. We will show that while there is promising data in specific diseases, there remain many unanswered questions. Only through a deeper understanding of our complex internal ecosystem will we be able to move to the next stage of targeted microbial therapy.

Clinical Presentation and Outcomes of Diagnostic Endoscopy in Newly Presenting Children With Gastrointestinal Symptoms.

OBJECTIVES: Paediatric endoscopy is an important diagnostic tool; however, there is little published data to guide clinicians in selecting patients for endoscopy. This study aimed to evaluate a single centre's experience of newly presenting children focusing on presenting symptoms, investigations, and diagnostic yield. METHODS: Clinical factors and endoscopic plus histological findings over a 6-month period were assessed. Only first diagnostic endoscopies were included. All biopsies were reviewed in a weekly histopathology multidisciplinary team meeting with a final agreed outcome. Abnormal histology was used as the criterion standard for reporting abnormality. RESULTS: A total of 218 endoscopies were reviewed in 164 children. Approximately 65% were histologically normal (49% of children had macroscopically and histologically normal findings). Macroscopic and histological abnormalities (respectively) were 44% and 28% of oesophagogastroduodenoscopy (OGD) patients, 25% and 25% of colonoscopy alone, and 53% and 53% of those undergoing both OGD and colonoscopy (OGD&Col). For OGD-only patients, excluding those with raised anti-tissue transglutaminase antibodies, vomiting led to the highest rate of abnormal histology (22%). For colonoscopy-only and OGD&Col patients, per rectum bleeding led to the highest rates of abnormal histology (14% and 29%, respectively), after excluding those with laboratory abnormalities (anaemia and raised erythrocyte sedimentation rate) suggestive of inflammatory bowel disease. CONCLUSIONS: This study showed that half of all first diagnostic endoscopies in our unit had neither macroscopic nor histological abnormalities. There was discrepancy between macroscopic abnormalities and histological findings in OGD. Prospective studies are needed to develop guidelines in appropriately predicting abnormality and selecting patients for endoscopy.

Systemic Inflammatory Response Syndrome After Major Abdominal Surgery Predicted by Early Upregulation of TLR4 and TLR5.

OBJECTIVES: To study innate immune pathways in patients undergoing hepatopancreaticobiliary surgery to understand mechanisms leading to enhanced inflammatory responses and identifying biomarkers of adverse clinical consequences. BACKGROUND: Patients undergoing major abdominal surgery are at risk of life-threatening systemic inflammatory response syndrome (SIRS) and sepsis. Early identification of at-risk patients would allow tailored postoperative care and improve survival. METHODS: Two separate cohorts of patients undergoing major hepatopancreaticobiliary surgery were studied (combined n = 69). Bloods were taken preoperatively, on day 1 and day 2 postoperatively. Peripheral blood mononuclear cells and serum were separated and immune phenotype and function assessed ex vivo. RESULTS: Early innate immune dysfunction was evident in 12 patients who subsequently developed SIRS (postoperative day 6) compared with 27 who did not, when no clinical evidence of SIRS was apparent (preoperatively or days 1 and 2). Serum interleukin (IL)-6 concentration and monocyte Toll-like receptor (TLR)/NF-κB/IL-6 functional pathways were significantly upregulated and overactive in patients who developed SIRS (P < 0.0001). Interferon α-mediated STAT1 phosphorylation was higher preoperatively in patients who developed SIRS. Increased TLR4 and TLR5 gene expression in whole blood was demonstrated in a separate validation cohort of 30 patients undergoing similar surgery. Expression of TLR4/5 on monocytes, particularly intermediate CD14CD16 monocytes, on day 1 or 2 predicted SIRS with accuracy 0.89 to 1.0 (areas under receiver operator curves). CONCLUSIONS: These data demonstrate the mechanism for IL-6 overproduction in patients who develop postoperative SIRS and identify markers that predict patients at risk of SIRS 5 days before the onset of clinical signs.

Increased production of retinoic acid by intestinal macrophages contributes to their inflammatory phenotype in patients with Crohn's disease.

BACKGROUND & AIMS: Reduced generation of all-trans retinoic acid (RA) by CD103(+) intestinal dendritic cells (DCs) is linked to intestinal inflammation in mice. However, the role of RA in intestinal inflammation in humans is unclear. We investigated which antigen-presenting cells (APCs) produce RA in the human intestine and whether generation of RA is reduced in patients with Crohn's disease (CD). METHODS: Ileal and colonic tissues were collected from patients with CD during endoscopy or surgery, and healthy tissues were collected from subjects who were undergoing follow-up because of rectal bleeding, altered bowel habits, or cancer (controls). Cells were isolated from the tissue samples, and APCs were isolated by flow cytometry. Retinaldehyde dehydrogenase (RALDH) activity was assessed by Aldefluor assay, and ALDH1A expression was measured by quantitative real-time polymerase chain reaction. Macrophages were derived by incubation of human blood monocytes with granulocyte-macrophage colony-stimulating factor (GM-CSF). RESULTS: CD103(+) and CD103(-) DCs and CD14(+) macrophages from healthy human intestine had RALDH activity. Although ALDH1A1 was not expressed by DCs, it was the predominant RALDH enzyme isoform expressed by intestinal CD14(+) macrophages and their putative precursors, CD14(+) monocytes. RALDH activity was up-regulated in all 3 populations of APCs from patients with CD; in CD14(+) macrophages, it was associated with local induction of ALDH1A1 expression. Blocking of RA receptor signaling during GM-CSF-mediated differentiation of monocytes into macrophages down-regulated CD14 and HLA-DR expression and reduced the development of tumor necrosis factor α-producing inflammatory macrophages. CONCLUSIONS: RA receptor signaling promotes differentiation of human tumor necrosis factor α-producing inflammatory macrophages in vitro. In vivo, more CD14(+) macrophages from the intestinal mucosa of patients with CD than from controls are capable of generating RA, which might increase the inflammatory phenotype of these cells. Strategies to reduce the generation of RA by CD14(+) macrophages could provide new therapeutic options for patients with CD.

Proinflammatory Vδ2+ T cells populate the human intestinal mucosa and enhance IFN-γ production by colonic αß T cells.

In nonhuman primates, Vγ9Vδ2(+) (Vδ2)T cells proliferate and accumulate in mucosal tissues following microbial activation. Human Vδ2T cells produce proinflammatory cytokines in response to bacterial species that colonize the gut, but the role played by Vδ2T cells in intestinal immunity is unknown. We hypothesized that circulating Vδ2T cells can populate the human intestine and contribute to mucosal inflammation. Cell suspensions prepared from peripheral blood and intestinal biopsies were stimulated with microbial phosphoantigen (1-hydroxy-2-methyl-2-buten-4-yl 4-diphosphate [HDMAPP]) and analyzed by flow cytometry to determine Vδ2T cell phenotype, cytokine production, and proliferative potential. Circulating Vδ2T cells expressed gut-homing integrin α4ß7 (>70%), which was coexpressed with skin-associated cutaneous leukocyte Ag by up to 15% of the total population. However, Vδ2T cell activation with HDMAPP and exposure to retinoic acid (signaling via retinoic acid receptor α) increased α4ß7 expression and enhanced binding to mucosal addressin cell adhesion molecule-1 in vitro while simultaneously suppressing cutaneous leukocyte Ag, thereby generating a committed gut-tropic phenotype. Confocal microscopy and flow cytometry identified frequent Vδ2T cells that migrated out of human intestinal biopsies and comprised both CD103(+) and CD103(-) subsets that produced TNF-α and IFN-γ upon phosphoantigen exposure, with more frequent cytokine-producing cells in the CD103(-) population. Activated intestinal Vδ2T cells expressed CD70 and HLA-DR but were unable to drive the proliferation of allogeneic naive CD4(+) T cells. Instead, phosphoantigen-activated CD103(-) Vδ2T cells increased T-bet expression and enhanced IFN-γ production by autologous colonic αß T cells via an IFN-γ-dependent mechanism. These data demonstrate that circulating Vδ2T cells display enhanced gut-homing potential upon microbial activation and populate the human intestinal mucosa, generating functionally distinct CD103(+) and CD103(-) subsets that can promote inflammation by colonic αß T cells.

Transitional care of adolescents with inflammatory bowel disease to adult services varies widely across Australia and New Zealand.

Background and Aim: Children and adolescents account for approximately 14% of inflammatory bowel disease (IBD) diagnoses. At an appropriate age and level of development adolescents with IBD have their care transferred from the pediatric to adult clinical team during a process termed "transition". The study aim was to survey pediatric gastroenterologists throughout Australasia to identify commonality in the transition process to contribute to standardized guideline development. Methods: A descriptive survey captured key variables: transition clinic format, process and infrastructure, transition assessments, and guidelines. The survey was distributed electronically to 59 Pediatric Gastroenterologists throughout Australasia in January 2023. Results: Seventeen (29%) clinicians completed the survey: Australia 13 (76%). New Zealand 4 (24%). Thirteen (76%) respondents had access to a dedicated IBD transition clinic. Adolescents attended transition clinics 1-7 times, and the main processes transferred were: prescription provision, biologic appointments, and adult team contacts. Transition was first discussed age 13-15 years (53%), or 16-18 years (47%), with the main discussion topics including: continuing adherence (88%), smoking (59%), alcohol use (59%), recreational drug use (59%). Transition readiness assessments were done infrequently (24%). The minority (24%) used formal guidelines to inform the transition process, but 15 (88%) considered the development of a standardized Australasian guideline as beneficial/extremely beneficial. Conclusions: This survey highlighted that transition care for adolescents with IBD is variable across Australasia. Australasian guideline development may optimize the transition process for adolescents with IBD and improve their longitudinal outcomes.

Pediatric to Adult Transition in Inflammatory Bowel Disease: Consensus Guidelines for Australia and New Zealand.

BACKGROUND: The incidence of pediatric inflammatory bowel disease (IBD) is rising, and there is an increasing need to support adolescents when they transition to adult care. Evidence supports the use of a structured transition process but there is great variation across Australasia. The study aim was to develop evidence and expert opinion-based consensus statements to guide transitional care services in IBD. METHODS: A modified UCLA-RAND methodology was employed to develop consensus statements. An IBD expert steering committee was formed and a systematic literature review was conducted to guide the drafting of consensus statements. A multidisciplinary group was formed comprising 16 participants (clinicians, nurses, surgeons, psychologists), who anonymously voted on the appropriateness and necessity of the consensus statements using Likert scales (1 = lowest, 9 = highest) with a median ≥7 required for inclusion. Patient support groups, including direct input from young people with IBD, informed the final recommendations. RESULTS: Fourteen consensus statements were devised with key recommendations including use of a structured transition program and transition coordinator, mental health and transition readiness assessment, key adolescent discussion topics, allied health involvement, age for transition, and recommendations for clinical communication and handover, with individualized patient considerations. Each statement reached median ≥8 for appropriateness, and ≥7 for necessity, in the first voting round, and the results were discussed in an online meeting to refine statements. CONCLUSIONS: A multidisciplinary group devised consensus statements to optimize pediatric to adult transitional care for adolescents with IBD. These guidelines should support improved and standardized delivery of IBD transitional care within Australasia.

Transitional care practices for adolescents with inflammatory bowel disease vary across Australasia, and a need for standardized care has been identified. A multidisciplinary team developed Consensus Guidelines to facilitate standardized transition from the pediatric to adult healthcare setting across Australasia.

Epithelially Restricted Interferon Epsilon Protects Against Colitis.

BACKGROUND & AIMS: Type I interferon (T1IFN) signalling is crucial for maintaining intestinal homeostasis. We previously found that the novel T1IFN, IFNε, is highly expressed by epithelial cells of the female reproductive tract, where it protects against pathogens. Its function has not been studied in the intestine. We hypothesize that IFNε is important in maintaining intestinal homeostasis. METHODS: We characterized IFNε expression in mouse and human intestine by immunostaining and studied its function in the dextran sulfate sodium (DSS) colitis model using both genetic knockouts and neutralizing antibody. RESULTS: We demonstrate that IFNε is expressed in human and mouse intestinal epithelium, and expression is lost in inflammation. Furthermore, we show that IFNε limits intestinal inflammation in mouse models. Regulatory T cell (Treg) frequencies were paradoxically decreased in DSS-treated IFNε-/- mice, suggesting a role for IFNε in maintaining the intestinal Treg compartment. Colitis was ameliorated by transfer of wild-type Tregs into IFNε-/- mice. This demonstrates that IFNε supports intestinal Treg function. CONCLUSIONS: Overall, we have shown IFNε expression in intestinal epithelium and its critical role in gut homeostasis. Given its known role in the female reproductive tract, we now show IFNε has a protective role across multiple mucosal surfaces.

Disease-specific loss of microbial cross-feeding interactions in the human gut.

Many gut microorganisms critical to human health rely on nutrients produced by each other for survival; however, these cross-feeding interactions are still challenging to quantify and remain poorly characterized. Here, we introduce a Metabolite Exchange Score (MES) to quantify those interactions. Using metabolic models of prokaryotic metagenome-assembled genomes from over 1600 individuals, MES allows us to identify and rank metabolic interactions that are significantly affected by a loss of cross-feeding partners in 10 out of 11 diseases. When applied to a Crohn's disease case-control study, our approach identifies a lack of species with the ability to consume hydrogen sulfide as the main distinguishing microbiome feature of disease. We propose that our conceptual framework will help prioritize in-depth analyses, experiments and clinical targets, and that targeting the restoration of microbial cross-feeding interactions is a promising mechanism-informed strategy to reconstruct a healthy gut ecosystem.

Bacterial clade-specific analysis identifies distinct epithelial responses in inflammatory bowel disease.

Abnormal immune responses to the resident gut microbiome can drive inflammatory bowel disease (IBD). Here, we combine high-resolution, culture-based shotgun metagenomic sequencing and analysis with matched host transcriptomics across three intestinal sites (terminal ileum, cecum, rectum) from pediatric IBD (PIBD) patients (n = 58) and matched controls (n = 42) to investigate this relationship. Combining our site-specific approach with bacterial culturing, we establish a cohort-specific bacterial culture collection, comprising 6,620 isolates (170 distinct species, 32 putative novel), cultured from 286 mucosal biopsies. Phylogeny-based, clade-specific metagenomic analysis identifies key, functionally distinct Enterococcus clades associated with either IBD or health. Strain-specific in vitro validation demonstrates differences in cell cytotoxicity and inflammatory signaling in intestinal epithelial cells, consistent with the colonic mucosa-specific response measured in patients with IBD. This demonstrates the importance of strain-specific phenotypes and consideration of anatomical sites in exploring the dysregulated host-bacterial interactions in IBD.

Optimal assessment of paediatric IBD with MRI and barium follow-through.

OBJECTIVES: The present UK criterion standard for assessing children with suspected inflammatory bowel disease (IBD) is upper endoscopy, ileocolonoscopy, and barium follow-through (BaFT). Significant doses of radiation, unpalatable contrast, and volume intolerance are involved with BaFT. Practice in investigating Crohn disease (CD) is changing with the increasing use of magnetic resonance imaging (MRI). The aim of the present study was to compare BaFT and a new abdominal MRI protocol in a paediatric IBD population. METHODS: All consecutive patients with a new diagnosis of IBD or requiring reassessment from September 2008 to December 2010 were investigated with both abdominal MRI and BaFT in accordance with a specific local paediatric IBD protocol. The studies were reported by nonblinded radiologists with an interest in gastrointestinal imaging. The reports were compared in conjunction with case note review. RESULTS: Eighty-seven patients underwent both BaFT and MRI abdomen. Thirty-one percent of patients had additional pathology on MRI, not seen on the BaFT. Sixty-seven percent of patients (n=59) had an MRI finding equivalent to BaFT. Using histology as a criterion standard for detecting terminal ileal disease, BaFT had a sensitivity and specificity of 76% and 67%, and MRI had a sensitivity and specificity of 83% and 95%, respectively. CONCLUSIONS: This is the largest series of small bowel MRI in a paediatric population. MRI reports were at least equivalent to BaFT. MRI had higher sensitivity and, particularly, specificity in detecting terminal ileal pathology. These findings suggest that MRI should become the criterion standard investigation in children with IBD in centres with appropriate expertise, with zero radiation exposure being highly advantageous.