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Introduction In pediatric Crohn's disease ileocecal resection is performed reluctantly as postoperative recurrence is frequent. Anti-tumor necrosis factor (TNF) therapy reduces postoperative recurrence rates but increases the risk for infections. Materials and Methods We retrospectively reviewed pediatric Crohn's disease patients who underwent ileocecal resection in our center. We compared disease activity and z-scores for height, weight, and body mass index of patients, who continuously received perioperative anti-TNF therapy (TNF + ), with those who did not (TNF–). Results Of 29 patients (48% females), 13 and 16 were grouped to TNF+ and TNF–, respectively. Patients' characteristics did not differ between groups, except a longer follow-up time in TNF–. We saw significant postoperative improvement but no normalization in z-scores for weight (1.78 vs. 0.77, p Conclusion In patients with localized Crohn's disease an ileocecal resection leads to short-term postoperative improvement of disease activity, body mass index, weight, and growth. For relevant catch-up growth an earlier intervention is necessary. Continuous perioperative anti-TNF therapy had no increased risk of perioperative infections.

ZusammenfassungDas menschliche Mikrobiom und im speziellen die gastrointestinale Mikrobiota sind mit Gesundheit und Krankheit assoziiert. Eine Störung ihrer Zusammensetzung oder Funktion (Dysbiose) spielen eine Rolle bei der Entstehung von kindergastroenterologischen Krankheitsbildern. Der fäkale Mikrobiota-Transfer (FMT) ist eine spezielle Intervention, bei der intestinale Mikrobiota eines gesunden Spenders transferiert werden.In diesem Review beschreiben wir die aktuelle Studienlage bezüglich FMT bei pädiatrischen Patient*innen. Für rezidivierende C. difficile-Infektionen bestehen eine gute Datenlage und Empfehlungen der entsprechenden Fachgesellschaften. Bei der Behandlung von chronisch-entzündlichen Darmerkrankungen (CED) mittels FMT liegen erste Daten vor, die auf eine Reduktion der Krankheitsschwere hindeuten.Nebenwirkungen traten in Studien häufig auf, zeigten sich aber meist milde und transient. Zu in der Pädiatrie besonders bedeutsamen langfristigen Nebenwirkungen eines FMT existieren kaum Daten.Bei der praktischen Durchführung besteht große Unklarheit, welche Modalitäten und Applikationsrouten angewendet werden sollten. Rechtlich gilt Spenderstuhl im deutschsprachigen Raum als Arzneimittel, für das keine Zulassung vorliegt.Insgesamt sind die Erkenntnisse zu den physiologischen Zusammenhängen, Wirkungen und Nebenwirkungen noch unzureichend und rechtliche Rahmenbedingungen erschweren die Durchführung. Weitere klinische Studien auf dem Gebiet sind zwingend notwendig.

Background and aims Exclusive enteral nutrition is recommended as a first-line treatment in active pediatric Crohn’s Disease, but its mechanism of action is still not clear. We aimed to assess alterations in the metabolic profile of newly diagnosed pediatric Crohn’s Disease patients before and during exclusive enteral nutrition therapy. Methods Plasma samples from 14 pediatric Crohn’s Disease patients before and after 3–4 weeks on exclusive enteral nutrition were analyzed using mass spectrometry. T-test, fold change and orthogonal partial least squares discriminant analysis were used for mining significant features. Correlation analysis was performed between the annotated features and the weighted pediatric Crohn’s disease activity index using Pearson r distance. Results Among the 13 compounds which decreased during exclusive enteral nutrition, most are related to diet, while one is a bacterial metabolite, Bacteriohopane-32,33,34,35-tetrol. The phosphatidic acid metabolite PA(15:1/18:0) was significantly reduced and correlated with the weighted pediatric Crohn’s disease activity index. Lipids increased during exclusive enteral nutrition therapy included phosphatidylethanolamines; PE(24:1/24:1), PE(17:2/20:2) and one lactosylceramide; LacCer(d18:1/14:0). Conclusion Food additives and other phytochemicals were the major metabolites, which decreased following the exclusion of a regular diet during exclusive enteral nutrition. An alteration in bacterial biomarkers may reflect changes in intestinal microbiota composition and metabolism. Thus, metabolomics provides an opportunity to characterize the molecular mechanisms of dietary factors triggering Crohn’s Disease activity, and the mechanisms of action of exclusive enteral nutrition, thereby providing the basis for the development and evaluation of improved intervention strategies for prevention and treatment.

Crohn’s disease (CD) is associated with changes in the microbiota, and murine models of CD-like ileo-colonic inflammation depend on the presence of microbial triggers. Increased abundance of unknown Clostridiales and the microscopic detection of filamentous structures close to the epithelium of TnfΔARE mice pointed towards segmented filamentous bacteria (SFB), a commensal well-known to induce the maturation of Th17 cell-derived immune responses that is highly implicated in the pathogenesis of IBD. We show that the abundance of SFB strongly correlates with the severity of CD-like ileal inflammation in TnfΔARE and SAMP/Yit mice. SFB mono-colonization of germ-free TnfΔARE mice confirmed the causal link and resulted in severe ileo-colonic inflammation, characterized by elevated tissue levels of Tnf and Il-17, neutrophil infiltration and loss of Paneth and goblet cell function. Co-colonization of SFB in human-microbiota associated TnfΔARE mice confirmed that SFB presence is indispensable for disease development. Screening of 412 ileal and colonic mucosal biopsies from IBD patients using previously published and newly designed human SFB-specific primer sets showed no presence of SFB in human tissue samples. Simulating the protective effect of exclusive enteral nutrition (EEN) by feeding SFB mono-colonized TnfΔARE mice EEN-like purified diet antagonized SFB colonization and prevented disease development in TnfΔARE mice, clearly demonstrating the important role of diet in modulating this IBD-related but murine pathobiont.

BACKGROUND: It is important to identify patients with monogenic IBD as management may differ from classical IBD. In this position statement we formulate recommendations for the use of genomics in evaluating potential monogenic causes of IBD across age groups. METHODS: The consensus included paediatric IBD specialists from the Paediatric IBD Porto group of the European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) and specialists from several monogenic IBD research consortia. We defined key topics and performed a systematic literature review to cover indications, technologies (targeted panel, exome and genome sequencing), gene panel setup, cost-effectiveness of genetic screening, and requirements for the clinical care setting. We developed recommendations that were voted upon by all authors and Porto group members (32 voting specialists). RESULTS: We recommend next-generation DNA-sequencing technologies to diagnose monogenic causes of IBD in routine clinical practice embedded in a setting of multidisciplinary patient care. Routine genetic screening is not recommended for all IBD patients. Genetic testing should be considered depending on age of IBD-onset (infantile IBD, very early-onset IBD, paediatric or young adult IBD), and further criteria, such as family history, relevant comorbidities, and extraintestinal manifestations. Genetic testing is also recommended in advance of hematopoietic stem cell transplantation. We developed a diagnostic algorithm that includes a gene panel of 75 monogenic IBD genes. Considerations are provided also for low resource countries. CONCLUSIONS: Genomic technologies should be considered an integral part of patient care to investigate patients at risk for monogenic forms of IBD.

Exclusive enteral nutrition induces remission, improves bone health and growth in paediatric Crohn's disease (CD) patients, but is highly demanding for patients. We investigated efficacy of partial enteral nutrition (PEN) on bone health, growth and course in CD patients and assessed microbial and metabolic changes induced by PEN.We performed a two centre, non-randomized controlled intervention study in quiescent CD patients aged19 years. Patients in intervention group received a liquid formula providing ~25% of daily energy for one year. At baseline, after 3, 6, 9 and 12 months, we collected data on bone, muscle (peripheral quantitative computertomography), anthropometry, disease activity (weighted paediatric CD activity index), metabolomic profile (liquid chromatography mass spectrometry), and faecal microbiome (16S rRNA gene sequencing).Of 41 CD patients, 22 received the intervention (PEN) (mean age 15.0 ± 1.9 years, 50% male), 19 served as controls (non-PEN) (12.8 ± 3.1 years, 58% male). At baseline, mean bone quality was comparable to reference population with no improvement during the intervention. Relapse rate was low (8/41, PEN 4/22 and non-PEN 4/19, ns). PEN was not associated with microbiota community changes (beta diversity) but significantly reduced species diversity. Metabolome changes with upregulation of phosphatidylcholines in PEN patients are likely related to lipid and fatty acid composition of the formula. PEN significantly improved growth in a subgroup with Tanner stage 1-3.In our cohort of paediatric CD patients, PEN did not affect bone health but improved growth in patients with a potential to grow.

The human microbiome and especially the gastrointestinal microbiota are associated with health and disease. Disturbance in the composition or function of fecal microbiota (dysbiosis) plays a role in the development of pediatric gastrointestinal diseases. Fecal microbiota transfer (FMT) is a special intervention, where microbiota are transferred from a healthy donor.In this review we describe the current state of knowledge for FMT in pediatric patients. There is satisfactory evidence concerning FMT in patients with recurrentDas menschliche Mikrobiom und im speziellen die gastrointestinale Mikrobiota sind mit Gesundheit und Krankheit assoziiert. Eine Störung ihrer Zusammensetzung oder Funktion (Dysbiose) spielen eine Rolle bei der Entstehung von kindergastroenterologischen Krankheitsbildern. Der fäkale Mikrobiota-Transfer (FMT) ist eine spezielle Intervention, bei der intestinale Mikrobiota eines gesunden Spenders transferiert werden.In diesem Review beschreiben wir die aktuelle Studienlage bezüglich FMT bei pädiatrischen Patient*innen. Für rezidivierende

ZusammenfassungEpidemiologische und klinische Beobachtungen sowie Tiermodelle weisen auf die Ernährung als Risikofaktor für die Entwicklung einer chronisch entzündlichen Darmerkrankung (CED) hin. Die exklusive enterale Ernährungstherapie (EET) ist das Musterbeispiel einer effektiven Entzündungskontrolle durch eine rein diätetische Intervention. Ausgehend davon haben Patienten, Familien und betreuende Fachkräfte des Gesundheitswesens ein großes Interesse, andere Ernährungsmodifikationen in der Behandlung von CED-Patienten einzusetzen, zum Beispiel eine partielle Ernährungstherapie (PET) mit spezifischer Diät wie die Crohnʼs Disease Exclusion Diet. Die folgende Stellungnahme fasst die aktuelle Datenlage zusammen und gibt Orientierung für Praxis und weitere Forschung.

Inflammatory bowel disease (IBD) is characterized by inappropriate immune responses to the microbiota in genetically susceptible hosts, but little is known about the pathways that link individual g...

Primary Epstein–Barr virus infection in pediatric patients with inflammatory bowel disease during immunomodulation with thiopurines has been associated with increased risk for malignancies or hemophagocytic lymphohistiocytosis. We determined Epstein–Barr virus (EBV) seroprevalence at inflammatory bowel disease (IBD) diagnosis and seroconversion during follow-up in a large single center cohort of children with IBD. EBV serology results and patient characteristics were retrospectively retrieved from the hospital documentation system. EBV seronegative patients at IBD diagnosis were prospectively retested. We report on IBD patients with symptomatic active EBV infection and a complicated disease course, and those diagnosed with malignancy with respect to EBV status and drug exposure. Of 402 patients, 194 (48%) had available EBV serology results at time of IBD diagnosis at a median of 12 years (IQR 9–14 years). Thereof, 102 (53%) were EBV-positive. Of 92 EBV-negative patients, 66 were retested and 17% showed a seroconversion at a mean follow-up time of 4.3 years (SD 3 years). Three children treated with azathioprine experienced acute clinically relevant EBV infection 2, 2.5, and 4 years after IBD diagnosis, two developed signs of hemophagocytic lymphohistiocytosis. Three cases of malignancy occurred in the cohort, though none seemed to be triggered by EBV. In conclusion, almost 50% of pediatric IBD patients were EBV-naïve following diagnosis and may be at increased risk to develop severe EBV infection during immunosuppressive therapy, potentially associated with complications such as hemophagocytic lymphohistiocytosis or malignancy.

Background: COVID-19-associated restrictions impact societies. We investigated the impact in a large cohort of inflammatory bowel disease (IBD) patients. Methods: Pediatric (pIBD) and adult patients and pIBD parents completed validated questionnaires for self-perceived stress (Perceived Stress Questionnaire, PSQ) and quality of life from July to October 2020 (1st survey) and March to April 2021 (2nd survey). Analyses were stratified by age groups (6–20, &gt, 20–40, &gt, 40–60, &gt, 60 years). Perceived risk of infection and harm from COVID-19 were rated on a 1–7 scale. An index for severe outcome (SIRSCO) was calculated. Multivariable logistic regression analysis was performed. Results: Of 820 invited patients, 504 (62%, 6–85 years) patients and 86 pIBD parents completed the 1st, thereof 403 (80.4%) the 2nd survey. COVID-19 restrictions resulted in cancelled doctoral appointments (26.7%), decreased physical activity, increased food intake, unintended weight gain and sleep disturbance. PSQ increased with disease activity. Elderly males rated lower compared to females or younger adults. PSQ in pIBD mothers were comparable to moderate/severe IBD adults. Infection risk and harm were perceived high in 36% and 75.4%. Multivariable logistic models revealed associations of higher perceived risk with &gt, 3 household members, job conditions and female gender, and of perceived harm with higher SIRSCO, unintended weight change, but not with gender or age. Cancelled clinic-visits were associated with both. SARS-CoV-2 antibodies prior 2nd infection wave were positive in 2/472 (0.4%). Conclusions: IBD patients report a high degree of stress and self-perceived risk of complications from COVID-19 with major differences related to gender and age. Low seroprevalence may indicate altered immune response.

Das Darmmikrobiom steht im Zusammenhang mit der Entstehung und dem Verlauf einer chronisch-entzundlichen Darmerkrankung (CED). Diese Zusammenhange sind bisher aber nur schlecht verstanden. Das Mikrobiom bei bestehender CED ist in seiner Zusammensetzung und Funktion gestort; ein Zustand, der als Dysbiose bezeichnet wird. Die Veranderungen im Mikrobiom konnen als diagnostischer und pradiktiver Biomarker nutzlich sein. Eine therapeutische Modifikation der mikrobiellen Dysbiose (z. B. durch Ernahrung, Antibiotika oder Transfer von fakalem Material [„fecal microbiota transplantation“, FMT]) konnte eine neue Behandlungsstrategie fur CED-Patienten darstellen. Obwohl die FMT eine effektive Therapie rezidivierender Clostridium-difficile-Infektionen darstellt, ist ihr Erfolg zur Korrektur einer CED-assoziierten Dysbiose bisher wenig uberzeugend und von variablem Patientenansprechen gepragt.

CTLA4-haploinsufficiency is a complex disease of immune dysregulation presenting with a broad spectrum of clinical manifestations. CTLA4-Fc fusion proteins such as abatacept have been described to alleviate immune dysregulation in several adult cases of CTLA4-haploinsufficiency. However, until now only few cases of pediatric CTLA4-haploinsufficiency treated with abatacept have been described. Here we present two pediatric cases of severe CTLA4-haploinsufficiency refractory to conventional immunosuppressive therapies that responded rapidly to treatment with abatacept. No side effects were observed during a follow-up period of 7–15 months. While one patient has successfully undergone HSCT the second patient continues to receive abatacept. Our cases demonstrate safe medium-term use of abatacept in the pediatric population.

Purpose Biallelic pathogenic NBAS variants manifest as a multisystem disorder with heterogeneous clinical phenotypes such as recurrent acute liver failure, growth retardation, and susceptibility to infections. This study explores how NBAS-associated disease affects cells of the innate and adaptive immune system. Methods Clinical and laboratory parameters were combined with functional multi-parametric immunophenotyping methods in fifteen NBAS-deficient patients to discover possible alterations in their immune system. Results Our study revealed reduced absolute numbers of mature CD56dim natural killer (NK) cells. Notably, the residual NK cell population in NBAS-deficient patients exerted a lower potential for activation and degranulation in response to K562 target cells, suggesting an NK cell–intrinsic role for NBAS in the release of cytotoxic granules. NBAS-deficient NK cell activation and degranulation was normalized upon pre-activation by IL-2 in vitro, suggesting that functional impairment was reversible. In addition, we observed a reduced number of naïve B cells in the peripheral blood associated with hypogammaglobulinemia. Conclusion In summary, we demonstrate that pathogenic biallelic variants in NBAS are associated with dysfunctional NK cells as well as impaired adaptive humoral immunity.

Little is known about the metabolic response of pediatric Crohn's disease (CD) patients to partial enteral nutrition (PEN) therapy and the impact of disease activity and inflammation. We analyzed plasma samples from a nonrandomized controlled intervention study investigating the effect of partial enteral nutrition (PEN) on bone health and growth throughout one year with untargeted metabolomics using high-performance liquid chromatography (HPLC) coupled with high-resolution mass spectrometry (HRMS). Thirty-four paired samples from two time points (baseline and 12 months) were analyzed. Patients (median age: 13.9 years, range: 7-18.9 years, 44% females) were in remission or had mild disease activity. The intervention group received a casein-based formula for 12 months, providing ~25% of estimated daily energy requirements. Sparse partial least squares discriminant analysis (splsda) was applied for group discrimination and identifying sources of variation to identify the impact of PEN. We also investigated the correlation of metabolites with inflammation markers, including erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and fecal calprotectin. After 12 months, our results show substantial difference between PEN and non-PEN groups in the metabolome of CD patients in remission or with mild disease activity. Inflammatory markers were associated with individual compounds and chemical classes such as isoprenoids and phospholipids. Identified compounds comprise metabolites produced by human or bacterial metabolism, as well as xenobiotics recognized as flavoring agents and environmental contaminants and their biotransformation products. Further longitudinal studies that also include patients with higher disease activity are warranted to evaluate the suitability of these metabolic biomarkers for predicting disease activity.

Epidemiological an clinical observations as well as results from animal studies indicate that nutrition can play a role in the development of inflammatory bowel disease (IBD). Exclusive enteral nutrition therapy represents an example for modulating inflammatory responses solely through diet modification. Therefore, caretakers, patients, families, doctors and nutritionists seek for more dietary options to control IBD. These options include partial enteral nutrition therapy as for example the socalled Crohn's disease exclusion diet. The following statement summarizes existing data and provides recommendations for the current management of enteral nutrition therapy in pediatric Crohn's disease.Epidemiologische und klinische Beobachtungen sowie Tiermodelle weisen auf die Ernährung als Risikofaktor für die Entwicklung einer chronisch entzündlichen Darmerkrankung (CED) hin. Die exklusive enterale Ernährungstherapie (EET) ist das Musterbeispiel einer effektiven Entzündungskontrolle durch eine rein diätetische Intervention. Ausgehend davon haben Patienten, Familien und betreuende Fachkräfte des Gesundheitswesens ein großes Interesse, andere Ernährungsmodifikationen in der Behandlung von CED-Patienten einzusetzen, zum Beispiel eine partielle Ernährungstherapie (PET) mit spezifischer Diät wie die Crohnʼs Disease Exclusion Diet. Die folgende Stellungnahme fasst die aktuelle Datenlage zusammen und gibt Orientierung für Praxis und weitere Forschung.

The GP130 cytokine receptor subunit encoded by IL6ST is the shared receptor for ten cytokines of the IL-6 family. We describe a homozygous non-synonymous variant in IL6ST (p.R281Q) in a patient with craniosynostosis and retained deciduous teeth. We characterize the impact of the variant on cytokine signaling in vitro using transfected cell lines as well as primary patient-derived cells and support these findings using a mouse model with the corresponding genome-edited variant Il6st p.R279Q. We show that human GP130 p.R281Q is associated with selective loss of IL-11 signaling without affecting IL-6, IL-27, OSM, LIF, CT1, CLC, and CNTF signaling. In mice Il6st p.R279Q lowers litter size and causes facial synostosis and teeth abnormalities. The effect on IL-11 signaling caused by the GP130 variant shows incomplete penetrance but phenocopies aspects of IL11RA deficiency in humans and mice. Our data show that a genetic variant in a pleiotropic cytokine receptor can have remarkably selective defects.

SummaryInflammatory bowel disease (IBD) is characterized by inappropriate immune responses to the microbiota in genetically susceptible hosts, but pathways that link individual genetic alterations to microbiota-dependent inflammation remain to be identified. Here, we show that loss of X-linked inhibitor of apoptosis protein (XIAP), a gene associated with Mendelian IBD, renders Paneth cells sensitive to microbiota-, tumor-necrosis factor (TNF)- and receptor-interacting protein kinase 3 (RIPK3)-dependent cell death. This is associated with deficiency in Paneth cell-derived antimicrobial peptides and alterations in the stratification and composition of the microbiota. Loss of XIAP is not sufficient to elicit intestinal inflammation, but provides susceptibility to pathobionts able to promote granulomatous ileitis in hosts deficient in XIAP, which can be prevented by administration of a Paneth cell-derived antimicrobial peptide. These data reveal a pathway critical for host-microbial cross-talk, which is required for intestinal homeostasis and the prevention of inflammation, and which is amenable to therapeutic targeting.

Background: Blockade of tumour necrosis factor (anti-TNF) is effective in patients with Crohn’s Disease but has been associated with infection risk and neurological complications such as demyelination. Niemann-Pick disease Type C1 (NPC1) is a lysosomal storage disorder presenting in childhood with neurological deterioration, liver damage and respiratory infections. Some NPC1 patients develop severe Crohn’s disease. Our objective was to investigate the safety and effectiveness of anti-TNF in NPC1 patients with Crohn’s disease. Methods: Retrospective data on phenotype and therapy response were collected in 2019-2020 for the time period 2014 to 2020 from patients in the UK, France, Germany and Canada with genetically confirmed NPC1 defects and intestinal inflammation. We investigated TNF secretion in peripheral blood mononuclear cells treated with NPC1 inhibitor in response to bacterial stimuli. Results: NPC1 inhibitor treated peripheral blood mononuclear cells (PBMCs) show significantly increased TNF production after lipopolysaccharide or bacterial challenge providing a rationale for anti-TNF therapy. We identified 4 NPC1 patients with Crohn’s disease (CD)-like intestinal inflammation treated using anti-TNF therapy (mean age of onset 8.1 years, mean treatment length 27.75 months, overall treatment period 9.25 patient years). Anti-TNF therapy was associated with reduced gastrointestinal symptoms with no apparent adverse neurological events. Therapy improved intestinal inflammation in 4 patients. Conclusions: Anti-TNF therapy appears safe in patients with NPC1 and is an effective treatment strategy for the management of intestinal inflammation in these patients.

Cytokines and lipid mediators are key regulators of inflammation; but how they are mechanistically linked is poorly understood. Here, Mukhopadhyay et al. show a novel regulation between cytokine IL-10 and lipid mediator PGE2 that functionally connects them to intestinal inflammation., Loss of IL-10 signaling in macrophages (Mφs) leads to inflammatory bowel disease (IBD). Induced pluripotent stem cells (iPSCs) were generated from an infantile-onset IBD patient lacking a functional IL10RB gene. Mφs differentiated from IL-10RB−/− iPSCs lacked IL-10RB mRNA expression, were unable to phosphorylate STAT3, and failed to reduce LPS induced inflammatory cytokines in the presence of exogenous IL-10. IL-10RB−/− Mφs exhibited a striking defect in their ability to kill Salmonella enterica serovar Typhimurium, which was rescuable after experimentally introducing functional copies of the IL10RB gene. Genes involved in synthesis and receptor pathways for eicosanoid prostaglandin E2 (PGE2) were more highly induced in IL-10RB−/− Mφs, and these Mφs produced higher amounts of PGE2 after LPS stimulation compared with controls. Furthermore, pharmacological inhibition of PGE2 synthesis and PGE2 receptor blockade enhanced bacterial killing in Mφs. These results identify a regulatory interaction between IL-10 and PGE2, dysregulation of which may drive aberrant Mφ activation and impaired host defense contributing to IBD pathogenesis.

Background and objective Recent evidence points toward an active immunological role of intra-abdominal adipose tissue in Crohn disease (CD). We quantified the abdominal adipose tissue compartments using magnetic resonance imaging (MRI) in 27 pediatric patients with CD compared with 14 controls undergoing MRI examination for other reasons. Methods Total (TAAT), subcutaneous (SCAT) and intra-abdominal (IAAT) adipose tissue areas were measured by semiautomatic segmentation on a transverse slice centered on the umbilicus (mean ± standard deviation in square centimeter) using standard T1-weighted sequences. IAAT/TAAT and IAAT/height ratios were calculated and analyzed for associations with disease duration, phenotype, or therapy. Results Patients with CD (median age 15.0 years, range 7.7-17.9, 18/27 boys, median disease duration 29 months, range 0-136) compared to controls (median age 13.9 years, range 3.3-17.8, 4/14 boys) had higher IAAT area (42.3 ± 21.0 vs 28.7 ± 11.6, P = 0.0494) but similar SCAT and TAAT areas (104.6 ± 72.8 vs 96.5 ± 50.8, P = 0.8170 and 146.9 ± 87.3 vs 125.3 ± 61.5, P = 0.7417, respectively). IAAT/TAAT ratio was higher in patients with CD compared to controls (0.32 ± 0.10 vs 0.24 ± 0.04, P = 0.0081). Patients with disease duration >2 years (n = 14) had higher IAAT/TAAT ratio than those with shorter disease and controls (0.35 ± 0.10 vs 0.28 ± 0.08, P = 0.0288 and 0.24 ± 0.04, P = 0.0009, respectively). In these patients, increased IAAT/height ratio was associated with complicated disease (P = 0.043, r = 0.573). No association was found between IAAT/TAAT ratio and actual disease activity or therapy. Conclusions IAAT is increased in pediatric CD and correlates with disease duration. Assessment of IAAT accumulation may be considered in future MRI scores for inflammation and bowel damage in CD and during follow-up of different therapeutic interventions.

Neben den klassischen chronisch-entzundlichen Darmerkrankungen (CED), M. Crohn und Colitis ulcerosa, konnen auch genetisch bedingte primare Immundefekte (PID) und intestinale Epitheldefekte mit einer CED oder CED-ahnlicher intestinaler Entzundung einhergehen. Dieser Leitthemenbeitrag gibt einen Uberblick uber monogene Ursachen der CED, die klinische Prasentation von betroffenen Patienten und das diagnostische Vorgehen bei Verdacht auf eine PID-assoziierte CED (PID-CED). Literaturrecherche zu genetischer und funktioneller Diagnostik von PID-CED. Mehr als 60 Gene sind mit einer monogenen CED assoziiert und fuhren zu einem heterogenen Spektrum klinischer Prasentationen. Bei den PID-CED handelt es sich um sehr seltene Erkrankungen. Die fruhe Manifestation der CED im Kleinkindalter ist ein Leitsymptom fur die PID-CED. Validierte funktionelle Diagnostik steht fur eine Reihe von PID wie septische Granulomatose, Interleukin(IL)-10-Signaldefekte, XIAP-Defizienz, Defekte der regulatorischen T(Treg)-Zellen oder Erkrankungen aus dem Spektrum „common variable immunodeficiency“(CVID)/„severe combined immunodeficiency“ (SCID) zur Verfugung. Ein genetisches Screening der PID-CED-Gene mithilfe der Multi-Gen-Panel‑, Exom- oder Genomsequenzierung erhoht die diagnostische Sensitivitat. Je nach zugrunde liegendem Gendefekt ermoglicht eine etablierte PID-CED-Diagnose personalisierte Therapien wie kurative Stammzelltransplantation oder die Anwendung signalwegspezifischer Biologika, ein Screening auf infektiose und maligne Komplikationen sowie die genetische Beratung von Patienten und ihren Familien. Zusatzlich konnen bei hamatopoetischen Defekten durch eine solche Diagnose geplante chirurgische Eingriffe wie Kolektomien vermieden werden. Die PID-CED-Diagnostik ermoglicht es, bei einem kleinen Anteil der CED-Patienten eine genetische Diagnose zu stellen und eine individualisierte Therapie zu beginnen.

Rezidivierende Bauchschmerzen bei Kindern sind ein haufiger Grund fur die Vorstellung beim Arzt. Aber nur selten haben die Beschwerden eine organische Ursache. Welche Basisdiagnostik hilft bei der Abklarung weiter? Was ist wenig hilfreich? Wann sollten Sie das Kind zu einem Spezialisten fur padiatrische Gastroenterologie uberweisen?

Die Zahl der Kinder und Jugendlichen mit chronisch entzundlicher Darmerkrankung (CED) steigt, v. a. in Landern mit westlichem Lebensstil. Weil die fruhzeitige Diagnose und Therapie den Krankheitsverlauf masgeblich beeinflussen, ist die enge Zusammenarbeit zwischen Kinderarzt und padiatrischen Gastroenterologen notwendig. Nach Ausschluss infektioser Ursachen muss bei chronischen oder rezidivierenden Beschwerden eine CED ausgeschlossen werden. Erhohte Konzentrationen der Inflammationsmarker im Stuhl (z. B. Calprotectin) sind sehr sensitiv bei aktiver CED, aber nicht spezifisch. Uberwiegend beinhaltet die Diagnostik die Endoskopie und die Dunndarmdarstellung. Neben medikamentoser und Ernahrungstherapie bei Morbus Crohn stehen neue Biologika und Immunmodulatoren zur Verfugung. Grundlage des Einsatzes sind Kenntnis der Wirkungen, potenziellen Nebenwirkungen, Interaktionen und individueller Risikofaktoren, die exakte diagnostische Einordnung der CED sowie die Bestimmung der Krankheitsaktivitat.

Background The COVID-19 pandemic affects clinical care, daily life and wellbeing of patients with IBD. During the contact restrictions, we realized anxiety among our IBD patients and unmet needs for healthcare. We investigated patient’s experience with telemedicine (TM) during the pandemic, their interest in future TM use, and their preference regarding a qualified IBD Nurse-led or a Medical Doctor-led (MD-led) teleconsultation at a large German IBD center. Methods Pediatric and adult patients who attended the IBD unit at least once between 7/2018 and 6/2020) were invited to a prospective survey (KoCo19-CED-1). Questions included items on IBD (phenotype, treatment and disease activity), comorbidities, healthcare utilization, demographic and socioeconomic factors, psychological burden and IBD-related quality of life during the COVID-19 pandemic. This sub-analysis presents patient’s experience with TM and their preference for a contact with an IBD Nurse. Results Of 820 identified IBD cases, 504 (62%) patients and/or their parents completed the survey between mid-July to mid-October 2020; 86 were children (aged 6 to 18 years) and 418 were adults (up to 85 years); 58.7% had Crohn’s disease and 35.7% Ulcerative Colitis. Current treatment with any immunosuppressive medication (mono- or combo-therapy with immunomodulators, biologics, JAK-inhibitors and/or corticosteroids) were reported by 79.6% (401/504) of patients. During the pandemic, an in-person visit was substituted with TM by an IBD Nurse or a medical doctor (MD) in 58 (11.6%) and 29 (5.8%) of the patients, with high satisfaction (88.5% vs 92.1 %, respectively, n.s.). Half of the patients (n=246) showed interest in future TM, thereof 60.2% preferred consultation with a MD, 1,6% with an IBD Nurse and 38.2% expressed no preference. Of patients with prior experience with an IBD Nurse-led TM (n=38), 96% are interested to use TM in the future. Rejection of future TM was related to no TM experience (p=0.001), having Crohn’s disease (p=0.032), receiving biologics (p=0.004), and self- or non-employment status (p=0.003), but not to gender, age, self-reported disease activity or disease duration. Conclusion Patient acceptance of TM is high, particular in those with previous TM experience, regardless of performed by MD or IBD Nurse. Our data support the statement on e-health in the N-ECCO 2018 Consensus giving an advanced IBD Nurse alongside with MD a key role to improve IBD care.

In some patients with extreme phenotypes of inflammatory bowel disease (IBD; in particular in those with infantile or very early onset IBD with

Objectives: The inflammatory process in Crohn disease (CD) involves the visceral fat, characterized by adipocyte hyperplasia and altered adipose tissue and serum concentrations of tumor necrosis factor (TNF), leptin, adiponectin and resistin. We investigated the effect of anti-TNF therapy with infliximab (IFX) on serum adipokine levels in pediatric CD. Methods: Serum concentrations of resistin (ng/mL), leptin (ng/mL), and total adiponectin (mu g/mL) were assessed by enzyme-linked immunosorbent assays (ELISA) in 18 pediatric CD patients (mean age 15.0 +/- 1.5 years) before first, second, and fourth IFX infusion (weeks 0, 2, and 14) and compared with baseline values from sex- and BMI-matched healthy controls (HC, mean age 13.4 +/- 1.6 years). Results: At baseline, CD patients (mean age 15.0 +/- 1.5 years, 10 of 18 boys) compared with HC (13.4 +/- 1.6 years, 7 of 15 boys) had higher resistin levels (median 14.7 ng/mL, range 5.1-50.5 vs 7.3 ng/mL, 0.5-14.5);P = 0.0002). At weeks 2 and 14, resistin decreased to 6.9 ng/mL (2.9-16.8) (P < 0.0001) and 9.2 ng/mL (4.1-20.6;P = 0.0011), respectively. Leptin and adiponectin were comparable between patients and HC at baseline. Leptin increased in girls from 9.5 ng/mL (4.0-30.1) to 16.0 ng/mL (7.9-35.2;P = 0.0156) and 17.2 ng/mL (10.8-26.8;P = 0.1953) at weeks 0, 2, and 14 respectively;with a trend in boys from 2 (0.6-12.9) to 2.8 (1.7-8.6;P = 0.0840) and 3.3 (1.34.6;P = 0.1309). Adiponectin peaked initially from 7.8 mu g/mL (4.6-11.9) at week 0 to 9.2 mu g/mL (4.1-20.7;P = 0.0005) at week 2 and thereafter fell to 6.5 mu g/mL (3.0-12.7;P = 0.0182) at week 14. Conclusions: TNF blockade is associated with changes in circulating adipokines. The marked early increase of the potent anti-inflammatory adiponectin may contribute to the rapid response to IFX in CD.

Neutrophils are critical and short-lived mediators of innate immunity that require constant replenishment. Their differentiation in the bone marrow requires extensive cytoplasmic and nuclear remodeling, but the processes governing these energy-consuming changes are unknown. While previous studies show that autophagy is required for differentiation of other blood cell lineages, its function during granulopoiesis has remained elusive. Here, we have shown that metabolism and autophagy are developmentally programmed and essential for neutrophil differentiation in vivo. Atg7-deficient neutrophil precursors had increased glycolytic activity but impaired mitochondrial respiration, decreased ATP production, and accumulated lipid droplets. Inhibiting autophagy-mediated lipid degradation or fatty acid oxidation alone was sufficient to cause defective differentiation, while administration of fatty acids or pyruvate for mitochondrial respiration rescued differentiation in autophagy-deficient neutrophil precursors. Together, we show that autophagy-mediated lipolysis provides free fatty acids to support a mitochondrial respiration pathway essential to neutrophil differentiation.

Objective Patients with Niemann–Pick disease type C1 (NPC1), a lysosomal lipid storage disorder that causes neurodegeneration and liver damage, can present with IBD, but neither the significance nor the functional mechanism of this association is clear. We studied bacterial handling and antibacterial autophagy in patients with NPC1. Design We characterised intestinal inflammation in 14 patients with NPC1 who developed IBD. We investigated bacterial handling and cytokine production of NPC1 monocytes or macrophages in vitro and compared NPC1-associated functional defects to those caused by IBD-associated nucleotide-binding oligomerization domain-containing protein 2 (NOD2) variants or mutations in X-linked inhibitor of apoptosis (XIAP). Results Patients with the lysosomal lipid storage disorder NPC1 have increased susceptibility to early onset fistulising colitis with granuloma formation, reminiscent of Crohn’s disease (CD). Mutations in NPC1 cause impaired autophagy due to defective autophagosome function that abolishes NOD2-mediated bacterial handling in vitro similar to variants in NOD2 or XIAP deficiency. In contrast to genetic NOD2 and XIAP variants, NPC1 mutations do not impair NOD2-receptorinteracting kinase 2 (RIPK2)-XIAP-dependent cytokine production. Pharmacological activation of autophagy can rescue bacterial clearance in macrophages in vitro by increasing the autophagic flux and bypassing defects in NPC1. Conclusions NPC1 confers increased risk of earlyonset severe CD. Our data support the concept that genetic defects at different checkpoints of selective autophagy cause a shared outcome of CD-like immunopathology linking monogenic and polygenic forms of IBD. Muramyl dipeptide-driven cytokine responses and antibacterial autophagy induction are parallel and independent signalling cascades downstream of the NOD2-RIPK2-XIAP complex.

Item does not contain fulltext IL-37 is a fundamental inhibitor of innate immunity. Human IL-37 has a caspase-1 cleavage site and translocates to the nucleus upon LPS stimulation. Here, we investigated whether caspase-1 processing affects IL-37-mediated suppression of LPS-induced cytokines and the release from cells by analyzing a caspase-1 cleavage site mutant IL-37 (IL-37D20A). Nuclear translocation of IL-37D20A is significantly impaired compared with WT IL-37 in transfected cells. LPS-induced IL-6 was decreased in cells expressing WT IL-37 but not IL-37D20A. The function of IL-37 in transfected bone marrow-derived macrophages is nucleotide-binding oligomerization domain-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome-dependent, because IL-37 transfection in apoptosis-associated speck-like protein containing a carboxyl-terminal caspase recruitment domain- and NLRP3-deficient cells does not reduce levels of IL-6 and IL-1beta upon LPS stimulation. IL-37-expressing macrophages release both precursor and mature IL-37, but only the externalization of mature IL-37 was dependent on ATP. Precursor and mature IL-37 was also secreted from human dendritic cells and peripheral blood mononuclear cells. To determine whether IL-37 is active in the extracellular compartment, we pretreated IL-37 transgenic mice with IL-37-neutralizing antibodies before LPS challenge. In IL-37-expressing mice, neutralizing IL-37 antibodies reversed the suppression of LPS-induced serum IL-6. In contrast, the addition of neutralizing antibody did not reverse suppression of LPS-induced IL-6 in mouse macrophages transfected with IL-37. Although caspase-1 is required for nuclear translocation of intracellular IL-37 and for secretion of mature IL-37, the release of the IL-37 precursor is independent of caspase-1 activation. IL-37 now emerges as a dual-function cytokine with intra- and extracellular properties for suppressing innate inflammation.

Schwerd et al. report a novel homozygous missense substitution in the cytokine co-receptor GP130 encoded by IL6ST. This is associated with defective IL-6, IL-11, OSM, and IL-27 signaling and causes immunodeficiency and skeletal abnormalities with similarities to STAT3 hyper-IgE syndrome., Multiple cytokines, including interleukin 6 (IL-6), IL-11, IL-27, oncostatin M (OSM), and leukemia inhibitory factor (LIF), signal via the common GP130 cytokine receptor subunit. In this study, we describe a patient with a homozygous mutation of IL6ST (encoding GP130 p.N404Y) who presented with recurrent infections, eczema, bronchiectasis, high IgE, eosinophilia, defective B cell memory, and an impaired acute-phase response, as well as skeletal abnormalities including craniosynostosis. The p.N404Y missense substitution is associated with loss of IL-6, IL-11, IL-27, and OSM signaling but a largely intact LIF response. This study identifies a novel immunodeficiency with phenotypic similarities to STAT3 hyper-IgE syndrome caused by loss of function of GP130.

Background & Aims Severe forms of inflammatory bowel disease (IBD) that develop in very young children can be caused by variants in a single gene. We performed whole-exome sequence (WES) analysis to identify genetic factors that might cause granulomatous colitis and severe perianal disease, with recurrent bacterial and viral infections, in an infant of consanguineous parents. Methods We performed targeted WES analysis of DNA collected from the patient and her parents. We validated our findings by a similar analysis of DNA from 150 patients with very-early-onset IBD not associated with known genetic factors analyzed in Toronto, Oxford, and Munich. We compared gene expression signatures in inflamed vs noninflamed intestinal and rectal tissues collected from patients with treatment-resistant Crohn's disease who participated in a trial of ustekinumab. We performed functional studies of identified variants in primary cells from patients and cell culture. Results We identified a homozygous variant in the tripartite motif containing 22 gene (TRIM22) of the patient, as well as in 2 patients with a disease similar phenotype. Functional studies showed that the variant disrupted the ability of TRIM22 to regulate nucleotide binding oligomerization domain containing 2 (NOD2)−dependent activation of interferon-beta signaling and nuclear factor−κB. Computational studies demonstrated a correlation between the TRIM22−NOD2 network and signaling pathways and genetic factors associated very early onset and adult-onset IBD. TRIM22 is also associated with antiviral and mycobacterial effectors and markers of inflammation, such as fecal calprotectin, C-reactive protein, and Crohn's disease activity index scores. Conclusions In WES and targeted exome sequence analyses of an infant with severe IBD characterized by granulomatous colitis and severe perianal disease, we identified a homozygous variant of TRIM22 that affects the ability of its product to regulate NOD2. Combined computational and functional studies showed that the TRIM22-NOD2 network regulates antiviral and antibacterial signaling pathways that contribute to inflammation. Further study of this network could lead to new disease markers and therapeutic targets for patients with very early and adult-onset IBD.

Inborn errors of the intestinal epithelial barrier function as well as the innate and adaptive mucosal immune responses toward the intestinal microbiota are a group of genetic disorders that confer susceptibility to monogenic and syndromal forms of inflammatory bowel disease (IBD). There is a continuous spectrum of genetic susceptibility from monogenic causative variants with complete Mendelian inheritance, over NOD2 variants with moderate penetrance to minute penetrance in most common susceptibility variants predisposing to conventional polygenic IBD. We discuss advances to understand monogenic IBD and review recently identified genetic defects. We describe an integrative model for genetic susceptibility variants of conventional IBD and monogenic IBD-like intestinal inflammation in the context of microbial commensal colonization and infection susceptibility.

The ATPase retinoid acid-inducible gene (RIG)-I senses viral RNA in the cytoplasm of infected cells and subsequently activates cellular antiviral defense mechanisms. RIG-I recognizes molecular structures that discriminate viral from host RNA. Here, we show that RIG-I ligands require base-paired structures in conjunction with a free 5′-triphosphate to trigger antiviral signaling. Hitherto unavailable chemically synthesized 5′-triphosphate RNA ligands do not trigger RIG-I-dependent IFN production in cells, and they are unable to trigger the ATPase activity of RIG-I without a base-paired stretch. Consistently, immunostimulatory RNA from cells infected with a virus recognized by RIG-I is sensitive to double-strand, but not single-strand, specific RNases. In vitro, base-paired stretches and the 5′-triphosphate bind to distinct sites of RIG-I and synergize to trigger the induction of signaling competent RIG-I multimers. Strengthening our model of a bipartite molecular pattern for RIG-I activation, we show that the activity of supposedly “single-stranded” 5′-triphosphate RNAs generated by in vitro transcription depends on extended and base-paired by-products inadvertently, but commonly, produced by this method. Together, our findings accurately define a minimal molecular pattern sufficient to activate RIG-I that can be found in viral genomes or transcripts.

Genetic and epigenetic plasticity allows tumors to evade single-targeted treatments. Here we direct Bcl2-specific short interfering RNA (siRNA) with 5'-triphosphate ends (3p-siRNA) against melanoma. Recognition of 5'-triphosphate by the cytosolic antiviral helicase retinoic acid-induced protein I (Rig-I, encoded by Ddx58) activated innate immune cells such as dendritic cells and directly induced expression of interferons (IFNs) and apoptosis in tumor cells. These Rig-I-mediated activities synergized with siRNA-mediated Bcl2 silencing to provoke massive apoptosis of tumor cells in lung metastases in vivo. The therapeutic activity required natural killer cells and IFN, as well as silencing of Bcl2, as evidenced by rescue with a mutated Bcl2 target, by site-specific cleavage of Bcl2 messenger RNA in lung metastases and downregulation of Bcl-2 protein in tumor cells in vivo. Together, 3p-siRNA represents a single molecule-based approach in which Rig-I activation on both the immune- and tumor cell level corrects immune ignorance and in which gene silencing corrects key molecular events that govern tumor cell survival.

PTEN hamartoma tumour syndrome (PHTS) is caused by heterozygous variants in PTEN and is characterised by tumour predisposition, macrocephaly, and cognition impairment. Bi-allelic loss of PTEN activity has not been reported so far and animal models suggest that bi-allelic loss of PTEN activity is embryonically lethal. Here, we report the identification of a novel homozygous variant in PTEN, NM_000314.4; c.545T>C; p.Leu182Ser, in two adolescent siblings with severe macrocephaly and mild intellectual disability. The variant is predicted to be damaging and is associated with significantly increased phospho-S6 downstream of PTEN. The absence of tumours in the two homozygous siblings as well as lack of symptoms of PHTS in the heterozygous carriers of the family suggest that this particular variant is functionally hypomorphic rather than deleterious.European Journal of Human Genetics advance online publication, 7 October 2015; doi:10.1038/ejhg.2015.209.