OBJECTIVES:Exclusive enteral nutrition (EEN) is the first-line treatment for pediatric Crohn's disease, but its mechanisms of action remain poorly understood. Our aim was to identify the mechanisms that could explain the anti-inflammatory effects of EEN, studying the nutritional composition and transforming growth factor-β (TGF-β) effects, in a mouse model of colitis. METHODS:Mice were treated with dextran sulfate sodium (DSS) to induce colitis. After DSS treatment, we compared two enteral nutrition formulas, and we evaluated the effect of TGF-β itself on clinical and microscopic inflammation, and intestinal permeability, by TGF-β-supplementation, -inhibition, or -deletion. Colonic crypts from DSS and EEN mice were cultured and their cellular properties were analyzed. RESULTS:Both EEN formulas improved weight recovery and disease activity index. In contrast, EEN mice treated with TGF-β formula presented faster weight recovery and decreased inflammatory parameters, with a normalized intestinal permeability, suggesting gut restitution and functionality. These functional improvements were not found in the absence of TGF-β in the formulas. Finally, organoids from colonic crypts treated with Modulen IBD® containing TGF-β showed enhanced survival and re-epithelialization capacity. CONCLUSIONS:Both EEN formulas have anti-inflammatory properties based on their nutritional composition. However, TGF-β plays a significant role in intestinal functional restitution.

Budesonide is a glucocorticoid with strong topical anti-inflammatory properties and minimal systemic effects due to extensive first-pass hepatic metabolism. It is designed for targeted delivery within the gastrointestinal (GI) tract and is available in oral and rectal formulations. Budesonide is indicated for various GI disorders, including Crohn's disease (CD, ulcerative colitis (UC) and eosinophilic oesophagitis (EoE), with specific formulations approved for different disease locations and severities. This narrative review evaluates the pharmacological profile, clinical applications and guideline recommendations surrounding the use of budesonide in both paediatric and adult GI disorders. Evidence from randomised controlled trials and real-world studies supports the efficacy of budesonide in inducing remission in mild to moderate ileocaecal CD. It is recommended by ESPGHAN/ECCO [European Society for Pediatric Gastroenterology, Hepatology, and Nutrition/European Crohn's and Colitis Organisation] guidelines as a therapeutic alternative in selected paediatric patients when exclusive enteral nutrition is not feasible. In UC, budesonide-multimatrix tablets and rectal foam formulations may be effective for distal and left-sided disease, though they are generally less effective than systemic corticosteroids or 5-aminosalicylic acid and are reserved for patients with contraindications to standard therapies. In EoE, topical swallowed budesonide has shown promising results in inducing clinical and histological remission, with increasing data supporting its use in children. Although budesonide is associated with fewer systemic adverse effects, long-term use may still pose risks such as growth suppression and hypothalamic-pituitary adrenal axis suppression, necessitating careful monitoring. Budesonide offers a valuable treatment option when used in alignment with disease phenotype, formulation properties and patient-specific considerations.

Inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), are characterized by intestinal inflammation and barrier dysfunction. While disruption of the intestinal barrier contributes to the pathogenesis of IBD, yet how colonic inflammation alters small intestinal homeostasis remains poorly defined. Here, we demonstrate that three models of colitis, including 2,4,6-Trinitrobenzenesulfonic acid (TNBS), Dextran Sulfate Sodium (DSS), and oxazolone, induce paracellular barrier dysfunction in the small intestine, with model-specific immune profiles. Th1/Th17-skewed responses (TNBS and DSS) were associated with microbiota-dependent upregulation of myosin light chain kinase (MLCK), RORγt⁺ CD4⁺ T cell expansion, and elevated expression of Nod2, which was not observed under Th2-dominant (oxazolone) conditions. Inhibition of MLCK restored barrier function and suppressed inflammation in a CD4⁺ T cell-dependent manner. Using Nod2-deficient and 2939insC mutant mice, we showed Nod2 as a critical regulator of small intestinal permeability during colitis. Bone marrow chimeras revealed compartment-specific roles of Nod2, with non-hematopoietic Nod2 sufficient to preserve epithelial integrity, while hematopoietic Nod2 expression is required to limit cytokine-mediated inflammation. Moreover, MLCK inhibition ameliorated intestinal lesions only in mice with Nod2 deficiency in the hematopoietic compartment. Finally, microbiota transfer experiments ruled out a causal role for dysbiosis in driving small intestinal permeability defects in Nod2-deficient mice. These findings uncover a Nod2-MLCK-CD4⁺ T cell axis linking colonic inflammation to small intestinal barrier dysfunction and highlight distinct immune-epithelial-microbial mechanisms shaping intestinal homeostasis during colitis.

Background: There are great changes in cystic fibrosis (CF) disease following introduction of modulator treatments. We aimed to focus on the evolution of hepatobiliary involvement following lumacaftor-ivacaftor (LI) and elexacaftor-tezacaftor-ivacaftor (ETI) initiation. Methods: A retrospective monocentric observational study included 62 CF children treated with CFTR modulators. Data were collected at initiation and after one year of treatment. The primary objective was to describe the evolution of hepatobiliary involvement under CFTR modulator treatment. Results: We identified hepatobiliary involvement before treatment in 37 patients (59.7 %). Fifteen had persistently (during >6 months) elevated liver enzymes (mostly ALT); 17 had abnormal ultrasound including 3 with nodular liver and 3 with pathological elastography; 5 had isolated splenomegaly. Biliary involvement was found in 19 patients. The evolution of hepatic parameters in the overall population was not significant (p > 0.05). However, we observed a trend towards improvement in laboratory values under treatment. There was only one inaugural diagnosis of nodular liver under LI and none under ETI. All patients had preserved liver function (PT>50 %). Conclusions: We did not find a significant improvement or worsening of hepatobiliary involvement under CFTR modulators. We hypothesize that it could be stabilized with these treatments, but this will need confirmation through further studies with longer follow-up and larger cohorts. The other hypothesis proposed is that biological monitoring may not be an accurate assessment of the hepatobiliary response to modulators. This study supports the safety of CFTR modulator use.

Anaemia is a frequent consequence of many gastrointestinal (GI) diseases in children and it can even be the initial presenting symptom of underlying chronic GI disease. The definition of anaemia is age and gender-dependent and it can be classified based on pathophysiology, red cell morphology, and clinical presentation. Although nutritional deficiencies, including GI malabsorption of nutrients and GI bleeding, play a major role, other pathophysiologic mechanisms seen in chronic GI diseases, whether inflammatory (e.g., inflammatory bowel disease) or not (e.g., coeliac disease and dysmotility), are causing anaemia. Drugs, such as proton pump inhibitors, mesalamine, methotrexate and sulfasalazine, are also a potential cause of anaemia. Not uncommonly, due to a combination of factors, such as iron deficiency and a chronic inflammatory state, the underlying pathophysiology may be difficult to decipher and a broad diagnostic work-up is required. The goal of treatment is correction of anaemia by supplementation of iron and vitamins. The first therapeutic step is to treat the underlying cause of anaemia including bleeding control, restoration of intestinal integrity and reduction of inflammatory burden. The route of iron and vitamin supplementation is guided by the severity of anaemia.

The aim of this review is to summarize the prevalence, etiology, pathogenesis, diagnosis, and treatments currently available for small intestinal bacterial overgrowth (SIBO) in children. SIBO is a clinical entity characterized by the presence of an excessive number of bacteria in the small bowel leading to several nonspecific gastrointestinal symptoms due to malabsorption and malnutrition, such as bloating, flatulence, belching, diarrhea, abdominal pain, nausea, steatorrhea, fatigue and stunted growth. Initially thought to develop specifically in the context of abnormal or postsurgical gastrointestinal anatomy, it has then been recognized that it can be associated with other nonsurgical conditions, such as gastrointestinal dysmotility, disorders of gut-brain interactions and chronic use of drugs. The uncertainty regarding the exact cut-off of excessive number of bacteria in the small bowel has led to the absence of a universally accepted definition of SIBO making well-designed research to assess the best diagnostic and therapeutic approaches challenging. Current available diagnostic tools includes duodenal/jejunal aspirate with culture and hydrogen breath tests, which all have some limitations and pitfalls that prevent accurate sampling. The treatment goal should be to treat the underlying causes, restore the healthy intestinal microflora, relieve the symptoms and address the associated complications. The use of antibiotics represents the treatment cornerstore. However, they are commonly used despite the scarce published evidence and the absence of agreement on the dose and duration of the treatment. Currently, data on best diagnostic and therapeutic strategies in children remain lacking. Novel diagnostic approaches for SIBO are emerging and may facilitate further research.

Understanding the interplay between biology and mechanics in tissue architecture is challenging, particularly in terms of 3D tissue organization. Addressing this challenge requires a biological model enabling observations at multiple levels from cell to tissue, as well as theoretical and computational approaches enabling the generation of a synthetic model that is relevant to the biological model and allowing for investigation of the mechanical stresses experienced by the tissue. Using a monolayer human colon epithelium organoid as a biological model, freely available tools (Fiji, Cellpose, Napari, Morphonet, or Tyssue library), and the commercially available Abaqus FEM solver, we combined vertex and FEM approaches to generate a comprehensive viscoelastic finite element model of the human colon organoid and demonstrated its flexibility. We imaged human colon organoid development for 120 hours, following the evolution of the organoids from an immature to a mature morphology. According to the extracted architectural/geometric parameters of human colon organoids at various stages of tissue architecture establishment, we generated organoid active vertex models. However, this approach did not consider the mechanical aspects involved in the organoids’ morphological evolution. Therefore, we applied a finite element method considering mechanical loads mimicking osmotic pressure, external solicitation, or active contraction in the vertex model by using the Abaqus FEM solver. Integration of finite element analysis (FEA) into the vertex model achieved a better fit with the biological model. Therefore, the FEM model provides a basis for depicting cell shape, tissue deformation, and cellular-level strain due to imposed stresses. In conclusion, we demonstrated that a combination of vertex and FEM approaches, combining geometrical and mechanical parameters, improves modeling of alterations in organoid morphology over time and enables better assessment of the mechanical cues involved in establishing the architecture of the human colon epithelium.

Patients with familial adenomatous polyposis (FAP) harbor mutations in the APC gene and will develop adenoma and early colorectal cancer. There is no validated treatment, and animal models are not sufficient to study FAP. Our aim was to investigate the early events associated with FAP using the intestinal organoid model in a single-center study using biopsies from nonadenomatous and adenomatous colonic mucosa of FAP patients and from healthy controls (HCs). We analyzed intestinal stem cell (ISC) activity and regulation through organoid development and expression of mRNA and proteins, as well as within colonic crypts. We used several compounds to regulate the signaling pathways controlling ISCs, such as WNT, EGFR, PI3K-AKT, TGF-beta, yes-associated protein (YAP), and protease-activated receptors. In addition to their high proliferative capacity, nonadenomatous and adenomatous organoids were characterized by cysts and cysts with buds, respectively, suggesting abnormal maturation. Adenomatous organoids were enriched in the stem cell marker LGR5 and dependent on EGF and TGF-beta for their growth. Downstream of EGFR, AKT, beta-catenin, and YAP were found to be activated in the adenomatous organoids. While the p110 beta isoform of PI3K was predominant in adenomatous organoids and essential for their growth, p110 alpha was associated with the immature state of nonadenomatous organoids. We conclude that organoids offer a relevant model for studying FAP, and this work highlights abnormal behaviors of immature cells in both nonadenomatous and adenomatous mucosa of FAP patients, which could be targeted therapeutically. (c) 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Crohn's disease (CD) and ulcerative colitis (UC), the two main subtypes of inflammatory bowel diseases (IBD), are chronic relapsing inflammatory disorders of the gastrointestinal tract. IBD are multifactorial diseases with a complex etiology, involving an intricate interaction between environmental and genetic factors. Since the discovery of NOD2 gene in 2001, genome-wide association studies have reported more than 200 IBD susceptibility loci. The strongest associations highlighted five main pathways as altered in IBD: bacterial sensing (NOD2), autophagy (ATG16L1, IRGM…), endoplasmic reticulum stress (XBP1, ARG2…), Th-17 immune pathway (IL23-receptor), and the vitamin D receptors (VDR). The pathophysiology of IBD results from an abnormal immune response toward an altered gut microbiota. Although the primum movens remains unknown, an increased intestinal permeability is clearly involved in the genesis of this abnormal crosstalk, leading to whole tissue inflammation. Thus, an excessive intestinal permeability, or "leaky gut", has been described to precede the development of CD. Moreover, in IBD, intestinal permeability is described to be a sensitive prognostic indicator of relapse in patients with quiescent IBD. Thus, the aim of this review is to highlight the molecular and cellular mechanisms by which the main pathways associated with IBD could contribute to alter the intestinal permeability to favour and/or exacerbate chronic inflammation, leading to debilitating diseases.

Graft versus host disease (GVHD) is a complication that frequently occurs after haematopoietic stem cell transplantation and concerns many children in paediatric haematology-oncology and bone marrow transplantation departments. It can affect various organs, with the skin, gastrointestinal tract and liver being the most commonly involved. To confirm intestinal GVHD and to rule out differential diagnoses endoscopy is frequently needed. Currently, there are no specific consensus recommendations concerning the best method for endoscopic exploration and medical management of this disease in children, with limited studies available, including a low number of patients. Sigmoidoscopy could be initially proposed under sedation. If sigmoidoscopy is normal or if a general anaesthesia is required, colonoscopy and upper endoscopy should be planned, avoiding duodenal biopsy because of the risk of duodenal haematoma. Regarding therapeutic options, corticosteroids are the first-line treatment for GVHD. Ruxolitinib, a Janus kinase inhibitor, is indicated for children aged 12 years and older with acute or chronic GVHD who have an inadequate response to corticosteroids or other systemic therapies. Nutritional support has a key role in the management of intestinal GVHD and should be considered to guarantee the best possible evolution of intestinal GVHD.

Background: Heterozygous familial hypercholesterolemia (HeFH) predisposes to premature cardiovascular diseases. Since 2015, the European Atherosclerosis Society has advocated initiation of statins at 8 -10 years of age and a low -density lipoprotein cholesterol (LDL-C) target of <135 mg/dL. Longitudinal data from large databases on pharmacological management of pediatric HeFH are lacking. Objective: Here, we describe treatment patterns and LDL-C goal attainment in pediatric HeFH using longitudinal real -world data. Methods: This was a retrospective and prospective multicenter cohort study (2015 -2021) of children with HeFH, diagnosed genetically or clinically, aged <18 years, and followed up in the National French Registry of FH (REFERCHOL). Data on the study population as well as treatment patterns and outcomes are summarized as mean +/- SD. Results: We analyzed the data of 674 HeFH children (age at last visit: 13.1 +/- 3.6 years; 82.0 % >= 10 years; 52.5 % females) who were followed up for a mean of 2.8 +/- 3.5 years. Initiation of lipid -lowering therapy was on average at 11.8 +/- 3.0 years of age for a duration of 2.5 +/- 2.8 years. At the last visit, among patients eligible for treatment (573), 36 % were not treated, 57.1 % received statins alone, 6.4 % statins with ezetimibe, and 0.2 % ezetimibe alone. LDL-C was 266 +/- 51 mg/dL before treatment and 147 +/- 54 mg/dL at the last visit (-44.7 %) in treated patients. Regarding statins, 3.3 %, 65.1 %, and 31.6 % of patients received high-, moderate-, and low -intensity statins, respectively. Overall, 59 % of children on statin therapy alone and 35.1 % on bitherapy did not achieve the LDL-C goal; fewer patients in the older age group did not reach the treatment goal. Conclusion: Pediatric patients with FH followed up in specialist lipid clinics in France receive late treatment, undertreatment, or suboptimal treatment and half of them do not reach the therapeutic LDL-C goal. Finding a more efficient framework for linking scientific evidence to clinical practice is needed. (c) 2024 French Society of Pediatrics. Published by Elsevier Masson SAS. All rights reserved.

Background Perinatal exposure to titanium dioxide (TiO 2 ), as a foodborne particle, may influence the intestinal barrier function and the susceptibility to develop inflammatory bowel diseases (IBD) later in life. Here, we investigate the impact of perinatal foodborne TiO 2 exposure on the intestinal mucosal function and the susceptibility to develop IBD-associated colitis. Pregnant and lactating mother mice were exposed to TiO 2 until pups weaning and the gut microbiota and intestinal barrier function of their offspring was assessed at day 30 post-birth (weaning) and at adult age (50 days). Epigenetic marks was studied by DNA methylation profile measuring the level of 5-methyl-2′-deoxycytosine (5-Me-dC) in DNA from colic epithelial cells. The susceptibility to develop IBD has been monitored using dextran-sulfate sodium (DSS)-induced colitis model. Germ-free mice were used to define whether microbial transfer influence the mucosal homeostasis and subsequent exacerbation of DSS-induced colitis. Results In pregnant and lactating mice, foodborne TiO 2 was able to translocate across the host barriers including gut, placenta and mammary gland to reach embryos and pups, respectively. This passage modified the chemical element composition of foetus, and spleen and liver of mothers and their offspring. We showed that perinatal exposure to TiO 2 early in life alters the gut microbiota composition, increases the intestinal epithelial permeability and enhances the colonic cytokines and myosin light chain kinase expression. Moreover, perinatal exposure to TiO 2 also modifies the abilities of intestinal stem cells to survive, grow and generate a functional epithelium. Maternal TiO 2 exposure increases the susceptibility of offspring mice to develop severe DSS-induced colitis later in life. Finally, transfer of TiO 2 -induced microbiota dysbiosis to pregnant germ-free mice affects the homeostasis of the intestinal mucosal barrier early in life and confers an increased susceptibility to develop colitis in adult offspring. Conclusions Our findings indicate that foodborne TiO 2 consumption during the perinatal period has negative long-lasting consequences on the development of the intestinal mucosal barrier toward higher colitis susceptibility. This demonstrates to which extent environmental factors influence the microbial-host interplay and impact the long-term mucosal homeostasis.

The tremendous and exponential production of plastics as well as its poor recycling leads to massive release in the environment questioning their outcomes on human health. Plastics are degraded into micro-plastic (MPL) and nano-plastic (NPL) that undergo weathering. MPL and NPL enter the human food chain via contaminated food, when animals are bred or vegetables grew on in plastic polluted environment and through the degradation of plastics food packaging. Ingested MPL or NPL can pass through epithelial barrier. This study focuses on consequences of oral perinatal exposure to polystyrene 50nm pristine or weathered (w) on intestinal disorders onset in offspring. Mouse were forced fed daily with 1.25mg of PS50 or PS50w starting at 15 days of gestation until pups weaned (Post Natal Day PND21). Oral tolerance protocol was induced at PND15 (nutritional switch) with ovalbumin (OVA) whereas DSS-induced colitis was performed in PND63 offspring. PS50 nor PS50w perinatal exposure did impair tolerance or immunization to OVA at PND15 in male or females. However, PS50 and PS50w perinatal exposure significantly worsened macroscopic score of DSS-induced colitis in both sexes. Perinatal exposure to PS50w appeared to be even more deleterious than PS50 for colitis exacerbation in males. In conclusion, early life exposure to PS50 or PS50w has long-lasting consequences on gut physiology by increasing the colonic severity of colitis while it does not modify oral tolerance establishment in early life. Those preliminary results questioned the kinetic of perinatal PS50 and PS50w exposure outcome over the life course and introduce the notion of imprinting. ### Competing Interest Statement The authors have declared no competing interest.

In 2019, the French National Authority for Health (Haute Autorit ⠂e de Sant ⠂e, HAS) published guidelines on the diagnosis of undernutrition. The present article focuses on the impact of switching from the 2012 guidelines of the Nutrition Committee of the French Paediatric Society (CNSFP) to the HAS guidelines on the frequency of hospital undernutrition in children. We selected for the period 2010-2019 from the ePINUT database: (1) all children aged more than 2 years with (2) clinically confirmed nutritional status in (3) French sites. The frequency of undernutrition was 15.4% vs. 28.8% using the CNSFP and HAS criteria, respectively (p < 0.01; n = 6304). When compared to non-malnourished children regardless of the criteria used, malnourished children: (1) stayed longer in hospital (CNSFP: 9.0 & PLUSMN; 11.8 vs. 6.5 & PLUSMN; 8.7 days, p < 0.01; HAS: 7.8 & PLUSMN; 10.1 vs. 6.4 & PLUSMN; 8.4 days, p < 0.01), (2) gained more weight during hospitalization (% of weight at admission) (CNSFP: +1.4 & PLUSMN; 4.1 vs. -0.3 & PLUSMN; 3.5%, p < 0.01; HAS: +2.3 & PLUSMN; 4.7 vs. -0.1 & PLUSMN; 3.4%, p < 0.01), and (3) received nutritional support more frequently during hospitalization (CNSFP: 20% vs. 5%, p < 0.01; HAS: 13% vs. 4%, p < 0.01). Switching to the HAS guidelines resulted in an almost twofold higher frequency of undernutrition in hospitalized children. Initiation of nutritional care remained low considering the nutritional status. The present study warrants interventional studies to determine which children may benefit more from nutritional therapy to improve their outcome. & COPY; 2022 French Society of Pediatrics. Published by Elsevier Masson SAS. All rights reserved.

Le gluten est une protéine contenue dans différentes céréales comme le blé, le seigle et l’orge. La partie toxique de cette protéine est la gliadine. Chez certains individus génétiquement prédisposés porteurs des allèles HLA DQ2 et/ou DQ8, la gliadine va déclencher une réponse immunitaire anormale à l’origine de maladie cœliaque. La maladie cœliaque est une maladie auto-immune diagnostiquée en présence d’auto-anticorps spécifiques et d’anomalies histologiques duodénales. Il existe d’autres pathologies liées à la consommation de gluten comme l’allergie au blé et l’hypersensibilité au gluten non cœliaque. L’allergie au blé est une entité bien définie avec un mécanisme IgE dépendant, des tests diagnostiques (IgE anti-blé et prick-tests) et une prise en charge connus. Par contre, l’hypersensibilité au gluten non cœliaque est une entité d’identification plus récente, rapportée souvent par les patients en raison de leurs symptômes, sans test diagnostique spécifique ; des experts ont proposé un challenge gluten versus placebo afin de préciser les personnes dont les troubles intestinaux et extra-intestinaux pourraient être améliorés par une alimentation sans gluten (ASG). Une ASG est indiquée dans la maladie cœliaque, à vie. Dans l’allergie au blé, elle est stricte mais l’allergie disparaît souvent chez l’enfant d’âge scolaire, permettant une réintroduction. Pour l’hypersensibilité au gluten non cœliaque, cette alimentation pourrait être moins stricte et transitoire. L’ASG et/ou sans caséine est parfois réalisée chez des personnes ayant des troubles du spectre autistique (TSA). Elle pourrait être efficace pour certains d’entre eux, mais elle n’est pas à recommander pour toutes les personnes ayant un TSA.