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BACKGROUND AND AIMS Inflammatory bowel disease (IBD) requires long-term drug therapy in most patients, posing a risk for adverse drug events with the need for discontinuation. In this study, we investigated adverse events (AE) necessitating drug discontinuation in pediatric and adolescent IBD patients. METHODS We used data prospectively collected from IBD patients below the age of 18 enrolled in the Swiss Inflammatory Bowel Disease Cohort Study (SIBDCS), namely demographic variables, medical characteristics, drug treatments and related AE. We analysed the frequency, type, and risk factors for AE necessitating drug discontinuation. RESULTS A total of 509 pediatric IBD patients fulfilled the inclusion criteria of which 262 (51.5%) were diagnosed with Crohn's disease (CD), 206 (40.5%) with ulcerative colitis (UC), and 41 (8%) with IBD-unclassified (IBD-U). In total, 132 (25.9%) presented with at least one drug-related AE that required drug cessation. Immunomodulators (methotrexate 29/120 (24.2%), azathioprine 57/372 (15.3%)) followed by tumor necrosis factor (TNF)-alpha antagonists (adalimumab 8/72 (11.1%), infliximab 22/227 (9.7%)) accounted for the highest proportions of AE necessitating treatment discontinuation. Treatment schemes with at least 3 concomitant drugs significantly amplified the risk for development of drug-related AE (OR = 2.50, 95%CI [1.50-4.17]) in all pediatric IBD patients. CONCLUSIONS Drug-related AE necessitating discontinuation are common in pediatric and adolescent inflammatory bowel disease patients. Caution needs to be taken in the case of concomitant drug use.

International audience; Establishing the relationship between gut microbiota and host health has become a main target of research in the last decade. Human gut microbiotaassociated animal models represent one alternative to human research, allowing for intervention studies to investigate causality. Recent cohort and in vitro studies proposed an altered gut microbiota and lactate metabolism with excessive H2 production as the main causes of infant colic. To evaluate H2 production by infant gut microbiota and to test modulation of gut colonizer lactose- and lactate-utilizer non-H2-producer, Cutibacterium avidum P279, we established and validated a gnotobiotic model using young germ-free rats inoculated with fecal slurries from infants younger than 3 months. Here, we show that infant microbiota-associated (IMA) rats inoculated with fresh feces from healthy (n = 2) and colic infants (n = 2) and fed infant formula acquired and maintained similar quantitative and qualitative fecal microbiota composition compared to the individual donor’s profile. We observed that IMA rats excreted high levels of H2, which were linked to a high abundance of lactate-utilizer H2-producer Veillonella. Supplementation of C. avidum P279 to colic IMA rats reduced H2 levels compared to animals receiving a placebo.Taken together, we report high H2 production by infant gut microbiota, whichmight be a contributing factor for infant colic, and suggest the potential ofC. avidum P279 in reducing the abdominal H2 production, bloating, and painassociated with excessive crying in colic infants.

The early intestinal colonization of functional microbial groups plays an essential role in infant gut health, with most studies targeting the initial colonization period from birth to 6 months of age. In a previous report, we demonstrated the metabolic cross-feeding of lactate and identified keystone species specified for lactate utilization in fecal samples of 40 healthy infants. We present here the extension of our longitudinal study for the period from 6 months to 2 years, with a focus on the colonization of functional groups involved in lactate metabolism and butyrate production. We captured the dynamic changes of the gut microbiota and reported a switch in the predominant lactate-producing and lactate-utilizing bacteria, from Veillonella producing propionate in the first year to Anaerobutyrycum hallii producing butyrate in the second year of life. The significant increase in butyrate producers and fecal butyrate concentration was also pinpointed to the weaning period between 6 and 10 months. Correlation analyses further suggested, for the first time, the metabolic cross-feeding of hydrogen in infants. In conclusion, our longitudinal study of 40 Swiss infants provides important insights into the colonization of functional groups involved in lactate metabolism and butyrate production in the first 2 years of life., Frontiers in Nutrition, 9, ISSN:2296-861X

INTRODUCTION A small but increasing number of patients with inflammatory bowel disease are diagnosed during childhood or adolescence, and disease distribution and severity at onset vary according to the age at diagnosis. Clinical factors present at the time of diagnosis can be predictive of the disease course. AIM The aim of this study was to characterize disease behavior and the cumulative complications and extraintestinal manifestations 10 years after the diagnosis and to assess their association with age at diagnosis. PATIENTS AND METHODS Data of patients participating with the Swiss IBD cohort study registry, a disease duration of 10 years and a complete data set were analyzed. The outcome was defined as the cumulative change of disease behavior, the occurrence of extra-intestinal manifestations or complications, and the necessity for medical or surgical interventions. RESULTS A total of 481 patients with Crohn's disease (CD) and 386 patients with ulcerative colitis (UC), grouped according to disease onset before 10, 17, 40, or after 40 years of age, were analyzed. Despite differences in sex, initial disease location, and smoking habits, at 10 years after the diagnosis, no difference was found regarding disease behavior in CD or regarding progression of disease extension in UC. Similarly, no age-of-onset-dependent cumulative need for medical or surgical therapies was found. However, higher rates of anemia and lower rates of arthralgia and osteopenia were found in both pediatric-onset CD and UC, and a tendency toward higher rates of stomatitis in pediatric-onset CD, and of primary sclerosing cholangitis and ankylosing spondylitis in pediatric-onset UC. CONCLUSION After 10 years of disease evolution, age at disease onset is not anymore associated with disease behavior but only with a small difference in the occurrence of specific extraintestinal manifestations and complications.

International audience

The high neuroactive potential of metabolites produced by gut microbes has gained traction over the last few years, with metagenomic-based studies suggesting an important role of microbiota-derived γ-aminobutyric acid (GABA) in modulating mental health. Emerging evidence has revealed the presence of the glutamate decarboxylase (GAD)-encoding gene, a key enzyme to produce GABA, in the prominent human intestinal genus Bacteroides. Here, we investigated GABA production by Bacteroides in culture and metabolic assays combined with comparative genomics and phylogenetics. A total of 961 Bacteroides genomes were analyzed in silico and 17 metabolically and genetically diverse human intestinal isolates representing 11 species were screened in vitro. Using the model organism Bacteroides thetaiotaomicron DSM 2079, we determined GABA production kinetics, its impact on milieu pH, and we assessed its role in mitigating acid-induced cellular damage. We showed that the GAD-system consists of at least four highly conserved genes encoding a GAD, a glutaminase, a glutamate/GABA antiporter, and a potassium channel. We demonstrated a high prevalence of the GAD-system among Bacteroides with 90% of all Bacteroides genomes (96% in human gut isolates only) harboring all genes of the GAD-system and 16 intestinal Bacteroides strains producing GABA in vitro (ranging from 0.09 to 60.84 mM). We identified glutamate and glutamine as precursors of GABA production, showed that the production is regulated by pH, and that the GAD-system acts as a protective mechanism against acid stress in Bacteroides, mitigating cell death and preserving metabolic activity. Our data also indicate that the GAD-system might represent the only amino acid-dependent acid tolerance system in Bacteroides. Altogether, our results suggest an important contribution of Bacteroides in the regulation of the GABAergic system in the human gut., Frontiers in Microbiology, 12, ISSN:1664-302X

Very-early-onset inflammatory bowel disease (VEO-IBD) is a heterogeneous phenotype associated with a spectrum of rare Mendelian disorders. Here, we perform whole-exome-sequencing and genome-wide genotyping in 145 patients (median age-at-diagnosis of 3.5 years), in whom no Mendelian disorders were clinically suspected. In five patients we detect a primary immunodeficiency or enteropathy, with clinical consequences (XIAP, CYBA, SH2D1A, PCSK1). We also present a case study of a VEO-IBD patient with a mosaic de novo, pathogenic allele in CYBB. The mutation is present in ~70% of phagocytes and sufficient to result in defective bacterial handling but not life-threatening infections. Finally, we show that VEO-IBD patients have, on average, higher IBD polygenic risk scores than population controls (99 patients and 18,780 controls; P, Adult forms of inflammatory bowel disease (IBD) are of a polygenic nature, but paediatric and very early onset (VEO) IBD also occur as monogenic forms. Here, using whole exome sequencing, the authors explore both the monogenic and polygenic contribution to VEO-IBD and characterize a rare somatic mosaic VEO-IBD patient.

Genetic defects that affect intestinal epithelial barrier function can present with very early-onset inflammatory bowel disease (VEOIBD). Using whole-genome sequencing, a novel hemizygous defect in NOX1 encoding NAPDH oxidase 1 was identified in a patient with ulcerative colitis-like VEOIBD. Exome screening of 1,878 pediatric patients identified further seven male inflammatory bowel disease (IBD) patients with rare NOX1 mutations. Loss-of-function was validated in p.N122H and p.T497A, and to a lesser degree in p.Y470H, p.R287Q, p.I67M, p.Q293R as well as the previously described p.P330S, and the common NOX1 SNP p.D360N (rs34688635) variant. The missense mutation p.N122H abrogated reactive oxygen species (ROS) production in cell lines, ex vivo colonic explants, and patient-derived colonic organoid cultures. Within colonic crypts, NOX1 constitutively generates a high level of ROS in the crypt lumen. Analysis of 9,513 controls and 11,140 IBD patients of non-Jewish European ancestry did not reveal an association between p.D360N and IBD. Our data suggest that loss-of-function variants in NOX1 do not cause a Mendelian disorder of high penetrance but are a context-specific modifier. Our results implicate that variants in NOX1 change brush border ROS within colonic crypts at the interface between the epithelium and luminal microbes.

A growing body of evidence supports the need for detailed attention to nutrition and diet in children with IBD. We aimed to define the steps in instituting dietary or nutritional management in light of the current evidence and to offer a useful and practical guide to physicians and dieticians involved in the care of paediatric IBD patients.

The metabolism of lactate is important for infant gut health and may lead to acute lactate and/or H2 accumulation, pain, and crying as observed in colicky infants. Functional human studies often faced ethical challenges due to invasive medical procedures; thus, in this study, we implemented PolyFermS fermentation models to mimic the infant proximal colon, which were inoculated with immobilized fecal microbiota of two 2-month-old infants. We investigated the impact of pH, retention time, and accumulation of dl-lactate on microbiota composition and metabolic activity. We found that a drop in pH from 6.0 to 5.0 led to increased LPB and decreased LUB concomitantly with lactate accumulation. Increasing the RT resulted in complete lactate consumption associated with increased LUB. Our data highlight for the first time the impact of key abiotic factors on the metabolism of lactate, which is an important intermediate product for ecology and infant health., The metabolism of lactate impacts infant gut health and may lead to acute accumulation of lactate and/or H2 associated with pain and crying of colicky infants. Because gut microbiota studies are limited due to ethical and safety concerns, in vitro fermentation models were developed as powerful tools to assess effects of environmental conditions on the gut microbiota. In this study, we established a continuous colonic fermentation model (PolyFermS), inoculated with immobilized fecal microbiota and mimicking the proximal colon of 2-month-old infants. We investigated the effects of pH and retention time (RT) on lactate metabolism and of lactate-utilizing bacteria (LUB) exhibiting little or no H2 production. We observed that a drop in pH from 6.0 to 5.0 increased the number of lactate-producing bacteria (LPB) and decreased LUB concomitantly with lactate accumulation. Increasing RT from 5 to 10 h at pH 5.0 resulted in complete lactate consumption associated with increased LUB. Supplementation with dl-lactate (60 mM) to mimic lactate accumulation promoted propionate and butyrate production with no effect on acetate production. We further demonstrated that lactate-utilizing Propionibacterium avidum was able to colonize the reactors 4 days after spiking, suggesting its ability to compete with other lactate-utilizing bacteria producing H2. In conclusion, we showed that PolyFermS is a suitable model for mimicking young infant colonic microbiota. We report for the first time pH and RT as strong drivers for composition and metabolic activity of infant gut microbiota, especially for the metabolism of lactate, which is a key intermediate product for ecology and infant health. IMPORTANCE The metabolism of lactate is important for infant gut health and may lead to acute lactate and/or H2 accumulation, pain, and crying as observed in colicky infants. Functional human studies often faced ethical challenges due to invasive medical procedures; thus, in this study, we implemented PolyFermS fermentation models to mimic the infant proximal colon, which were inoculated with immobilized fecal microbiota of two 2-month-old infants. We investigated the impact of pH, retention time, and accumulation of dl-lactate on microbiota composition and metabolic activity. We found that a drop in pH from 6.0 to 5.0 led to increased LPB and decreased LUB concomitantly with lactate accumulation. Increasing the RT resulted in complete lactate consumption associated with increased LUB. Our data highlight for the first time the impact of key abiotic factors on the metabolism of lactate, which is an important intermediate product for ecology and infant health.

The metabolism of lactate impacts infant gut health and may lead to acute accumulation of lactate and/or H2 associated with pain and crying of colicky infants. Because gut microbiota studies are limited due to ethical and safety concerns, in vitro fermentation models were developed as powerful tools to assess effects of environmental conditions on the gut microbiota. In this study, we established a continuous colonic fermentation model (PolyFermS), inoculated with immobilized fecal microbiota and mimicking the proximal colon of 2-month-old infants. We investigated the effects of pH and retention time (RT) on lactate metabolism and of lactate-utilizing bacteria (LUB) exhibiting little or no H2 production. We observed that a drop in pH from 6.0 to 5.0 increased the number of lactate-producing bacteria (LPB) and decreased LUB concomitantly with lactate accumulation. Increasing RT from 5 to 10 h at pH 5.0 resulted in complete lactate consumption associated with increased LUB. Supplementation with dl-lactate (60 mM) to mimic lactate accumulation promoted propionate and butyrate production with no effect on acetate production. We further demonstrated that lactate-utilizing Propionibacterium avidum was able to colonize the reactors 4 days after spiking, suggesting its ability to compete with other lactate-utilizing bacteria producing H2. In conclusion, we showed that PolyFermS is a suitable model for mimicking young infant colonic microbiota. We report for the first time pH and RT as strong drivers for composition and metabolic activity of infant gut microbiota, especially for the metabolism of lactate, which is a key intermediate product for ecology and infant health. IMPORTANCE: The metabolism of lactate is important for infant gut health and may lead to acute lactate and/or H2 accumulation, pain, and crying as observed in colicky infants. Functional human studies often faced ethical challenges due to invasive medical procedures; thus, in this study, we implemented PolyFermS fermentation models to mimic the infant proximal colon, which were inoculated with immobilized fecal microbiota of two 2-month-old infants. We investigated the impact of pH, retention time, and accumulation of dl-lactate on microbiota composition and metabolic activity. We found that a drop in pH from 6.0 to 5.0 led to increased LPB and decreased LUB concomitantly with lactate accumulation. Increasing the RT resulted in complete lactate consumption associated with increased LUB. Our data highlight for the first time the impact of key abiotic factors on the metabolism of lactate, which is an important intermediate product for ecology and infant health. ISSN:2379-5077

Background: The contemporary management of ambulatory ulcerative colitis (UC) continues to be challenging with ~20% of children needing a colectomy within childhood years. We thus aimed to standardize daily treatment of paediatric UC and inflammatory bowel diseases (IBD)-unclassified through detailed recommendations and practice points.Methods: These guidelines are a joint effort of the European Crohn's and Colitis Organization (ECCO) and the Paediatric IBD Porto group of European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN). An extensive literature search with subsequent evidence appraisal using robust methodology was performed before two face-to-face meetings. All 40 included recommendations and 86 practice points, were endorsed by 43 experts in Paediatric IBD with at least an 88% consensus rate.Results: These guidelines centre on initial use of mesalamine (including topical), before using steroids, thiopurines and, for more severe disease, anti-TNF. The use of other emerging therapies and the role of surgery are also covered. Algorithms are provided to aid therapeutic decision making based on clinical assessment and the paediatric UC activity index (PUCAI). Advice on contemporary therapeutic targets incorporating the use of calprotectin and the role of therapeutic drug monitoring are presented, as well as other management considerations around pouchitis, extraintestinal manifestations, nutrition, growth, psychology and transition. A brief section on disease classification using the PIBD-classes criteria and IBDU is also part of these guidelines.Conclusion: These guidelines provide a guide to clinicians managing children with UC and IBDU to provide modern management strategies while maintaining vigilance around appropriate outcomes and safety issues.

Background and aim: Acute severe colitis (ASC) is one of the few emergencies in paediatric gastroenterology. Tight monitoring and timely medical and surgical interventions may improve outcomes and minimize morbidity and mortality. We aimed to standardize daily treatment of ASC in children through detailed recommendations and practice points which are based on a systematic review of the literature and consensus of experts. Methods: These guidelines are a joint effort of the European Crohn's and Colitis Organization (ECCO) and the European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN). Fifteen predefined questions were addressed by working subgroups. An iterative consensus process, including two face-to-face meetings, was followed by voting by the national representatives of ECCO and all members of the Paediatric Inflammatory Bowel Disease (IBD) Porto group of ESPGHAN (43 voting experts). Results: A total of 24 recommendations and 43 practice points were endorsed with a consensus rate of at least 91% regarding diagnosis, monitoring and management of ASC in children. A summary flowchart is presented based on daily scoring of the Paediatric Ulcerative Colitis Activity Index (PUCAI). Several topics have been altered since the previous 2011 guidelines and from those published in adults. Discussion: These guidelines standardize the management of ASC in children in an attempt to optimize outcomes of this intensive clinical scenario.

Background and Aims: A growing body of evidence supports the need for detailed attention to nutrition and diet in children with inflammatory bowel disease (IBD). We aimed to define the steps in instituting dietary or nutritional management in light of the current evidence and to offer a useful and practical guide to physicians and dieticians involved in the care of pediatric IBD patients. Methods: A group of 20 experts in pediatric IBD participated in an iterative consensus process including 2 face-to-face meetings, following an open call to Nutrition Committee of the European Society of Pediatric Gastroenterology, Hepatology and Nutrition Porto, IBD Interest, and Nutrition Committee. A list of 41 predefined questions was addressed by working subgroups based on a systematic review of the literature. Results: A total of 53 formal recommendations and 47 practice points were endorsed with a consensus rate of at least 80% on the following topics: nutritional assessment ; macronutrients needs ; trace elements, minerals, and vitamins ; nutrition as a primary therapy of pediatric IBD ; probiotics and prebiotics ; specific dietary restrictions ; and dietary compounds and the risk of IBD. Conclusions: This position paper represents a useful guide to help the clinicians in the management of nutrition issues in children with IBD.

Sugar in Infants, Children and Adolescents

BACKGROUND AND AIMS Inflammatory bowel diseases (IBDs) may impair quality of life (QoL) in paediatric patients. We aimed to evaluate in a nationwide cohort whether patients experience QoL in a different way when compared with their parents. METHODS Sociodemographic and psychosocial characteristics were prospectively acquired from paediatric patients and their parents included in the Swiss IBD Cohort Study. Disease activity was evaluated by the Paediatric Crohn's Disease Activity Index (PCDAI) and the Paediatric Ulcerative Colitis Activity Index (PUCAI). We assessed QoL using the KIDSCREEN questionnaire. The QoL domains were analysed and compared between children and parents according to type of disease, parents' age, origin, education and marital status. RESULTS We included 110 children and parents (59 Crohn's disease [CD], 45 ulcerative colitis [UC], 6 IBD unclassified [IBDU]). There was no significant difference in QoL between CD and UC/IBDU, whether the disease was active or in remission. Parents perceived overall QoL, as well as 'mood', 'family' and 'friends' domains, lower than the children themselves, independently of their place of birth and education. However, better concordance was found on 'school performance' and 'physical activity' domains. Marital status and age of parents significantly influenced the evaluation of QoL. Mothers and fathers being married or cohabiting perceived significantly lower mood, family and friends domains than their children, whereas mothers living alone had a lower perception of the friends domain; fathers living alone had a lower perception of family and mood subscores. CONCLUSION Parents of Swiss paediatric IBD patients significantly underestimate overall QoL and domains of QoL of their children independently of origin and education.

The colonization of the infant gut is crucial for early life development. Although the composition and diversity of the infant gut microbiota (GM) has been well described at a taxonomic level, functional aspects of this ecosystem remain unexplored. In the infant gut, lactate is produced by a number of bacteria and plays an important role in the trophic chain of the fermentation process. However, little is known about the lactate-utilizing bacteria (LUB) community in infants and their impact on gut health. By combining culture-based and molecular methods, we intensively studied LUB in fecal samples of 40 healthy infants on both taxonomic and functional levels. We demonstrated metabolic cross-feeding of lactate and identified keystone species specified for lactate utilization. The interactions of such species and their metabolic outcome could have direct impacts on infant health, either beneficial (production of short chain fatty acids) or detrimental (accumulation of hydrogen or hydrogen sulfide). We identified mode of delivery as a strong determinant for lactate-producing and -utilizing bacteria levels. These findings present the early establishment of GM with a novel perspective and emphasize the importance of lactate utilization in infancy.

This is a follow up study of a multicenter randomised placebo-controlled trial in seven centres in five West European countries. The RCT assessed the effect of infant formula supplemented with a mixture of prebiotics (with neutral short-chain and long-chain oligosaccharides and pectin-derived acidic oligosaccharides) during infancy in term-born children (n=1130). In the follow-up study 672 children (60% of the study population) participated: 232 (56%) from the prebiotics group (PG), 243 (58%) from the control group (CG), and 197 (66%) from the non-randomised breast-fed group (BG). The primary outcome was the occurrence of febrile episodes at three to five years of age prospectively documented by the parents: in the PG 1.17 (interquartile range 0.50-2.08) episodes per year versus 1.20 (0.52-2.57) in the CG; and 1.48 (0.65-2.60) in the BG. This specific prebiotics mixture given during infancy in healthy non-atopic subjects does not decrease febrile episodes and therefore seems not to prevent infection between their third and fifth birthday.

The aetiology of colic, a functional gastrointestinal disorder in infants, is not yet resolved. Different mechanisms have been suggested involving the gut microbiota and intermediate metabolites such as lactate. Lactate can be metabolized by lactate-utilizing bacteria (LUB) to form different end-products. Using a functional approach, we hypothesized that H2 production and accumulation by LUB is associated with the development of colic. The LUB communities in the feces of forty infants, including eight colicky infants, were characterized using a combination of culture- and molecular-based methods, and metabolite concentrations were measured by HPLC. Interactions among LUB strains isolated from feces were investigated with pure and mixed cultures using anaerobic techniques. We emphasized high prevalence of crying, flatulence, colic and positive correlations thereof in the first 3 months of life. Crying infants showed significantly higher ratio of LUB non-sulfate-reducing bacteria (LUB non-SRB) (H2-producer), to LUB SRB (H2-utilizer) at 3 months. Colicky infants had significantly higher number of H2-producing Eubacterium hallii at 2 weeks compared to non-colicky infants. We revealed the function of Desulfovibrio piger and Eubacterium limosum to reduce H2 accumulation in co-cultures with H2-producing Veillonella ratti. Our data suggest that the balance between H2-producing and H2-utilizing LUB might contribute to colic symptoms., Scientific Reports, 7, ISSN:2045-2322

Very-early-onset inflammatory bowel disease (VEO-IBD) is a heterogeneous phenotype associated with a spectrum of rare Mendelian disorders. Here, we perform whole-exome-sequencing and genome-wide genotyping in 145 patients (median age-at-diagnosis of 3.5 years), in whom no Mendelian disorders were clinically suspected. In five patients we detect a primary immunodeficiency or enteropathy, with clinical consequences (XIAP, CYBA, SH2D1A, PCSK1). We also present a case study of a VEO-IBD patient with a mosaic de novo, pathogenic allele in CYBB. The mutation is present in ~70% of phagocytes and sufficient to result in defective bacterial handling but not life-threatening infections. Finally, we show that VEO-IBD patients have, on average, higher IBD polygenic risk scores than population controls (99 patients and 18,780 controls; P

Very-early-onset inflammatory bowel disease (VEO-IBD) is a heterogeneous phenotype associated with a spectrum of rare Mendelian disorders. Here, we perform whole-exome-sequencing and genome-wide genotyping in 145 patients (median age-at-diagnosis of 3.5 years), in whom no Mendelian disorders were clinically suspected. In five patients we detect a primary immunodeficiency or enteropathy, with clinical consequences (XIAP, CYBA, SH2D1A, PCSK1). We also present a case study of a VEO-IBD patient with a mosaic de novo, pathogenic allele in CYBB. The mutation is present in ~70% of phagocytes and sufficient to result in defective bacterial handling but not life-threatening infections. Finally, we show that VEO-IBD patients have, on average, higher IBD polygenic risk scores than population controls (99 patients and 18,780 controls; P

We evaluated the diagnostic delay (time from first symptoms to diagnosis) in 100 pediatric patients with Crohn disease (CD) and 75 patients with ulcerative colitis (UC). Median (interquartile range) diagnostic delay in patients with CD was 4 (2-8) (range 0-82) months compared with 2 (1-7) (range 0-52) months in patients with UC (P = 0.003). The time interval from first physician visit to inflammatory bowel disease diagnosis was longer in patients with CD and UC when compared to the time interval from symptom onset to first physician visit (CD: median 3 vs 1 months, P

The metabolism of lactate impacts infant gut health and may lead to acute accumulation of lactate and/or H2 associated with pain and crying of colicky infants. Because gut microbiota studies are limited due to ethical and safety concerns, in vitro fermentation models were developed as powerful tools to assess effects of environmental conditions on the gut microbiota. In this study, we established a continuous colonic fermentation model (PolyFermS), inoculated with immobilized fecal microbiota and mimicking the proximal colon of 2-month-old infants. We investigated the effects of pH and retention time (RT) on lactate metabolism and of lactate-utilizing bacteria (LUB) exhibiting little or no H2 production. We observed that a drop in pH from 6.0 to 5.0 increased the number of lactate-producing bacteria (LPB) and decreased LUB concomitantly with lactate accumulation. Increasing RT from 5 to 10 h at pH 5.0 resulted in complete lactate consumption associated with increased LUB. Supplementation with dl-lactate (60 mM) to mimic lactate accumulation promoted propionate and butyrate production with no effect on acetate production. We further demonstrated that lactate-utilizing Propionibacterium avidum was able to colonize the reactors 4 days after spiking, suggesting its ability to compete with other lactate-utilizing bacteria producing H2. In conclusion, we showed that PolyFermS is a suitable model for mimicking young infant colonic microbiota. We report for the first time pH and RT as strong drivers for composition and metabolic activity of infant gut microbiota, especially for the metabolism of lactate, which is a key intermediate product for ecology and infant health. IMPORTANCE: The metabolism of lactate is important for infant gut health and may lead to acute lactate and/or H2 accumulation, pain, and crying as observed in colicky infants. Functional human studies often faced ethical challenges due to invasive medical procedures; thus, in this study, we implemented PolyFermS fermentation models to mimic the infant proximal colon, which were inoculated with immobilized fecal microbiota of two 2-month-old infants. We investigated the impact of pH, retention time, and accumulation of dl-lactate on microbiota composition and metabolic activity. We found that a drop in pH from 6.0 to 5.0 led to increased LPB and decreased LUB concomitantly with lactate accumulation. Increasing the RT resulted in complete lactate consumption associated with increased LUB. Our data highlight for the first time the impact of key abiotic factors on the metabolism of lactate, which is an important intermediate product for ecology and infant health., mSystems, 4 (4), ISSN:2379-5077

BACKGROUND AND AIMS Length of diagnostic delay is associated with bowel strictures and intestinal surgery in adult patients with Crohn's disease [CD]. Here we assessed whether diagnostic delay similarly impacts on the natural history of paediatric CD patients. METHODS Data from the Swiss IBD Cohort Study were analysed. Frequency of CD-related complications [bowel stenosis, perianal fistula, internal fistula, any fistula, resection surgery, fistula/abscess surgery, any complication] at diagnosis and in the long term [up to 30 years after CD diagnosis] was compared between paediatric patients [diagnosed

Very-early-onset inflammatory bowel disease (VEO-IBD) is a heterogeneous phenotype associated with a spectrum of rare Mendelian disorders. Here, we perform whole-exome-sequencing and genome-wide genotyping in 145 patients (median age-at-diagnosis of 3.5 years), in whom no Mendelian disorders were clinically suspected. In five patients we detect a primary immunodeficiency or enteropathy, with clinical consequences (XIAP, CYBA, SH2D1A, PCSK1). We also present a case study of a VEO-IBD patient with a mosaic de novo, pathogenic allele in CYBB. The mutation is present in ~70% of phagocytes and sufficient to result in defective bacterial handling but not life-threatening infections. Finally, we show that VEO-IBD patients have, on average, higher IBD polygenic risk scores than population controls (99 patients and 18,780 controls; P < 4 × 10-10), and replicate this finding in an independent cohort of VEO-IBD cases and controls (117 patients and 2,603 controls; P < 5 × 10-10). This discovery indicates that a polygenic component operates in VEO-IBD pathogenesis.

Background: Optimal iodine intake during infancy is critical for brain development, but no estimated average requirement (EAR) is available for this age group. Objective: We measured daily iodine intake, excretion, and retention over a range of iodine intakes in early infancy to determine the minimum daily intake required to achieve iodine balance. Design: In a dose-response crossover study, we randomly assigned healthy infants (n = 11; mean ± SD age 13 ± 3 wk) to sequentially consume over 33 d 3 infant formula milks (IFMs) containing 10.5, 19.3, and 38.5 μg I/100 kcal, respectively. Each IFM was consumed for 11 d, consisting of a 6-d run-in period followed by a 4-d balance period and 1 run-out day. Results: Iodine intake (mean ± SD: 54.6 ± 8.1, 142.3 ± 23.1, and 268.4 ± 32.6 μg/d), excretion (55.9 ± 8.6, 121.9 ± 21.7, and 228.7 ± 39.3 μg/d), and retention (−1.6 ± 8.3, 20.6 ± 21.6, and 39.8 ± 34.3 μg/d) differed among the low, middle, and high iodine IFM groups (P < 0.001 for all). There was a linear relation between daily iodine intake and both daily iodine excretion and daily iodine retention. Zero balance (iodine intake = iodine excretion, iodine retention = 0 μg/d) was achieved at a daily iodine intake of 70 μg (95% CI: 60, 80 μg). Conclusion: Our data indicate the iodine requirement in 2- to 5-mo-old infants is 70 μg/d. Adding an allowance for accumulation of thyroidal iodine stores would produce an EAR of 72 μg and a recommended dietary allowance of 80 μg. This trial was registered at clinicaltrials.gov as NCT02045784., The American Journal of Clinical Nutrition, 104 (3), ISSN:0002-9165, ISSN:1938-3207

Very-early-onset inflammatory bowel disease (VEO-IBD) is a heterogeneous phenotype associated with a spectrum of rare Mendelian disorders. Here, we perform whole-exome-sequencing and genome-wide genotyping in 145 patients (median age-at-diagnosis of 3.5 years), in whom no Mendelian disorders were clinically suspected. In five patients we detect a primary immunodeficiency or enteropathy, with clinical consequences (XIAP, CYBA, SH2D1A, PCSK1). We also present a case study of a VEO-IBD patient with a mosaic de novo, pathogenic allele in CYBB. The mutation is present in ~70% of phagocytes and sufficient to result in defective bacterial handling but not life-threatening infections. Finally, we show that VEO-IBD patients have, on average, higher IBD polygenic risk scores than population controls (99 patients and 18,780 controls; P < 4 × 10−10), and replicate this finding in an independent cohort of VEO-IBD cases and controls (117 patients and 2,603 controls; P < 5 × 10−10). This discovery indicates that a polygenic component operates in VEO-IBD pathogenesis.

Background: The contemporary management of ambulatory ulcerative colitis (UC) continues to be challenging with similar to 20% of children needing a colectomy within childhood years. We thus aimed to standardize daily treatment of pediatric UC and inflammatory bowel diseases (IBD)-unclassified through detailed recommendations and practice points. Methods: These guidelines are a joint effort of the European Crohn's and Colitis Organization (ECCO) and the Paediatric IBD Porto group of European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN). An extensive literature search with subsequent evidence appraisal using robust methodology was performed before 2 face-to-face meetings. All 40 included recommendations and 86 practice points were endorsed by 43 experts in Paediatric IBD with at least an 88% consensus rate. Results: These guidelines discuss how to optimize the use of mesalamine (including topical), systemic and locally active steroids, thiopurines and, for more severe disease, biologics. The use of other emerging therapies and the role of surgery are also covered. Algorithms are provided to aid therapeutic decision-making based on clinical assessment and the Paediatric UC Activity Index (PUCAI). Advice on contemporary therapeutic targets incorporating the use of calprotectin and the role of therapeutic drug monitoring are presented, as well as other management considerations around pouchitis, extraintestinal manifestations, nutrition, growth, psychology, and transition. A brief section on disease classification using the PIBD-classes criteria and IBD-unclassified is also part of these guidelines. Conclusions: These guidelines provide a guide to clinicians managing children with UC and IBD-unclassified management to provide modem management strategies while maintaining vigilance around appropriate outcomes and safety issues.

Infant colic (IC) affects 5-19% of infants younger than five months of age and is characterized by crying, fussing or irritability that last more than three hours per day, during three or more days a week and occur without obvious cause. Several studies have identified an altered fecal microbiota in colic infants, a status of low-grade inflammation and high breath hydrogen (H2) excretion compared to healthy infants and different mechanisms have been hypothesized, but causality remains unclear. A newborn’s diet is based on breast milk or formula, with high content of lactose and for the former of human milk oligosaccharides (HMO), which could serve as substrate for microbial metabolism in the colon. The infant gut microbiota is characterized by high abundance of lactate-producing bacteria and consequently, to prevent accumulation and toxic effect, lactate must be concomitant metabolized by lactate-utilizing bacteria (LUB). The LUB community in infants until 4 months of age is mainly composed of propionate-producing bacteria, Bacteroides spp., Propionibacterium/Cutibacterium (former Propionibacterium spp.) and Veillonella spp., with lower numbers of butyrate-producing bacteria, Anaerostipes spp., Eubacterium hallii and Eubacterium limosum, and sulphide-reducing bacteria (SRB) like Desulfovibrio. Concomitantly with lactate utilization, there is formation of H2 and hydrogen sulphide (H2S) by some LUB members, gases associated with pain and intestinal discomfort in humans. The theoretical model sustaining this thesis states that the over-production of detrimental lactate, H2 and H2S is a contributing factor causing IC. Propionibacterium/Cutibacterium convert lactate into propionate, acetate and CO2, without H2. In doing so, they could prevent lactate accumulation and divert lactate from the production of harmful metabolites, thus potentially alleviating colic symptoms in infants. Therefore, the aim of this thesis was to investigate the role of Propionibacterium/Cutibacterium during gut colonization and in the alleviation of IC. We first characterized the abundance, diversity and persistence of Propionibacterium/Cutibacterium in a small infant cohort at 2 (n=19), 4 (n=37), 8 (n=38) and 12 (n=32) weeks of age. For this purpose, we developed and validated a quantitative PCR method to enumerate Propionibacterium/Cutibacterium in infant feces that we used together with culture-based enumeration to investigate colonization dynamic in infants. The prevalence of Propionibacterium/Cutibacterium was high (84%) at 2 weeks of age and decreased to 41% by 12 weeks of age. Persistence of Propionibacterium/Cutibacterium was dependent on colonization levels at 2 weeks and decreased simultaneously with introduction of milk-formula in the diet and increasing abundance of butyrate-producing bacteria. The development of a selective medium with lactate as sole carbon source and supplemented with antibiotics allowed for the isolation of 87 C. avidum isolates from infant feces (n=10; age range: 1.5-26 weeks). Colonization potential and metabolic effects of non-hemolytic C. avidum isolates were tested in an in vitro continuous intestinal fermentation model mimicking infant proximal colon conditions. C. avidum spiked daily at 108 or 109 cells mL-1 colonized, decreased formate, and persisted during the washout period. We identified correlations between Propionibacterium/Cutibacterium and lactate-producers in two reactors as well as in infant feces. To gain further insights on the evolutionary adaption of C. avidum, we used novel phylogenetic markers to explore the relationship of infant C. avidum to C. avidum strains from other body sites. We described a subpopulation C. avidum depicting specific phenotypic characteristics (negative hemolysis, α-galactosidase and β-glucuronidase activity), which suggest adaptation to the infant gut. We further observed ability to utilize in vitro an array of energy sources (D- and L-lactate, glycerol, glucose, galactose, N-acetyl-D-glucosamine and maltodextrins) normally available in the infant gut, which could support their colonization. In addition, we observed increased growth and propionate production by C. avidum P279 in co-culture with infant Bifidobacterium strains further indicating their role as lactate-utilizers. For the last step, we developed a gnotobiotic animal model of germ-free rats inoculated with fecal slurries from two- to three-month-old infants, either healthy (n=2) or colicky (n=2). Quantitative PCR and 16S rRNA gene amplicon sequencing revealed engraftment of dominant fecal microbiota in infant-microbiota associated rats (IMA) independently of the dominant taxa in donors. We identified an altered functionality, with high H2 excretion compared to previous gnotobiotic experiments using fecal microbiota from healthy adults and irritably bowel syndrome patients in IMA rats. We used this new model to investigate the effect of C. avidum P279, selected for its colonization ability observed in in vitro colonic fermentations, on metabolism, especially on levels of H2 production and on microbial composition in IMA rats. In line with our hypothesis, colic IMA rats supplemented with C. avidum P279 excreted significantly lower levels of H2 after intervention compared to animals assigned to placebo treatment. Overall, our findings provide novel scientific data regarding infant gut colonization by C. avidum and their role as lactate-degraders and propionate-producers in the infant gut. Our data showed increased microbial production of H2 by the infant GM and potential ability of C. avidum P279 to reduce it. Based on our observations, we propose a new mechanistic model with intestinal production of H2 as key factor for IC development. Future research focusing on the relationship between H2 metabolism and the inflammatory and nociceptive response of the host may help to further elucidate the mechanism behind IC.