Abstract Background Milk fat globule membrane (MFGM) and lactoferrin (LF) are human-milk bioactive components demonstrated to support gastrointestinal and immune development. Significantly fewer diarrhea and respiratory-associated adverse events through 18 mo of age were previously reported in healthy term infants fed a cow-milk–based infant formula with an added source of bovine MFGM and bovine LF through 12 mo of age. Objectives The aim was to compare microbiota and metabolite profiles in a subset of study participants. Methods Stool samples were collected at baseline (10–14 d of age) and day 120. Bacterial community profiling was performed via 16S rRNA gene sequencing and alpha and beta diversity were analyzed (QIIME 2). Differentially abundant taxa were determined using linear discriminant analysis effect size (LefSE) and visualized (Metacoder). Untargeted stool metabolites were analyzed (HPLC/MS) and expressed as the fold-change between group means (control to MFGM+LF ratio). Results Alpha diversity increased significantly in both groups from baseline to 4 mo. Subtle group differences in beta diversity were demonstrated at 4 mo (Jaccard distance; R2 = 0.01, P = 0.042). Specifically, Bacteroides uniformis and Bacteroides plebeius were more abundant in the MFGM+LF group at 4 mo. Metabolite profile differences for MFGM+LF versus control included lower fecal medium-chain fatty acids, deoxycarnitine, and glycochenodeoxycholate, and some higher fecal carbohydrates and steroids (P < 0.05). After applying multiple test correction, the differences in stool metabolomics were not significant. Conclusions Addition of bovine MFGM and LF in infant formula was associated with subtle differences in stool microbiome and metabolome by 4 mo of age, including increased prevalence of Bacteroides species. Stool metabolite profiles may be consistent with altered microbial metabolism. This trial was registered at https://clinicaltrials.gov as NCT02274883.

Background: Compared to breast-fed (BF), formula-fed (FF) infants exhibit more rapid weight gain, a different fecal microbial profile, as well as elevated serum insulin, insulin growth factor 1 (IGF-1), and branched chain amino acids (BCAAs). Since infant formula contains more protein and lower free amino acids than breast milk, it is thought that protein and/or free amino acids may be key factors that explain phenotypic differences between BF and FF infants. Methods: Newborn rhesus monkeys (Macaca mulatta) were either exclusively BF or fed regular formula or reduced protein formula either supplemented or not with a mixture of amino acids. Longitudinal sampling and clinical evaluation were performed from birth to 16 weeks including anthropometric measurements, intake records, collection of blood for hematology, serum biochemistry, hormones, and metabolic profiling, collection of urine for metabolic profiling, and collection of feces for 16s rRNA fecal microbial community profiling. Results: Reducing protein in infant formula profoundly suppressed intake, lowered weight gain and improved the FF-specific metabolic phenotype in the first month of age. This time-dependent change paralleled an improvement in serum insulin. All lower protein FF groups showed reduced protein catabolism with lower levels of blood urea nitrogen (BUN), urea, ammonia, albumin, creatinine, as well as lower excretion of creatinine in urine compared to infants fed regular formula. Levels of fecal microbes (Bifidobacterium and Ruminococcus from the Ruminococcaceae family), that are known to have varying ability to utilize complex carbohydrates, also increased with protein reduction. Adding free amino acids to infant formula did not alter milk intake or fecal microbial composition, but did significantly increase urinary excretion of amino acids and nitrogen-containing metabolites. However, despite the lower protein intake, these infants still exhibited a distinct FF-specific metabolic phenotype characterized by accelerated weight gain, higher levels of insulin and C-peptide as well as elevated amino acids including BCAA, lysine, methionine, threonine and asparagine. Conclusions: Reducing protein and adding free amino acids to infant formula resulted in growth and metabolic performance of infants that were more similar to BF infants, but was insufficient to reverse the FF-specific accelerated growth and insulin-inducing high BCAA phenotype.

Lactose intolerance is a major concern driving the growth of lactose-free foods including lactose-free infant formula. It is unknown what the metabolic consequence is of consumption of a formula where lactose has been replaced with corn syrup solids (CSS). Here, a randomized double-blinded intervention study was conducted where exclusively formula-fed infants were fed formula containing either lactose or CSS-based infant formula and compared with an equal number of exclusively breast-fed infants. Plasma metabolites and insulin were measured at baseline, 15, 30, 60, 90 and 120 min after feeding. Differences in plasma metabolite profiles for formula-fed infants included a rapid increase in circulating amino acids, creatinine and urea compared with breast-fed infants. At 120 min post-feeding, insulin was significantly elevated in formula-fed compared with breast-fed infants. Infants fed lactose-based formula had the highest levels of glucose at 120 min, and leucine, isoleucine, valine and proline at 90 and 120 min, whereas infants fed CSS-based formula had the lowest levels of non-esterified fatty acids at all time points, and glucose at 120 min. Overall, these differences highlight that changes in infant formula composition impact infant metabolism, and show that metabolomics is a powerful tool to help with development of improved infant formulas.

A complex set of interactions between the microbiome, gut and brain modulate responses to visceral pain. These interactions occur at the level of the gastrointestinal mucosa, and via local neural, endocrine or immune activity; as well as by the production of factors transported through the circulatory system, like bacterial metabolites or hormones. Various psychological, infectious and other stressors can disrupt this harmonious relationship and alter both the microbiome and visceral pain responses. There are critical sensitive periods that can impact visceral pain responses in adulthood. In this review we provide a brief background of the intestinal microbiome and emerging concepts of the bidirectional interactions between the microbiome, gut and brain. We also discuss recent work in animal models, and human clinical trials using prebiotics and probiotics that alter the microbiome with resultant alterations in visceral pain responses.

BackgroundIncreasing evidence indicates a positive effect of probiotics on the nervous system. The objective of this study was to determine if probiotic Lactobacillus rhamnosus GG (LGG) and/or prebiotics polydextrose/galactooligosaccharide (PDX/GOS) can alter the colonic sensitivity in a neonatal rat model of chronic visceral hyperalgesia and to determine whether altered sensitivity is associated with changes in neurotransmitter levels in the brain.MethodsChronic visceral hyperalgesia was induced in rats by intracolonic administration of zymosan for 3days during postnatal day 14-16 (P14-P16). After weaning (P21), these pups were divided into groups that received either (1) control diet (CD), (2) PDX/GOS, (3) LGG, or (4) PDX/GOS + LGG. These diets were continued until visceral sensitivity was tested at P60. The viscero-motor response (VMR) to graded colorectal distension (CRD) was determined by measuring the electromyographic (EMG) activity from the abdominal external oblique muscles. The levels of neurotransmitters and biogenic amines were quantified in the frontal cortex, subcortex, brain stem, and cerebellum.Key ResultsAt P60, the VMR to CRD in the neonatal zymosan-treated rats was significantly higher than neonatal saline-treated rats. In contrast, neonatal zymosan-treated rats that received PDX/GOS or LGG did not exhibit visceral hyperalgesia. The levels of serotonin, noradrenaline, and dopamine were significantly altered in LGG-treated rats compared to other groups.Conclusions & InferencesResults document that in rats LGG can attenuate neonatally induced chronic visceral pain measured in adulthood. Prolonged intake of LGG alters some key brain neurotransmitters and biogenic amines that could be involved in pain modulation.

Objectives:Limited published data describe the long-term effects of behavioral strategies to wean children from gastrostomy tube (GT) feeding dependence. This study presents data relating to nutritional and psychosocial outcomes observed during a 1-year period in medically complex GT feeding-dependent patients who completed an inpatient behavioral-based tube weaning protocol.Methods:This was a retrospective study of prospectively and retrospectively collected data associated with a clinical cohort of 77 children diagnosed as having a feeding disorder, GT feeding dependence (>1 year), and an inability to maintain acceptable growth via oral feeding completing an inpatient tube weaning protocol. Nutritional data (percentage of ideal body weight, and oral energy intake as percent ofenergy goal) and psychosocial data (mealtime behavior problems, quality of caregiver and child interactions, and parenting stress) were assessed pre- and post-hospitalization. Nutritional data were also monitored longitudinally at 1, 3, 6, and 12 months postreatment. Data were grouped for retrospective analysis.Results:Mealtime environment and feeding behaviors significantly improved, and all of the patients demonstrated reductions in tube dependence aside from 1 treatment failure. Fifty-one percent of patients were fully weaned from tube feeding after 2 weeks and an additional 12% completed weaning in the outpatient follow-up clinic within 1 year. Patients maintained nutritional stability at the 1-year posttreatment follow-up appointment.Conclusions:Inpatient behavioral interventions are highly effective and safe for transitioning long-term tube feeding children to oral feeding.

Chronic intestinal pseudo-obstruction (CIP) is characterized by recurrent intestinal obstruction without any mechanical obstruction (1). The management is mainly supportive and the majority require total parenteral nutrition (TPN) support. Central venous lines (CVL) sepsis and, rarely, hemophagocytic lymphohistiocytosis (HLH) are reported with TPN use. HLH is characterized by fever, splenomegaly, and hemophagocytosis in bone marrow and other tissues (2). HLH in children with CIP and TPN has rarely been reported. We report 2 children with CIP who were receiving home TPN and presented with a febrile illness, which progressed to secondary HLH, also known as macrophage activation syndrome. A 12-year-old girl with CIP receiving home TPN for 2 years presented with fever and hematemesis. She was receiving 7.2 g/kg carbohydrates, 1.8 g/kg amino acids, and 3.1 g/kg lipids. Antibiotics were started for presumed CVL infection after obtaining blood cultures that grew no pathogens. Fever persisted and she developed pancytopenia and coagulopathy. This was attributed to sepsis. Because her condition worsened in spite of antibiotics, other laboratory tests were ordered, which were significant for elevated serum ferritin and triglycerides and low fibrinogen. HLH was considered, and bone marrow (BM) biopsy showed hemophagocytosis consistent with HLH. Immune evaluation and flow cytometry were normal. Because lipids have been reported to trigger HLH, the lipid infusion was discontinued and she was managed conservatively and her condition improved. She was discharged while receiving TPN without lipid and started on oral essential fatty acid (EFA) supplementation. She has had no further episodes of HLH after 3 years of follow-up. A 7-year-old boy with CIP receiving home TPN for 3 years presented with fever and axillary lymphadenopathy. He was receiving 9.9 g/kg of carbohydrates, 2 g/kg of amino acids, and 3.2 g/kg of lipids. He was treated with meropenem and gentamicin for pseudomonas CVL sepsis 2 weeks earlier. Blood cultures and viral studies were negative. His fever persisted and he developed multiorgan dysfunction. His serum ferritin and triglycerides were elevated. BM biopsy showed hemophagocytosis consistent with HLH. Immune evaluation was normal. Because of the severity of the condition and the development of multiorgan dysfunction, he was treated with corticosteroids, etoposide, intravenous immunoglobulin, and cyclosporine for 4 weeks with a corticosteroid taper. After a prolonged hospital stay for multiple complications, he was discharged while receiving TPN without lipid and oral EFA. He remained well after 3 years of follow-up. DISCUSSION The typical presentation of HLH includes persistent fever and splenomegaly, often in the setting of an acute infection; however, in some children, the initial presentation is atypical and characteristic findings may be absent. It is therefore important for the clinician to consider the diagnosis of HLH, even if the early presentation is atypical because mortality is high without appropriate treatment. The HLH study group proposed diagnostic guidelines (Table 1) (3). Establishing HLH diagnosis in children with CIP is further complicated by the fact that some of the features associated with HLH are commonly seen with CVL sepsis.TABLE 1: Revised diagnostic guidelines for HLHHLH can be seen as part of primary lymphohistiocytosis (genetic mutations) or secondary to infections, malignancy, and autoimmune disease. The distinction between primary and secondary HLH is not always possible because the triggers for both forms can occur with viral infection. The pathophysiology of HLH is unclear, but it appears to involve persistent stimulation of immune response. In primary HLH, genetic defects in the cytotoxic granulocyte pathway result in failure to clear the antigen, leading to persistent stimulation of CD8 cytotoxic lymphocytes, interferon-γ, macrophages, and natural killer cells. This results in excessive amounts of cytokine production, BM infiltration, and organ dysfunction characteristic of HLH. Grossman et al (4) proposed another model wherein expanded immune cytotoxic system failed to contract after effective clearance of antigen as shown in Jak3-deficient mice. We describe 2 patients with HLH features, as shown in Table 2. Extensive evaluations for immune and infectious etiology were negative. It is unclear whether the occurrence of a rare disorder such as HLH in children with CIP represents a chance occurrence or a potential risk of HLH in this patient population. Possible causes for HLH in our patients include lipid infusion, chronic bacterial overgrowth, unidentified mitochondrial or genetic defect, and an unknown viral pathogen, all of which may alter immune function. Previous reports suggest an association of TPN with lipids and HLH. There are case reports of “fat overload syndrome” and recommended withdrawal with gradual reintroduction of lipids at a lower dosage (5,6). Goulet et al (7) reported clinical, hematologic, and immunologic abnormalities in 7 children following prolonged use of intravenous fat emulsion. The macrophage system was hyperactive in this group of patients and was thought to be related to intravenous fat emulsion in TPN. They recommended reducing the lipid infusion during acute illness. It is interesting to note that many of the features reported in their patients resemble HLH. This raises the question of the role of lipid infusion in children receiving TPN in inducing HLH-like illness. It is possible that the lipids combined with an infectious etiology caused these episodes to be triggered and present so significant clinically because lipids have been shown to activate monocyte and can cause coagulopathy in sick children (8).TABLE 2: Diagnostic criterion for HLH in our patientsWe decided to reduce the lipids to <1 g · kg−1 · day−1 and the patients were given EFA. The authors acknowledge that there is no convincing evidence that this strategy was clinically effective in prevention of reoccurrence of HLH in our patients; however, reduction of lipid infusion and monitoring of laboratory tests, including ferritin during systemic infection, should be considered in patients who do not follow the expected clinical course. On the basis of our 2 cases, HLH may occur in patients receiving TPN. Because HLH can mimic line sepsis in children receiving TPN, it should be considered in the differential diagnosis in patients with negative workup and persistent fever. Increased awareness and a high index of suspicion of HLH in patients not responding to CVL infection treatment may help decrease delay in diagnosis because prompt intervention prevents irreversible end-organ damage, mortality, and recurrence of secondary HLH.

Objectives: The aim of the present study was to evaluate the variability in interpretation of colon manometry (CM) in children.Methods: Fifty-seven colon motility studies were independently reviewed by 5 observers. Each observer was required to report on the colonic motility during fasting, after administration of a meal, and after bisacodyl stimulation. They were also asked to comment whether CM study was normal or abnormal and whether in their opinion the postprandial recording provided clinically useful information.Results: The median (range) agreement regarding the presence of high-amplitude propagating contractions (HAPC) was 83% (80%-92%). The interpretation of gastrocolonic response produced the most inconsistent results with median (range) agreemnet of 64% (53%-95%). The postprandial period was reported to be useful in only 3% to 24% of the studies. The median (range) agreement regarding the overall interpretation of the study being either normal or abnormal was 87% (83%-90%).Conclusions: The most easily recognizable contraction pattern during CM is the high-amplitude propagating contractions. Visual interpretation of the gastrocolonic response produces the most inconsistent results and maximum variability. Abbreviated CM studies without the postprandial period or routine calculation of the motility index to evaluate gastrocolonic response can help make colon manometries more objective and reliable.

OBJECTIVES:The aim of the study was to compare oro-anal transit time (OTT) measured by radio-opaque markers with colon motility (CM) findings in children with chronic constipation and to assess clinical outcomes in children with chronic constipation evaluated by OTT and CM studies.METHODS:Twenty-four children with chronic constipation (12 girls; median age 12 years [3-18 years]; median symptoms 87 months [6-186 months]) who underwent OTT and CM studies were reviewed. The OTT was determined using commercially available Sitzmarks. Patients were studied for a median of 23 months (4-60 months) and outcomes reviewed.RESULTS:All 5 children with normal OTT had normal CM; however, only 47% (9/19) of children with slow OTT had an abnormal CM. The abnormal CM findings were total colonic pseudo-obstruction in 3 and left colonic pseudo-obstruction in 6 children. Of the 9 children with abnormal CM, 5 were managed surgically, 1 with medicine escalation, and 3 were lost to follow-up; all 6 children with known follow-up have more bowel movements and less soiling. Of the 15 children with normal CM, 10 were managed with medication escalation, 3 with behavioral intervention, and 2 surgically. Of these 15 children, 8 improved, 1 did not change, 2 worsened, and 4 were lost to follow-up.CONCLUSIONS:OTT studies may be helpful to predict which children should be referred for CM studies. Normal OTT studies may predict normal colon manometry; however, abnormal OTT studies may not predict abnormalities in colonic manometry in children with chronic constipation. Therefore, patients with slow transit marker studies should be assessed by colon manometry to evaluate colon neuromuscular integrity.

A caregiver questionnaire that assesses mealtime problems in children aged 2 to 6 years old was developed. Community caregivers (n = 712) completed the Mealtime Behavior Questionnaire (MBQ) and measures of child behavior and family mealtime behaviors and environment. Exploratory and confirmatory factor analyses revealed and validated the MBQ's 4 subscales (food refusal/avoidance; food manipulation; mealtime aggression/distress; and choking/, gagging/vomiting). Mealtime problems occurred from osometimeso to oalwayso for 1% to 61% of the sample. The MBQ demonstrated excellent to fair internal consistencies, and preliminary evidence for validity was found.

Es sollte ein internationaler Konsensus zur Definition der gastroösophagealen Refluxkrankheit (GÖRK) in der Pädiatrie erzielt werden.

An international consensus on the definition of gastroesophageal reflux disease (GERD) in pediatrics was sought.After a systematic literature search, a set of key statements was developed by an international panel of pediatric gastroenterologists and voted anonymously in a modified Delphi process. The strength of each statement was assessed using the GRADE system.Consensus was reached on 98% of the 59 statements. Consensus items of particular note were: (1) GERD is present when reflux of gastric contents causes troublesome symptoms and/or complications. The definition is restricted in the case of children under similar to 8 years, due to unreliable reporting of incriminating symptoms; (2) the primary role of histology is to exclude other conditions, rather than to establish the diagnosis of GERD; (3) Barrett's esophagus characterizes an esophageal metaplasia that is intestinal metaplasia-positive or -negative; (4) extraesophageal conditions may be associated with GERD, but for most of these conditions causality remains to be established.The consensus statements were developed by means of a rigorous process and can form the basis for clinical trials and practice guidelines.

La kinésithérapie respiratoire est régulièrement proposée, notamment aux enfants atteints de mucoviscidose. Ces mêmes enfants présentent des reflux gastro-œsophagiens qui ont été mis en relation avec certaines manœuvres de kinésithérapie.Évaluer l’influence de deux techniques de kinésithérapie respiratoire sur la survenue du reflux gastro-œsophagien chez l’enfant.Étude prospective portant sur 29 enfants venant en consultation pour un examen de pH-métrie. Après l’installation de la sonde de pH-métrie, chaque enfant a reçu deux séances de kinésithérapie respiratoire en position assise de 10 minutes chacune avec une pause de 5 minutes entre les deux. Les deux manœuvres pratiquées étaient l’expiration lente prolongée (ELPr) et le PEP-masque. L’ordre dans lequel les manœuvres étaient appliquées était randomisé. Le tracé de la pH-métrie a été analysé en aveugle lorsque toutes les séances ont été exécutées.Sur 29 sujets, 21 % ont présenté un reflux gastro-œsophagien pendant la kinésithérapie. Aucune relation n’a été trouvée entre le nombre d’enfants présentant un reflux pendant la kinésithérapie respiratoire et la présence d’un reflux pathologique (p = 0,411) ni le type de technique (p = 0,219).L’application en position assise de l’ELPr et du PEP-masque chez des enfants peut provoquer un reflux gastro-œsophagien.Chest physiotherapy is regularly prescribed for children, particularly in cystic fibrosis. Gastro-oesophageal reflux is common in this disease and is associated with certain chest physiotherapy manoeuvres.To evaluate the influence of two chest physiotherapy techniques on gastro-oesophageal reflux in children.Twenty-nine children were investigated by routine pHmetry. During the examination, they performed two chest physiotherapy manoeuvres in a seated position for 10 minutes each with a 5 minutes rest between them. The two manoeuvres used were a slow expiration technique (ELPr) and positive expiratory pressure (PEP). It was a prospective study and the order of manoeuvres was randomised. The pH traces were analysed blindly when all the studies had been completed.In the sample, 21% of children had gastro-oesophageal reflux during the physiotherapy session. No relationship was found between reflux during physiotherapy and pathological reflux (P = 0.411) nor the physiotherapy technique used (P = 0.219).The use of these two chest physiotherapy techniques in children in a seated position can produce gastro-oesophageal reflux.