Robert J. Shulman

Feeding Strategies for Premature Infants: Beneficial Outcomes of Feeding Fortified Human Milk Versus Preterm Formula

Background. In a large-scale study of feeding strategies in premature infants (early vs later initiation of enteral feeding, continuous vs bolus tube-feeding, and human milk vs formula), the feeding of human milk had more effect on the outcomes measured than any other strategy studied. Therefore, this report describes the growth, nutritional status, feeding tolerance, and health of participating premature infants who were fed fortified human milk (FHM) in comparison with those who were fed exclusively preterm formula (PF). Methods. Premature infants were assigned randomly in a balanced two-way design to early (gastrointestinal priming for 10 days) versus late initiation of feeding (total parenteral nutrition only) and continuous infusion versus intermittent bolus tube-feeding groups. The type of milk was determined by parental choice and infants to receive their mothers milk were randomized separately from those to receive formula. The duration of the study spanned the entire hospitalization of the infant. To evaluate human milk versus formula feeding, we compared outcomes of infants fed >50 mL · kg−1 · day−1 of any human milk (averaged throughout the hospitalization) with those of infants fed exclusively PF. Growth, feeding tolerance, and health status were measured daily. Serum indices of nutritional status were measured serially, and 72-hour nutrient balance studies were conducted at 6 and 9 weeks postnatally. Results. A total of 108 infants were fed either >50 mL · kg−1 · day−1 human milk (FHM,n = 62) or exclusively PF (n = 46). Gestational age (28 ± 1 weeks each), birth weight (1.07 ± 0.17 vs 1.04 ± 0.19 kg), birth length and head circumference, and distribution among feeding strategies were similar between groups. Infants fed FHM were discharged earlier (73 ± 19 vs 88 ± 47 days) despite significantly slower rates of weight gain (22 ± 7 vs 26 ± 6 g · kg−1 · day−1), length increment (0.8 ± 0.3 vs 1.0 ± 0.3 cm · week−1), and increment in the sum of five skinfold measurements (0.86 ± 0.40 vs 1.23 ± 0.42 mm · week−1) than infants fed PF. The incidence of necrotizing enterocolitis and late-onset sepsis was less in the FHM group. Overall, there were no differences in any measure of feeding tolerance between groups. Milk intakes of infants fed FHM were significantly greater than those fed PF (180 ± 13 vs 157 ± 10 mL · kg−1 · day−1). The intakes of nitrogen and copper were higher and magnesium and zinc were lower in group FHM versus PF. Fat and energy absorption were lower and phosphorus, zinc, and copper absorption were higher in group FHM versus PF. The postnatal retention (balance) surpassed the intrauterine accretion rate of nitrogen, phosphorus, magnesium, zinc, and copper in the FHM group, and of nitrogen, magnesium, and copper in the PF group. Conclusions. Although the study does not allow a comparison of FHM with unfortified human milk, the data suggest that the unique properties of human milk promote an improved host defense and gastrointestinal function compared with the feeding of formula. The benefits of improved health (less sepsis and necrotizing enterocolitis) associated with the feeding of FHM outweighed the slower rate of growth observed, suggesting that the feeding of FHM should be promoted actively in premature infants.

Gastrointestinal Microbiome Signatures of Pediatric Patients With Irritable Bowel Syndrome

BACKGROUND & AIMS The intestinal microbiomes of healthy children and pediatric patients with irritable bowel syndrome (IBS) are not well defined. Studies in adults have indicated that the gastrointestinal microbiota could be involved in IBS. METHODS We analyzed 71 samples from 22 children with IBS (pediatric Rome III criteria) and 22 healthy children, ages 7-12 years, by 16S ribosomal RNA gene sequencing, with an average of 54,287 reads/stool sample (average 454 read length = 503 bases). Data were analyzed using phylogenetic-based clustering (Unifrac), or an operational taxonomic unit (OTU) approach using a supervised machine learning tool (randomForest). Most samples were also hybridized to a microarray that can detect 8741 bacterial taxa (16S rRNA PhyloChip). RESULTS Microbiomes associated with pediatric IBS were characterized by a significantly greater percentage of the class γ-proteobacteria (0.07% vs 0.89% of total bacteria, respectively; P < .05); 1 prominent component of this group was Haemophilus parainfluenzae. Differences highlighted by 454 sequencing were confirmed by high-resolution PhyloChip analysis. Using supervised learning techniques, we were able to classify different subtypes of IBS with a success rate of 98.5%, using limited sets of discriminant bacterial species. A novel Ruminococcus-like microbe was associated with IBS, indicating the potential utility of microbe discovery for gastrointestinal disorders. A greater frequency of pain correlated with an increased abundance of several bacterial taxa from the genus Alistipes. CONCLUSIONS Using 16S metagenomics by PhyloChip DNA hybridization and deep 454 pyrosequencing, we associated specific microbiome signatures with pediatric IBS. These findings indicate the important association between gastrointestinal microbes and IBS in children; these approaches might be used in diagnosis of functional bowel disorders in pediatric patients.

Fasting and cognitive function

The effects of short-term fasting (skipping breakfast) on the problem-solving performance of 9 to 11 yr old children were studied under the controlled conditions of a metabolic ward. The behavioral test battery included an assessment of IQ, the Matching Familiar Figure Test and Hagen Central Incidental Test. Glucose and insulin levels were measured in blood. All assessments were made under fasting and non-fasting conditions. Skipping breakfast was found to have adverse effects on the childrens late morning problem-solving performance. These findings support observations that the timing and nutrient composition of meals have acute and demonstrable effects on behavior.

Brain–Gut Microbiome Interactions and Functional Bowel Disorders

Alterations in the bidirectional interactions between the intestine and the nervous system have important roles in the pathogenesis of irritable bowel syndrome (IBS). A body of largely preclinical evidence suggests that the gut microbiota can modulate these interactions. A small and poorly defined role for dysbiosis in the development of IBS symptoms has been established through characterization of altered intestinal microbiota in IBS patients and reported improvement of subjective symptoms after its manipulation with prebiotics, probiotics, or antibiotics. It remains to be determined whether IBS symptoms are caused by alterations in brain signaling from the intestine to the microbiota or primary disruption of the microbiota, and whether they are involved in altered interactions between the brain and intestine during development. We review the potential mechanisms involved in the pathogenesis of IBS in different groups of patients. Studies are needed to better characterize alterations to the intestinal microbiome in large cohorts of well-phenotyped patients, and to correlate intestinal metabolites with specific abnormalities in gut-brain interactions.

Maturation of oral feeding skills in preterm infants

Aim: Safe and successful oral feeding requires proper maturation of sucking, swallowing and respiration. We hypothesized that oral feeding difficulties result from different temporal development of the musculatures implicated in these functions.

Increased gastrointestinal permeability and gut inflammation in children with functional abdominal pain and irritable bowel syndrome.

OBJECTIVES To determine gastrointestinal (GI) permeability and fecal calprotectin concentration in children 7 to 10 years of age with functional abdominal pain and irritable bowel syndrome (FAP/IBS) versus control subjects and ascertain potential relationships with pain symptoms and stooling. STUDY DESIGN GI permeability and fecal calprotectin concentration were measured. Children kept a 2-week diary of pain episodes and stooling pattern. RESULTS Proximal GI permeability was greater in the FAP/IBS group (n = 93) compared with control subjects (n = 52) (0.59 +/- 0.50 vs 0.36 +/- 0.26, respectively; mean +/- SD; P < .001) as was colonic permeability (1.01 +/- 0.67 vs 0.81 +/- 0.43, respectively; P < .05). Gastric and small intestinal permeability were similar. Fecal calprotectin concentration was greater in children with FAP/IBS compared with control children (65.5 +/- 75.4 microg/g stool vs 43.2 +/- 39.4, respectively; P < .01). Fecal calprotectin concentration correlated with pain interference with activities (P = .01, r(2) = 0.36). There was no correlation between GI permeability and pain related symptoms. Neither permeability nor fecal calprotectin correlated with stool form. CONCLUSIONS Children with FAP/IBS have evidence of increased GI permeability and low-grade GI inflammation, with the latter relating to the degree to which pain interferes with activities.

Randomised clinical trial: gut microbiome biomarkers are associated with clinical response to a low FODMAP diet in children with the irritable bowel syndrome.

A low fermentable oligosaccharides, disaccharides, monosaccharides and polyols (FODMAP) diet can ameliorate symptoms in adult irritable bowel syndrome (IBS) within 48 h.

Mechanisms of Disease: update on the molecular etiology and fundamentals of parenteral nutrition associated cholestasis

Since its introduction into clinical practice, parenteral nutrition has revolutionized the care of premature neonates. Serum transaminase and bilirubin levels are commonly elevated in infants on parenteral nutrition, but their normalization is typical in the setting of short-term administration of parenteral nutrition uncomplicated by sepsis. Premature infants who require long-term parenteral nutrition are, however, at severe risk for developing life-threatening hepatic complications. These complications include cirrhosis, liver failure, and the concomitant risks of sepsis, coagulopathy and death. Premature infants and those with short-bowel syndrome are most susceptible to these morbid outcomes. Although it has been more than a quarter of a century since parenteral nutrition was first introduced and its association with hepatic complications described, the precise etiology of parenteral nutrition associated cholestasis (PNAC) remains a mystery; however, our understanding of the molecular components that contribute to PNAC has improved substantially. In this Review, we summarize the fundamentals of PNAC, describe animal models of the disease, review the hepatic bile acid transporters that are crucial for bile acid homeostasis, and define the roles that endotoxin, genetics, and the components of parenteral nutrition are likely to have in the molecular pathogenesis of this life-threatening condition.

The intestinal microbiome, probiotics and prebiotics in neurogastroenterology

The brain-gut axis allows bidirectional communication between the central nervous system (CNS) and the enteric nervous system (ENS), linking emotional and cognitive centers of the brain with peripheral intestinal functions. Recent experimental work suggests that the gut microbiota have an impact on the brain-gut axis. A group of experts convened by the International Scientific Association for Probiotics and Prebiotics (ISAPP) discussed the role of gut bacteria on brain functions and the implications for probiotic and prebiotic science. The experts reviewed and discussed current available data on the role of gut microbiota on epithelial cell function, gastrointestinal motility, visceral sensitivity, perception and behavior. Data, mostly gathered from animal studies, suggest interactions of gut microbiota not only with the enteric nervous system but also with the central nervous system via neural, neuroendocrine, neuroimmune and humoral links. Microbial colonization impacts mammalian brain development in early life and subsequent adult behavior. These findings provide novel insights for improved understanding of the potential role of gut microbial communities on psychological disorders, most particularly in the field of psychological comorbidities associated with functional bowel disorders like irritable bowel syndrome (IBS) and should present new opportunity for interventions with pro- and prebiotics.

Parenteral nutrition in infants and children.

Parenteral nutrition (PN) came of age in 1964 with the demonstration that beagle puppies could be nourished successfully from 12 weeks of age to maturity by providing all nutrients intravenously (1). The first total parenteral nutrition of an infant with extreme short bowel syndrome followed in 1967 (1). Since them many lessons have been learned as a result of complications of PN. These have included nutrient deficiencies and excesses, infections, complications of inadequate or excessive energy and protein intake, liver disease, and toxicities from product contamination. Our patients have paid the price for these lessons, but fortunately improved survival has also resulted. These incidents have reinforced to us the physicians the axiom that “good judgment comes from experience . . . and experience comes from bad judgment.” (2). Along the way we have learned much about nutrition, infection, liver pathophysiology, and child development (e.g., yes, infants really can “unlearn” how to suck and swallow). Have we learned so much that administration of PN can now be placed on autopilot? The question posed to the authors when this review was solicited was whether the art and science of PN had reached the stage where administration could be treated as a routine clinical algorithm such as diarrhea or croup. Do we only need to check the weight, calculate the administration rate and check the box next to “Standard Child Solution” on the PN pharmacy order sheet? Is there really anything new in PN? Our immediate reaction was to take offense, feel hurt, and shake our heads in disbelief that anyone could be so foolish as to think such things. However, as we thought about it, we realized that the question is pertinent and perceptive. Like the clinical pathways set out for common illnesses such as diarrhea and croup, the question is not so much how to follow the roadmap but rather, when not to follow it. Thus, our review will focus on two areas: 1) Common misconceptions surrounding the use of PN; and 2) When should “standard PN” (i.e., checking the weight and the box on the order sheet) not be used. These questions have lead us to review recent developments in PN (in the past 5–7 years). Whenever possible we will take an evidenced-based approach to the data. Unless specified, the studies we will discuss were carried out in pediatric patients. The risk of any review is that it is old hat to some and very new to others. We have done our best to strike a middle ground. Because it could be a subject unto itself, we will not review PN-associated cholestasis, although when pertinent, some comments will be made.