Mark A. Underwood

Amniotic Fluid: Not Just Fetal Urine Anymore

Amniotic fluid (AF) is a complex substance essential to fetal well-being. This article reviews recent discoveries and the current understanding of the origin and circulation of AF and its nutritive, protective, and diagnostic functions. Future directions for AF research are also discussed.

Human α-Defensin 6 Promotes Mucosal Innate Immunity Through Self-Assembled Peptide Nanonets

Netting the Bad Guys Antimicrobial peptides are an evolutionarily conserved component of innate immunity in the intestine. One family, α-defensins, typically exert their antimicrobial effects through microbicidal activity against bacteria. Humans express only two α-defensins, human defensin 5 (HD5) and HD6. HD5 exhibits bactericidal activity and plays a role in shaping the bacterial composition of the gut. HD6, on the other hand, does not show bactericidal activity and its function in the gut is unclear. Now, Chu et al. (p. 477, published online 21 June; see the Perspective by Ouellette and Selsted) show that HD6 protects against bacterial pathogens. Rather than killing them directly, HD6 binds to bacteria surface proteins and, through a process of self-assembly, forms fibrils and nanonets that ensnare invading bacterial pathogens. Rather than killing bacteria directly, a gut antimicrobial peptide forms netlike structures that ensnare invading bacteria. Defensins are antimicrobial peptides that contribute broadly to innate immunity, including protection of mucosal tissues. Human α-defensin (HD) 6 is highly expressed by secretory Paneth cells of the small intestine. However, in contrast to the other defensins, it lacks appreciable bactericidal activity. Nevertheless, we report here that HD6 affords protection against invasion by enteric bacterial pathogens in vitro and in vivo. After stochastic binding to bacterial surface proteins, HD6 undergoes ordered self-assembly to form fibrils and nanonets that surround and entangle bacteria. This self-assembly mechanism occurs in vivo, requires histidine-27, and is consistent with x-ray crystallography data. These findings support a key role for HD6 in protecting the small intestine against invasion by diverse enteric pathogens and may explain the conservation of HD6 throughout Hominidae evolution.

Cost, causes and rates of rehospitalization of preterm infants

Objective:To examine hospital readmissions for premature infants during the first year of life.Study Design:The California maternal and newborn/infant hospital discharge records were examined for subsequent readmission during the first year of life for all newborns from 1992 to 2000. Discharge diagnoses, hospital days, demographic data and hospital charges for infants born preterm (<36 weeks gestation) were identified and evaluated.Result:About 15% of preterm infants required at least one rehospitalization within the first year of life (average cost per readmission

Human milk for the premature infant

8468, average annual cost in excess of

Stool Microbiota and Vaccine Responses of Infants

41 million). Infants with gestational age <25 weeks had the highest rate of readmission (31%) and longest average length of stay (12 hospital days). The largest cohort, infants born at 35 weeks gestation, had the highest total cost of readmission (

A randomized placebo-controlled comparison of 2 prebiotic/probiotic combinations in preterm infants: impact on weight gain, intestinal microbiota, and fecal short-chain fatty acids.

92.9 million). The most common cause of rehospitalization was acute respiratory disease. There was no decrease in the number or cost of readmissions of premature infants for respiratory syncytial virus infections following the introduction of palivizumab in 1998.Conclusion:After initial discharge, premature infants continue to have significant in-patient health-care needs and costs.

Bifidobacterium longum subspecies infantis : champion colonizer of the infant gut

Premature infants are at risk for growth failure, developmental delays, necrotizing enterocolitis, and late-onset sepsis. Human milk from women delivering prematurely has more protein and higher levels of bioactive molecules. Human milk must be fortified for premature infants to achieve adequate growth. Mothers own milk improves growth and neurodevelopment, decreases the risk of necrotizing enterocolitis and late-onset sepsis, and should be the primary enteral diet for premature infants. Donor milk is a resource for premature infants whose mothers are unable to provide an adequate supply of milk. Challenges include the need for pasteurization, nutritional and biochemical deficiencies, and limited supply.

Human milk glycomics and gut microbial genomics in infant feces show a correlation between human milk oligosaccharides and gut microbiota: A proof-of-concept study

OBJECTIVE: Oral vaccine efficacy is low in less-developed countries, perhaps due to intestinal dysbiosis. This study determined if stool microbiota composition predicted infant oral and parenteral vaccine responses. METHODS: The stool microbiota of 48 Bangladeshi infants was characterized at 6, 11, and 15 weeks of age by amplification and sequencing of the 16S ribosomal RNA gene V4 region and by Bifidobacterium-specific, quantitative polymerase chain reaction. Responses to oral polio virus (OPV), bacille Calmette-Guérin (BCG), tetanus toxoid (TT), and hepatitis B virus vaccines were measured at 15 weeks by using vaccine-specific T-cell proliferation for all vaccines, the delayed-type hypersensitivity skin-test response for BCG, and immunoglobulin G responses using the antibody in lymphocyte supernatant method for OPV, TT, and hepatitis B virus. Thymic index (TI) was measured by ultrasound. RESULTS: Actinobacteria (predominantly Bifidobacterium longum subspecies infantis) dominated the stool microbiota, with Proteobacteria and Bacteroidetes increasing by 15 weeks. Actinobacteria abundance was positively associated with T-cell responses to BCG, OPV, and TT; with the delayed-type hypersensitivity response; with immunoglobulin G responses; and with TI. B longum subspecies infantis correlated positively with TI and several vaccine responses. Bacterial diversity and abundance of Enterobacteriales, Pseudomonadales, and Clostridiales were associated with neutrophilia and lower vaccine responses. CONCLUSIONS: Bifidobacterium predominance may enhance thymic development and responses to both oral and parenteral vaccines early in infancy, whereas deviation from this pattern, resulting in greater bacterial diversity, may cause systemic inflammation (neutrophilia) and lower vaccine responses. Vaccine responsiveness may be improved by promoting intestinal bifidobacteria and minimizing dysbiosis early in infancy.

A quantitative and comprehensive method to analyze human milk oligosaccharide structures in the urine and feces of infants

Objective: To compare the effect of 2 prebiotic/probiotic products on weight gain, stool microbiota, and stool short-chain fatty acid (SCFA) content of premature infants. Patients and Methods: This randomized, blinded, placebo-controlled trial included 90 premature infants treated with either a dietary supplement containing 2 lactobacillus species plus fructooligosaccharides (CUL, Culturelle, ConAgra, Omaha, NE), a supplement containing several species of lactobacilli and bifidobacteria plus fructooligosaccharides (PBP, ProBioPlus DDS, UAS Laboratories, Eden Prairie, MN), or placebo (a dilute preparation of Pregestamil formula) twice daily for 28 days or until discharge if earlier. The primary outcome was weight gain. Secondary outcomes were stool bacterial analysis by culture and 16S rDNA quantitative polymerase chain reaction and stool SCFA content measured by high performance liquid chromatography. Results: Both prebiotic/probiotic combinations contained more bacterial species than noted on the label. No significant effect on infant growth of either prebiotic/probiotic supplement was observed. By cultures, 64% of infants receiving PBP became colonized with bifidobacteria, compared with 18% of infants receiving CUL and 27% of infants receiving placebo (chi-square, P = 0.064). No differences were noted between groups in colonization rates for lactobacilli, Gram-negative enteric bacteria, or staphylococci. By 16S rDNA polymerase chain reaction analysis, the bifidobacteria content in the stools of the infants receiving PBP was higher than in the infants receiving CUL or placebo (Kruskal-Wallis, P = 0.011). No significant differences in stool SCFA content were detected between groups. No adverse reactions were noted. Conclusions: Infants receiving PBP were more likely to become colonized with bifidobacteria. No significant differences in weight gain or stool SCFA content were detected.

The Impact of the Milk Glycobiome on the Neonate Gut Microbiota

Oligosaccharides are abundant in human milk. Production of these highly diverse structures requires significant energy expenditure by the mother and yet these human milk oligosaccharides offer no direct nutritive value to her infant. A primary function of human milk oligosaccharides is to shape the infant’s intestinal microbiota with life-long consequences. Bifidobacterium longum subspecies infantis (B. infantis) is unique among gut bacteria in its prodigious capacity to digest and consume any human milk oligosaccharide structure, the result of a large repertoire of bacterial genes encoding an array of glycosidases and oligosaccharide transporters not found in other bacterial species. In vitro, B. infantis grows better than other bacterial strains in the presence of human milk oligosaccharides, displays anti-inflammatory activity in premature intestinal cells, and decreases intestinal permeability. In premature infants, B. infantis given in combination with human milk increases B. infantis and decreases Enterobacteriaceae in the feces. Probiotics containing B. infantis decrease the risk of necrotizing enterocolitis in premature infants. Colonization with B. infantis is also associated with increased vaccine responses. Probiotic organisms have historically been selected based on ease of production and stability. The advantages of B. infantis, selected through coevolution with human milk glycans, present an opportunity for focused manipulation of the infant intestinal microbiota.