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1.  Perinatal Programming of Asthma: The Role of Gut Microbiota 
Perinatal programming, a dominant theory for the origins of cardiovascular disease, proposes that environmental stimuli influence developmental pathways during critical periods of prenatal and postnatal development, inducing permanent changes in metabolism. In this paper, we present evidence for the perinatal programming of asthma via the intestinal microbiome. While epigenetic mechanisms continue to provide new explanations for the programming hypothesis of asthma development, it is increasingly apparent that the intestinal microbiota plays an independent and potentially interactive role. Commensal gut bacteria are essential to immune system development, and exposures disrupting the infant gut microbiota have been linked to asthma. This paper summarizes the recent findings that implicate caesarean delivery, breastfeeding, perinatal stress, probiotics, and antibiotics as modifiers of infant gut microbiota in the development of asthma.
doi:10.1155/2012/932072
PMCID: PMC3216351  PMID: 22110540
2.  Maternal perspectives on the use of probiotics in infants: a cross-sectional survey 
Background
Probiotic products that may modify the intestinal microbiota are becoming increasingly available and known to consumers due to their potential to prevent or treat many pediatric health conditions. As scientific knowledge of the health benefits of probiotics increases, it is important to identify factors that may prevent their successful integration into patient care as well as to ensure effective translation of research findings. The aim of this study was to describe maternal perspectives on probiotics and their use in infants.
Methods
Mothers with a child aged two years or younger enrolled in the Alberta Pregnancy Outcomes and Nutrition (APrON) study were invited by email to complete a 29 item self-administered web-based questionnaire.
Results
A total of 413 mothers of the 1327 contacted completed the questionnaire. The majority (99.3%) of respondents had heard of probiotics and were aware that they contained live bacteria (87.0%); 89.3% had used a product containing probiotics themselves but only 50.8% had given one to their infant. Most mothers indicated they believed that probiotics were beneficial (73.1%) and none thought they were harmful. Over a third of mothers did not feel informed enough to make a decision on whether probiotics were safe to use in infants (36.6%).
Conclusions
The study demonstrates that awareness and understanding of probiotics is high among mothers in Alberta, Canada. However, there is still uncertainty regarding the benefit of probiotics as well as safety in infants which could be important factors determining therapeutic use in the future. Further studies that demonstrate beneficial effects and safety of probiotics in healthy infants as well as targeted knowledge translation should help to address these potential concerns.
doi:10.1186/1472-6882-14-366
PMCID: PMC4193129  PMID: 25267264
Probiotics; Infant; Mother; Nutrition; Natural health products; Cross-sectional survey
7.  Infant gut microbiota and the hygiene hypothesis of allergic disease: impact of household pets and siblings on microbiota composition and diversity 
Background
Multiple studies have demonstrated that early-life exposure to pets or siblings affords protection against allergic disease; these associations are commonly attributed to the “hygiene hypothesis”. Recently, low diversity of the infant gut microbiota has also been linked to allergic disease. In this study, we characterize the infant gut microbiota in relation to pets and siblings.
Methods
The study population comprised a small sub-sample of 24 healthy, full term infants from the Canadian Healthy Infant Longitudinal Development (CHILD) birth cohort. Mothers reported on household pets and siblings. Fecal samples were collected at 4 months of age, and microbiota composition was characterized by high-throughput signature gene sequencing.
Results
Microbiota richness and diversity tended to be increased in infants living with pets, whereas these measures were decreased in infants with older siblings. Infants living with pets exhibited under-representation of Bifidobacteriaceae and over-representation of Peptostreptococcaceae; infants with older siblings exhibited under-representation of Peptostreptococcaceae.
Conclusions
This study provides new evidence that exposure to pets and siblings may influence the early development of the gut microbiota, with potential implications for allergic disease. These two traditionally protective “hygiene hypothesis” factors appear to differentially impact gut microbiota composition and diversity, calling into question the clinical significance of these measures. Further research is required to confirm and expand these findings.
doi:10.1186/1710-1492-9-15
PMCID: PMC3655107  PMID: 23607879
Infants; Gut microbiota; Gut microbiome; Hygiene hypothesis; Microflora hypothesis; Pets; Siblings; Atopy; Allergic disease; Environmental exposures
8.  Gut microbiota of healthy Canadian infants: profiles by mode of delivery and infant diet at 4 months 
Background:
The gut microbiota is essential to human health throughout life, yet the acquisition and development of this microbial community during infancy remains poorly understood. Meanwhile, there is increasing concern over rising rates of cesarean delivery and insufficient exclusive breastfeeding of infants in developed countries. In this article, we characterize the gut microbiota of healthy Canadian infants and describe the influence of cesarean delivery and formula feeding.
Methods:
We included a subset of 24 term infants from the Canadian Healthy Infant Longitudinal Development (CHILD) birth cohort. Mode of delivery was obtained from medical records, and mothers were asked to report on infant diet and medication use. Fecal samples were collected at 4 months of age, and we characterized the microbiota composition using high-throughput DNA sequencing.
Results:
We observed high variability in the profiles of fecal microbiota among the infants. The profiles were generally dominated by Actinobacteria (mainly the genus Bifidobacterium) and Firmicutes (with diverse representation from numerous genera). Compared with breastfed infants, formula-fed infants had increased richness of species, with overrepresentation of Clostridium difficile. Escherichia–Shigella and Bacteroides species were underrepresented in infants born by cesarean delivery. Infants born by elective cesarean delivery had particularly low bacterial richness and diversity.
Interpretation:
These findings advance our understanding of the gut microbiota in healthy infants. They also provide new evidence for the effects of delivery mode and infant diet as determinants of this essential microbial community in early life.
doi:10.1503/cmaj.121189
PMCID: PMC3602254  PMID: 23401405
10.  Influence of Socioeconomic Status Trajectories on Innate Immune Responsiveness in Children 
PLoS ONE  2012;7(6):e38669.
Objectives
Lower socioeconomic status (SES) is consistently associated with poor health, yet little is known about the biological mechanisms underlying this inequality. In children, we examined the impact of early-life SES trajectories on the intensity of global innate immune activation, recognizing that excessive activation can be a precursor to inflammation and chronic disease.
Methods
Stimulated interleukin-6 production, a measure of immune responsiveness, was analyzed ex vivo for 267 Canadian schoolchildren from a 1995 birth cohort in Manitoba, Canada. Childhood SES trajectories were determined from parent-reported housing data using a longitudinal latent-class modeling technique. Multivariate regression was conducted with adjustment for potential confounders.
Results
SES was inversely associated with innate immune responsiveness (p = 0.003), with persistently low-SES children exhibiting responses more than twice as intense as their high-SES counterparts. Despite initially lower SES, responses from children experiencing increasing SES trajectories throughout childhood were indistinguishable from high-SES children. Low-SES effects were strongest among overweight children (p<0.01). Independent of SES trajectories, immune responsiveness was increased in First Nations children (p<0.05) and urban children with atopic asthma (p<0.01).
Conclusions
These results implicate differential immune activation in the association between SES and clinical outcomes, and broadly imply that SES interventions during childhood could limit or reverse the damaging biological effects of exposure to poverty during the preschool years.
doi:10.1371/journal.pone.0038669
PMCID: PMC3369855  PMID: 22685596
12.  HYPOXIA INDUCES AUTOPHAGIC CELL DEATH IN APOPTOSIS-COMPETENT CELLS THROUGH A MECHANISM INVOLVING BNIP3 
Autophagy  2007;4(2):195-204.
Hypoxia (lack of oxygen) is a physiological stress often associated with solid tumors. Hypoxia correlates with poor prognosis since hypoxic regions within tumors are considered apoptosis-resistant. Autophagy (cellular “self digestion”) has been associated with hypoxia during cardiac ischemia and metabolic stress as a survival mechanism. However, although autophagy is best characterized as a survival response, it can also function as a mechanism of programmed cell death. Our results show that autophagic cell death is induced by hypoxia in cancer cells with intact apoptotic machinery. We have analyzed two glioma cell lines (U87, U373), two breast cancer cell lines (MDA-MB-231, ZR75) and one embryonic cell line (HEK293) for cell death response in hypoxia (<1% O2). Under normoxic conditions, all five cell lines undergo etoposide-induced apoptosis whereas hypoxia fails to induce these apoptotic responses. All five cell lines induce an autophagic response and undergo cell death in hypoxia. Hypoxia-induced cell death was reduced upon treatment with the autophagy inhibitor 3-methyladenine, but not with the caspase inhibitor z-VAD-fmk. By knocking down the autophagy proteins Beclin-1 or ATG5, hypoxia-induced cell death was also reduced. The pro-cell death Bcl-2 family member BNIP3 (Bcl-2/adenovirus E1B 19kDa-interacting protein 3) is upregulated during hypoxia and is known to induce autophagy and cell death. We found that BNIP3 over-expression induced autophagy, while expression of BNIP3 siRNA or a dominant-negative form of BNIP3 reduced hypoxia-induced autophagy. Taken together, these results suggest that prolonged hypoxia induces autophagic cell death in apoptosis-competent cells, through a mechanism involving BNIP3.
PMCID: PMC3164855  PMID: 18059169 CAMSID: cams1903
autophagy; hypoxia; autophagic cell death; BNIP3; cancer
13.  Probiotic supplementation during pregnancy or infancy for the prevention of asthma and wheeze: systematic review and meta-analysis 
Objective To evaluate the association of probiotic supplementation during pregnancy or infancy with childhood asthma and wheeze.
Design Systematic review and meta-analysis of randomised controlled trials.
Data sources Medline, Embase, and Central (Cochrane Library) databases from inception to August 2013, plus the World Health Organization’s international clinical trials registry platform and relevant conference proceedings for the preceding five years. Included trials and relevant reviews were forward searched in Web of Science.
Review methods Two reviewers independently identified randomised controlled trials evaluating probiotics administered to mothers during pregnancy or to infants during the first year of life. The primary outcome was doctor diagnosed asthma; secondary outcomes included wheeze and lower respiratory tract infection.
Results We identified 20 eligible trials including 4866 children. Trials were heterogeneous in the type and duration of probiotic supplementation, and duration of follow-up. Only five trials conducted follow-up beyond participants’ age of 6 years (median 24 months), and none were powered to detect asthma as the primary outcome. The overall rate of doctor diagnosed asthma was 10.7%; overall rates of incident wheeze and lower respiratory tract infection were 33.3% and 13.9%, respectively. Among 3257 infants enrolled in nine trials contributing asthma data, the risk ratio of doctor diagnosed asthma in participants randomised to receive probiotics was 0.99 (95% confidence interval 0.81 to 1.21, I2=0%). The risk ratio of incident wheeze was 0.97 (0.87 to 1.09, I2=0%, 9 trials, 1949 infants). Among 1364 infants enrolled in six trials, the risk ratio of lower respiratory tract infection after probiotic supplementation was 1.26 (0.99 to 1.61, I2=0%). We adjudicated most trials to be of high (ten trials) or unclear (nine trials) risk of bias, mainly due to attrition.
Conclusions We found no evidence to support a protective association between perinatal use of probiotics and doctor diagnosed asthma or childhood wheeze. Randomised controlled trials to date have not yielded sufficient evidence to recommend probiotics for the primary prevention of these disorders. Extended follow-up of existing trials, along with further clinical and basic research, are needed to accurately define the role of probiotics in the prevention of childhood asthma.
Systematic review registration PROSPERO (CRD42013004385).
doi:10.1136/bmj.f6471
PMCID: PMC3898421  PMID: 24304677

Results 1-13 (13)