Meghan B. Azad

Superoxide is the major reactive oxygen species regulating autophagy.

Autophagy is involved in human diseases and is regulated by reactive oxygen species (ROS) including superoxide (O2•−) and hydrogen peroxide (H2O2). However, the relative functions of O2•− and H2O2 in regulating autophagy are unknown. In this study, autophagy was induced by starvation, mitochondrial electron transport inhibitors, and exogenous H2O2. We found that O2•− was selectively induced by starvation of glucose, L-glutamine, pyruvate, and serum (GP) whereas starvation of amino acids and serum (AA) induced O2•− and H2O2. Both types of starvation induced autophagy and autophagy was inhibited by overexpression of SOD2 (manganese superoxide dismutase, Mn-SOD), which reduced O2•− levels but increased H2O2 levels. Starvation-induced autophagy was also inhibited by the addition of catalase, which reduced both O2•− and H2O2 levels. Starvation of GP or AA also induced cell death that was increased following treatment with autophagy inhibitors 3-methyladenine, and wortamannin. Mitochondrial electron transport chain (mETC) inhibitors in combination with the SOD inhibitor 2-methoxyestradiol (2-ME) increased O2•− levels, lowered H2O2 levels, and increased autophagy. In contrast to starvation, cell death induced by mETC inhibitors was increased by 2-ME. Finally, adding exogenous H2O2 induced autophagy and increased intracellular O2•− but failed to increase intracellular H2O2. Taken together, these findings indicate that O2•− is the major ROS-regulating autophagy.

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.

HYPOXIA INDUCES AUTOPHAGIC CELL DEATH IN APOPTOSIS-COMPETENT CELLS THROUGH A MECHANISM INVOLVING BNIP3

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 (

Infant antibiotic exposure and the development of childhood overweight and central adiposity

Background:Obesity has been associated with disruption of the gut microbiota, which is established during infancy and vulnerable to disruption by antibiotics.Objectives:To investigate the association between early-life antibiotic exposure and subsequent development of overweight and central adiposity.Methods:Provincial health-care records were linked to clinical and survey data from a Canadian longitudinal birth cohort study. Antibiotic exposure during the first year of life was documented from prescription records. Overweight and central adiposity were determined from anthropometric measurements at ages 9 (n=616) and 12 (n=431). Associations were determined by multiple logistic regression.Results:Infants receiving antibiotics in the first year of life were more likely to be overweight later in childhood compared with those who were unexposed (32.4 versus 18.2% at age 12, P=0.002). Following adjustment for birth weight, breastfeeding, maternal overweight and other potential confounders, this association persisted in boys (aOR 5.35, 95% confidence interval (CI) 1.94–14.72) but not in girls (aOR 1.13, CI 0.46–2.81). Similar gender-specific associations were found for overweight at age 9 (aOR 2.19, CI 1.06–4.54 for boys; aOR 1.20, CI 0.53–2.70 for girls) and for high central adiposity at age 12 (aOR 2.85, CI 1.24–6.51 for boys; aOR 1.59, CI 0.68–3.68 for girls).Conclusions:Among boys, antibiotic exposure during the first year of life was associated with an increased risk of overweight and central adiposity in preadolescence, indicating that antibiotic stewardship is particularly important during infancy. Given the current epidemic of childhood obesity and the high prevalence of infant antibiotic exposure, further studies are necessary to determine the mechanisms underlying this association, to identify the long-term health consequences, and to develop strategies for mitigating these effects when antibiotic exposure cannot be avoided.

Impact of maternal intrapartum antibiotics, method of birth and breastfeeding on gut microbiota during the first year of life: a prospective cohort study.

Dysbiosis of the infant gut microbiota may have long‐term health consequences. This study aimed to determine the impact of maternal intrapartum antibiotic prophylaxis (IAP) on infant gut microbiota, and to explore whether breastfeeding modifies these effects.

Infant gut microbiota and food sensitization: associations in the first year of life

The gut microbiota is established during infancy and plays a fundamental role in shaping host immunity. Colonization patterns may influence the development of atopic disease, but existing evidence is limited and conflicting.

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).

Early life exposures: impact on asthma and allergic disease.

Purpose of reviewTo identify and discuss recent studies relating prenatal and early-life environmental exposures to the development of asthma and allergic disease. Recent findingsNew studies show that prenatal and early-life stress can alter infant immune profiles, increasing risk for asthma and allergy. Mounting evidence implicates indoor and outdoor air pollution in the origins of allergic disease, while Vitamin D intake and a Mediterranean diet may be protective. The role of early-life fever and infection remain controversial, with recent studies yielding conflicting results and new evidence indicating that previous studies may have been confounded. New studies are increasingly focused on environmental ‘imprinting’ of the infant gut microbiota, which is a critical determinant of immune system development. Early exposures impacting the intestinal microbiota include mode of delivery, infant diet, and use of antibiotics – factors that are also associated with childhood asthma and allergic disease. SummaryThis overview highlights environmental exposures during the in-utero and ex-utero time periods that are potential stimuli for the early programming of asthma and allergy. Special consideration is given for the potential role of intestinal microbiota. Future studies in this field promise to inform health policy and intervention strategies for the prevention of asthma and allergic disease.

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.

Nonnutritive sweeteners and cardiometabolic health: a systematic review and meta-analysis of randomized controlled trials and prospective cohort studies.

BACKGROUND Nonnutritive sweeteners, such as aspartame, sucralose and stevioside, are widely consumed, yet their long-term health impact is uncertain. We synthesized evidence from prospective studies to determine whether routine consumption of non-nutritive sweeteners was associated with long-term adverse cardiometabolic effects. METHODS We searched MEDLINE, Embase and Cochrane Library (inception to January 2016) for randomized controlled trials (RCTs) that evaluated interventions for nonnutritive sweeteners and prospective cohort studies that reported on consumption of non-nutritive sweeteners among adults and adolescents. The primary outcome was body mass index (BMI). Secondary outcomes included weight, obesity and other cardiometabolic end points. RESULTS From 11 774 citations, we included 7 trials (1003 participants; median follow-up 6 mo) and 30 cohort studies (405 907 participants; median follow-up 10 yr). In the included RCTs, nonnutritive sweeteners had no significant effect on BMI (mean difference −0.37 kg/m2; 95% confidence interval [CI] −1.10 to 0.36; I2 9%; 242 participants). In the included cohort studies, consumption of nonnutritive sweeteners was associated with a modest increase in BMI (mean correlation 0.05, 95% CI 0.03 to 0.06; I2 0%; 21 256 participants). Data from RCTs showed no consistent effects of nonnutritive sweeteners on other measures of body composition and reported no further secondary outcomes. In the cohort studies, consumption of nonnutritive sweeteners was associated with increases in weight and waist circumference, and higher incidence of obesity, hypertension, metabolic syndrome, type 2 diabetes and cardiovascular events. Publication bias was indicated for studies with diabetes as an outcome. INTERPRETATION Evidence from RCTs does not clearly support the intended benefits of nonnutritive sweeteners for weight management, and observational data suggest that routine intake of nonnutritive sweeteners may be associated with increased BMI and cardiometabolic risk. Further research is needed to fully characterize the long-term risks and benefits of nonnutritive sweeteners. Protocol registration: PROSPERO-CRD42015019749