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Impact of Cesarean Delivery and Breastfeeding on Secretory Immunoglobulin A in the Infant Gut Is Mediated by Gut Microbiota and Metabolites.
Chen, YY, Tun, HM, Field, CJ, Mandhane, PJ, Moraes, TJ, Simons, E, Turvey, SE, Subbarao, P, Scott, JA, Kozyrskyj, AL
Metabolites. 2023;(2)
Abstract
How gut immunity in early life is shaped by birth in relation to delivery mode, intrapartum antibiotic prophylaxis (IAP) and labor remains undetermined. We aimed to address this gap with a study of secretory Immunoglobulin A (SIgA) in the infant gut that also tested SIgA-stimulating pathways mediated by gut microbiota and metabolites. Among 1017 Canadian full-term infants, gut microbiota of fecal samples collected at 3 and 12 months were profiled using 16S rRNA sequencing; C. difficile was quantified by qPCR; fecal metabolites and SIgA levels were measured by NMR and SIgA enzyme-linked immunosorbent assay, respectively. We assessed the putative causal relationships from birth events to gut microbiota and metabolites, and ultimately to SIgA, in statistical sequential mediation models, adjusted for maternal gravida status in 551 infants. As birth mode influences the ability to breastfeed, the statistical mediating role of breastfeeding status and milk metabolites was also evaluated. Relative to vaginal birth without maternal IAP, cesarean section (CS) after labor was associated with reduced infant gut SIgA levels at 3 months (6.27 vs. 4.85 mg/g feces, p < 0.05); this association was sequentially mediated through gut microbiota and metabolites of microbial or milk origin. Mediating gut microbiota included Enterobacteriaceae, C. difficile, and Streptococcus. The milk or microbial metabolites in CS-SIgA mediating pathways were galactose, fucose, GABA, choline, lactate, pyruvate and 1,2-propanediol. This cohort study documented the impact of birth on infant gut mucosal SIgA. It is the first to characterize gut microbe-metabolite mediated pathways for early-life SIgA maturation, pathways that require experimental verification.
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Effectiveness of Probiotic, Prebiotic, and Synbiotic Supplementation to Improve Perinatal Mental Health in Mothers: A Systematic Review and Meta-Analysis.
Desai, V, Kozyrskyj, AL, Lau, S, Sanni, O, Dennett, L, Walter, J, Ospina, MB
Frontiers in psychiatry. 2021;12:622181
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Maternal mental health problems in the perinatal period are a global public health challenge. As many as one in five women develop depression and/or anxiety in the postpartum period, making them the most common complications of pregnancy and delivery. The aim of this study was to evaluate the evidence on the administration of prebiotic, probiotic, and/or synbiotic supplements during pregnancy to reduce the risk of mental health problems in the perinatal period. This study is a systemic review and meta-analysis of four studies of which three where included in the qualitative and quantitative synthesis. Results indicate limited evidence about the effectiveness of probiotics administered during pregnancy to reduce the risk of maternal mental health disorders and highlighted the lack of evidence on prebiotics and synbiotics supplementation to inform their use for similar purposes. Authors conclude that there is the need for future trials targeting microbiota interventions that test probiotic/prebiotic/synbiotic interventions that redress specific dysbioses in pregnancy gut microbiota that arise from poor mental health.
Abstract
Introduction: There is an emerging interest in modulating the gut microbiota to target the gut-brain axis and improve maternal mental health in the perinatal period. This systematic review evaluated the effectiveness of prebiotics, probiotics, and synbiotics supplementation during pregnancy to reduce the risk of maternal mental health problems in the perinatal period. Methods: Electronic biomedical databases and clinical trial registries were searched from database inception through August 2020 to identify randomized controlled clinical trials (RCTs) evaluating the effect of probiotic, prebiotic, or synbiotic supplements administered to women during pregnancy on measures of perinatal depression, anxiety, and other mental health outcomes. Study selection, risk of bias appraisal, and data extraction were independently performed by two reviewers. Pooled mean differences (MD) and odds ratios (pOR) with 95% confidence intervals (CI) were calculated in random-effects meta-analyses for the outcomes of interest in the review. Results: From 3,868 studies identified through the search strategy, three RCTs of low risk of bias involving 713 participants were included, all three testing probiotics. There were no differences between probiotics and control groups in the mean depression scores (MD -0.46; 95% CI -2.16, 1.25) at end of follow-up. Although statistical significance was not achieved, probiotics showed an advantage in the proportion of participants scoring below an established cut-off for depression (pOR 0.68; 95% CI 0.43, 1.07). Compared to placebo, probiotics in pregnancy reduced anxiety symptoms (MD -0.99; 95% CI -1.80, -0.18); however, this advantage was not translated in a reduction in the proportion of participants scoring above an established cut-off for anxiety (pOR 0.65; 95% CI 0.23, 1.85). There were no differences between probiotics and control groups in global mental health scores at end of follow-up (MD 1.09; 95% CI -2.04, 4.22). Conclusion: There is limited but promising evidence about the effectiveness of probiotics during pregnancy to reduce anxiety symptoms and reduce the proportion of women scoring ABOVE a cut-off depression score. There is a lack of RCT evidence supporting prebiotics and synbiotics supplementation for similar purposes in the perinatal period. More research is needed before prebiotics, probiotics, and synbiotics are recommended to support maternal mental health and well-being in the perinatal period. Systematic Review Registration: PROSPERO, CRD42019137158.
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Ethnicity Associations With Food Sensitization Are Mediated by Gut Microbiota Development in the First Year of Life.
Tun, HM, Peng, Y, Chen, B, Konya, TB, Morales-Lizcano, NP, Chari, R, Field, CJ, Guttman, DS, Becker, AB, Mandhane, PJ, et al
Gastroenterology. 2021;(1):94-106
Abstract
BACKGROUND AND AIMS Increasing evidence supports the role of early-life gut microbiota in developing atopic diseases, but ecological changes to gut microbiota during infancy in relation to food sensitization remain unclear. We aimed to characterize and associate these changes with the development of food sensitization in children. METHODS In this observational study, using 16S rRNA amplicon sequencing, we characterized the composition of 2844 fecal microbiota in 1422 Canadian full-term infants. Atopic sensitization outcomes were measured by skin prick tests at age 1 year and 3 years. The association between gut microbiota trajectories, based on longitudinal shifts in community clusters, and atopic sensitization outcomes at age 1 and 3 years were determined. Ethnicity and early-life exposures influencing microbiota trajectories were initially examined, and post-hoc analyses were conducted. RESULTS Four identified developmental trajectories of gut microbiota were shaped by birth mode and varied by ethnicity. The trajectory with persistently low Bacteroides abundance and high Enterobacteriaceae/Bacteroidaceae ratio throughout infancy increased the risk of sensitization to food allergens, particularly to peanuts at age 3 years by 3-fold (adjusted odds ratio [OR] 2.82, 95% confidence interval [CI] 1.13-7.01). A much higher likelihood for peanut sensitization was found if infants with this trajectory were born to Asian mothers (adjusted OR 7.87, 95% CI 2.75-22.55). It was characterized by a deficiency in sphingolipid metabolism and persistent Clostridioides difficile colonization. Importantly, this trajectory of depleted Bacteroides abundance mediated the association between Asian ethnicity and food sensitization. CONCLUSIONS This study documented an association between persistently low gut Bacteroides abundance throughout infancy and sensitization to peanuts in childhood. It is the first to show a mediation role for infant gut microbiota in ethnicity-associated development of food sensitization.
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Clostridioides difficile Colonization Is Differentially Associated With Gut Microbiome Profiles by Infant Feeding Modality at 3-4 Months of Age.
Drall, KM, Tun, HM, Morales-Lizcano, NP, Konya, TB, Guttman, DS, Field, CJ, Mandal, R, Wishart, DS, Becker, AB, Azad, MB, et al
Frontiers in immunology. 2019;:2866
Abstract
Colonization with Clostridioides difficile occurs in up to half of infants under the age of 3 months, is strongly influenced by feeding modality and is largely asymptomatic. In spite of this, C. difficile's presence has been associated with susceptibility to chronic disease later in childhood, perhaps by promoting or benefiting from changes in infant gut microbiome development, including colonization with pathogenic bacteria and disrupted production of microbial bioactive metabolites and proteins. In this study, the microbiomes of 1554 infants from the CHILD Cohort Study were described according to C. difficile colonization status and feeding mode at 3-4 months of age. C. difficile colonization was associated with a different gut microbiome profile in exclusively breastfed (EBF) vs. exclusively formula fed (EFF) infants. EBF infants colonized with C. difficile had an increased relative abundance of Firmicutes and Proteobacteria, decreased relative abundance of Bifidobacteriaceae, greater microbiota alpha-diversity, greater detectable fecal short chain fatty acids (SCFA), and lower detectable fecal secretory Immunoglobulin A (sIgA) than those not colonized. Similar but less pronounced differences were seen among partially breastfed infants (PBF) but EFF infants did not possess these differences in the gut microbiome according to colonization status. Thus, breastfed infants colonized with C. difficile appear to possess a gut microbiome that differs from non-colonized infants and resembles that of EFF infants, but the driving force and direction of this association remains unknown. Understanding these compositional differences as drivers of C. difficile colonization may be important to ensure future childhood health.
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Roles of Birth Mode and Infant Gut Microbiota in Intergenerational Transmission of Overweight and Obesity From Mother to Offspring.
Tun, HM, Bridgman, SL, Chari, R, Field, CJ, Guttman, DS, Becker, AB, Mandhane, PJ, Turvey, SE, Subbarao, P, Sears, MR, et al
JAMA pediatrics. 2018;(4):368-377
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Abstract
IMPORTANCE Maternal overweight, which often results in cesarean delivery, is a strong risk factor for child overweight. Little is known about the joint contribution of birth mode and microbiota in the infant gut to the association between maternal prepregnancy overweight and child overweight. OBJECTIVE To investigate the association of birth mode with microbiota in the infant gut, and whether this mediates the association between maternal and child overweight. DESIGN, SETTING, AND PARTICIPANTS An observational study was conducted of 935 full-term infants born between January 1, 2009, and December 31, 2012, in the Canadian Healthy Infant Longitudinal Development (CHILD) birth cohort. Maternal prepregnancy body mass index (BMI) was calculated as weight in kilograms divided by height in meters squared using height and weight data taken from medical records or maternal report. Infant gut microbiota were profiled with 16S ribosomal RNA sequencing in fecal samples collected at a mean (SD) age of 3.7 (1.0) months. At ages 1 and 3 years, BMI z scores adjusted for age and sex were generated according to World Health Organization criteria. Statistical analysis was conducted from January 29 to June 15, 2017. EXPOSURES Mothers of normal weight (BMI, 18.5-24.9) and overweight or obese (BMI, ≥25.0) mothers. MAIN OUTCOME AND MEASURES Risk of overweight and obesity (>97th percentile BMI z scores) among children at ages 1 and 3 years. RESULTS Of the 935 mother-infant pairs in the study (mean [SD] age, 32.5 [4.5] years) 382 (40.9%) were overweight, 69 of 926 infants (7.5%) were overweight at age 1 year, and 90 of 866 infants (10.4%) were overweight at age 3 years. Compared with being born vaginally to a mother of normal weight, infants born vaginally to overweight or obese mothers were 3 times more likely to become overweight at age 1 year (adjusted odds ratio [OR], 3.33; 95% CI, 1.49-7.41), while cesarean-delivered infants of overweight mothers had a 5-fold risk of overweight at age 1 year (adjusted OR, 5.02; 95% CI, 2.04-12.38). Similar risks were also observed at age 3 years. Multiple mediator path modeling revealed that birth mode and infant gut microbiota (Firmicutes species richness, especially of the Lachnospiraceae family) sequentially mediated the association between maternal prepregnancy overweight and childhood overweight at ages 1 and 3 years. Bacterial genera belonging to the Lachnospiraceae family were more abundant in infants of overweight mothers; however, the participating genera of Lachnospiraceae differed between infants delivered vaginally and those delivered via cesarean birth. CONCLUSIONS AND RELEVANCE This study found evidence of a novel sequential mediator pathway involving birth mode and Firmicutes species richness (especially higher abundance of Lachnospiraceae) for the intergenerational transmission of overweight.
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Meta-analysis of effects of exclusive breastfeeding on infant gut microbiota across populations.
Ho, NT, Li, F, Lee-Sarwar, KA, Tun, HM, Brown, BP, Pannaraj, PS, Bender, JM, Azad, MB, Thompson, AL, Weiss, ST, et al
Nature communications. 2018;(1):4169
Abstract
Previous studies on the differences in gut microbiota between exclusively breastfed (EBF) and non-EBF infants have provided highly variable results. Here we perform a meta-analysis of seven microbiome studies (1825 stool samples from 684 infants) to compare the gut microbiota of non-EBF and EBF infants across populations. In the first 6 months of life, gut bacterial diversity, microbiota age, relative abundances of Bacteroidetes and Firmicutes, and predicted microbial pathways related to carbohydrate metabolism are consistently higher in non-EBF than in EBF infants, whereas relative abundances of pathways related to lipid metabolism, vitamin metabolism, and detoxification are lower. Variation in predicted microbial pathways associated with non-EBF infants is larger among infants born by Caesarian section than among those vaginally delivered. Longer duration of exclusive breastfeeding is associated with reduced diarrhea-related gut microbiota dysbiosis. Furthermore, differences in gut microbiota between EBF and non-EBF infants persist after 6 months of age. Our findings elucidate some mechanisms of short and long-term benefits of exclusive breastfeeding across different populations.
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7.
Gut microbial metabolism defines host metabolism: an emerging perspective in obesity and allergic inflammation.
Kumari, M, Kozyrskyj, AL
Obesity reviews : an official journal of the International Association for the Study of Obesity. 2017;(1):18-31
Abstract
The presence of >100 trillion microorganisms (collectively called gut microbiota) in our large intestine is essential for the maintenance of health. The gut microbiota starts to develop before birth and matures within first three years of life. The Western diet and lifestyle have been implicated in causing an imbalance of gut microbial communities and their metabolites that consequence in disease states, such as obesity and asthma. With more than 13% of the world population currently living with obesity and one out of 10 children diagnosed with asthma, we explore here the recent developments in the biosynthesis and mode of action of the key metabolites in relation to these two chronic inflammatory conditions.
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Maternal sensitivity and social support protect against childhood atopic dermatitis.
Letourneau, NL, Kozyrskyj, AL, Cosic, N, Ntanda, HN, Anis, L, Hart, MJ, Campbell, TS, Giesbrecht, GF, ,
Allergy, asthma, and clinical immunology : official journal of the Canadian Society of Allergy and Clinical Immunology. 2017;:26
Abstract
BACKGROUND Many studies have identified associations between qualities of maternal-child relationships and childhood asthma, but few have examined associations with childhood atopic dermatitis (AD), a common precursor to asthma. Moreover, maternal psychological distress, including prenatal and postnatal depression, anxiety and stress, may increase risk, while social support from partners may reduce risk for childhood AD. We sought to uncover the association between maternal-infant relationship qualities (maternal sensitivity towards infant behavioral signals, controlling behavior, and unresponsiveness) and child AD after accounting for risk (i.e., prenatal and postnatal maternal depression, anxiety and stress) and protective (i.e., social support) factors. METHODS We conducted a secondary analysis of data collected on a subsample of 242 women and their infants enrolled during pregnancy in the ongoing Alberta Pregnancy Outcomes and Nutrition cohort study. Inclusion criteria required mothers to be >16 years of age, English speaking and <22 weeks gestational age at enrollment. Data on depression, anxiety and stress in the prenatal and postnatal periods and physician diagnosis of childhood AD at 18 months were gathered via maternal report. Maternal sensitivity, unresponsiveness and controlling behaviours were assessed via videotaped observations using the Child-Adult Relationship Experimental (CARE)-Index at 6 months of infant age. RESULTS Higher maternal sensitivity, or the inability of the mother to appropriately understand and respond to infant needs based on behavioral signals, predicted reduced odds of AD independent of and in combination with low prenatal and postnatal anxiety and high paternal support. After adjustment, higher maternal controlling behaviours and unresponsiveness also predicted greater odds of AD. CONCLUSIONS Low maternal sensitivity is a risk factor for childhood AD, independently and in combination with perinatal anxiety and low social support. Thus, interventions that improve maternal-infant relationship quality, especially sensitivity, reduce anxiety and improve social support from partners could reduce odds of childhood AD.
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Human Milk and Allergic Diseases: An Unsolved Puzzle.
Munblit, D, Peroni, DG, Boix-Amorós, A, Hsu, PS, Van't Land, B, Gay, MCL, Kolotilina, A, Skevaki, C, Boyle, RJ, Collado, MC, et al
Nutrients. 2017;(8)
Abstract
There is conflicting evidence on the protective role of breastfeeding in relation to the development of allergic sensitisation and allergic disease. Studies vary in methodology and definition of outcomes, which lead to considerable heterogeneity. Human milk composition varies both within and between individuals, which may partially explain conflicting data. It is known that human milk composition is very complex and contains variable levels of immune active molecules, oligosaccharides, metabolites, vitamins and other nutrients and microbial content. Existing evidence suggests that modulation of human breast milk composition has potential for preventing allergic diseases in early life. In this review, we discuss associations between breastfeeding/human milk composition and allergy development.
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Probiotic supplementation during pregnancy or infancy for the prevention of asthma and wheeze: systematic review and meta-analysis.
Azad, MB, Coneys, JG, Kozyrskyj, AL, Field, CJ, Ramsey, CD, Becker, AB, Friesen, C, Abou-Setta, AM, Zarychanski, R
BMJ (Clinical research ed.). 2013;:f6471
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Abstract
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, I(2)=0%). The risk ratio of incident wheeze was 0.97 (0.87 to 1.09, I(2)=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, I(2)=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).