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    Reduced diversity of the intestinal microbiota during infancy is associated with increased risk of allergic disease at school age. Bisgaard Hans,Li Nan,Bonnelykke Klaus,Chawes Bo Lund Krogsgaard,Skov Thomas,Paludan-Müller Georg,Stokholm Jakob,Smith Birgitte,Krogfelt Karen Angeliki The Journal of allergy and clinical immunology BACKGROUND:Changes in the human microbiome have been suggested as a risk factor for a number of lifestyle-related disorders, such as atopic diseases, possibly through a modifying influence on immune maturation in infancy. OBJECTIVES:We aimed to explore the association between neonatal fecal flora and the development of atopic disorders until age 6 years, hypothesizing that the diversity of the intestinal microbiota influences disease development. METHODS:We studied the intestinal microbiota in infants in the Copenhagen Prospective Study on Asthma in Childhood, a clinical study of a birth cohort of 411 high-risk children followed for 6 years by clinical assessments at 6-month intervals, as well as at acute symptom exacerbations. Bacterial flora was analyzed at 1 and 12 months of age by using molecular techniques based on 16S rRNA PCR combined with denaturing gradient gel electrophoresis, as well as conventional culturing. The main outcome measures were the development of allergic sensitization (skin test and specific serum IgE), allergic rhinitis, peripheral blood eosinophil counts, asthma, and atopic dermatitis during the first 6 years of life. RESULTS:We found that bacterial diversity in the early intestinal flora 1 and 12 months after birth was inversely associated with the risk of allergic sensitization (serum specific IgE P = .003; skin prick test P = .017), peripheral blood eosinophils (P = .034), and allergic rhinitis (P = .007). There was no association with the development of asthma or atopic dermatitis. CONCLUSIONS:Reduced bacterial diversity of the infant's intestinal flora was associated with increased risk of allergic sensitization, allergic rhinitis, and peripheral blood eosinophilia, but not asthma or atopic dermatitis, in the first 6 years of life. These results support the general hypothesis that an imbalance in the intestinal microbiome is influencing the development of lifestyle-related disorders, such as allergic disease. 10.1016/j.jaci.2011.04.060
    Early intestinal Bacteroides fragilis colonisation and development of asthma. Vael Carl,Nelen Vera,Verhulst Stijn L,Goossens Herman,Desager Kristine N BMC pulmonary medicine BACKGROUND:The 'hygiene hypothesis' suggests that early exposure to microbes can be protective against atopic disease. The intestinal microbial flora could operate as an important postnatal regulator of the Th1/Th2 balance. The aim of the study was to investigate the association between early intestinal colonisation and the development of asthma in the first 3 years of life. METHODS:In a prospective birth cohort, 117 children were classified according to the Asthma Predictive Index. A positive index included wheezing during the first three years of life combined with eczema in the child in the first years of life or with a parental history of asthma. A faecal sample was taken at the age of 3 weeks and cultured on selective media. RESULTS:Asthma Predictive Index was positive in 26/117 (22%) of the children. The prevalence of colonisation with Bacteroides fragilis was higher at 3 weeks in index+ compared to index- children (64% vs. 34% p < 0,05). Bacteroides fragilis and Total Anaerobes counts at 3 weeks were significantly higher in children with a positive index as compared with those without. After adjusting for confounders a positive association was found between Bacteroides fragilis colonisation and Asthma Predictive Index (odds ratio: 4,4; confidence interval: 1,7 - 11,8). CONCLUSION:Bacteroides fragilis colonisation at age 3 weeks is an early indicator of possible asthma later in life. This study could provide the means for more accurate targeting of treatment and prevention and thus more effective and better controlled modulation of the microbial milieu. 10.1186/1471-2466-8-19
    Associations between infant fungal and bacterial dysbiosis and childhood atopic wheeze in a nonindustrialized setting. Arrieta Marie-Claire,Arévalo Andrea,Stiemsma Leah,Dimitriu Pedro,Chico Martha E,Loor Sofia,Vaca Maritza,Boutin Rozlyn C T,Morien Evan,Jin Mingliang,Turvey Stuart E,Walter Jens,Parfrey Laura Wegener,Cooper Philip J,Finlay Brett The Journal of allergy and clinical immunology BACKGROUND:Asthma is the most prevalent chronic disease of childhood. Recently, we identified a critical window early in the life of both mice and Canadian infants during which gut microbial changes (dysbiosis) affect asthma development. Given geographic differences in human gut microbiota worldwide, we studied the effects of gut microbial dysbiosis on atopic wheeze in a population living in a distinct developing world environment. OBJECTIVE:We sought to determine whether microbial alterations in early infancy are associated with the development of atopic wheeze in a nonindustrialized setting. METHODS:We conducted a case-control study nested within a birth cohort from rural Ecuador in which we identified 27 children with atopic wheeze and 70 healthy control subjects at 5 years of age. We analyzed bacterial and eukaryotic gut microbiota in stool samples collected at 3 months of age using 16S and 18S sequencing. Bacterial metagenomes were predicted from 16S rRNA data by using Phylogenetic Investigation of Communities by Reconstruction of Unobserved States and categorized by function with Kyoto Encyclopedia of Genes and Genomes ontology. Concentrations of fecal short-chain fatty acids were determined by using gas chromatography. RESULTS:As previously observed in Canadian infants, microbial dysbiosis at 3 months of age was associated with later development of atopic wheeze. However, the dysbiosis in Ecuadorian babies involved different bacterial taxa, was more pronounced, and also involved several fungal taxa. Predicted metagenomic analysis emphasized significant dysbiosis-associated differences in genes involved in carbohydrate and taurine metabolism. Levels of the fecal short-chain fatty acids acetate and caproate were reduced and increased, respectively, in the 3-month stool samples of children who went on to have atopic wheeze. CONCLUSIONS:Our findings support the importance of fungal and bacterial microbiota during the first 100 days of life on the development of atopic wheeze and provide additional support for considering modulation of the gut microbiome as a primary asthma prevention strategy. 10.1016/j.jaci.2017.08.041
    Association Between Use of Acid-Suppressive Medications and Antibiotics During Infancy and Allergic Diseases in Early Childhood. Mitre Edward,Susi Apryl,Kropp Laura E,Schwartz David J,Gorman Gregory H,Nylund Cade M JAMA pediatrics Importance:Allergic diseases are prevalent in childhood. Early exposure to medications that can alter the microbiome, including acid-suppressive medications and antibiotics, may influence the likelihood of allergy. Objective:To determine whether there is an association between the use of acid-suppressive medications or antibiotics in the first 6 months of infancy and development of allergic diseases in early childhood. Design, Setting, and Participants:A retrospective cohort study was conducted in 792 130 children who were Department of Defense TRICARE beneficiaries with a birth medical record in the Military Health System database between October 1, 2001, and September 30, 2013, with continued enrollment from within 35 days of birth until at least age 1 year. Children who had an initial birth stay of greater than 7 days or were diagnosed with any of the outcome allergic conditions within the first 6 months of life were excluded from the study. Data analysis was performed from April 15, 2015, to January 4, 2018. Exposures:Exposures were defined as having any dispensed prescription for a histamine-2 receptor antagonist (H2RA), proton pump inhibitor (PPI), or antibiotic. Main Outcomes and Measures:The main outcome was allergic disease, defined as the presence of food allergy, anaphylaxis, asthma, atopic dermatitis, allergic rhinitis, allergic conjunctivitis, urticaria, contact dermatitis, medication allergy, or other allergy. Results:Of 792 130 children (395 215 [49.9%] girls) included for analysis, 60 209 (7.6%) were prescribed an H2RA, 13 687 (1.7%) were prescribed a PPI, and 131 708 (16.6%) were prescribed an antibiotic during the first 6 months of life. Data for each child were available for a median of 4.6 years. Adjusted hazard ratios (aHRs) in children prescribed H2RAs and PPIs, respectively, were 2.18 (95% CI, 2.04-2.33) and 2.59 (95% CI, 2.25-3.00) for food allergy, 1.70 (95% CI, 1.60-1.80) and 1.84 (95% CI, 1.56-2.17) for medication allergy, 1.51 (95% CI, 1.38-1.66) and 1.45 (95% CI, 1.22-1.73) for anaphylaxis, 1.50 (95% CI, 1.46-1.54) and 1.44 (95% CI, 1.36-1.52) for allergic rhinitis, and 1.25 (95% CI, 1.21-1.29) and 1.41 (95% CI, 1.31-1.52) for asthma. The aHRs after antibiotic prescription in the first 6 months of life were 2.09 (95% CI, 2.05-2.13) for asthma, 1.75 (95% CI, 1.72-1.78) for allergic rhinitis, 1.51 (95% CI, 1.38-1.66) for anaphylaxis, and 1.42 (95% CI, 1.34-1.50) for allergic conjunctivitis. Conclusions and Relevance:This study found associations between the use of acid-suppressive medications and antibiotics during the first 6 months of infancy and subsequent development of allergic disease. Acid-suppressive medications and antibiotics should be used during infancy only in situations of clear clinical benefit. 10.1001/jamapediatrics.2018.0315
    Food diversity in infancy and the risk of childhood asthma and allergies. Nwaru Bright I,Takkinen Hanna-Mari,Kaila Minna,Erkkola Maijaliisa,Ahonen Suvi,Pekkanen Juha,Simell Olli,Veijola Riitta,Ilonen Jorma,Hyöty Heikki,Knip Mikael,Virtanen Suvi M The Journal of allergy and clinical immunology BACKGROUND:Recently, the bacterial diversity of the intestinal flora and the diversity of various environmental factors during infancy have been linked to the development of allergies in childhood. Food is an important environmental exposure, but the role of food diversity in the development of asthma and allergies in childhood is poorly defined. OBJECTIVE:We studied the associations between food diversity during the first year of life and the development of asthma and allergies by age 5 years. METHODS:In a Finnish birth cohort we analyzed data on 3142 consecutively born children. We studied food diversity at 3, 4, 6, and 12 months of age. Asthma, wheeze, atopic eczema, and allergic rhinitis were measured by using the International Study of Asthma and Allergies in Childhood questionnaire at age 5 years. RESULTS:By 3 and 4 months of age, food diversity was not associated with any of the allergic end points. By 6 months of age, less food diversity was associated with increased risk of allergic rhinitis but not with the other end points. By 12 months of age, less food diversity was associated with increased risk of any asthma, atopic asthma, wheeze, and allergic rhinitis. CONCLUSION:Less food diversity during the first year of life might increase the risk of asthma and allergies in childhood. The mechanisms for this association are unclear, but increased dietary antigen exposure might contribute to this link. 10.1016/j.jaci.2013.12.1069
    Neonatal gut microbiota associates with childhood multisensitized atopy and T cell differentiation. Fujimura Kei E,Sitarik Alexandra R,Havstad Suzanne,Lin Din L,Levan Sophia,Fadrosh Douglas,Panzer Ariane R,LaMere Brandon,Rackaityte Elze,Lukacs Nicholas W,Wegienka Ganesa,Boushey Homer A,Ownby Dennis R,Zoratti Edward M,Levin Albert M,Johnson Christine C,Lynch Susan V Nature medicine Gut microbiota bacterial depletions and altered metabolic activity at 3 months are implicated in childhood atopy and asthma. We hypothesized that compositionally distinct human neonatal gut microbiota (NGM) exist, and are differentially related to relative risk (RR) of childhood atopy and asthma. Using stool samples (n = 298; aged 1-11 months) from a US birth cohort and 16S rRNA sequencing, neonates (median age, 35 d) were divisible into three microbiota composition states (NGM1-3). Each incurred a substantially different RR for multisensitized atopy at age 2 years and doctor-diagnosed asthma at age 4 years. The highest risk group, labeled NGM3, showed lower relative abundance of certain bacteria (for example, Bifidobacterium, Akkermansia and Faecalibacterium), higher relative abundance of particular fungi (Candida and Rhodotorula) and a distinct fecal metabolome enriched for pro-inflammatory metabolites. Ex vivo culture of human adult peripheral T cells with sterile fecal water from NGM3 subjects increased the proportion of CD4 cells producing interleukin (IL)-4 and reduced the relative abundance of CD4CD25FOXP3 cells. 12,13-DiHOME, enriched in NGM3 versus lower-risk NGM states, recapitulated the effect of NGM3 fecal water on relative CD4CD25FOXP3 cell abundance. These findings suggest that neonatal gut microbiome dysbiosis might promote CD4 T cell dysfunction associated with childhood atopy. 10.1038/nm.4176
    Exposure to household furry pets influences the gut microbiota of infant at 3-4 months following various birth scenarios. Tun Hein M,Konya Theodore,Takaro Tim K,Brook Jeffrey R,Chari Radha,Field Catherine J,Guttman David S,Becker Allan B,Mandhane Piush J,Turvey Stuart E,Subbarao Padmaja,Sears Malcolm R,Scott James A,Kozyrskyj Anita L, Microbiome BACKGROUND:Early-life exposure to household pets has the capacity to reduce risk for overweight and allergic disease, especially following caesarean delivery. Since there is some evidence that pets also alter the gut microbial composition of infants, changes to the gut microbiome are putative pathways by which pet exposure can reduce these risks to health. To investigate the impact of pre- and postnatal pet exposure on infant gut microbiota following various birth scenarios, this study employed a large subsample of 746 infants from the Canadian Healthy Infant Longitudinal Development Study (CHILD) cohort, whose mothers were enrolled during pregnancy between 2009 and 2012. Participating mothers were asked to report on household pet ownership at recruitment during the second or third trimester and 3 months postpartum. Infant gut microbiota were profiled with 16S rRNA sequencing from faecal samples collected at the mean age of 3.3 months. Two categories of pet exposure (i) only during pregnancy and (ii) pre- and postnatally were compared to no pet exposure under different birth scenarios. RESULTS:Over half of studied infants were exposed to at least one furry pet in the prenatal and/or postnatal periods, of which 8% were exposed in pregnancy alone and 46.8% had exposure during both time periods. As a common effect in all birth scenarios, pre- and postnatal pet exposure enriched the abundance of Oscillospira and/or Ruminococcus (P < 0.05) with more than a twofold greater likelihood of high abundance. Among vaginally born infants with maternal intrapartum antibiotic prophylaxis exposure, Streptococcaceae were substantially and significantly reduced by pet exposure (P < 0.001, FDRp = 0.03), reflecting an 80% decreased likelihood of high abundance (OR 0.20, 95%CI, 0.06-0.70) for pet exposure during pregnancy alone and a 69% reduced likelihood (OR 0.31, 95%CI, 0.16-0.58) for exposure in the pre- and postnatal time periods. All of these associations were independent of maternal asthma/allergy status, siblingship, breastfeeding exclusivity and other home characteristics. CONCLUSIONS:The impact of pet ownership varies under different birth scenarios; however, in common, exposure to pets increased the abundance of two bacteria, Ruminococcus and Oscillospira, which have been negatively associated with childhood atopy and obesity. 10.1186/s40168-017-0254-x
    Caesarean section and children's health: A quasi-experimental design. Polos Jessica,Fletcher Jason Population studies The prevalence of inflammatory child health conditions-such as asthma, eczema, and food allergy-and their associated costs have increased rapidly over the last 30 years. While environmental factors likely underpin these increases, recent studies explain only a fraction of the trend and rely on associational methods. Caesarean (or C-) section rates increased dramatically in the period of interest, and this method of delivery is an understudied environmental factor linked to child health outcomes via the gut microbiome. We fuse 22 years of birth cohort data from the United States National Surveys of Children's Health with C-section rates from the National Vital Statistics System generated for subgroups based on state, sex, race, Hispanic origin, and birth year. Then, we model the effects of C-section on rates of asthma, eczema, and food allergy using a quasi-experimental fixed effects design. We find that C-section significantly predicts food allergy, with qualitatively significant implications. 10.1080/00324728.2019.1624810
    A prospective microbiome-wide association study of food sensitization and food allergy in early childhood. Savage Jessica H,Lee-Sarwar Kathleen A,Sordillo Joanne,Bunyavanich Supinda,Zhou Yanjiao,O'Connor George,Sandel Megan,Bacharier Leonard B,Zeiger Robert,Sodergren Erica,Weinstock George M,Gold Diane R,Weiss Scott T,Litonjua Augusto A Allergy BACKGROUND:Alterations in the intestinal microbiome are prospectively associated with the development of asthma; less is known regarding the role of microbiome alterations in food allergy development. METHODS:Intestinal microbiome samples were collected at age 3-6 months in children participating in the follow-up phase of an interventional trial of high-dose vitamin D given during pregnancy. At age 3, sensitization to foods (milk, egg, peanut, soy, wheat, walnut) was assessed. Food allergy was defined as caretaker report of healthcare provider-diagnosed allergy to the above foods prior to age 3 with evidence of IgE sensitization. Analysis was performed using Phyloseq and DESeq2; P-values were adjusted for multiple comparisons. RESULTS:Complete data were available for 225 children; there were 87 cases of food sensitization and 14 cases of food allergy. Microbial diversity measures did not differ between food sensitization and food allergy cases and controls. The genera Haemophilus (log fold change -2.15, P=.003), Dialister (log fold change -2.22, P=.009), Dorea (log fold change -1.65, P=.02), and Clostridium (log fold change -1.47, P=.002) were underrepresented among subjects with food sensitization. The genera Citrobacter (log fold change -3.41, P=.03), Oscillospira (log fold change -2.80, P=.03), Lactococcus (log fold change -3.19, P=.05), and Dorea (log fold change -3.00, P=.05) were underrepresented among subjects with food allergy. CONCLUSIONS:The temporal association between bacterial colonization and food sensitization and allergy suggests that the microbiome may have a causal role in the development of food allergy. Our findings have therapeutic implications for the prevention and treatment of food allergy. 10.1111/all.13232
    High level of fecal calprotectin at age 2 months as a marker of intestinal inflammation predicts atopic dermatitis and asthma by age 6. Orivuori L,Mustonen K,de Goffau M C,Hakala S,Paasela M,Roduit C,Dalphin J-C,Genuneit J,Lauener R,Riedler J,Weber J,von Mutius E,Pekkanen J,Harmsen H J M,Vaarala O, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology BACKGROUND:Gut microbiota and intestinal inflammation regulate the development of immune-mediated diseases, such as allergies. Fecal calprotectin is a biomarker of intestinal inflammation. OBJECTIVE:We evaluated the association of early-age fecal calprotectin levels to the later development of allergic diseases in children from farming and non-farming environments and further studied the effect of gut microbiota on the fecal calprotectin levels. METHODS:Fecal calprotectin was measured from 758 infants participating in the PASTURE study at the age of 2 months using the ELISA method. Serum-specific IgE levels were measured at 6 years of age. Data of environmental factors, doctor-diagnosed atopic dermatitis (AD) and asthma were collected by questionnaire. Multivariate logistic regression models were used for analysis. The composition of fecal microbiota was analysed in a subgroup of 120 infants with 16S rRNA pyrosequencing. The effect of Escherichia coli lipopolysaccharide (LPS) on in vitro monocyte IL-10 secretion was studied by flow cytometry. RESULTS:The infants with high fecal calprotectin levels at 2 months, that is above the 90th percentile, had an increased risk of developing AD and asthma/asthmatic bronchitis by the age of 6 years (aOR 2.02 (1.06-3.85) and 2.41 (1.25-4.64), respectively). High fecal calprotectin levels correlated negatively with fecal Escherichia. LPS from E. coli stimulated production of IL-10 in monocytes. CONCLUSION AND CLINICAL RELEVANCE:High degree intestinal inflammation at 2 months of age, detected as high fecal calprotectin, predicted asthma and AD by the age of 6 years and was linked to low abundance of fecal Escherichia. Impaired IL-10 activation due to the lack of colonization with E. coli could explain the intestinal inflammation associated high fecal calprotectin and later risk of asthma and AD. Our results have implications for the design of probiotic treatments and suggest that early intestinal colonization has long-term health effects. 10.1111/cea.12522
    Early infancy microbial and metabolic alterations affect risk of childhood asthma. Arrieta Marie-Claire,Stiemsma Leah T,Dimitriu Pedro A,Thorson Lisa,Russell Shannon,Yurist-Doutsch Sophie,Kuzeljevic Boris,Gold Matthew J,Britton Heidi M,Lefebvre Diana L,Subbarao Padmaja,Mandhane Piush,Becker Allan,McNagny Kelly M,Sears Malcolm R,Kollmann Tobias, ,Mohn William W,Turvey Stuart E,Finlay B Brett Science translational medicine Asthma is the most prevalent pediatric chronic disease and affects more than 300 million people worldwide. Recent evidence in mice has identified a "critical window" early in life where gut microbial changes (dysbiosis) are most influential in experimental asthma. However, current research has yet to establish whether these changes precede or are involved in human asthma. We compared the gut microbiota of 319 subjects enrolled in the Canadian Healthy Infant Longitudinal Development (CHILD) Study, and show that infants at risk of asthma exhibited transient gut microbial dysbiosis during the first 100 days of life. The relative abundance of the bacterial genera Lachnospira, Veillonella, Faecalibacterium, and Rothia was significantly decreased in children at risk of asthma. This reduction in bacterial taxa was accompanied by reduced levels of fecal acetate and dysregulation of enterohepatic metabolites. Inoculation of germ-free mice with these four bacterial taxa ameliorated airway inflammation in their adult progeny, demonstrating a causal role of these bacterial taxa in averting asthma development. These results enhance the potential for future microbe-based diagnostics and therapies, potentially in the form of probiotics, to prevent the development of asthma and other related allergic diseases in children. 10.1126/scitranslmed.aab2271
    Intestinal microbiome is related to lifetime antibiotic use in Finnish pre-school children. Korpela Katri,Salonen Anne,Virta Lauri J,Kekkonen Riina A,Forslund Kristoffer,Bork Peer,de Vos Willem M Nature communications Early-life antibiotic use is associated with increased risk for metabolic and immunological diseases, and mouse studies indicate a causal role of the disrupted microbiome. However, little is known about the impacts of antibiotics on the developing microbiome of children. Here we use phylogenetics, metagenomics and individual antibiotic purchase records to show that macrolide use in 2-7 year-old Finnish children (N=142; sampled at two time points) is associated with a long-lasting shift in microbiota composition and metabolism. The shift includes depletion of Actinobacteria, increase in Bacteroidetes and Proteobacteria, decrease in bile-salt hydrolase and increase in macrolide resistance. Furthermore, macrolide use in early life is associated with increased risk of asthma and predisposes to antibiotic-associated weight gain. Overweight and asthmatic children have distinct microbiota compositions. Penicillins leave a weaker mark on the microbiota than macrolides. Our results support the idea that, without compromising clinical practice, the impact on the intestinal microbiota should be considered when prescribing antibiotics. 10.1038/ncomms10410
    Maternal intestinal flora and wheeze in early childhood. Lange N E,Celedón J C,Forno E,Ly N P,Onderdonk A,Bry L,Delaney M L,DuBois A M,Gold D R,Weiss S T,Litonjua A A Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology BACKGROUND:Increasing evidence links altered intestinal flora in infancy to eczema and asthma. No studies have investigated the influence of maternal intestinal flora on wheezing and eczema in early childhood. OBJECTIVE:To investigate the link between maternal intestinal flora during pregnancy and development of wheeze and eczema in infancy. METHODS:A total of 60 pregnant women from the Boston area gave stool samples during the third trimester of their pregnancy and answered questions during pregnancy about their own health, and about their children's health when the child was 2 and 6 months of age. Quantitative culture was performed on stool samples and measured in log(10)colony-forming units (CFU)/gram stool. Primary outcomes included infant wheeze and eczema in the first 6 months of life. Atopic wheeze, defined as wheeze and eczema, was analysed as a secondary outcome. RESULTS:In multivariate models adjusted for breastfeeding, day care attendance and maternal atopy, higher counts of maternal total aerobes (TA) and enterococci (E) were associated with increased risk of infant wheeze (TA: OR 2.32 for 1 log increase in CFU/g stool [95% CI 1.22, 4.42]; E: OR 1.57 [95% CI 1.06, 2.31]). No organisms were associated with either eczema or atopic wheeze. CONCLUSIONS AND CLINICAL RELEVANCE:In our cohort, higher maternal total aerobes and enterococci were related to increased risk of infant wheeze. Maternal intestinal flora may be an important environmental exposure in early immune system development. 10.1111/j.1365-2222.2011.03950.x
    Early antibiotic exposure and development of asthma and allergic rhinitis in childhood. Ni Jeffrey,Friedman Hannah,Boyd Bridget C,McGurn Andrew,Babinski Piotr,Markossian Talar,Dugas Lara R BMC pediatrics BACKGROUND:The prevalence of pediatric allergic diseases has increased rapidly in the United States over the past few decades. Recent studies suggest an association between the increase in allergic disease and early disturbances to the gut microbiome. The gut microbiome is a set of intestinal microorganisms that begins to form during birth and is highly susceptible to disturbance during the first year of life. Early antibiotic exposure may negatively impact the gut microbiota by altering the bacterial composition and causing dysbiosis, thus increasing the risk for developing childhood allergic disease. METHODS:We performed a retrospective chart review of data in Loyola University Medical Center's (LUMC) Epic system from 2007 to 2016. We defined antibiotic exposure as orders in both the outpatient and inpatient settings. Inclusion criteria were being born at LUMC with at least two follow up visits. Asthma and allergic rhinitis diagnoses were obtained using ICD 9 and ICD 10 codes. We controlled for multiple confounding factors. Using Stata, bivariate logistic regression was performed between antibiotics from 0 to 12 months of life and development of disease. This analysis was repeated for total lifetime antibiotics. We defined statistically significant as p < .05. RESULTS:The administration of antibiotics within the first 12 months of life was significantly associated with lifetime asthma (OR 2.66; C. I 1.11-6.40) but not allergic rhinitis. There was a significant association between lifetime antibiotics and asthma (OR 3.54; C. I 1.99-6.30) and allergic rhinitis (OR 2.43; C. I 1.43-4.11). CONCLUSION:Antibiotic administration in the first year of life and throughout lifetime is significantly associated with developing asthma and allergic rhinitis. These results provide support for a conservative approach regarding antibiotic use in early childhood. 10.1186/s12887-019-1594-4
    Reduced Akkermansia muciniphila and Faecalibacterium prausnitzii levels in the gut microbiota of children with allergic asthma. Demirci M,Tokman H B,Uysal H K,Demiryas S,Karakullukcu A,Saribas S,Cokugras H,Kocazeybek B S Allergologia et immunopathologia INTRODUCTION AND OBJECTIVES:The amounts of Akkermansia muciniphila and Faecalibacterium prausnitzii in gut microbiota are reduced in patients with allergic diseases compared to healthy controls. We aimed to quantify levels of A. muciniphila and F. prausnitzii amounts using real-time quantitative PCR (qPCR) in the gut microbiota of children with allergic asthma and in healthy controls. MATERIALS AND METHODS:In total, 92 children between the ages of three and eight who were diagnosed with asthma and 88 healthy children were included in the study and bacterial DNA was isolated from the stool samples using the stool DNA isolation Kit. qPCR assays were studied with the microbial DNA qPCR Kit for A. muciniphila and microbial DNA qPCR Kit for F. prausnitzii. RESULTS:Both bacterial species showed a reduction in the patient group compared to healthy controls. A. muciniphila and F. prausnitzii were found to be 5.45±0.004, 6.74±0.01 and 5.71±0.002, 7.28±0.009 in the stool samples of the asthma and healthy control groups, respectively. CONCLUSIONS:F. prausnitzii and A. muciniphila may have induced anti-inflammatory cytokine IL-10 and prevented the secretion of pro-inflammatory cytokines like IL-12. These findings suggest that A. muciniphila and F. prausnitzii may suppress inflammation through its secreted metabolites. 10.1016/j.aller.2018.12.009
    Gut microbial-derived butyrate is inversely associated with IgE responses to allergens in childhood asthma. Chiu Chih-Yung,Cheng Mei-Ling,Chiang Meng-Han,Kuo Yu-Lun,Tsai Ming-Han,Chiu Chun-Che,Lin Gigin Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology BACKGROUND:A comprehensive metabolomics-based approach to address the impact of specific gut microbiota on allergen sensitization for childhood rhinitis and asthma is still lacking. METHODS:Eighty-five children with rhinitis (n = 27) and with asthma (n = 34) and healthy controls (n = 24) were enrolled. Fecal metabolomic analysis with H-nuclear magnetic resonance (NMR) spectroscopy and microbiome composition analysis by bacterial 16S rRNA sequencing were performed. An integrative analysis of their associations with allergen-specific IgE levels for allergic rhinitis and asthma was also assessed. RESULTS:Amino acid, β-alanine, and butanoate were the predominant metabolic pathways in the gut. Among them, amino acid metabolism was negatively correlated with the phylum Firmicutes, which was significantly reduced in children with rhinitis and asthma. Levels of histidine and butyrate metabolites were significantly reduced in children with rhinitis (P = 0.029) and asthma (P = 0.009), respectively. In children with asthma, a reduction in butyrate-producing bacteria, including Faecalibacterium and Roseburia spp., and an increase in Clostridium spp. were negatively correlated with fecal amino acids and butyrate, respectively (P < 0.01). Increased Escherichia spp. accompanied by increased β-alanine and 4-hydroxybutyrate appeared to reduce butyrate production. Low fecal butyrate was significantly associated with increased total serum and mite allergen-specific IgE levels in children with asthma (P < 0.05). CONCLUSION:A reduced fecal butyrate is associated with increased mite-specific IgE levels and the risk of asthma in early childhood. Fecal β-alanine could be a specific biomarker connecting the metabolic dysbiosis of gut microbiota, Clostridium and Escherichia spp., in childhood asthma. 10.1111/pai.13096
    Shifts in Lachnospira and Clostridium sp. in the 3-month stool microbiome are associated with preschool age asthma. Stiemsma Leah T,Arrieta Marie-Claire,Dimitriu Pedro A,Cheng Jasmine,Thorson Lisa,Lefebvre Diana L,Azad Meghan B,Subbarao Padmaja,Mandhane Piush,Becker Allan,Sears Malcolm R,Kollmann Tobias R, ,Mohn William W,Finlay B Brett,Turvey Stuart E Clinical science (London, England : 1979) Asthma is a chronic disease of the airways affecting one in ten children in Westernized countries. Recently, our group showed that specific bacterial genera in early life are associated with atopy and wheezing in 1-year-old children. However, little is known about the link between the early life gut microbiome and the diagnosis of asthma in preschool age children. To determine the role of the gut microbiota in preschool age asthma, children up to 4 years of age enrolled in the Canadian Healthy Infant Longitudinal Development (CHILD) study were classified as asthmatic (n=39) or matched healthy controls (n=37). 16S rRNA sequencing and quantitative PCR (qPCR) were used to analyse the composition of the 3-month and 1-year gut microbiome of these children. At 3 months the abundance of the genus, Lachnospira (L), was decreased (P=0.008), whereas the abundance of the species, Clostridium neonatale (C), was increased (P=0.07) in asthmatics. Quartile analysis of stool composition at 3-months revealed a negative association between the ratio of these two bacteria (L/C) and asthma risk by 4 years of age [quartile 1: odds ratio (OR)=15, P=0.02, CI (confidence interval)= 1.8-124.7; quartile 2: OR=1.0, ns; quartile 3: OR=0.37, ns]. We conclude that opposing shifts in the relative abundances of Lachnospira and C. neonatale in the first 3 months of life are associated with preschool age asthma, and that the L/C ratio may serve as a potential early life biomarker to predict asthma development. 10.1042/CS20160349
    The role of antimicrobial treatment during pregnancy on the neonatal gut microbiome and the development of atopy, asthma, allergy and obesity in childhood. Milliken Sarah,Allen Ruridh M,Lamont Ronald F Expert opinion on drug safety INTRODUCTION:The use of antibiotics prenatally, during pregnancy, or neonatally may have adverse effects on the neonatal gut microbiome, and adversely affect the development of the infant immune system, leading to childhood atopy, asthma, allergy and obesity. AREAS COVERED:Vaginal eubiosis and dysbiosis from molecular-based, cultivation-independent techniques, and how this affects the neonatal gut microbiome and early development of the immune system, the association between maternal antibiotics and the beneficial role of vitamin D in the development of atopy, asthma, allergy and obesity, efforts to reduce the use of antibiotics in pregnancy and therapeutic interventions such as vaginal 'seeding', probiotics, breastfeeding and neonatal dietary supplementation. EXPERT OPINION:Currently available research gives insufficient attention to confounding variables. There remains uncertainty as to whether it is relevant that the mother suffered from the same condition as the purported infant outcome variable, for which she may have received antibiotics. In most studies, there is a lack of control for the number of antibiotic courses administered, the timing of use, the use of broad spectrum or narrow range antibiotics, the indication for antibiotics, the dose-dependent nature of the effect, the class of antibiotics used, or a varying degree of risk. 10.1080/14740338.2019.1579795
    Maturation of the gut microbiome and risk of asthma in childhood. Stokholm Jakob,Blaser Martin J,Thorsen Jonathan,Rasmussen Morten A,Waage Johannes,Vinding Rebecca K,Schoos Ann-Marie M,Kunøe Asja,Fink Nadia R,Chawes Bo L,Bønnelykke Klaus,Brejnrod Asker D,Mortensen Martin S,Al-Soud Waleed Abu,Sørensen Søren J,Bisgaard Hans Nature communications The composition of the human gut microbiome matures within the first years of life. It has been hypothesized that microbial compositions in this period can cause immune dysregulations and potentially cause asthma. Here we show, by associating gut microbial composition from 16S rRNA gene amplicon sequencing during the first year of life with subsequent risk of asthma in 690 participants, that 1-year-old children with an immature microbial composition have an increased risk of asthma at age 5 years. This association is only apparent among children born to asthmatic mothers, suggesting that lacking microbial stimulation during the first year of life can trigger their inherited asthma risk. Conversely, adequate maturation of the gut microbiome in this period may protect these pre-disposed children. 10.1038/s41467-017-02573-2