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Exposure to household furry pets influences the gut microbiota of infants at 3–4 months following various… 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 Apr 6, 2017

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RESEARCH Open AccessExposure to household furry petsinfluences the gut microbiota of infants at3–4 months following various birthscenariosHein M. Tun1, Theodore Konya2, Tim K. Takaro3, Jeffrey R. Brook2, Radha Chari4, Catherine J. Field5, David S. Guttman6,Allan B. Becker7, Piush J. Mandhane1, Stuart E. Turvey8, Padmaja Subbarao9, Malcolm R. Sears10, James A. Scott2,Anita L. Kozyrskyj1* and the CHILD Study InvestigatorsAbstractBackground: 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 ofinfants, changes to the gut microbiome are putative pathways by which pet exposure can reduce these risks to health. Toinvestigate the impact of pre- and postnatal pet exposure on infant gut microbiota following various birth scenarios, thisstudy 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 wereasked to report on household pet ownership at recruitment during the second or third trimester and 3 monthspostpartum. Infant gut microbiota were profiled with 16S rRNA sequencing from faecal samples collected at the meanage of 3.3 months. Two categories of pet exposure (i) only during pregnancy and (ii) pre- and postnatally were comparedto 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, ofwhich 8% were exposed in pregnancy alone and 46.8% had exposure during both time periods. As a common effect inall 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 intrapartumantibiotic 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 exposureduring pregnancy alone and a 69% reduced likelihood (OR 0.31, 95%CI, 0.16–0.58) for exposure in the pre- and postnataltime periods. All of these associations were independent of maternal asthma/allergy status, siblingship, breastfeedingexclusivity and other home characteristics.Conclusions: The impact of pet ownership varies under different birth scenarios; however, in common, exposure to petsincreased the abundance of two bacteria, Ruminococcus and Oscillospira, which have been negatively associated withchildhood atopy and obesity.Keywords: Pets, Infant gut microbiota, Birth, Prenatal, Postnatal* Correspondence: kozyrsky@ualberta.ca1Department of Pediatrics, University of Alberta, 3-527 Edmonton ClinicHealth Academy, 11405–87th Avenue, Edmonton, AB T6G IC9, CanadaFull list of author information is available at the end of the article© The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link tothe Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Tun et al. Microbiome  (2017) 5:40 DOI 10.1186/s40168-017-0254-xBackgroundMicrobial colonization of the infant gastrointestinal tractis an essential process in our life cycle, and microbiota-host interactions during this developmental stage of lifehave a significant influence on future health. Followingbirth, the gut microbiota of newborns is characterized bylow diversity, dominated by facultative anaerobes suchas the Proteobacteria, after which the diversity of strictanaerobes within the Firmicutes and Bacteroidetes phylaincreases towards an adult-like profile by 1 year of age[1–3]. Throughout this development, microbial compos-ition is shaped by a number of factors including gesta-tional age, mode of delivery (vaginal vs. caesarean),infant diet (breast milk vs. formula) and antibiotic treat-ment (direct vs. indirect via mother) [4, 5]. Among sev-eral environmental determinants that influence postnatalgut microbial development, rising rates of pet ownershipglobally have stimulated interest on the impact of house-hold furry pets.The notion that pets provide an immune benefit tohuman health stems from the hygiene hypothesis, firstproposed by David Strachan in 1989 [6] and subse-quently supported by several epidemiological studies[7–12], which attributes risk of allergic disease to overlyhygienic environments. With further evidence that gutmicrobial dysbiosis during infancy is associated with thedevelopment of allergic disease, this notion has been re-vised as the ‘microbiota hypothesis’ [13]. Despite rapidmicrobial colonization of the gut after birth, environ-mental microbes in the antenatal and/or early postnatalperiod represent a critical exposure for early-life im-mune programming that may have long-term conse-quences. A pooled analysis of 7000 householdsdocumented that dog ownership during the first 2 yearsof life reduced sensitization to allergens in early child-hood, although the evidence for asthma prevention wasless clear [14]. In a meta-analysis of six studies that eval-uated prenatal exposure to household pets, a loweredrisk for allergic disease (atopic dermatitis, asthma) in off-spring was found, especially for prenatal dog ownership[10]. Havstad et al. [15] documented lowered IgE levelsuntil 2 years of age following pet exposure during preg-nancy, which were not altered by postnatal pet owner-ship. Further, the prenatal pet association was strongestfor children born by caesarean section (CS). Still othershave found that postnatal pet ownership modified early-life risk factors for metabolic diseases. In the absence ofhousehold pets, Cassidy-Bushrow et al. [16] reported atwofold higher risk of obesity at the age of 2 in CS-delivered infants compared to those born vaginally.However, no association was found between CS deliveryand toddler obesity in the presence of pet ownership.In a pilot study of 24 infants, our group observed highermicrobial richness and diversity of the infant gut in thepresence of household pets at 3 months of age withunder-representation of Bifidobacteriaceae and over-representation of Peptostreptococcaceae [17]. Nermes etal. [11] found counts of Bifidobacterium breve to be lowerbut Bifidobacterium longum to be higher in non-wheezinginfants exposed to pets. In their subsequent analysis [18],pet-exposed infants harboured more animal-specific Bifi-dobacterium pseudolongum, indicating the bacterial trans-fer from pets to infants. Moreover, our previous findingsalso highlighted that pets can alter house dust microbiota[19]. This study is a follow-up to our previous pilot study,undertaking an evaluation of the influence of householdpets on faecal microbial composition at 3–4 months afterbirth in a large subsample of 746 infants from the Canad-ian Healthy Infant Longitudinal Development (CHILD)national population-based birth cohort. In this study, weaimed to determine the existence of gut microbial associa-tions with prenatal and/or postnatal pet exposures underdifferent scenarios, independent of siblingship and othercovariates.MethodsStudy designThis study involved a subsample of 804 infants fromthree study sites (Edmonton, Vancouver and Winni-peg) of the CHILD cohort (www.canadianchildstu-dy.ca). Mothers of the studied infants were enrolledduring pregnancy between 2009 and 2012. Themothers were asked about pet ownership in a stan-dardized questionnaire at recruitment in the secondor third trimester of pregnancy and 3 monthspostpartum. Microbiota analysis was performed onfaecal samples collected from infants at 3–4 months,with complete pre- and postnatal pet exposure data(n = 753). A pet exposure variable denoting four mu-tually exclusive categories was created as follows: (1)no pet exposure in the pre- or postnatal periods, (2)only prenatal pet exposure, (3) both pre- and postna-tal pet exposure and (4) only postnatal pet exposure(Fig. 1a). Due to the limited number of infants (n = 7)in the fourth category, we excluded that categoryfrom the analysis, leaving 746 with complete data forsubsequent analysis. Table 1 shows demographic char-acteristics of the studied infants with differential petexposure status. Data on other covariates were ob-tained from hospital records (mode of delivery, intra-partum antibiotic prophylaxis (IAP)) or fromstandardized questionnaires completed by mothers(maternal race, maternal asthma and allergy statusduring pregnancy, type of home, size of household,type of floor, presence of siblings, breastfeeding statusand infant antibiotic exposure before 3 months).Written informed consent was obtained from parentsTun et al. Microbiome  (2017) 5:40 Page 2 of 14at enrollment. This study was approved by the ethicsboard at the University of Alberta.Faecal microbiota analysisFaecal samples of infants were collected at the mean ageof 3.34 months (range 2.7–4.3) using a standard protocolduring a planned home visit. Methods of sample collec-tion, DNA extraction and amplification, 16S rRNA se-quencing and taxonomic classification have beenpreviously described [20, 21]. Briefly, samples were refrig-erated immediately after collection and during transportand stored at −80 °C until analysis. Genomic DNA was ex-tracted from 80 to 200 mg of stool using the QIAampDNA Stool Mini kit (Qiagen, Venlo, the Netherlands).The V4 hypervariable region of the bacterial 16S rRNAgene was amplified by PCR using universal bacterialprimers: V4-515f: 5′ AAT GAT ACG GCG ACC ACCGAG ATC TAC ACT ATG GTA ATT GTG TGC CAGCMG CCG CGG TAA-3′, V4-806r:5′–CAA GCA GAAGAC GGC ATA CGA GAT XXXXXXXXXXXX AGTCAG TCA GCC GGA CTA CHV GGG TWT CTA AT-3′. For sample multiplexing, reverse primers were bar-coded uniquely for each sample (barcoded sequence wasdenoted in the primer sequence by Xs). Each 25 μl PCRmixture contained 12.5 μl 2x Kapa2G Hotstart mix (KapaBiosystems, Wilmington, MA), 0.6 μM of both forwardand reverse primers and 2 μl genomic DNA (5 ng/μl).PCR amplification consisted of an initial denaturation stepfor 3 min at 94 °C, followed by 20 cycles of denaturationfor 30 s at 94 °C, annealing for 30 s at 50 °C and an exten-sion step for 30 s at 72 °C. PCR reactions for each samplewere performed in triplicate with a negative control inabFig. 1 a Pet exposure and other covariates (at prenatal and postnatal) that influence the infant gut microbiota. b General impact of pet exposureand other covariates on gut microbiota measurements of infants at 3–4 months. Circle sizes and colour intensity represent the magnitude ofcorrelation. Red circles = positive correlations; blue circles = negative correlations. Antibiotic exposure of infants was collective consideration ofboth indirect exposure (maternal IAP) and direct exposure (IV and oral antibiotics)Tun et al. Microbiome  (2017) 5:40 Page 3 of 14Table 1 Population characteristics and associations with exposure to household petsOverall Households with at least 1 furry petNo exposure Only prenatal Both pre- and postnatal P value tocompare 3 exposure groupsN (%)746 (100)N (%)337 (45.2)N (%)60 (8.0)N (%)349 (46.8)Birth modeVaginal, IAP− 375 (50.3) 171 (45.6) 32 (8.5) 172 (45.9) 0.88Vaginal, IAP+ 176 (23.6) 75 (42.6) 14 (8.0) 87 (49.4)Caesarean, scheduled 87 (11.7) 42 (48.3) 4 (4.6) 41 (47.1)Caesarean, emergency 108 (14.5) 49 (45.4) 10 (9.3) 49 (45.4)Study sitesEdmonton 216 (29.0) 80 (37.0) 19 (8.8) 117 (54.2) <0.001Vancouver 286 (38.3) 158 (55.2) 16 (5.6) 112 (39.2)Winnipeg 244 (32.7) 99 (40.6) 25 (10.2) 120 (49.2)Maternal raceCaucasian 561 (75.3) 223 (39.8) 49 (8.7) 289 (51.5) <0.001Other 78 (10.5) 38 (48.7) 5 (6.4) 35 (44.9)Asian 106 (14.2) 76 (71.7) 6 (5.7) 24 (22.6)Maternal asthma during pregnancyNo 675 (90.6) 307 (45.5) 53 (7.9) 315 (46.7) 0.98Yes 70 (9.4) 31 (44.3) 6 (8.6) 33 (47.1)Maternal allergy during pregnancyNo 271 (36.6) 133 (49.1) 24 (8.9) 114 (42.1) 0.19Yes 470 (63.4) 204 (43.4) 36 (7.7) 230 (48.9)Type of homeSingle (house) 592 (79.4) 251 (42.4) 53 (9.0) 288 (48.6) 0.007Multiple (condo/apartment) 154 (20.6) 86 (55.8) 7 (4.5) 61 (39.6)Size of household < 3No 414 (55.5) 190 (45.9) 34 (8.2) 190 (45.9) 0.86Yes 332 (44.5) 147 (44.3) 26 (7.8) 159 (47.9)Changed house (from 18 weeks of pregnancy to 3 months)No 683 (91.6) 309 (45.2) 51 (7.5) 323 (47.3) 0.15Yes 63 (8.4) 28 (44.4) 9 (14.3) 26 (41.3)Type of floorNot carpeted 360 (48.3) 156 (43.3) 25 (6.9) 179 (49.7) 0.58Partially carpeted 235 (31.5) 110 (46.8) 21 (8.9) 104 (44.3)Completely carpeted 151 (20.2) 71 (47.0) 14 (9.3) 66 (43.7)SiblingsNo 379 (52.6) 162 (42.7) 28 (7.4) 189 (49.9) 0.21Yes 342 (47.4) 166 (48.5) 28 (8.2) 148 (43.3)Antibiotic exposure (0–3 months)aNo 317 (43.8) 142 (44.8) 26 (8.2) 149 (47.0) 0.98Yes 407 (56.2) 184 (45.2) 32 (7.9) 191 (46.9)Breastfeeding status at 3 monthsNo 126 (16.9) 46 (36.5) 14 (11.1) 66 (52.4) 0.17Partial 229 (30.7) 101 (44.1) 18 (7.9) 110 (48.0)Exclusive 391 (52.4) 190 (48.6) 28 (7.2) 173 (44.2)Comparisons by chi-square testaAntibiotic exposure of infants = collective consideration of both indirect exposure (maternal IAP) and direct exposure (IV andoral antibiotics)Tun et al. Microbiome  (2017) 5:40 Page 4 of 14each run. One hundred nanograms of pooled PCR prod-uct from each sample was concentrated using an AmiconUltra-4 30K centrifugal filter (Millipore, Billerica, MA,USA), run on a 1.4% agarose gel, extracted and cleanedwith the GENE-CLEAN Turbo Kit (MP Biomedicals Inc,Solon, OH, USA).Pooled PCR amplicons were subjected to paired-endsequencing by Illumina Miseq platform. Using a QIIMEpipeline (v1.6.0, qiime.org) [22], forward and reversereads were assembled using PandaSeq for a final lengthof 144 bp (unassemblable sequences discarded), demulti-plexed and filtered against the GREENGENES referencedatabase (v13.8) [23] to remove all sequences with <60%similarity. Remaining sequences were clustered withUsearch61 at 97% sequence similarity against theGREENGENES database (closed picking algorithm), andtaxonomic assignment was achieved using the RDP clas-sifier [24] constrained by GREENGENES. After taxo-nomic assignment, operational taxonomic units (OTUs)representing bacterial origin were selected, and bacterialOTUs with overall relative abundance below 0.0001were excluded from subsequence for downstream ana-lyses. To avoid the bias due to variation in sequencingdepths among samples, data were rarefied to 13,000 se-quences per sample.Statistical analysisWith the recommended pipeline in QIIME, relative abun-dance of bacterial OTUs was summarized at the phylum,family and genus levels. Microbial alpha diversity withinsamples was calculated with three standard indices(Chao1, Shannon and Simpson). Microbial communitydifferences between samples (beta diversity) were exam-ined by the permutational multivariate analysis of vari-ance (PERMANOVA) comparison of unweightedUNIFRAC distance matrices, with 1000 permutations.Spearman correlation analyses were performed to addressassociations between pet exposure, other covariates andmicrobiota measures, and illustrated using the R packagecorrplot. Median richness, diversity and relative abun-dance of dominant taxonomic groups were compared bynon-parametric Kruskal-Wallis (KW) test, followed bypost hoc comparisons between non-exposed and pet ex-posure groups using the Mann-Whitney U test. As shownin previous reports [20, 25], ratios of specific taxa arecommonly evaluated due to the co-existence nature of gutmicrobiota. We evaluated three ratios: Firmicutes to Bac-teroidetes (F/B) ratio, Firmicutes to Proteobacteria (F/P)ratio and Enterobacteriaceae to Bacteroidaceae (E/B) ratio.Since caesarean birth and maternal IAP are major micro-biota disruption exposures [21], we performed our ana-lyses within four different birth scenarios for infants born:(1) vaginally without IAP, (2) vaginally with IAP, (3) byscheduled CS and (4) by emergency CS. To restrict theeffects of siblingship and exclusively breastfeeding, com-parisons were conducted for specific groups with or with-out siblings, non-exclusively breastfed infants, as well asnon-exclusively breastfed infants without siblings. Inde-pendent associations between microbiota abundance andpet exposure were tested by multiple variable logistic re-gression, with microbiota measures categorised as aboveand below the median.To identify discriminative taxonomic biomarkers, thelinear discriminant analysis effect size (LEfSE) was deter-mined with a LDA log score cut-off of 2, followed by theKruskal-Wallis test with the Dunn’s multiple comparisontest, using no pet exposure as the reference group. Ex-cluded were infants from non-Caucasian mothers, thosewith direct antibiotic exposure from birth to 3 months ofage and infants exclusively breastfed.ResultsStudy population and exposures to household furry petsIn this population cohort of 746 infants, less than half ofhouseholds had no pets (45.2%, n = 337), 8% (n = 60) ofhouseholds owned pets only during the index pregnancy(48.3% dog only, 36.1% cat only, 8.3% both dog and cat,and 7.3% other furry pets) and 46.8% (n = 349) ownedfurry pets both in the pregnancy and postnatal time pe-riods (44.1% dog only, 33.8% cat only, 20.1% both dogand cat, 2% other furry pets). Table 1 shows householdcharacteristics for each pet exposure category. Signifi-cant differences by pet ownership were found accordingto study location (P < 0.001), maternal race (P < 0.001)and type of home (P = 0.007).Overall community structure of gut microbiota, diversityand richness of gut microbiotaSignificant microbial community differences were de-tected by PERMANOVA by prenatal (pseudo F = 2.03, P= 0.001), as well as pre- and postnatal exposures (pseudoF = 1.51, P = 0.005) in all children. Under individual birthscenarios, the impact of any pet exposure was significantonly for infants born by emergency CS (pseudo F = 2.02,P = 0.001) (Additional file 1: Table S1). Overall microbialrichness of the infant gut and species richness within theFirmicutes phylum were significantly elevated with petexposure during pregnancy alone (Additional file 2:Table S2). Upon stratification by birth mode, thesetrends remained but statistical significance was lost, ex-cept for species richness of Firmicutes in vaginally borninfants without IAP exposure (Additional file 3: TableS3). Reduced species richness within the Proteobacteriaphylum became more statistically significant among in-fants who were born vaginally without IAP exposure (es-pecially for prenatal exposure alone) and who were bornby emergency CS (for both pre- and postnatal exposure)(Additional file 3: Table S3). Although there was noTun et al. Microbiome  (2017) 5:40 Page 5 of 14significant impact on overall microbial diversity (Shan-non index), pre- and postnatal pet exposure significantlyincreased the species richness (Chao1) and diversity(Shannon) within the Firmicutes phylum (Additional file2: Table S2). After stratification by birth scenario, thesetrends were consistent but were not statistically signifi-cant (Additional file 3: Table S3).Taxonomic composition of gut microbiotaVaginal with no IAPAmong the dominant phyla, Proteobacteria were under-represented among infants born vaginally with no IAPwhen pets were present (P = 0.005, FDRp = 0.07, Table 2).This reduced abundance was more prominent when petexposure was solely prenatal, whereas the impact of pre-and postnatal pet ownership became more statisticallysignificant in non-exclusively breastfed infants (Add-itional file 4: Table S4). In conjunction with depletedProteobacterial abundance, significant increases to theFirmicutes/Proteobacteria (F/P) ratio were observed bypet exposure (P = 0.003, FDRp = 0.05, Table 2). The im-pact of pre- and postnatal exposure on the F/P ratio alsobecame more significant in non-exclusively breastfed in-fants (Additional file 4: Table S4).With prenatal pet exposure alone, there was a twofoldodds for high abundance of Vellionellaceae and unclassi-fied Lachnospiraceae; high F/P ratios were also morelikely (Fig. 2 and Additional file 5: Table S5). Thesemicrobiota associations were attenuated when exposureto furry pets continued in the postnatal period. Collect-ively, pre- and postnatal pet ownership was associatedwith 1.5-fold increases to high Firmicutes species rich-ness in infants, and high abundance of Verrucomicrobia-ceae and of genus Clostridium (Fig. 2 and Additional file5: Table S5).Vaginal with IAPAt the family level, median abundance of Streptococcaceaewere substantially and significantly reduced by prenatalpet exposure (P < 0.001, FDRp = 0.03, Table 2). However,the prenatal only association was attenuated in the ab-sence of older siblings at home. Pre- and postnatal pet ex-posure also enriched the Bacteroidaceae, an elevation notseen in non-exclusively breastfed infants (Additional file 4:Table S4).Twofold increases were found in the odds of high di-versity within the Firmicutes and of high abundancewith Bacteroidaceae. The E/B ratio was reduced by 53%(95%CI 0.25–0.89) and high abundance of Streptococca-ceae by almost one third (95%CI 0.16–0.58) comparedto infants without pet exposure in the pre- and postnataltime periods (Fig. 2 and Additional file 5: Table S5).High Streptococcaceae levels were also substantially lesslikely for infants exposed to pets only during pregnancy(unadjusted OR 0.20, 95%CI 0.06–0.70) (Fig. 2 andAdditional file 5: Table S5).Following exposure to pets during pregnancy andpostnatally, a rare member of Proteobacteria, genus Bilo-phila, was depleted after vaginal birth with maternal IAPand no exclusive breastfeeding (P = 0.02, log LDA scoreof 3.5, Additional file 6: Table S6 and Additional file 7:Figure S1).Emergency CSEnrichment of the median abundance of Bifidobacteria-ceae was observed in infants born by emergency CS withpet exposure (P = 0.003, FDRp = 0.05, Table 2), an associ-ation which disappeared in non-exclusively breastfed in-fants (Additional file 4: Table S4). There was asubstantial and significant link between prenatal pet ex-posure and high abundance of Bifidobacteriaceae(unadjusted OR 7.53, 95%CI 1.44–39.50, Additional file5: Table S5). Concurrently, high species richness withinProteobacteria and high levels of Enterobacteriaceaewere much less likely to be present (Fig. 2 andAdditional file 5: Table S5). When emergency CSwas not followed by exclusive breastfeeding, thecombined impact of pet exposure during pregnancyand postpartum was reduced abundance of the genusCitrobacter (P = 0.03, log LDA score of 3.4) andgenus Lactococcus (P = 0.03, log LDA score of 2.5,Additional file 6: Table S6 and Additional file 7:Figure S1).All birth scenariosAt the genus level, Ruminococcus and Oscillospira wereover-represented in infants exposed to pets in all birthscenarios (P < 0.05) (Fig. 1b and Table 3). With the ex-ception of vaginal birth with no IAP, these associationswere less statistically significant among infants withnon-exclusive breastfeeding (Additional file 8: Table S7).Prenatal pet exposure alone was associated with highabundance of Ruminococcus (unadjusted OR 2.98,95%CI 1.30–6.81) and Oscillospira (unadjusted OR 2.56,95%CI 1.19–5.53, Fig. 2 and Additional file 5: Table S5)following vaginal birth with no IAP. Associations withgenus Oscillospira were unchanged with continuing petexposure in these infants. More than twofold increasesin the odds for high abundance of Ruminococcus (un-adjusted OR 2.43, 95%CI 1.29–4.59) were also observedfollowing IAP in vaginal birth. In a subgroup of theseIAP-exposed infants who were not exclusively breastfedafterwards, the Ruminococcaceae population was signifi-cantly enriched by prenatal pet exposure alone (P =0.002, and log LDA score of 4.2, Additional file 6: TableS6 and Additional file 7: Figure S1).Among the few associations found in infants delivered byscheduled CS, a threefold likelihood in high abundance ofTun et al. Microbiome  (2017) 5:40 Page 6 of 14Table 2 Relative abundance of dominant phyla and families in faecal microbiota of infants at 3–4 months, according to birthscenarios and pet exposureBirth scenarios Dominant taxaa Pet exposure status (N = 746)No exposure337 (45.2%)Median (IQR)Only prenatal60 (8.0%)Median (IQR)Both pre- and postnatal349 (46.8%)Median (IQR)P FDRpVaginal, IAP− 171 (45.6%) 32 (8.5%) 172 (45.9%)Actinobacteria 6.7 (2.4–16.1) 4.3 (1.3–13.2) 7.2 (1.8–18.9) 0.29 0.84Bifidobacteriaceae 5.4 (1.3–14.6) 5.2 (0.3–14.8) 4.9 (0.99–13.6) 0.96 0.96Bacteroidetes 38.6 (2.0–6.9) 37.7 (2.5–73.9) 35.2 (0.87–67.0) 0.71 0.88Bacteroidaceae 18.1 (0.09–58.4) 1.28 (0.07–35.84) 7.6 (0.07–54.32) 0.41 0.88Porphyromonadaceae 0.01 (0.00–0.13) 0.01 (0.00–0.60) 0.01 (0.00–0.15) 0.92 0.95Firmicutes 17.3 (5.5–32.3) 22.9 (10.1–40.3) 16.2 (7.9–32.3) 0.44 0.88Streptococcaceae 0.65 (0.21–1.8) 1.1 (0.23–2.8) 0.57 (0.18–1.9) 0.59 0.88Clostridiaceae 0.33 (0.02–2.1) 0.35 (0.09–1.8) 0.45 (0.06–2.9) 0.52 0.88Lachnospiraceae 2.6 (0.03–9.4) 4.7 (0.16–12.3) 2.2 (0.04–10.4) 0.59 0.88Rumminococcaceae 0.09 (0.00–1.10) 0.62 (0.00–2.5) 0.05 (0.00–1.7) 0.55 0.88Vellionellaceae 4.4 (0.48–17.2) 9.7 (3.4–17.7) 6.2 (1.2–20.3) 0.17 0.72Proteobacteria 17.6 (9.7–37.4) 7.2 (2.0–28.6)** 15.5 (7.6–35.4) 0.005 0.07Enterobacteriaceae 17.0 (6.5–37.8) 12.0 (3.9–47.0) 14.7 (4.8–37.7) 0.61 0.88Verrucomicrobia 0.00 (0.00–0.01) 0.00 (0.00–0.01) 0.00 (0.00–0.01) 0.36 0.88Verrucomicrobiaceae 0.00 (0.00–0.01) 0.00 (0.00–0.01) 0.00 (0.00–0.02)* 0.05 0.45F/B ratio 0.47 (0.1–6.2) 0.58 (0.15–12.6) 0.57 (0.15–23.3) 0.67 0.88F/P ratio 0.91 (0.29–2.3) 2.5 (0.77–11.6)*** 1.0 (0.39–3.4) 0.003 0.05E/B ratio 0.84 (0.15–353.7) 21.0 (0.12–333.7) 1.3 (0.12–487.6) 0.92 0.95Vaginal, IAP+ 75 (42.6%) 14 (8.0%) 87 (49.4%)Actinobacteria 2.1 (0.24–10.9) 2.7 (0.52–4.4) 4.0 (0.56–17.8) 0.18 0.72Bifidobacteriaceae 6.9 (1.3–20.3) 3.7 (1.7–10.9) 3.6 (1.4–14.5) 0.69 0.88Bacteroidetes 2.8 (0.07–61.3) 33.7 (0.05–66.9) 21.3 (0.05–69.9) 0.9 0.95Bacteroidaceae 9.5 (0.08–43.2) 27.6 (0.04–66.5) 35.2 (0.65–65.0)** 0.01 0.12Porphyromonadaceae 0.01 (0.00–0.28) 0.00 (0.00–0.14) 0.01 (0.00–0.29) 0.52 0.88Firmicutes 20.7 (8.2–53.4) 21.1 (5.3–57.9) 17.1 (7.4–46.7) 0.89 0.95Streptococcaceae 1.0 (0.38–4.1) 0.27 (0.1–0.62)** 0.43 (0.2–0.97)*** <0.001 0.03Clostridiaceae 0.49 (0.02–2.7) 0.36 (0.1–5.1) 0.29 (0.03–2.0) 0.73 0.88Lachnospiraceae 1.8 (0.07–10.1) 1.6 (0.03–4.3) 2.4 (0.09–11.4) 0.54 0.88Rumminococcaceae 0.33 (0.01–1.6) 0.03 (0.00–3.1) 0.12 (0.00–1.2) 0.76 0.88Vellionellaceae 6.7 (0.7–18.3) 2.6 (0.41–34.4) 3.0 (0.56–11.1) 0.32 0.85Proteobacteria 22.9 (11.3-42.5) 26.7 (10.9–52.1) 15.3 (4.5–40.1) 0.06 0.48Enterobacteriaceae 19.7 (7.2–40.5) 19.2 (6.5–47.2) 13.7 (5.0–33.0) 0.38 0.88Verrucomicrobia 0.00 (0.00–0.01) 0.00 (0.00–0.01) 0.00 (0.00–0.01) 0.7 0.88Verrucomicrobiaceae 0.00 (0.00–0.01) 0.00 (0.00–0.00) 0.00 (0.00–0.01) 0.74 0.88F/B ratio 10.3 (0.21–494.0) 0.49 (0.1–1333.3) 1.8 (0.15–819.4) 0.96 0.96F/P ratio 0.88 (0.31–2.5) 1.0 (0.14–3.1) 1.4 (0.54–3.6) 0.14 0.63E/B ratio 1.7 (0.23–460.4) 2.5 (0.16–1307.1) 0.43 (0.1–64.3)** 0.02 0.21Caesarean, scheduled 42 (48.3%) 4 (4.6%) 41 (47.1%)Actinobacteria 5.3 (0.89–23.2) 4.7 (0.58–20.9) 9.1 (2.4–17.1) 0.63 0.88Bifidobacteriaceae 11.3 (3.1–17.0) 0.04 (0.02–17.1) 8.3 (2.4–19.5) 0.26 0.78Tun et al. Microbiome  (2017) 5:40 Page 7 of 14Oscillospira (95%CI 1.27–7.67) was observed with com-bined prenatal and postnatal pet exposure. High levels ofboth genus Oscillospira (unadjusted OR 3.54, 95%CI 1.54–8.14) and genus Ruminococcus (unadjusted OR 2.53, 95%CI1.11–5.75) were more likely among infants born via emer-gency CS. In the absence of exclusive breastfeeding afteremergency CS, unclassified Ruminococcaceae weresignificantly enriched (P = 0.03, log LDA score of 4.0,Additional file 6: Table S6 and Additional file 7: Figure S1).Independence from covariatesTo test independence of associations between pet expos-ure and high microbial diversity, high abundance of mi-crobes and their ratios, we conducted adjustedTable 2 Relative abundance of dominant phyla and families in faecal microbiota of infants at 3–4 months, according to birthscenarios and pet exposure (Continued)Bacteroidetes 0.13 (0.04–0.62) 30.1 (0.1–61.2) 0.11 (0.05–0.66) 0.58 0.88Bacteroidaceae 8.0 (0.06–63.1) 3.6 (0.03–28.3) 3.9 (0.11–52.7) 0.56 0.88Porphyromonadaceae 0.01 (0.00–0.07) 0.00 (0.00–0.00) 0.01 (0.00–0.07) 0.07 0.5Firmicutes 31.2 (13.3–55.0) 8.5 (4.5–31.2) 39.2 (16.1–52.8) 0.12 0.63Streptococcaceae 0.50 (0.3–2.1) 0.15 (0.11–1.2) 0.40 (0.16–1.6) 0.24 0.78Clostridiaceae 0.77 (0.05–4.4) 3.9 (0.43–16.4) 0.64 (0.09–2.6) 0.74 0.88Lachnospiraceae 2.1 (0.05–10.2) 5.0 (0.81–28.5) 1.7 (0.05–8.3) 0.71 0.88Rumminococcaceae 0.08 (0.01–1.8) 3.5 (0.16–9.5) 0.05 (0.00–2.5) 0.41 0.88Vellionellaceae 3.4 (0.36–10.7) 2.7 (0.93–13.1) 4.9 (0.92–22.7) 0.54 0.88Proteobacteria 33.2 (11.4–51.8) 44.4 (13.9–79.9) 34.2 (13.5–50.4) 0.67 0.88Enterobacteriaceae 16.1 (8.9–35.7) 25.6 (15.9–73.1) 21.8 (8.0–47.1) 0.46 0.88Verrucomicrobia 0.00 (0.00–0.01) 0.00 (0.00–0.00) 0.00 (0.00–0.01) 0.33 0.85Verrucomicrobiaceae 0.00 (0.00–0.00) 0.00 (0.00–0.02) 0.00 (0.00–0.01) 0.23 0.78F/B ratio 169.0 (22.8–859.8) 18.2 (0.07–1230.1) 218 (35.0–980.4) 0.33 0.85F/P ratio 1.2 (0.35–3.1) 0.41 (0.12–0.75) 1.1 (0.6–3.1) 0.13 0.63E/B ratio 1.5 (0.13–353.6) 287 (3.4–907.5) 4.3 (0.19–214.4) 0.57 0.88Caesarean, emergency 49 (45.4%) 10 (9.3%) 49 (45.4%)Actinobacteria 7.4 (1.4–20.5) 5.6 (3.3–13.5) 6.1 (0.4–16.9) 0.72 0.88Bifidobacteriaceae 3.5 (0.08–7.0) 28.8 (12.7–71.9)*** 3.4 (0.57–18.1) 0.003 0.05Bacteroidetes 0.10 (0.03–0.23) 0.15 (0.1–50.6) 0.10 (0.05–1.3) 0.14 0.63Bacteroidaceae 31.2 (0.07–66.7) 0.19 (0.08–22.1) 5.0 (0.07–67.1) 0.77 0.88Porphyromonadaceae 0.01 (0.00–0.14) 0.00 (0.00–0.13) 0.01 (0.00–0.04) 0.19 0.72Firmicutes 33.3 (19.6–55.1) 48.1 (15.1–67.3) 33.9 (17.5–59.5) 0.74 0.88Streptococcaceae 0.59 (0.15–1.5) 3.5 (1.7–6.8)** 0.58 (0.21–1.1) 0.003 0.05Clostridiaceae 0.38 (0.04–7.5) 0.17 (0.01–3.1) 0.70 (0.02–3.7) 0.64 0.88Lachnospiraceae 2.9 (0.05–7.3) 3.8 (0.05–5.7) 1.6 (0.26–9.1) 0.77 0.88Rumminococcaceae 0.14 (0.00–2.6) 0.01 (0.01–0.91) 0.08 (0.00–0.58) 0.25 0.78Vellionellaceae 3.8 (0.56–10.9) 2.3 (0.2–4.8) 2.2 (0.41–13.0) 0.6 0.88Proteobacteria 36.7 (19.3–56.4) 27.8 (12.6–38.2) 22.0 (7.7–51.5)* 0.08 0.52Enterobacteriaceae 20.3 (6.3–40.1) 10.2 (5.7–55.2) 15.0 (8.1–43.1) 0.88 0.95Verrucomicrobia 0.00 (0.00–0.01) 0.00 (0.00–0.01) 0.00 (0.00–0.01) 0.81 0.91Verrucomicrobiaceae 0.00 (0.00–0.01) 0.01 (0.00–0.02) 0.00 (0.00–0.01) 0.14 0.63F/B ratio 281 (52.7–1092.0) 362 (0.23–777.5) 252 (10.9–910.5) 0.63 0.88F/P ratio 1.2 (0.47–2.8) 1.4 (0.65–4.1) 1.8 (0.65–4.6) 0.22 0.78E/B ratio 0.84 (0.09–480.7) 4.3 (0.7–322.8) 10.0 (0.13–336.3) 0.87 0.95IQR interquartile range, F/B Firmicutes/Bacteroidetes, F/P Firmicutes/Proteobacteria, E/B Enterobacteriaceae/Bacteroidaceae, FDR false discovery ratePost hoc comparisons between no exposure group and either group of exposure were done by Mann-Whitney U test. *P < 0.05; **P < 0.01; ***P < 0.0001aDominant taxa have overall median relative abundance >1% at −3–4 months; phyla are in the plain text and families are italicized. Comparisons bynonparametric Kruskal-Wallis test with FDR correction for multiple testingTun et al. Microbiome  (2017) 5:40 Page 8 of 14logistic regression (Fig. 2 and Additional file 5: TableS5). Sequential adjustment for potential confoundingvariables (Table 1) such as study location, maternalrace, maternal history of allergy and asthma duringpregnancy, type of home, siblingship, antibiotic ex-posure and breastfeeding status at 3 months showedthat associations between pet ownership and infantgut microbiota were generally robust and independ-ent of these early-life events and environmental ex-posures. Some associations were moderatelyattenuated with adjustment, especially for breastfeed-ing status, maternal race and siblingship (Fig. 2 andAdditional file 5: Table S5).DiscussionIn this general population cohort of 746 Canadian in-fants, we observed higher overall species richness andchanges to taxon abundance in gut microbiota of infantsexposed to furry pets during pregnancy or continuing tothe postnatal period. These findings are in agreementwith our previous report [17] of postnatal pet exposureon 3-month gut microbiota but not with studies in laterinfancy [26]. Moreover, elevations in microbial speciesrichness in this study were evident with prenatal pet ex-posure. Since several studies including our own withinthe same cohort have reported low microbiota richnessin early life to be associated with food sensitization andother atopic diseases [20, 27, 28], higher microbial rich-ness with prenatal pet exposure may confer protectionagainst the development of atopy.Our study revealed that pet exposure significantly in-creased species richness in the phylum Firmicutes, com-posed of families like the Clostridiaceae, Lachnospiraceaeand Ruminococcaceae. These families of the Firmicutesare obligate anaerobes which reduce the oxidative state ofthe gut [29]; they are common constituents of the gutmicrobiota of healthy infants and severely depleted inmalnourished infants [30]. In particular, we found Rumi-nococcus, or Oscillospira, belonging to the Ruminococca-ceae, to be more abundant (median levels and levels abovethe median) among infants exposed to pets pre- and post-natally across all birth scenarios. Associations with rumi-nococcal abundance above the median were independentof all covariates, but attenuated after adjustment forbreastfeeding status and maternal race. Prenatal pet ex-posure alone was sufficient to produce associations withRuminococcus or Oscillospira, even under conditions ofundisturbed gut microbiota following vaginal birth and noIAP. Of note, enrichment in faecal Oscillospira was amongthe few changes observed for pet ownership within infantsdelivered by scheduled CS.Oscillospira is an enigmatic bacterium which has neverbeen isolated in culture, but has been detected by 16SrRNA gene surveys of the human microbiome inFig. 2 Likelihoods of infant gut microbiota measures at 3–4 months according to pet exposure (parental alone vs. both pre- and postnatal) andvarious birth scenarios (a Vaginal, IAP-, b Vaginal, IAP+, c Shecduled Caesarean, and d Emergency Caesarean), with individual adjustments forpotential confounding variables: Model A: location, B: Maternal race, C: Maternal asthma and D: maternal allergy during pregnancy, E: Type ofhome, F: Moving home, G: Siblingship, H: Antibiotic exposure, and I: Breastfeeding statusTun et al. Microbiome  (2017) 5:40 Page 9 of 14Table 3 Relative abundance of dominant genera in faecal microbiota of infants at 3–4 months, according to birth scenarios and petexposureBirth scenarios Dominant generaa Pet exposure status (N = 746)No exposure337 (45.17%)Median (IQR)Only prenatal60 (8.0%)Median (IQR)Both pre- and postnatal349 (46.78%)Median (IQR)P FDRpVaginal,IAP−171 (45.6%) 32 (8.5%) 172 (45.9%)Bifidobacterium 5.3 (1.8–14.9) 2.2 (0.68–13.0) 6.3 (1.6–17.8) 0.21 0.63Bacteroides 31.2 (0.36–62.4) 29.9 (2.4–62.9) 31.5 (0.61–60.7) 0.66 0.86Parabacteroides 0.01 (0.00–0.5) 0.16 (0.00–2.9) 0.01 (0.00–0.51) 0.13 0.51Streptococcus 0.62 (0.13–2.1) 0.46 (0.21–1.4) 0.59 (0.21–1.8) 0.81 0.86Unclassified Clostridiaceae 0.03 (0.00–0.45) 0.09 (0.00–0.46) 0.07 (0.01–0.49) 0.45 0.81Clostridium 0.01 (0.00–0.38) 0.01 (0.00–0.29) 0.02 (0.00–0.42) 0.15 0.51Unclassified Lachnospiraceae 0.02 (0.00–1.6) 0.38 (0.02–4.8)* 0.05 (0.01–1.5)* 0.02 0.16Ruminococcus 0.02 (0.00–1.2) 0.43 (0.01–1.5)* 0.05 (0.00–2.6)* 0.03 0.21Oscillospira 0.00 (0.00–0.04) 0.07 (0.00–2.3)* 0.01 (0.00–0.7)*** <0.001 0.04Veillonella 1.5 (0.16–14.9) 2.9 (0.13–9.1) 1.6 (0.24–7.6) 0.89 0.91Unclassified Enterobacteriaceae 15.5 (7.0–31.9) 5.4 (1.3–28.4)** 13.3 (4.6–34.8) 0.02 0.16Akkermansia 0.00 (0.00–0.01) 0.00 (0.00–0.01) 0.00 (0.00–0.01) 0.42 0.81Vaginal,IAP+75 (42.6%) 14 (8.0%) 87 (49.4%)Bifidobacterium 2.0 (0.06–9.9) 2.2 (0.36–4.1) 3.7 (0.27–16.8) 0.25 0.69Bacteroides 0.67 (0.05–59.2) 33.7 (0.04–56.3) 12.0 (0.05–69.6) 0.84 0.88Parabacteroides 0.01 (0.00–0.03) 0.00 (0.00–1.12) 0.00 (0.00–0.02) 0.95 0.95Streptococcus 0.43 (0.21–1.6) 0.47 (0.12–0.93) 0.59 (0.2–3.6) 0.34 0.81Unclassified Clostridiaceae 0.08 (0.01–0.88) 0.30 (0.01–3.5) 0.09 (0.01–1.0) 0.49 0.81Clostridium 0.03 (0.00–0.86) 0.07 (0.02–1.9) 0.04 (0.00–1.0) 0.47 0.81Unclassified Lachnospiraceae 0.02 (0.00–3.8) 0.66 (0.01–4.1) 0.08 (0.01–3.2) 0.55 0.83Ruminococcus 0.01 (0.00–0.44) 0.02 (0.00–1.28) 0.03 (0.01–1.88)*** 0.004 0.1Oscillospira 0.00 (0.00–0.56) 0.02 (0.00–2.8) 0.01 (0.00–0.65) 0.66 0.86Veillonella 3.2 (0.3–13.9) 0.63 (0.19–13.7) 2.7 (0.24–11.8) 0.69 0.86Unclassified Enterobacteriaceae 20.3 (8.7–37.3) 21.8 (9.8–503) 12.5 (3.6–37.0)* 0.06 0.29Akkermansia 0.00 (0.00–0.01) 0.00 (0.00–0.01) 0.00 (0.00–0.01) 0.74 0.86Caesarean, scheduled 42 (48.3%) 4 (4.6%) 41 (47.1%)Bifidobacterium 5.0 (0.37–21.6) 3.7 (0.51–19.9) 8.2 (1.3–16.9) 0.76 0.86Bacteroides 0.08 (0.04–0.44) 30.0 (0.08–61.1) 0.10 (0.05–0.42) 0.49 0.81Parabacteroides 0.00 (0.00–0.01) 0.00 (0.00–0.04) 0.00 (0.00–0.01) 0.74 0.86Streptococcus 0.80 (0.29–2.1) 0.46 (0.13–0.75) 1.6 (0.39–3.7) 0.15 0.51Unclassified Clostridiaceae 0.15 (0.01–1.5) 0.13 (0.02–1.7) 0.40 (0.06–1.6) 0.58 0.84Clostridium 0.04 (0.01–1.5) 0.16 (0.02–0.59) 0.28 (0.02–1.7) 0.54 0.82Unclassified Lachnospiraceae 0.04 (0.00–8.7) 2.0 (0.46–22.6) 0.05 (0.00–7.1) 0.42 0.81Ruminococcus 0.02 (0.00–1.9) 0.00 (0.00–0.01) 0.01 (0.00–1.7) 0.26 0.69Oscillospira 0.00 (0.00–0.16) 0.00 (0.00–0.01) 0.03 (0.00–0.89)* 0.04 0.24Veillonella 7.0 (1.04–16.3) 3.6 (1.14–5.41) 6.2 (1.57–29.7) 0.53 0.82Unclassified Enterobacteriaceae 27.7 (10.1–45.2) 34.9 (13.1–74.7) 30.5 (10.8–47.8) 0.79 0.86Akkermansia 0.00 (0.00–0.01) 0.00 (0.00–0.00) 0.00 (0.00–0.01) 0.36 0.81Caesarean, emergency 49 (45.4%) 10 (9.3%) 49 (45.4%)Bifidobacterium 6.5 (1.2–18.0) 4.8 (1.9–12.4) 5.3 (0.18–16.8) 0.75 0.86Tun et al. Microbiome  (2017) 5:40 Page 10 of 14association with leanness or lower body mass index inboth infants and adults [31–35]. Members of the genusOscillospira are highly heritable, predominate in the leanhost and are positively associated with the leanness-promoting bacterium, Christensenella minuta [32]. Esco-ber et al. [34] also reported decreasing abundance ofOscillospira with obesity in three different geographicalregions, despite substantial differences in gut microbialcomposition. As confirmed by meta-analysis [33], theabundance of Oscillospira has also been found to benegatively associated with paediatric inflammatory boweldisease [36]. The health-promoting effects of Oscillospiraare not fully understood. Unlike Ruminococcus, they arenot fibre degraders but rather, produce butyrate by rely-ing on fermentation products secreted by other bacterialspecies or on sugars liberated from host mucins [37].This is supported by an elegant animal study comparingthe microbiota response to fasting across different verte-brates [38]. In this study, Oscillospira were observed tobe the only genus whose levels increased during fasting,indicating their ability to degrade host glycans such asfucose, sialic acids and glucuronic acid.Members of Ruminococcus have also been detected inthe stool of neonates and infants [39] but are reportedlyabsent in some infants delivered vaginally or by CS [40].Like the Oscillospira, they are also present in dogs andcats [41]. The role of ruminococci in infant health is alsopoorly understood. Among their noticeable functions,these microbes stimulate the production and degrad-ation of mucin [42], vital to the maintenance of an intactmicrobiota-mucin barrier. They are also fibre degraders[43] and predominant in formula-fed infants [44, 45].Yet, ruminococci are still found in breastfed infants andinterestingly, their colonization depends on theoligosaccharide content of breast milk [46]. Lastly, theyproduce ruminococcin A, a bacteriocin which can in-hibit various pathogenic species of Clostridium [47]. Inour previous study within the same cohort, we observeda strong link between low levels of Ruminococcaceaeand food sensitization at age 1, even after adjustment formajor microbiota-disrupting events [20].Our current study also suggests the potential for petownership to assist in reducing the burden of group BStreptococcus (GBS) in infants by lowering the abundanceof its family, Streptococcaceae. According to a recentpaper from McCloskey et al. [48], antenatal pet exposurehas been linked to reduced cardiovascular risk of infantsborn to mothers colonized with GBS during pregnancy. InCanada and elsewhere, the major indication for providingIAP is to prevent GBS infection in newborns [49]. Withinvaginally born infants with IAP, we found that prenatal petexposure reduced the abundance of faecal Streptococca-ceae; this association could not be explained by sibling-ship, breastfeeding status or other covariates. Withmechanisms for microbe interactions to be elucidated, itis conceivable that bacteriocin produced from Ruminococ-cus, a microbe which was more abundant in study infantswhen Streptococcaceae were depleted, inhibits growth ofstreptococci. However, others have found lowered abun-dance of Oscillospira but elevated levels of Ruminococcusto co-occur with a greater abundance of Streptococcaceaeat 6 months following vaginal GBS colonization in primar-ily formula-fed infants [50].Under birth scenarios involving vaginal delivery, Pro-teobacteria became less abundant in infants with postna-tal pet exposure which commenced prenatally. Afteremergency CS, the following changes with pet exposurewere observed for Proteobacteria: reduced speciesTable 3 Relative abundance of dominant genera in faecal microbiota of infants at 3–4 months, according to birth scenarios and petexposure (Continued)Bacteroides 0.08 (0.03–0.17) 0.13 (0.05–17.1) 0.09 (0.04–1.3) 0.19 0.61Parabacteroides 0.00 (0.00–0.01) 0.01 (0.00–0.02)* 0.00 (0.00–0.01) 0.05 0.27Streptococcus 1.2 (0.5–3.0) 0.64 (0.13–5.1) 0.96 (0.27–2.7) 0.48 0.81Unclassified Clostridiaceae 0.36 (0.02–3.3) 0.30 (0.01–0.67) 0.31 (0.04–1.6) 0.65 0.86Clostridium 0.19 (0.02–2.4) 0.04 (0.00–1.1) 0.20 (0.02–1.2) 0.63 0.86Unclassified Lachnospiraceae 0.03 (0.01–5.2) 0.39 (0.01–1.6) 0.77 (0.01–9.2) 0.41 0.81Ruminococcus 0.00 (0.00–0.03) 0.00 (0.00–0.33) 0.22 (0.00–4.6)** 0.01 0.16Oscillospira 0.01 (0.00–0.45) 0.00 (0.00–1.2) 0.19 (0.01–2.8)** 0.02 0.16Veillonella 9.2 (2.98–26.2) 8.6 (4.3–42.4) 8.1 (0.53–23.8) 0.45 0.81Unclassified Enterobacteriaceae 34.1 (16.5–54.1) 18.1 (7.5–32.9) 16.4 (6.3–48.4) 0.1 0.44Akkermansia 0.00 (0.00–0.01) 0.00 (0.00–0.01) 0.00 (0.00–0.01) 0.81 0.86IQR interquartile range, FDR false discovery ratePost hoc comparisons between no exposure group and either group of exposure were done by Mann-Whitney U test. *P < 0.05; **P < 0.01; ***P < 0.0001aDominant genera have overall median relative abundance >1% at 3–4 months; phyla are in plain text and families are in italics. Comparisons by nonparametricKruskal-Wallis test with FDR correction for multiple testingTun et al. Microbiome  (2017) 5:40 Page 11 of 14richness, and abundance of Enterobacteriaceae and ofCitrobacter. Pet exposure was also significantly associ-ated with reduced Enterobacteriaceae among infantsborn vaginally without IAP but not exclusively breastfedafterwards. While our findings appear to contradict re-ports of greater Escherichia coli colonization in the vagi-nal microbiome of pregnant women who own pets [51],the timing of microbial changes in the developmentaltrajectory of infant microbiota is important to consider.Following vaginal delivery, Proteobacteria (especially En-terobacteriaceae) are dominant within 3 months afterbirth, while Bacteroidetes and Firmicutes become moreprevalent as the gut microbiota matures towards anadult-like profile [52]. A bloom of Proteobacteria in thegut can indicate instability in the microbial community[53]; greater abundance (along with a higher abundanceof streptococci) in 6-month-old infants has predicted fu-ture adiposity [54]. Using the E/B ratio as an indicatorfor gut microbiota maturity, we previously reported thata higher ratio predicted food sensitization at age 1 [20];in the current study, pet exposure lowered the E/B ratioin vaginally born infants exposed to IAP. Using anotherratio to represent gut microbiota maturity in the currentstudy, pet exposure was linked to a higher F/P ratio fol-lowing vaginal birth in the absence of maternal IAP. Ofnote, Ruminococcus and Oscillospira were also elevatedunder these circumstances.Additional discussion of the differential impact of petexposure on scheduled versus emergency CS is warranted.When compared to scheduled CS, our previous study alsoreported a distinct microbiota profile in infants born viaemergency CS, posited to be a function of the multiplicityof exposures, such as repeated antibiotic treatment andprolonged hospitalization [21]. Here, we also found agreater number of pet-associated microbial changes in in-fants born by emergency CS. Recurrent antibiotic expos-ure or hospitalization may render gut microbiota moresensitive to colonization by other microbes [55]. It is alsoconceivable that pet-induced changes of the maternalmicrobiome are transmitted to a greater extent duringlabour prior to an emergency CS than in the absence oflabour with scheduled CS.Our current study has several strengths, including theapplication of high-throughput deep sequencing to pro-file gut microbiota in a longitudinal population cohort,with a representative and large sample size. Predomin-ance of Proteobacteria in gut microbiota at 3 monthsand its higher prevalence in CS-delivered infants wereconsistent with observations in other birth cohorts. Un-like other studies, our study tested the differential im-pact of pet exposure according to various birth modes,with the aim of providing more translational informationfor practitioners. Finally, we implemented statisticalmodelling and sensitivity analyses to explore whetherobserved associations were attributable to confoundingcovariates. On the other hand, the use of 16S rRNA se-quencing in our study may have resulted in under-representation of organisms such as bifidobacteria. Thesensitivity of this technique also did not allow identifica-tion at the species level, which is possible with high-throughput microbial culturomics [56], as well as tar-geted PCR or phenotypic culturing [57]. Metagenomicsequencing was not conducted, which would enablecharacterization of the functional properties of microbialchanges with pet exposure. Since the majority of house-holds in our study owned at least one dog, a larger sam-ple is required to differentiate the effects of different petspecies (e.g. dog and or cat) in future studies.ConclusionsWith increasing ownership of pets in our modern life-style and reports of their beneficial effects, the questionof pet ownership is becoming a common one for preg-nant women. Our findings highlighted the differentialimpact of pet exposure on infant gut microbiota follow-ing variant birth scenarios; however, in common, theabundance of Ruminococcus and Oscillospira were foundto be increased independent of other factors. In addition,our finding of reduced streptococcal colonization withprenatal pet ownership may lower the risk for childhoodmetabolic and atopic disease. Further research is neededto link the pet-related microbiota changes with healthoutcomes of infants in the CHILD cohort, as well as inother populations.Additional filesAdditional file 1: Table S1. PERMANOVA analysis used to evaluatemicrobial community differences of infant gut at 3–4 months due to petexposures following different birth scenarios. (DOCX 35 kb)Additional file 2: Table S2. Effects of pet exposure on richness anddiversity in infant faecal microbiota at 3–4 months. (DOCX 78 kb)Additional file 3: Table S3. Richness and diversity of infant faecalmicrobiota at 3–4 months according to birth scenarios and pet exposure.(DOCX 146 kb)Additional file 4: Table S4. Relative abundance of dominant phylaand families in faecal microbiota of infants belonged to different stratifiedgroups, according to birth scenarios and pet exposure. (DOCX 105 kb)Additional file 5: Table S5. Crude and adjusted likelihoods ofmicrobiota measurements at 3–4 months according to birth scenariosand pet exposure episodes. (DOCX 126 kb)Additional file 6: Table S6. Linear discriminant analysis (LDA) scoresfor differentially abundant bacterial taxa due to pet exposure in formula-fed infants born by Caucasian mothers without prior direct antibiotic ex-posure until 3 months old following different birth scenarios (P < 0.05).(DOCX 54 kb)Additional file 7: Figure S1. Pet exposure associated changes in gutmicrobiota of selected infants from Caucasian mothers with noanitobiotic exposure and no exclusi ve breastfeeding at 3 monthsfollowing different birth scenarios. (PDF 839 kb)Tun et al. Microbiome  (2017) 5:40 Page 12 of 14Additional file 8: Table S7. Relative abundance of dominant genera infaecal microbiota of infants belonged to different stratified groups,according to birth scenarios and pet exposure. (DOCX 102 kb)AbbreviationsCHILD: Canadian Healthy Infant Longitudinal Development; CS: Caesareansection; IAP: Intrapartum antibiotic prophylaxisAcknowledgementsThe authors would like to thank all the families who took part in this study,and the whole CHILD team, which includes interviewers, computer andlaboratory technicians, clerical workers, research scientists, volunteers,managers, receptionists and nurses. Anita Kozyrskyj and James Scott willserve as the guarantors for the contents of this paper.CHILD study investigators include Sears MR, (Director), McMaster University;Subbarao P (co-Director), The Hospital for Sick Children; Anand SS, McMasterUniversity; Azad M, University of Manitoba; Becker AB, University of Manitoba;Befus AD, University of Alberta; Brauer M, University of British Columbia;Brook JR, University of Toronto; Chen E, Northwestern University, Chicago;Cyr M, McMaster University; Daley D, University of British Columbia; Dell S,Sick Children’s Hospital; Denburg JA, McMaster University; Duan Q, Queen’sUniversity; Eiwegger T, The Hospital for Sick Children; Grasemann H, SickChildren’s Hospital; HayGlass K, University of Manitoba; Hegele R, SickChildren’s Hospital; Holness DL, University of Toronto; Hystad P, Oregon StateUniversity; Kobor MS, University of British Columbia; Kollmann TR, Universityof British Columbia; Kozyrskyj AL, University of Alberta; Laprise C, Universitédu Québec à Chicoutimi; Lou WYW, University of Toronto; Macri J, McMasterUniversity; Mandhane PM, University of Alberta; Miller G, NorthwesternUniversity, Chicago; Moraes T, Sick Children’s Hospital; Paré PD, University ofBritish Columbia; Ramsey C, University of Manitoba; Ratjen F, Sick Children’sHospital; Sandford A, University of British Columbia; Scott JA, University ofToronto; Scott J, University of Toronto; Silverman F, University of Toronto;Simons E, University of Manitoba; Takaro T, Simon Fraser University; TebbuttS, University of British Columbia; To T, Sick Children’s Hospital; Turvey SE,University of British Columbia.FundingThis research was specifically funded by the CIHR Canadian MicrobiomeInitiative (Grant No. 227312). The Canadian Institutes of Health Research(CIHR) and the Allergy, Genes and Environment (AllerGen) Network ofCentres of Excellence provided core support for the CHILD study. HMT holdsan Alberta Innovates-Postdoctoral Fellowship in Health.Availability of data and materialsThe datasets used and/or analysed during the current study are availablefrom the corresponding author on reasonable request.Authors’ contributionsDr Kozyrskyj had full access to all the data in the study and takesresponsibility for the integrity of the data and the accuracy of the dataanalysis. HMT and AK designed the study. TK, DSG and JAS carried out theamplicon sequencing. HMT and JAS performed the bioinformatics analysis,and HMT and AK performed the statistical analysis and interpretation. HMTwrote the manuscript with the input from the other authors. All authors readand approved the final manuscript.Competing interestsThe authors declare that they have no competing interests.Consent for publicationNot applicableEthics approval and consent to participateWritten informed consent was obtained from parents at enrollment.This study was approved by the ethics board at the University of Alberta.Publisher’s NoteSpringer Nature remains neutral with regard to jurisdictional claims inpublished maps and institutional affiliations.Author details1Department of Pediatrics, University of Alberta, 3-527 Edmonton ClinicHealth Academy, 11405–87th Avenue, Edmonton, AB T6G IC9, Canada. 2DallaLana School of Public Health, University of Toronto, Toronto, ON, Canada.3Faculty of Health Sciences, Simon Fraser University, Burnaby, BC, Canada.4Department of Obstetrics and Gynecology, University of Alberta, Edmonton,AB, Canada. 5Department of Agricultural, Food and Nutritional Science,University of Alberta, Edmonton, AB, Canada. 6Centre for the Analysis ofGenome Evolution and Function, University of Toronto, Toronto, ON, Canada.7Department of Pediatrics and Child Health, Children’s Hospital ResearchInstitute of Manitoba, University of Manitoba, Winnipeg, MB, Canada.8Department of Pediatrics, Child & Family Research Institute, BC Children’sHospital, University of British Columbia, Vancouver, BC, Canada. 9Departmentof Pediatrics, Hospital for Sick Children, University of Toronto, Toronto, ON,Canada. 10Department of Medicine, McMaster University, Hamilton, ON,Canada.Received: 8 December 2016 Accepted: 14 March 2017References1. 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