TABLE 1

Studies in Which Researchers Relate the Early-Life Microbiome With Health Outcomes in Later Childhood and Adulthood

Research ObjectiveStudy Population or Animal ModelEarly-Life Factors and Timing of ExposureTiming of Microbiome Analysis or InterventionHealth Outcome and Timing of AssessmentSummary of FindingsRef. No.
NEC
 To assess microbial dysbiosis before NEC in a systematic review and meta-analysisSystematic review and meta-analysis of 14 human fecal microbiome studies of NECNoneVariations in the microbiome before NEC developmentNEC at ∼30 wk postconceptionIncreased proteobacteria and decreased firmicutes and bacteroidetes preceded NEC onset. Antibiotics, diet, and mode of delivery do contribute to microbial dysbiosis associated with NEC. However, causality related to these factors cannot be determined57
 To determine if 1 or more gut bacterial taxa differ between cases of NEC and controlsProspective human cohort analysis (primary cohort, n = 122; secondary cohorts, n = 44)NoneVariations in the microbiome before NEC developmentNEC in very low birth wt infantsIncreases in gammaproteobacteria and decreases in negativicutes and clostridia-negativicutes classes over time preceded NEC development58
 To enhance strain-level resolution of NEC-associated pathogens by using deep shotgun metagenomics sequencingProspective human cohort analysis (n = 166)NoneVariations in the microbiome before NEC developmentNEC in infancyVariations in the microbiome were detected before NEC development. However, at 17–22 d postpartum, infants with high antibiotic treatment were enriched for E coli. The group later identified uropathogenic E coli as a major risk factor for NEC and associated death59
 To compare the efficacy and safety of enteral probiotic administration in preventing NECSystematic review and meta-analysis of 24 randomized or quasi-randomized controlled trials in humansNoneEnteral probiotic supplementation before NEC developmentStage II and stage III NEC in infancyEnteral probiotic supplementation significantly reduced the incidence of NEC and mortality in infants60
 To assess the intestinal microbiota composition before NEC development in infants who developed NEC and controlsProspective human cohort analysis (n = 38)NoneVariations in the microbiome before NEC developmentNEC in infancyAn average of 7 samples were collected per subject and the temporal changes in microbiome composition were assessed. Throughout early life, before the development of NEC, different microbial populations dominate the gut and are associated with NEC development. In addition, the microbiome compositional progression appears to be associated with the timing of NEC onset61
 To identify microbial and metabolic biomarkers of NECNested case-control design (n = 35)NoneVariations in the microbiome before NEC developmentNEC in infancyLower α diversity 4–9 d postbirth was associated with NEC development. Microbiomes of subjects tended to cluster according to NEC status. These microbial variations were associated with shifts in urine metabolites, namely alanine and histidine62
 To determine if gut microbiome composition can be used to predict NEC severityProspective human cohort analysis (n = 30)NoneVariations in the microbiome before NEC developmentNEC in infancyVariations in the microbiome were not associated with NEC severity. There were also no differences in the microbiome post-NEC compared with controls63
 To assess whether fecal microbiota transplantation is an effective treatment of NECWild-type and Grx1−/− mouse models of NECNoneFecal microbiota transplant from 1 to 4 d postbirthNEC 5 d postbirthFecal microbiota transplant from healthy 6–8-wk-old mice to mouse pups conditioned for NEC reduced NEC incidence and severity compared with controls. This was dependent on Grx1. The mechanism of action is potentially through TLR-mediated inflammation and gut permeability64
 To determine if patients at risk for NEC can be identified by their meconium and early postnatal microbiotaProspective human cohort analysis (n = 33)Early enteral feeding and breast milkVariations in meconium microbiome and neonatal microbiome before NECNEC in infancyClostridium perfringens and Bacteroides dorei were increased in the meconium of infants who developed NEC. C perfringens abundance persisted in neonatal stool samples. The amount of breast milk before NEC and earlier enteral feeding was negatively associated with NEC and associated with increased lactate-producing bacilli65
 To compare enteral versus parenteral antibiotics in preventing formula-induced NEC lesions in pigsPiglet model of NECAntibiotic-inducedEnteral and parenteral antibiotic treatment (for 5 d post birth)NEC in preterm pigletsEnteral antibiotics prevented NEC lesions, whereas lesions in piglets that were treated with parenteral antibiotics were increased. Enteral antibiotics decreased bacterial load and abundances of Gram-positive bacteria in the intestine. It is suggested that delayed colonization (particularly with Gram-positive bacteria) may prevent NEC. However, although microbiome variations correlate with NEC, they do not necessarily precede NEC66
 To determine if total parenteral nutrition, before the start of enteral feeding, can prevent NEC-associated gut dysfunction and inflammationPiglet model of NECEnteral and total parenteral nutritionVariations in the microbiome after feeding methodsNEC in preterm pigletsEnteral feeding increased microbial diversity and the abundance of Clostridium species. Density of C perfringens was associated with NEC severity. Microbiome variations correlate with NEC but do not necessarily precede NEC67
 To identify microbial profiles before NEC diagnosisProspective human cohort analysis (n = 369)NoneVariations in the microbiome before NEC diagnosisNEC in infancyIdentification of 2 fecal microbiota profiles associated with NEC development (C perfringens type A dominant and Klebsiella dominant)68
 To characterize epigenome to microbiome crosstalk at critical neonatal stages of developmentTissue-based (immature enterocytes) and mouse models (dexamethasone or 5-azacytidine to induce epigenetic changes)Prenatal dexamethasone or 5-azacytidine treatmentMicrobiome to epigenome crosstalk in perinatal lifeTLR and tight junction-signaling pathways in offspringPrenatal dexamethasone and azacytidine treatment alters DNA methylation of tight junction and TLR genes and associated inflammatory pathways in fetuses and guts of 2-wk-old offspring. Both prenatal exposures also altered the offspring microbiome. Azacytidine treatment induces global demethylation, suggesting that the pre- and neonatal epigenome influences neonatal microbial colonization69
Asthma and atopic disease
 To analyze the microbiome of infants before atopic disease development at 1 y of ageNested case-control design (n = 319) and Ovalbumin-challenged mouse models of asthmaNoneVariations in the 3-mo-old gut microbiomeAtopy and wheezing at 1 y of ageFour bacterial taxa (Faecalibacterium, Lachnospira, Veillonella, and Rothia) were decreased among infants with atopy and wheezing at 1 y of age. Supplementation of asthma-induced mice with these 4 bacteria ameliorated airway inflammation4
 To analyze the microbiota of infants before asthma development by 4 y of ageNested case-control design (n = 319)NoneVariations in the 3-mo-old gut microbiomeAsthma by 4 y of ageDecreased Lachnospira/Clostridium neonatale ratio at 3 mo of age was associated with asthma by 4 y of age5
 To characterize the bacterial and fungal microbiomes in neonates before asthma development at 4 y of ageProspective human cohort analysis (n = 168)NoneVariations in gut microbiome 35 d postbirthAsthma at 4 y of ageVariations in bacterial and fungal taxa at 35 d postbirth associated with highest relative risk of asthma. Sterile fecal water from the highest-risk group induces CD4+ T-cell dysfunction70
 To characterize the early-life critical window associated with exacerbated allergic airways responses in miceOvalbumin-challenged mouse modelAntibiotic-inducedPerinatal (in utero and through weaning)Asthma induced later in lifePerinatal vancomycin exposure promotes expansion of firmicutes and exacerbates airway inflammation in mice71
 To analyze the effects of perinatal antibiotic treatment on development of hypersensitivity pneumonitisTh1/Th17-mediated mouse modelAntibiotic-inducedPerinatal antibiotic exposureHypersensitivity pneumonitis in adulthoodPerinatal streptomycin promotes expansion of bacteroidetes and results in exaggerated hypersensitivity pneumonitis72
 To characterize the cellular mechanisms associated with diet or microbiota-mediated immune regulationWild-type, Gpr43−/−, and HDAC9−/− house dust mite mouse models of AAD; nested case-control design (n = 40)Maternal acetate or high-fiber diet; maternal serum levels of acetatePrenatal antibiotic exposure; prenatal acetate exposureAAD induced in adulthood; coughing and wheeze by 1 y of ageHigh-fiber diet or acetate feeding of dams in pregnancy prevents robust AAD in adult offspring. Maternal serum levels of acetate were inversely associated with general practitioner visits for coughing and wheezing in the first 12 mo of life73
 To analyze the infant microbiota in association with food sensitizationNested case-control design (n = 166)NoneVariations in the gut microbiome at 3 mo of ageFood sensitivity at 1 y of ageDecreased α diversity and increased enterobacteriaceae/bacteroidaceae ratio associated with food sensitization to at least 1 food allergen (milk, egg, peanut, soy) at 1 y of age.74
 To analyze the early-life microbiota in association with resolution of cow’s milk allergyNested case-control design (n = 226 subjects with milk allergy)NoneVariations in the gut microbiome at 3–6 mo of ageMilk allergy resolution by 8 y of ageFirmicutes and clostridia were enriched in microbiomes of subjects whose milk allergy resolved by 8 y of age. Bacteroidetes and Enterobacter were enriched among those whose milk allergy did not resolve by 8 y of age75
 To investigate age-dependent microbial modulation of iNKTs in mouse models of IBD and asthmaOvalbumin-challenged mouse modelNoneExposure to maternal gut microbiome at birthAsthma induced later in lifeNeonatal exposure to a conventional microbiota (compared with GF conditions) increased iNKT in the lungs and protected against allergic asthma induced in adulthood. In addition, hypomethylation of CXCL16, driven by the microbiome, was associated with iNKT induction, implicating the microbiome in gene regulation76
 To analyze the role of the early-life lung microbiota in allergen-induced airway inflammationMouse model of house dust mite–induced airway inflammationNone2-wk window of susceptibility (lung microbiome)Asthma induced later in lifeVariations in the lung microbiome (shift from gammaproteobacteria and firmicutes to bacteroidetes) associated with decreased aeroallergen responsiveness and increased Helios T-regulatory cells. This is mediated by PD-L1. Blockage of PD-L1 in the first 2 wk of life results in enhanced allergic airway inflammation77
 To analyze the nasopharyngeal microbiome in infancy in association with respiratory disease later in lifeProspective human cohort study (n = 234)NoneVariations in the nasopharyngeal microbiome 7–9 wk postbirthChronic wheezing at 5–10 y of ageChildren who developed chronic wheezing at 5–7 y of age and were atopic by age 2 were twice as likely to have been colonized with asymptomatic Streptococcus78
 To determine if variations in the skin microbiome in early life are associated with atopic dermatitisNested case-control design (n = 20)NoneVariations in the skin (antecubital fossa) microbiome at 2 mo of ageAtopic dermatitis at 1 y of ageColonization of antecubital fossa at 2 mo of age with Staphylococcus was associated with decreased incidence of atopic dermatitis at 1 y of age79
 To analyze associations between neonatal gut Bifidobacterium species and eczema or atopy development in the first year of lifeNested case-control design (n = 117)Colonization patterns influenced by household pets, number of siblings, and maternal allergic statusVariations in Bifidobacterium species at 1 wk and 3 mo of ageAtopic dermatitis at 1 y of ageVariations in Bifidobacterium species at 1 wk and 3 mo of age were associated with risk of eczema at 1 y of age. However, the microbiome was not analyzed after 3 mo of age80
 To analyze associations between proportions of IgA coating and bacteria bound to IgA in infancy and allergy development later in lifeNested case-control design (n = 48)NoneIgA and total bacterial load measured at 1 wk and 1 y of ageAsthma, allergic rhinoconjunctivitis, allergic urticaria, and eczema by 7 y of ageAt 12 mo of age, children with allergic disease (particularly asthma) displayed a lower proportion of IgA bound to fecal bacteria. IgA recognition patterns for the microbiota varied between children with allergies and healthy children at 1 wk of age81
 To analyze fecal microbial diversity and bacterial abundances in the first year of life in association with asthma and allergies later in lifeNested case-control design (n = 47)NoneMicrobial diversity at 1 mo of ageAsthma at 7 y of ageChildren with asthma displayed lower overall microbial diversity than children without asthma82
 To investigate the infant intestinal microbiota composition in association with maternal prenatal stress and infant healthNested case-control design (n = 56)Prenatal stressVariations in the microbiome at postnatal days 7, 14, 28, 80, and 110GI symptoms and allergic response by 3 mo of ageInfants exposed to prenatal stress displayed more GI symptoms (38% compared with 22%) and allergic reactions (43% compared with 0%), which were associated with variations in the microbiome. This microbiome was characterized by less lactic acid bacteria and Akkermansia and greater Escherichia, Enterobacter, and Serratia83
Obesity and metabolism
 To analyze if the early-life microbiota composition is associated with childhood BMI and if antibiotic use modifies this associationNested case-control design from 2 cohorts (Bibo cohort, n = 87; Flora cohort, n = 75)Antibiotic treatmentVariations in the gut microbiome at 3 mo of ageBMI at 5–6 yIn the 3-mo-old microbiome, relative abundance of streptococci was positively associated with BMI at 5–6 y of age, and relative abundance of bifidobacteria was negatively associated with BMI at 5–6 y of age. Among children with a history of multiple antibiotic courses, the firmicutes phylum was significantly associated with BMI. However, microbiome composition was not measured at any other time point84
 To analyze the impact of diet on the early-life microbiome in a primate modelPrimate model (high-fat versus standard diet)Maternal high-fat diet during pregnancy and breastfeedingVariations in the offspring microbiome compositionShifts in microbial metabolic pathwaysIn this study, a link to a specific health outcome was not established. However, a maternal high-fat diet did alter the microbiome composition of offspring macaques, which persisted in juvenile macaques. Offspring displayed altered metabolic pathways on the basis of maternal diet. Additionally, these functional pathways (amino acid, carbohydrate, and lipid metabolism) correlated with abundances of specific gut bacteria44
 To determine if the placental microbiome varies in association with birth wtProspective human cohort analysis 
(n = 24)NoneVariations in the placental microbiome compositionBirth wtLow birth wt infants displayed lower gut microbiome richness and variations in the abundances of specific bacterial taxa compared with normal birth wt infants. Lactobacillus percentage was positively correlated with birth wt24
 To analyze the effect of early-life microbial perturbation with antibiotic treatment on host metabolism and adiposityMouse model (high-fat versus standard diet)Antibiotic-inducedLDP exposure from birth through weaningBody composition in adulthoodCompared with controls and mice exposed to long-term LDP, mice exposed to LDP for 4 or 8 wk after birth displayed elevated caloric intake and faster total mass and fat mass accumulation. The authors also report that the penicillin-selected microbiota can induce metabolic changes when transferred to GF mice6
 To better understand how early-life antibiotic use alters the gut microbiome composition and metabolic developmentMouse model (high fat versus standard diet)Antibiotic-inducedPulsed antibiotic treatment completed shortly after weaningBody composition from 3–6 wkEarly-life pulsed antibiotic treatment accelerates total mass and bone growth. The authors also report that response to high-fat diet is altered depending on the particular antibiotic and number of courses used to perturb the microbiota85
 To analyze the impact of maternal prepregnancy BMI on the infant gut microbiome composition and functional potentialNested case-control design (n = 39)Maternal prepregnancy obesityVariations in infant microbiome composition and functionInfant metabolism at 18 mo of ageFirmicutes were reported enriched in children born to mothers at a normal wt, whereas bacteroidetes were enriched in infants born to women who were obese. In this study, a link to an infant health outcome was not established, but differential microbiome metabolic functions that were based on whether infants were born to mothers at a normal wt or to women who were obese was identified86
 To investigate the effect of cadmium exposure on the early-life gut microbiota and metabolism in adulthoodSPF mouse modelCadmium exposure 1 wk before parental matingVariations in the microbiome composition observed at 8 wk and at adulthood (20 wk)Body composition measured in adulthoodCadmium exposure in parental mice resulted in increased fat accumulation in male offspring. Alterations in microbiome composition occurred before measurements of body composition. In addition, through microbiota transfer experiments, the group reported that fat accumulation was driven by the cadmium-exposed microbiome87
 To determine if the early-life gut microbiota composition is associated with wt development in early childhoodNested case-control design (n = 49)NoneVariations in the microbiome composition between 6 and 12 mo of ageBMI measured at 7 y of ageGreater abundance of Staphylococcus aureus in children who were obese in infancy. Greater abundances of bifidobacteria in children at a normal wt in infancy88
 To investigate the effects of early-life factors on the trajectory of gut microbial development and childhood adiposityProspective human cohort analysis (n = 75)Gestational age and delivery modeVariations in the microbiome before 6 mo of ageAdiposity at 18 mo of ageInfants with high Bifidobacterium and Collinsella at a later age displayed lower adiposity at 18 mo of age. Infants who acquired these taxa at 6 mo showed the lowest adiposity at 18 mo. In addition, acquisition of these bacterial taxa was influenced by length of gestation and delivery mode89
 To analyze the effect of subtherapeutic antibiotic administration on the gut microbiome and host metabolismMouse model of antibiotic-induced adiposityAntibiotic-inducedVariations in the microbiome measured before sacrificeBody composition measured in adulthood (16–20 wk)The authors generated a mouse model of adiposity by exposing mice in early life to antibiotics. Variations in microbial composition before adiposity measurement was not assessed. However, the antibiotics did alter the microbiome composition, SCFA metabolism, and hepatic metabolism of fatty acids and lipids90
 To analyze the association between the early-life gut microbiome composition and BMI in childhoodProspective human cohort analysis (n = 138)NoneVariations in the microbiome composition within the first year of ageBMI SD score between 1 and 3 y of ageAbundance of Bacteroides fragilis at 3 and 26 wk of age is associated with BMI SD score between 1 and 3 y of age. Abundance of Staphylococcus at 3 and 52 wk is inversely associated with BMI SD score between 1 and 3 y91
Neurodevelopment
 To determine if limited nesting stress alters offspring microbiota, corticosterone levels, and intestinal permeabilityRat model of limited nesting stressLimited nesting stressVariations in the gut microbiome composition 21 d post birth (at weaning)Limited nesting stress from postnatal days 2–10Limited-nesting pups had hypercorticosteronemia, enhanced intestinal permeability, decreased microbial diversity, and variations in specific microbial taxa92
 To determine if maternal high-fat-diet-induced obesity is associated with social behavioral deficits and altered microbiota in the offspringHigh-fat diet mouse modelMaternal high-fat dietVariations in the gut microbiome composition in offspringBehavior exams on 7–12-wk-old offspring miceA maternal high-fat diet induces compositional variations in the gut microbiome of offspring mice. Offspring mice of mothers on a high-fat diet cohoused with mice born of mothers raised on a regular diet displayed normal social behavior. In addition, reintroduction of L reuteri (lacking in offspring mice of a mother on a high-fat diet) restored normal social behavior in these mice93
 To determine if cognitive ability is associated with particular infant gut microbiota profilesProspective human cohort analysis (n = 89)Group 2 was more likely to have been breastfed, less likely to have been born by cesarean delivery, and associated with white ethnicity. Having older siblings was associated with increased α diversity3 groups of subjects were identified on the basis of their 1-y microbiome analysisCognitive outcomes at 1 and 2 y of ageThree groups of subjects were identified on the basis of their microbiome. Group 1 displayed high abundance of Faecalibacterium, group 2 displayed high abundance of Bacteroides, and group 3 displayed high abundance of ruminococcaceae. Individual Mullen scales differed between groups. α diversity was negatively associated with individual Mullen scales at 2 y of age (expressive language and visual reception)94
 To determine if maternal prenatal stress alters the microbial intrauterine environment and behavior in offspringMouse model of prenatal stressPrenatal stressVariations in placental microbiome and fecal microbiome of offspringAnxiety-like behavior in offspringPrenatal maternal stress was associated with variations in the microbiome of dams, offspring, and in the placenta. Additionally, prenatal stress is associated with increased IL-1β in the placenta and reduced brain-derived neurotrophic factor in placenta and adult offspring amygdala7
 To determine if probiotic administration in early life modifies maternal separation-induced gut dysfunctionRat model (stress induced by maternal separation)Maternal separation in early life (day 4 to day 19)Variations in microbiome and gut function in offspringHypothalamus-pituitary-adrenal axis activityIncreased corticosterone levels and altered colonic mucosal barrier function in maternally separated rat pups. Early-life administration of probiotics (composed of Lactobacillus rhamnosus and Lactobacillus helveticus strains) to rat pups ameliorates these findings and persists to adulthood95
 To determine if early-life stress alters the gut-brain axisRat model (stress induced by maternal separation)Maternal separation in early lifeVariations in microbiome composition in rat pupsSymptoms of psychiatric disorders and irritable bowel syndromeIncreased plasma corticosterone and increased tumor necrosis factor-α and interferon-γ. Also, the microbiome composition varied in the maternally separated group compared with the rats that were not maternally separated96
 To examine the effects of prenatal and early-life exposure to propionic acid and LPS on offspring gut microbial metabolism, locomotor activity, and anxiety-like behaviorRat modelNonePre- and postnatal LPS or propionic acid exposureBehavior traits in offspringPrenatal propionic acid increased anxiety-like behavior in male and female adolescent offspring. Postnatal propionic acid increased anxiety-like behavior in female offspring only. Prenatal propionic acid and LPS induced developmental delays (including delays in eye opening)97
 To determine if colonization by gut microbiota in early life impacts brain development and adult behaviorGF and SPF mouse modelsNoneOffspring of previously GF mice colonized with SPF microbiotaBehavior in adulthoodAdult colonized offspring displayed similar behaviors compared with SPF mice. These mice spent less time exploring the open arms in the maze (less locomotor activity). Additionally, colonized mice expressed less synaptophysin and PSD-95 in the striatum compared with GF mice, suggesting the microbiome is involved in programming brain development98
 To determine if a maternal high-fat-diet-altered microbiome can modify offspring behaviorMouse model colonized with maternal high-fat-diet-shaped microbiotaMaternal high-fat dietFemale mice transplanted with high-fat diet microbiomeBehavior traits in offspringFemale mice were transplanted with a high-fat-diet- or control low-fat-diet-associated gut microbiome. Offspring of these mice displayed altered behavior in a sex-dependent manner. Offspring mice displayed less stress after maternal separation. Male offspring displayed decreased exploratory and cognitive behaviors, which is indicative of increased anxiety. Female mice displayed increases in adiposity and body wt99
 To analyze the microbial and molecular mechanisms that underlie the gut-brain axisGF and conventionally raised mouse modelsNoneGF mice colonized after weaningNeuronal activity in the amygdalaAbsence of a microbiota in early life results in differential gene expression, exon usage, RNA editing, and upstream gene regulation in the amygdala. This was similar to mice who were raised GF for their entire lives but varied when compared with conventionalized mice100
 To examine whether variations in the vaginal microbiome are associated with varied offspring programmingMouse model of prenatal stressPrenatal stressVariations in the maternal vaginal and neonatal gut microbiomeMetabolic and neurologic programming and in offspringLactobacillus abundance is decreased in the vaginal microbiome and in neonates born to dams exposed to early prenatal stress. Other bacterial population abundances also varied in offspring exposed to early prenatal stress. Early prenatal stress altered metabolic profiles and amino acid availability in the brain101
Immune-mediated diseases (IBD, T1D, etc)
 To investigate age-dependent microbial modulation of iNKTs in mouse models of IBD and asthmaMouse model of oxazolone-induced colitisNoneSPF-colonization during pregnancy lead to SPF-colonized offspringColitis induced later in lifeNeonatal exposure to a conventional microbiota compared with GF conditions protected mice from oxazolone-induced colitis76
 To determine if and how early-life exposure to antibiotics changes susceptibility to IBDMouse model DSS-induced colitisAntibiotic-inducedLDP after weaningColitis induced later in lifeLDP-treated mice displayed transient gut microbial compositional alterations, including eradication of segmented filamentous bacteria. In addition, after DSS-induced colitis, LDP mice displayed reduced colitis symptoms, Il-17 expression, and ileal Th17 differentiation compared with mice exposed to metronidazole, enrofloxacin, and controls. Finally, the authors report penicillin’s effects are dependent on eradiation of segmented filamentous bacteria, implicating the microbiome as the mediator between this early life exposure and colitis development102
 To explore the influence of gut dysbiosis in the progression of T1DNOD mouse modelAntibiotic-inducedAntibiotic treatment in early life (conception until 40 wk postnatal)Spontaneous diabetes later in lifeAntibiotics were administered to NOD mice from conception until 40 wk postnatal development. Treatment with antibiotics increased incidence of T1D in male mice. Antibiotic treatment also resulted in near ablation of the gut microbiome at 8 wk of age, which may partially explain the increased T1D incidence in male mice103
 To determine if exposure to prenatal antibiotics can protect offspring from T1DNOD mouse modelAntibiotic-inducedPrenatal antibiotic treatment induced variations in offspring and maternal microbiomesSpontaneous diabetes later in lifePrenatal neomycin and vancomycin treatment resulted in differential shifts in the offspring and maternal microbiomes. Offspring treated prenatally with neomycin were protected from T1D development, whereas offspring treated prenatally with vancomycin displayed accelerated T1D development. The antibiotic treatment also resulted in altered immune profiles, such as increased T-cell–mediated inflammation in mice treated with vancomycin and altered antigen-presenting cell phenotypes in mice treated with neomycin104
 To determine the impact of targeting Gram-negative gut bacteria at various time points in early life on T1D developmentNOD mouse modelAntibiotic-inducedPrenatal antibiotic treatment induced variations in offspring microbiomeSpontaneous diabetes later in lifePregnant, NOD mice treated with an antibiotic mixture (neomycin, polymyxin B, and streptomycin) were protected from T1D compared with mice treated postnatally. Microbiota transfer from these mice to untreated mice resulted in protection from T1D105
 To compare the effects of pulsed therapeutic antibiotics or continuous low-dose antibiotics in early life on T1D developmentNOD mouse modelAntibiotic-inducedPulsed antibiotic treatment induced variations in 6-wk-old microbiomeSpontaneous diabetes later in lifePulsed postnatal treatment with tylosin altered the mouse microbiome and accelerated T1D development compared with mice treated with subtherapeutic penicillin from pregnancy to week 12106
 To analyze the association between the infant gut microbiome and T1D developmentProspective human cohort analysis (n = 33)NoneVariations in the microbiome before diagnosis with T1DT1D diagnosis at ∼3 y of ageT1D disease state was distinguishable by the gut microbiome composition. Seroconverted subjects diagnosed with T1D displayed a marked decrease in α diversity before diagnosis when compared with seroconverted subjects not diagnosed with T1D and nonseroconverted subjects107
 To analyze the effect of peripartum cefoperazone administration on the maternal and offspring microbiota and IBD in the offspringSPF IL-10 knock-out mouse model combined with DSS-induced colitisAntibiotic-inducedPeripartum antibiotic treatment induced gut dysbiosis in offspring that persists to adulthoodSpontaneous colitis later in lifePeripartum exposure to cefoperazone increases risk of spontaneous colitis in offspring. Antibiotics also contribute to immune skewing and promote gut dysbiosis that persists to adulthood. Additionally, as demonstrated by fecal transplant to GF IL-10 knock-out dams, immune skewing is mediated by the antibiotic-induced dysbiosis108
 To analyze the impact of a maternal high-fiber diet on T-regulatory cell differentiation in the offspringSPF GPR41−/− mouse modelMaternal high-fiber diet during pregnancy and breastfeedingIncreased plasma SCFAsIncreased thymic and peripheral T-regulatory cellsCompared with offspring from maternal mice fed a normal diet, high-fiber diet during pregnancy and breastfeeding resulted in increased plasma SCFAs in the offspring. These offspring also displayed higher frequencies of thymic and peripheral T-regulatory cells, which may be prompted by increased SCFA levels46
  • AAD, allergic airways disease; CD4+, cluster of differentiation 4; CXCL16, chemokine ligand 16; DSS, dextran sodium sulfate; GI, gastrointestinal; GPR41, G protein–coupled receptor 41; GPR43, G protein–coupled receptor 43; Grx1, Glutaredoxin-1; HDAC9, histone deacetylase 9; IgA, immunoglobulin A; IL-1β, interleukin 1 beta; IL-10, interleukin 10; IL-17, interleukin 17; iNKT, invariant natural killer T cell; LPS, lipopolysaccharide; NOD, nonobese diabetic; PD-L1, programmed death ligand-1; PSD-95, postsynaptic density protein 95; Ref., reference; Th1, T-helper 1; Th17, T-helper 17; TLR, Toll-like receptor; T1D, type 1 diabetes.