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. 2018 Oct 23;9(5):e01751-18.
doi: 10.1128/mBio.01751-18.

Gut Microbiota in the First 2 Years of Life and the Association with Body Mass Index at Age 12 in a Norwegian Birth Cohort

Maggie A Stanislawski  1 , Dana Dabelea  2   3 , Brandie D Wagner  4 , Nina Iszatt  5 , Cecilie Dahl  6 , Marci K Sontag  2   7 , Rob Knight  8   9   10 , Catherine A Lozupone #  11 , Merete Eggesbø #  5
Affiliations

Gut Microbiota in the First 2 Years of Life and the Association with Body Mass Index at Age 12 in a Norwegian Birth Cohort

Maggie A Stanislawski et al. mBio. .

Abstract

Childhood obesity is a growing problem worldwide. Recent research suggests that the gut microbiota may play an important and potentially causal role in the development of obesity and may be one mechanism that explains the transgenerational transmission of obesity risk. Here we examine the early-life gut microbiota at days 4, 10, 30, 120, 365, and 730 and the association with body mass index (BMI) z-scores at age 12 in a Norwegian prospective cohort (n = 165), and evaluate how these BMI-associated taxa relate to maternal overweight/obesity (Ow/Ob) and excessive gestational weight gain (GWG). We performed 16S rRNA gene sequencing on the gut microbiota samples. Taxonomic phylogeny at days 10 and 730 was significantly associated with childhood BMI, and the gut microbiota taxa at two years of age explained over 50% of the variation in childhood BMI in this cohort. The subset of the early-life taxa within the gut microbiota that best predicted later childhood BMI showed substantial overlap with the maternal taxa most strongly associated with maternal Ow/Ob and excessive GWG. Our results show an association between the infant gut microbiota and later BMI, and they offer preliminary evidence that the infant gut microbiota, particularly at 2 years of age, may have potential to help identify children at risk for obesity.IMPORTANCE Understanding the role of the early-life gut microbiota in obesity is important because there may be opportunities for preventive strategies. We examined the relationships between infant gut microbiota at six times during the first two years of life and BMI at age 12 in a birth cohort of 165 children and their mothers. We found that the gut microbiota from early life to two years shows an increasingly strong association with childhood BMI. This study provides preliminary evidence that the gut microbiome at 2 years of age may offer useful information to help to identify youth who are at risk for obesity, which could facilitate more-targeted early prevention efforts.

Keywords: children; infants; microbiota; obesity.

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Figures

FIG 1
FIG 1
Evaluation of the association between the gut microbiota taxonomic composition at 6 time points in early life with BMI z-score at age 12. This plot shows the estimated P values from unadjusted (circles) and adjusted (squares) Microbiome Regression-Based Kernel Association Tests of the unweighted (coral) and weighted (blue) UniFrac distance matrices and BMI z-scores at age 12. These UniFrac measures capture qualitative and quantitative differences in phylogeny, respectively. Dashed lines show P = 0.05 (black) and P = 0.1 (gray). Adjusted models controlled for breastfeeding, delivery mode, antibiotic exposures, gestational age at birth, and twin status.
FIG 2
FIG 2
Amount of variation in BMI z-score at age 12 explained by the infant gut microbiota at each sampling time. This plot shows the estimated R2 values with 95% confidence intervals from the repeated cross-validation of the random forests to predict childhood BMI z-scores based on infant gut microbiota characteristics at each sampling time, both unadjusted and adjusted for confounding factors (breastfeeding, delivery mode, antibiotic exposures, gestational age at birth, and twin status).
FIG 3
FIG 3
The infant gut microbiota taxa and alpha diversity measures at each sampling time that were most highly predictive of BMI z-score at age 12. Infant gut microbiota taxa and diversity measures (OTUs listed with OTU, phylum, and most specific level of known taxonomic classification) over the first 2 years of life that were selected as most predictive of childhood BMI z-score in random forests at six points (grouped vertically). We used linear regressions in order to assess the direction of association between these features at each sampling time with BMI z-score at age 12, controlling for confounding factors (breastfeeding, delivery mode, antibiotic exposures, gestational age at birth, and twin status). While a feature may have been selected as predictive of BMI only at a certain sampling time, we plotted the linear associations at all times (horizontal axis) in order to assess the temporal consistency of the association. Since the assumptions underlying random forests and linear regressions are very different, we would not expect important features to necessarily be significant in regressions. The colors represent the regression coefficients for each feature: red indicates a positive relationship between the feature and childhood BMI, e.g., higher abundance corresponds with higher BMI; green indicates negative relationships; gray indicates that the regression model failed to converge (NA). The column labeled “maternal taxa” shows whether these gut microbiota species or diversity measures were also associated with maternal overweight/obesity (Ow/Ob), excessive gestational weight gain (GWG), or both, in the maternal gut microbiota at the time of delivery; Fig. 5 provides more detail and Fig. S4 shows the association between these BMI-associated infant taxa and maternal characteristics.
FIG 4
FIG 4
Spaghetti plots of BMI z-scores over time by Ow/Ob status at age 12. The regression lines (denoted by thicker lines) show that BMI z-scores were fairly constant between ages 2 and 12 for children who were not Ow/Ob at age 12, but there was an increase in BMI z-scores during this time for children who became Ow/Ob. At age 2, there was no significant difference between BMI z-scores of children who later became Ow/Ob and those who did not.
FIG 5
FIG 5
Venn diagrams showing the overlap between gut microbiota (a) OTUs and (b) species associated with maternal overweight/obesity (Ow/Ob) and excessive gestational weight gain (GWG) in the maternal taxa at the time of delivery and those predictive of childhood BMI in the infant gut microbiota taxa during the first 2 years of life. The OTUs are listed with OTU, phylum, and most specific level of known taxonomic classification; “species” are listed as phylum and most specific level of known taxonomic classification. The numbers in parentheses show at which time points in the infant these taxa were predictive of childhood BMI. Due to the large number of taxa associated with child BMI (green circle), these are not all listed by name but are shown in Fig. 3.
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