The relationship between the gut microbiome and the risk of respiratory infections among newborns

Abstract

Background: Emerging evidence points to a critical role of the developing gut microbiome in immune maturation and infant health; however, prospective studies are lacking.

Methods: We examined the occurrence of infections and associated symptoms during the first year of life in relation to the infant gut microbiome at six weeks of age using bacterial 16S rRNA V4-V5 gene sequencing (N = 465) and shotgun metagenomics (N = 185). We used generalized estimating equations to assess the associations between longitudinal outcomes and 16S alpha diversity and metagenomics species.

Results: Here we show higher infant gut microbiota alpha diversity was associated with an increased risk of infections or respiratory symptoms treated with a prescription medicine, and specifically upper respiratory tract infections. Among vaginally delivered infants, a higher alpha diversity was associated with an increased risk of all-cause wheezing treated with a prescription medicine and diarrhea involving a visit to a health care provider. Positive associations were specifically observed with Veillonella species among all deliveries and Haemophilus influenzae among cesarean-delivered infants.

Conclusion: Our findings suggest that intestinal microbial diversity and the relative abundance of key taxa in early infancy may influence susceptibility to respiratory infection, wheezing, and diarrhea.

Keywords: Biomarkers; Epidemiology; Microbiome; Paediatric research.

Fig. 1. Dot and Whisker plots of adjusted relative risk estimates and 95% confidence intervals from GEE analysis of 6-week-old infant stool 16S V4–V5 rRNA sequencing alpha diversity and infections and symptoms of infection over the first year of life.

Overall GEE adjusted for maternal BMI, delivery type, sex, breast feeding at six weeks, perinatal antibiotic use, and gestational age. GEE stratified by delivery mode (vaginal and cesarean) adjusted for maternal BMI, sex, breast feeding at six weeks, perinatal antibiotic use, and gestational age. Red, blue, turquoise, pink, and green points represent relative risk for all infections and symptoms, upper RTI, lower RTI, wheezing, and diarrhea outcomes respectively. Vertical lines above and below points represent upper and lower confidence bands. Relative risk estimates represent an increased risk of having an additional infection or symptom of infection or an increased risk of experiencing wheezing or diarrhea with each doubling of the inverse Simpson index. Upper RTI, lower RTI, and wheezing outcomes are those diagnosed by a physician for which a medication was prescribed. Diarrhea outcomes are those diagnosed by a physician for whom no medication was prescribed. Numbers above upper confidence bands indicate the total number of outcomes, which may be greater than N due to repeated measures. Sample sizes were N = 464 for overall and N = 125 for cesarean delivery for diarrhea analyses due to missing data. GEE generalized estimating equation, N sample size, RR relative risk, RTI respiratory tract infection.

Fig. 2. Volcano plots of GEE adjusted relative risk estimates of the number of infections and symptoms over the first year of life in relation to 6-week metagenomics species relative abundance.

Estimates shown for taxa prevalent in over 10% of subjects. The gray line represents a log10-transformed FDR threshold of 0.1. Blue points indicate statistically significant taxa at α = 0.05. Red points indicate taxa selected by FDR correction. Gray points indicate all other taxa. The size of the points is scaled by relative abundance. Relative risk estimates represent an increased risk of having additional infections or symptoms of infection with each doubling of relative abundance. a Volcano plot of unstratified GEE adjusted for maternal BMI, delivery type, sex, breast feeding at six weeks, perinatal antibiotic use, and gestational age. b Volcano plot of vaginal deliveries adjusted for maternal BMI, sex, breast feeding at six weeks, perinatal antibiotic use, and gestational age. c Volcano plot of cesarean deliveries adjusted for maternal BMI, sex, breast feeding at six weeks, perinatal antibiotic use, and gestational age. Three taxa were removed due to high RRs and low p-values. GEE generalized estimating equation, N sample size, RR relative risk.

Fig. 3. Forest plot of metagenomics species associated with the number of infections and symptoms of infections in the first year of life.

Species selected by FDR correction presented in the forest plot. Species for vaginal deliveries did not meet the FDR threshold of 0.1. Squares represent RR, and horizontal lines represent 95% confidence intervals. Green represents a positive association, and purple represents a negative association. Relative risk estimates represent an increased risk of having an additional upper respiratory infection or an increased risk of experiencing diarrhea with each doubling of the relative abundance. N sample size, RTI respiratory tract infection, RR relative risk.