The early life microbiome plays important roles in host immunological and metabolic development. Because the incidence of type 1 diabetes (T1D) has been increasing substantially in recent decades, we hypothesized that early-life antibiotic use alters gut microbiota, which predisposes to disease. Using non-obese diabetic mice that are genetically susceptible to T1D, we examined the effects of exposure to either continuous low-dose antibiotics or pulsed therapeutic antibiotics (PAT) early in life, mimicking childhood exposures. We found that in mice receiving PAT, T1D incidence was significantly higher, and microbial community composition and structure differed compared with controls. In pre-diabetic male PAT mice, the intestinal lamina propria had lower Th17 and Treg proportions and intestinal SAA expression than in controls, suggesting key roles in transducing the altered microbiota signals. PAT affected microbial lipid metabolism and host cholesterol biosynthetic gene expression. These findings show that early-life antibiotic treatments alter the gut microbiota and its metabolic capacities, intestinal gene expression and T-cell populations, accelerating T1D onset in non-obese diabetic mice.

BackgroundThere is a rapid decline in moderate-to-vigorous physical activity (MVPA) during middle childhood and adolescence. Information on the environmental factors implicated in this decline is limited. This study focuses on family factors associated with the rate of decline in objectively measured physical activity during middle childhood and adolescence.MethodsLongitudinal analysis of 801 participants from 10 US sites in the NICHD Study of Early Child Care and Youth Development whose data included accelerometer-determined levels of moderate-to-vigorous physical activity (MVPA) between ages 9 and 15 years, as well as family process, BMI and demographic information. The sample included an even split of boys (49%) and girls (51%), was predominantly white (77%), and contained about 26% low income and 19% single parent families. The outcome measure was mean MVPA. It was based on 4 to 7 days of monitored physical activity.ResultsBoys with lower parental monitoring scores and more days of parental encouragement had significantly more minutes of MVPA at age 9 years. The effect of parental monitoring, however, was moderated by early puberty. High parental monitoring was associated with decreased activity levels for boys experiencing later puberty and increased activity for boy experiencing early puberty. Minutes of MVPA for boys living in the Midwest decreased at significantly faster rates than boys living in any other region; and boys in the South declined faster than boys in the West. Girls in the Midwest and South declined faster than girls in the West and Northeast. Among girls, more days of parental exercise and transportation to activities were associated with more MVPA per day at age 9. However, more parental transportation to activities and less monitoring was associated with faster linear declines in daughters' MVPA between the ages of 9 and 15 years. For girls who experienced puberty early, parental encouragement was associated with more MVPA.ConclusionsParenting processes, such as monitoring and encouragement, as well as the parents' own level of physical activity, showed significant, but small, gender-specific associations with MVPA levels at age nine and the linear rate of decline in MVPA between ages 9 and 15.

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The high-fat, high-calorie diets of westernized cultures contribute to the global obesity epidemic, and early life exposure to antibiotics may potentiate those dietary effects. Previous experiments with mice had shown that sub-therapeutic antibiotic treatment (STAT)—even restricted to early life—affected the gut microbiota, altered host metabolism, and increased adiposity throughout the lifetime of the animals. Here we carried out a large-scale cohousing experiment to investigate whether cohousing STAT and untreated (Control) mice would transfer the STAT-perturbed microbiota and transmit its impact on weight. We exposed pregnant dams and their young offspring to either low-dose penicillin (STAT) or water (Control) until weaning, and then followed the offspring as they grew and endured a switch from normal to high-fat diet at week 17 of life. Cohousing, which started at week 4, rapidly approximated the microbiota within cages, lowering the weight of STAT mice relative to non-cohoused mice. The effect, however, varied between cages, and was restricted to the first 16 weeks when diet consisted of normal chow. Once mice switched to high-fat diet, the microbiota α- and β-diversity expanded and the effect of cohousing faded: STAT mice, again, were heavier than control mice independently of cohousing. Metabolomics revealed serum metabolites associated with STAT exposure, but no significant differences were detected in glucose or insulin tolerance. Our results show that cohousing can partly ameliorate the impact of STAT on the gut microbiota but not prevent increased weight with high-fat diet. These observations have implications for microbiota therapies aimed to resolve the collateral damage of antibiotics and their load on human obesity.