Type 1 diabetes (T1D) incidence is increasing worldwide, with decreasing age of onset, suggesting that early-life environmental exposures may be involved. The first 3 years of life (also termed a ‘window of opportunity’) may represent the most critical period for dietary interventions aimed at gut microbiota modulation for improving child growth and development. In this context, disruption of early-life interactions between host and gut microbiota could have lasting effects by affecting host immunological and metabolic development.

A recent study, led by Dr. Martin J. Blaser from the Departments of Medicine and Microbiology at New York University Langone Medical Centre in New York (USA), has found that early-life antibiotic exposure in non-obese diabetic mice may accelerate T1D development.

The researchers used non-obese diabetic (NOD) mice that were genetically susceptible to T1D to examine the effects of exposure to either continuous low-dose antibiotics or pulsed therapeutic antibiotics (PAT) early in life; PAT mimicked the doses used to treat many infections in early childhood.

NOD mice were exposed to sub-therapeutic continuous (STAT), PAT, or no antibiotics (control). NOD male mice exposed to PAT had a higher T1D incidence (53%) than controls (26%). No significant effects were seen in experimental PAT female mice or in the STAT group. Because control females developed higher T1D incidence than males, these findings suggest that males may have a protective gut microbiota that is eliminated by PAT. Male PAT mice also had significantly higher insulitis scores than controls. These data provide evidence that early-life PAT exposures accelerate T1D development and inflammation of pancreatic islets in NOD mice.

Events in the intestine before T1D development were examined by studying tissues of 6-week-old mice. PAT exposure decreased proportions of small intestinal lamina propria regulatory T (Treg) and T helper (Th)-17 cells in male (but not female) mice, which was consistent with the sex-specific T1D differences seen in the first experiment.

In addition, in mice receiving PAT, microbial community composition and structure differed compared with controls. For instance, the 3-week-old PAT males had nearly complete caecal and ileal loss of Bacteroidetes and Actinobacteria, which are involved in training the immune system to be less prone to self-attack. Akkermansia and Enterococcus were identified as significantly T1D-accelerating in PAT. Seven weeks after antibiotic cessation, intestinal microbial richness partially recovered. For the STAT mice, richness recovered after antibiotic cessation as well. All together, these data indicate that PAT selected for distinctive microbial community structure, persisting weeks after antibiotic cessation, before T1D onset.

From a functional point of view, PAT altered metabolic gene expression pathways as well as metabolite composition in caecum, liver, and serum. PAT increased liver-specific and serum-detectable lipid species and the expression of ileal genes involved in cholesterol biosynthesis, while affecting carbohydrate, lipid, and amino-acid metabolites. Metabolic characteristics observed in the PAT mice were consistent with findings in both humans and in NOD models for accelerated T1D.

In addition to global PAT effects on both immune and metabolic responses, PAT exposure led to decreased caecal butyrate, which was consistent with previous research showing that non-diabetic children have a more balanced gut microbiota in which butyrate-producing species appear to hold a pivotal position.

Intestinal microbiota transfer to germ-free mice produced immunological changes resembling those seen in the microbe donors, which provides evidence that early-life antibiotic-altered microbiota is sufficient to confer the altered immune phenotypes.

In conclusion, early-life therapeutic-dose antibiotic exposure in NOD mice may accelerate T1D development. Although other environmental changes could also contribute to T1D development in humans, these findings provide preliminary evidence that altered early-life immune and metabolic responses may accelerate T1D onset.




Livanos AE, Greiner TU, Vangay P, et al. Antibiotic-mediated gut microbiome perturbation accelerates development of type 1 diabetes in mice. Nat Microbiol. 2016; 1: 16140. doi: 10.1038/nmicrobiol.2016.140.