Background: Evidence for the “hygiene hypothesis” in the etiology of inflammatory bowel diseases (IBD) is not fully established. Epidemiological studies show that children exposed to antibiotics during the first year of life have an increased risk of IBD development. However, underlying cellular and molecular mechanisms remain enigmatic. We aim to determine how perturbations in host–microbial symbiosis during childhood impact intestinal immunity and increase the risk to develop IBD at adult age.
Methods: The impact on the immune system of a decreased exposure to microbiota was assessed during suckling, weaning and adulthood. Dextran sodium sulfate (DSS)-induced colitis was used as the experimental model of IBD. The differential response to DSS in conventional mice treated with a cocktail of antibiotic from birth until 2, 4, 6 or 12 weeks of age was compared to untreated mice. In addition, colitis severity in adult germ-free (GF) mice and in GF mice colonized during the neonatal period or after weaning was compared to conventional mice.
Results: The production of pro-inflammatory cytokines (e.g. TNF-α and IFN-γ) in ileum and in colon was increased around weaning under specific pathogen-free (SPF) but not in germ-free conditions. We show that the gut microbiota produces short chain fatty acids (SCFA) that induce the pro-inflammatory response during the weaning period. Exposition of germ-free mice to SPF conditions only at weaning, but not later, protects the intestine of adult mice from DSS-induced colitis. Conversely, antibiotic treatment during weaning results in increased sensitivity to DSS-induced colitis at adult age. Treatment with selective antibiotics revealed that the protective effect of gut microbiota is associated with the presence of Gram-positive bacteria, probably through the production of SCFA. This protective effect of SCFAs early in life is dependent of regulatory T cells expressing the transcription factor RORγt (Retinoid-Acid Receptor-related Orphan Receptor gamma t).
Conclusions: Our study reveals how host-microbial symbiosis early in life determines the colitis severity in adult mice.