Developmental Stage, Solid Food Introduction and Suckling Cessation Differentially Influence the Co-maturation of the Gut Microbiota and Intestinal Epithelium in Rabbits

Background In mammals, the establishment around weaning of a symbiotic relationship between the gut microbiota and its host determines long-term health. Objective The aim of this study was to identify the factors driving the co-maturation of the gut microbiota and intestinal epithelium at the suckling-to-weaning transition. We hypothesized that developmental stage, solid food ingestion and suckling cessation contribute to this process. Methods From birth to day 18, Hyplus rabbits were exclusively suckling. From day 18 to day 25, rabbits were i) exclusively suckling or ii) suckling and ingesting solid food or iii) exclusively ingesting solid food. The microbiota (16S amplicon sequencing), metabolome (nuclear magnetic resonance) and epithelial gene expression (high-throughput qPCR) were analyzed in the caecum at day 18 and 25. Results The microbiota structure and metabolic activity were modified with age when rabbits remained exclusively suckling. The epithelial gene expression of nutrient transporters, proliferation markers and innate immune factors were also regulated with age (e.g., 1.5-fold decrease of TLR5). Solid food ingestion by suckling rabbits had a major effect on the gut microbiota by increasing its α-diversity, remodeling its structure (e.g., 6.3-fold increase of Ruminococcaceae) and metabolic activity (e.g., 4.6-fold increase of butyrate). Solid food introduction also regulated the gene expression of nutrient transporters, differentiation markers and innate immune factors in the epithelium (e.g., 3-fold increase of NOS2). Suckling cessation had no effect on the microbiota while it regulated the expression of genes involved in epithelial differentiation and immunoglobulin transport (e.g., 2.5-increase of PIGR). Conclusion In rabbits, the maturation of the microbiota at the suckling-to-weaning transition is driven by the introduction of solid food and to a lesser extent by developmental stage. In contrast, the maturation of the intestinal epithelium at the suckling-to-weaning transition is under the influence of developmental stage, solid food introduction and suckling cessation.