Acetate increases the maturation of the preterm intestinal epithelium

Background Preterm infants are susceptible to develop necrotizing enterocolitis (NEC), due to their immature intestinal epithelium. Compared to formula milk, breastfeeding decreases the risk of NEC development, potentially due to the human milk oligosaccharides (HMOs) in breast milk. Importantly, preterm infants lack bifidobacteria, which ferment HMOs to short-chain-fatty-acids, most abundantly to acetate. Therefore, we investigated the effect of acetate-supplementation on the maturation of the intestinal epithelium. Results Compared to organoids derived from adult intestine, fetal organoids show clear characteristics of immaturity, exemplified by their persistent spheroid morphology, high expression of fetal markers, and the lack of the crypt-villus structural organization. In fetal organoids, acetate increased markers for differentiated and stem cells, while at the same time inhibiting proliferation, indicative of epithelial maturation. Acetate treatment changes fetal organoid morphology from progenitor cells to a columnar epithelium morphology, equivalent to what is seen in intestinal development. Moreover, we observe increased brush border formation characteristics of absorptive enterocyte cells. Mechanistically, acetate increased Wnt activity in HEK293T cells and in fetal intestinal organoids via acetylation of ß-catenin and binding of ß-catenin to TCF4, leading to enhanced Wnt target gene transcription and the repression of fetal markers. Conclusion We conclude that acetate supplementation leads to Wnt activation, via inducing ß-catenin acetylation and TCF4 binding, associated with epithelial cell maturation and microvilli development. Therefore, the microbiota-dependent breakdown of HMOs into acetate by bacteria emerges as an important factor of gut maturation in preterm infants. Acetate supplementation therefore holds promise to decrease the risk of NEC development.