Gut microbiota promotes stem cell differentiation. Gut microbiota promotes stem cell differentiation through stromal niches in early postnatal development

Intestinal stem cells become mature, and their niche, called the crypt, develops after birth, which coincides with gut microbiota exposure, but how this exposure influences stem cell differentiation remains unclear. By performing single cell analysis of stem cells and macrophages, and employing both genetic and antibiotics-treated mouse models as well as organoid co-culture, we demonstrate that gut microbiota promotes stem cell differentiation into Paneth cells through the activation of critical stromal niche components. Gut microbiota controls the size and heterogeneity of macrophage populations that secrete Wnt ligands, thereby maintaining the proliferation of mesenchymal niche cells. Paneth cell differentiation, when impaired by antibiotic treatment, promotes necrotizing enterocolitis (NEC), a deadly infant disease, while treatment with Lactobacillus, which in NEC is dramatically less abundant, rescues NEC-like pathology through the activation of macrophage and mesenchymal cell niches. Together, our work defines the gut microbiota-mediated regulation of stem cell niches during early postnatal development