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

At birth, newborns are exposed to gut microbiota, which plays a critical role in host physiology. A reduced level of microbial diversity has been associated with necrotizing enterocolitis (NEC), one of the most deadly diseases in premature infants, but the underlying disease mechanisms are still poorly understood. Although the epithelial turnover of germ free mice is significantly delayed compared to conventionally raised mice, it remains unclear how gut microbiota exposure in the early postnatal period promotes stem cell renewal and differentiation. By analyzing genetic and experimental mouse models and performing single cell analysis, we demonstrate that gut microbiota promotes stem cell differentiation through the activation of critical stromal niche components. Our single cell analysis reveals that gut microbiota controls the size and heterogeneity of macrophage populations that secrete Wnt ligands, thereby maintaining the proliferation of intestinal telocytes, a recently identified gut mesenchymal stem cell niche. We show that stem cell differentiation, when impaired by antibiotic treatment promotes NEC, while treatment with Lactobacillus, which in NEC is dramatically less abundant, rescues NEC-like pathology through the activation of macrophage and telocyte niches. Our work highlights the mechanisms of how gut microbiota-facilitate mesenchymal niche proliferation which supports stem cell differentiation in early postnatal development. Overall design: Identification and comparision of the Lgr5 cell differentiation in gut microbiota composition change