Gut microbiota promotes stem cell differentiation through macrophage and mesenchymal niches in early postnatal development

• Published in: Immunity (Cambridge, Mass.) Vol. 55; no. 12; pp. 2300 - 2317.e6
• Main Authors: Kim, Ji-Eun, Li, Bo, Fei, Lijiang, Horne, Rachael, Lee, Dorothy, Loe, Adrian Kwan, Miyake, Hiromu, Ayar, Eda, Kim, Dae-Kyum, Surette, Michael G., Philpott, Dana J., Sherman, Philip, Guo, Guoji, Pierro, Agostino, Kim, Tae-Hee
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 13.12.2022
• Subjects: Animals; antibiotics; Cell Differentiation - physiology; Enterocolitis, Necrotizing; Gastrointestinal Microbiome; intestine; Macrophages; Mice; microbiota; necrotizing enterocolitis; Paneth cells; Paneth Cells - physiology; stem cell niche; Wnt signaling; microbiota; stem cell niche; Wnt signaling; necrotizing enterocolitis; macrophages; intestine; Paneth cells; antibiotics
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2022.11.003

Intestinal stem cell maturation and development coincide with gut microbiota exposure after birth. Here, we investigated how early life microbial exposure, and disruption of this process, impacts the intestinal stem cell niche and development. Single-cell transcriptional analysis revealed impaired stem cell differentiation into Paneth cells and macrophage specification upon antibiotic treatment in early life. Mouse genetic and organoid co-culture experiments demonstrated that a CD206+ subset of intestinal macrophages secreted Wnt ligands, which maintained the mesenchymal niche cells important for Paneth cell differentiation. Antibiotics and reduced numbers of Paneth cells are associated with the deadly infant disease, necrotizing enterocolitis (NEC). We showed that colonization with Lactobacillus or transfer of CD206+ macrophages promoted Paneth cell differentiation and reduced NEC severity. Together, our work defines the gut microbiota-mediated regulation of stem cell niches during early postnatal development. [Display omitted] •Microbiota regulate intestinal stem cell differentiation and macrophage polarization•CD206+ intestinal macrophages promote mesenchymal niche cell proliferation•Antibiotic treatment impairs gut stem cell niches and promotes NEC pathogenesis•Lactobacillus or macrophage treatment partially rescues NEC-like phenotypes Intestinal development coincides with microbial exposure after birth, but how they influence each other is unresolved. Here, Kim et al. report that postnatal gut microbiota promote stem cell differentiation through regulation of a macrophage and mesenchymal niche. This niche is disrupted by antibiotics but can be partially rescued by Lactobacillus.