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

Ji-Eun Kim; Bo Li; Lijiang Fei; Rachael Horne; Dorothy Lee; Adrian Kwan Loe; Hiromu Miyake; Eda Ayar; Dae-Kyum Kim; Michael G Surette; Dana J Philpott; Philip Sherman; Guoji Guo; Agostino Pierro; Tae-Hee Kim

doi:10.1016/j.immuni.2022.11.003

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

Immunity. 2022 Dec 13;55(12):2300-2317.e6. doi: 10.1016/j.immuni.2022.11.003. Epub 2022 Dec 5.

Authors

Ji-Eun Kim¹, Bo Li², Lijiang Fei³, Rachael Horne⁴, Dorothy Lee², Adrian Kwan Loe¹, Hiromu Miyake², Eda Ayar¹, Dae-Kyum Kim⁵, Michael G Surette⁶, Dana J Philpott⁷, Philip Sherman⁴, Guoji Guo³, Agostino Pierro², Tae-Hee Kim⁸

Affiliations

¹ Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
² General and Thoracic Surgery, The Hospital for Sick Children, University of Toronto, Toronto, ON M5G 1X8, Canada.
³ Center for Stem Cell and Regenerative Medicine, Zhejiang University of School of Medicine, Hangzhou 310058, China.
⁴ Program in Cell Biology, Division of Gastroenterology, Hepatology & Nutrition, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Laboratory Medicine and Pathology, University of Toronto, Toronto, ON M5S 1A8, Canada.
⁵ Center for Personalized Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14203, USA.
⁶ Department of Biochemistry and Biomedical Sciences, Department of Medicine, McMaster University, 1280 Main St. W, Hamilton, ON L8S 4L8, Canada.
⁷ Department of Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada.
⁸ Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada. Electronic address: tae-hee.kim@sickkids.ca.

PMID: 36473468
DOI: 10.1016/j.immuni.2022.11.003

Abstract

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.

Keywords: Paneth cells; Wnt signaling; antibiotics; intestine; macrophages; microbiota; necrotizing enterocolitis; stem cell niche.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Differentiation / physiology
Enterocolitis, Necrotizing*
Gastrointestinal Microbiome*
Macrophages
Mice
Paneth Cells / physiology

Abstract

Publication types

MeSH terms

Grants and funding