title: Luminal microbes promote monocyte-stem cell interactions across a healthy colonic epithelium.
abstract: The intestinal epithelium forms a vital barrier between luminal microbes and the underlying mucosal immune system. Epithelial barrier function is maintained by continuous renewal of the epithelium and is pivotal for gut homeostasis. Breaching of the barrier causes mobilization of immune cells to promote epithelial restitution. However, it is not known whether microbes at the luminal surface of a healthy epithelial barrier influence immune cell mobilization to modulate tissue homeostasis. Using a mouse colonic mucosal explant model, we demonstrate that close proximity of luminal microbes to a healthy, intact epithelium results in rapid mucus secretion and movement of Ly6C(+)7/4(+) monocytes closer to epithelial stem cells. These early events are driven by the epithelial MyD88-signaling pathway and result in increased crypt cell proliferation and intestinal stem cell number. Over time, stem cell number and monocyte-crypt stem cell juxtapositioning return to homeostatic levels observed in vivo. We also demonstrate that reduced numbers of tissue Ly6C+ monocytes can suppress Lgr5EGFP+ stem cell expression in vivo and abrogate the response to luminal microbes ex vivo. The functional link between monocyte recruitment and increased crypt cell proliferation was further confirmed using a crypt-monocyte coculture model. This work demonstrates that the healthy gut epithelium mediates communication between luminal bacteria and monocytes, and monocytes can modulate crypt stem cell number and promote crypt cell proliferation to help maintain gut homeostasis.
authors.affiliation: Gut Health and Food Safety Institute Strategic Program, Institute of Food Research, Norwich, Norfolk NR4 7UA, United Kingdom;
authors.forename: Dagmara A
authors.initials: DA
authors.lastname: Skoczek
authors.affiliation: Gut Health and Food Safety Institute Strategic Program, Institute of Food Research, Norwich, Norfolk NR4 7UA, United Kingdom;
authors.forename: Petr
authors.initials: P
authors.lastname: Walczysko
authors.affiliation: Gut Health and Food Safety Institute Strategic Program, Institute of Food Research, Norwich, Norfolk NR4 7UA, United Kingdom;
authors.forename: Nikki
authors.initials: N
authors.lastname: Horn
authors.affiliation: School of Biological Sciences, University of East Anglia, Norwich, Norfolk NR4 7TJ, United Kingdom; and.
authors.forename: Alyson
authors.initials: A
authors.lastname: Parris
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, Cambridgeshire CB10 1SA, United Kingdom.
authors.forename: Simon
authors.initials: S
authors.lastname: Clare
authors.affiliation: School of Biological Sciences, University of East Anglia, Norwich, Norfolk NR4 7TJ, United Kingdom; and.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Williams
authors.affiliation: Gut Health and Food Safety Institute Strategic Program, Institute of Food Research, Norwich, Norfolk NR4 7UA, United Kingdom; anastasia.sobolewski@ifr.ac.uk.
authors.forename: Anastasia
authors.initials: A
authors.lastname: Sobolewski
mesh_terms: D000818:Animals; D000950:Antigens, Ly / Q000235:genetics / Q000276:immunology; D001419:Bacteria / Q000276:immunology*; D049109:Cell Proliferation; D005260:Female; D006801:Humans; D007413:Intestinal Mucosa / Q000166:cytology / Q000276:immunology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009000:Monocytes / Q000166:cytology / Q000276:immunology*; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000276:immunology; D013234:Stem Cells / Q000166:cytology / Q000276:immunology*
chemical_list: D000950:Antigens, Ly; C116884:LGR5 protein, human; C493597:Lgr5 protein, mouse; C494192:Ly-6C antigen, mouse; D043562:Receptors, G-Protein-Coupled