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.

Microbiota and host immune responses: a love–hate relationship

“…Luminal bacteria promote mucus secretion and movement of monocytes closer to epithelial stem cells through an epithelial MyD88‐signalling pathway. Increased proximity of monocytes to epithelial stem cells results in increased crypt cell proliferation and intestinal stem cell numbers, which could be beneficial during intestinal injury response. Studies comparing GF mice to mice colonized with three strains of bacteria ( E. coli K‐12, Staphylococcus xylosus and Enterococcus faecalis ) reveal that GF mice have delayed microbial clearance, reduced inflammatory responses to intravenous E. coli K12 infection and a decreased myeloid cell pool size .…”

Haemocytes control stem cell activity in the Drosophila intestine

“…Work in vertebrates has implicated immune cells in the induction of mitotic activity and regeneration in intestinal epithelia 23 , 24 , 25 . In Drosophila , macrophage-like hemocytes constitute a major population of blood cells 26 that mediate infection responses and tissue repair 27 , yet if and how these cells influence regeneration in the intestinal epithelium has not been addressed.…”

Macrophage engulfment of a cell or nanoparticle is regulated by unavoidable opsonization, a species-specific ‘Marker of Self’ CD47, and target physical properties

“…Fast forward eons to organisms like humans that gain nutrition through a highly differentiated and multi-cellular digestive tract, and phagocytosis is a highly efficient process used only by specialized cells of the mononuclear phagocyte system (MPS). Microbes (in and on us) remain major targets as they not only out-number and out-proliferate our own cells but also invade through any and all compromised tissue barriers [2]. The principal cell types of the MPS are macrophages which reside in every tissue and monocytes that circulate out of the bone marrow to enter a tissue and differentiate to macrophages [3••,4].…”