Lactobacillus accelerates ISCs regeneration to protect the integrity of intestinal mucosa through activation of STAT3 signaling pathway induced by LPLs secretion of IL-22

Abstract

The regeneration of intestinal epithelial are maintained by continuous differentiation and proliferation of intestinal stem cells (ISCs) under physiological and pathological conditions. However, little is known about the regulatory effect of intestinal microbiota on its recovery ability to repair damaged mucosal barrier. In this study, we established intestinal organoids and lamina propria lymphocytes (LPLs) co-cultured system, plus mice experiments, to explore the protective effect of Lactobacillus reuteri D8 on integrity of intestinal mucosa. We found that only live L. reuteri D8 was effective in protecting the morphology of intestinal organoids and normal proliferation of epithelial stained with EdU under TNF-α treatment, which was also further verified in mice experiments. L. reuteri D8 colonized in the intestinal mucosa and ameliorated intestinal mucosa damage caused by DSS treatment, including improvement of body weight, colon length, pathological change, and proliferation level. The repair process stimulated by L. reuteri D8 was also accompanied with increased numbers of Lgr5 and lysozyme cells both in intestinal organoids and mice intestine. Furthermore, we demonstrated that D8 metabolite indole-3-aldehyde stimulated LPLs to secret IL-22 through aryl hydrocarbon receptor (AhR) and then induced phosphorylation of STAT3 to accelerate proliferation of intestinal epithelial, thus recovering damaged intestinal mucosa. Our findings indicate L. reuteri protects intestinal barrier and activates intestinal epithelial proliferation, which sheds light on treatment approaches for intestinal inflammation based on ISCs with probiotics Lactobacillus and daily probiotic consumption in heath foods.

Lactobacillus Protects Against S. Typhimurium–Induced Intestinal Inflammation by Determining the Fate of Epithelial Proliferation and Differentiation

“…The proliferation of the intestinal epithelium due to the presence of intestinal stem cells (ISCs) constitutes the basis for the maintenance of the intestinal mucosal barrier against pathogen invasion and intestinal inflammation. [ The intestinal microbiota is continuously in contact with the epithelium and affects niches of ISCs to influence the proliferation and differentiation of the epithelium . Moreover, Wnt signaling directly controls cell fate, such as proliferation, differentiation, and apoptosis .…”

Organoids – New Models for Host–Helminth Interactions

“…Similarly, neural cells induce stem cell division of gastric [68] and intestinal [69,70] organoids, while also supporting tuft cell survival [69]. Co-culture with immune cells includes: (i) intraepithelial lymphocytes that proliferate and incorporate in the organoid epithelium [71]; (ii) macrophages that enhance barrier function and maturity of enteroid monolayers and respond to infections with E. coli [72]; (iii) lamina propria lymphocytes that mediate commensal protection of the epithelium [73]; and (iv) dendritic cells that alter stem cell fate by inhibiting secretory lineage and drive absorptive lineage [74]. The anaerobic nature of the majority of the members of the intestinal microbiota complicates its co-culture in 2D organoid systems that grow under normal oxygen concentrations [5,75].…”

“…The anaerobic nature of the majority of the members of the intestinal microbiota complicates its co-culture in 2D organoid systems that grow under normal oxygen concentrations [5,75]. However, introduction of some oxygen-tolerant microbiota members (and their components and by-products), in organoid cultures and other intestinal models, has allowed their influence on the intestinal SCN to be studied [62,73,75].…”

Microbial Metabolites and Intestinal Stem Cells Tune Intestinal Homeostasis

“…Hou and co‐workers reported that IAld promotes intestinal stem cell proliferation through stimulation of IL‐22 secretion in lamina propria lymphocytes. [ 110 ] They found that colonization of Lactobacillus reuteri in mice significantly increased intestinal epithelial proliferation and Paneth cell population via upregulation of IL‐22. Previously, IL‐22 was found to induce phosphorylation of STAT3, a JAK/STAT signaling effector molecule, which results in expansion of mouse small intestine organoids.…”