br Disclosure summary br Acknowledgments

Disclosure summary
Acknowledgments
Introduction Symbionts are live microorganisms that seem to promote host defense systems and regulate intestinal homeostasis, preventing gut infectious and inflammatory diseases (Fuller, 1989, Sartor, 2004). Numerous studies have shown the beneficial effects of different types of symbionts in gut-related diseases such as ulcerative colitis, Crohn’s disease, pouchitis, and irritable bowel syndrome in human and animal models (Bibiloni et al., 2005, Gionchetti et al., 2000, O'Mahony et al., 2005). The intestinal epithelium contains stem L-Phenylephrine mg in the crypt and their transit-amplifying daughter cells as well as terminally differentiated functional cells in the villus that help to prevent intestinal pathology (Clevers, 2013). Through a self-renewal process, the intestinal epithelium is continuously renewed every 3 to 5 days (Stevens and Leblond, 1947). Intestinal stem cells (ISCs) differentiate into functional intestinal cells, such as Paneth, goblet, enteroendocrine, enterocytes, and tuff cells, and enterocytes (Cheng and Leblond, 1974, Gerbe et al., 2011, Li and Clevers, 2010). ISCs express leucine-rich repeat-containing G-protein-coupled receptor 5 (Lgr5) on their surfaces, which is located between Paneth cells that secrete anti-microbial peptides such as lysozyme and defensins (Barker et al., 2007, Sato et al., 2009). A previous study demonstrated that Paneth cells regulate the maintenance and differentiation of Lgr5+ ISCs (Sato et al., 2011). Among the earliest studies, Wnt signaling was found to play an indispensable role for stem cell niches and for supporting stem cell self-renewal within the wide spectrum of Wnt effects on various target cells (Farin et al., 2012, Kabiri et al., 2014, Pinto et al., 2003). Another study showed mutations in TCF4, the ultimate outcome of the Wnt pathway, resulting in loss of ISCs and subsequent breakdown of the intestine (Korinek et al., 1998). Conversely, stimulation of Wnt signaling by the addition of β-catenin, another outcome of the Wnt pathway, could lead to expansion of stem cells in both hematopoietic and hair follicle systems (Gat et al., 1998). Treatment with isolated Wnt3a protein on the hematopoietic stem cells enhances the self-renewal function (Willert et al., 2003). A more recent study revealed that Wnt/β-catenin signaling supports gut homeostasis by maintaining self-renewal of Lgr5+ stem cells in the crypt (Clevers and Nusse, 2012). Secreted Wnt proteins bind to LRP5/6 and Frizzled co-receptors present on epithelial crypt cells, leading to an increase in β-catenin protein (de Lau et al., 2011). Gut microbiota affects nutrient acquisition and energy regulation of the host. The microbiota produces short-chain fatty acid (SCFA; i.e., acetate, butyrate, and propionate) and lactate, which are important energy sources for the host (Muegge et al., 2011, Turnbaugh et al., 2006). The G-protein-coupled receptor (Gpr) is indispensable for activating signaling molecules for many aspects of immunologic and metabolic functions. Several studies have sought a cross-relationship between commensal bacteria-derived metabolites and the Gprs. Of these receptors, Gpr41 and -43 are specific for SCFA (Brown et al., 2003). SCFA-Gpr43 interactions profoundly influence the inflammatory responses, which showed exacerbated inflammation in various disease models, such as colitis, arthritis, and asthma, in Gpr43−/− mice (Maslowski et al., 2009). Activation of SCFA-Gpr43 interactions suppresses insulin signaling in adipocytes, which inhibits fat accumulation in adipose tissue and promotes the metabolism of glucose in other tissues (Kimura et al., 2013). In addition, Gpr120, a receptor for the ω-3 fatty acids, exerts potent anti-inflammatory effects on macrophages in vitro and on obese mice in vivo (Oh et al., 2014). Previous studies found that Gpr81 is a specific receptor for lactate (Cai et al., 2008, Ge et al., 2008, Liu et al., 2009); however, the relationship between the lactate derived from symbionts and Gpr81 signaling associated with cellular functions in the gut is not known.