Interplay between intestinal macrophages and microbiota
Macrophages form a well-established cell-type of the innate immune system that probe the host or invading microbes using pattern recognition receptors and exhibit efficient phagocytic and bactericidal activity [65]. Studies using germ-free or gnotobiotic mice models reported the potential role of gut microbiota in modulating macrophage phenotypes in the colon. Emerging studies have demonstrated the functional association of macrophages and gut microbiota that might be crucial to further understand and treat several diseases associated with gut dysbiosis-induced leaky gut syndrome. Despite the association of pro-inflammatory M1 and M2 macrophage phenotype in intestinal inflammatory and repair conditions respectively [66], the role of specific bacterial species on modulating macrophage phenotype is less studied. For example, bacteria such as Enterococcus faecalispolarize colonic macrophages toward the proinflammatory M1 phenotype in mice [67]. In addition, few studies have demonstrated an indirect association of dysbiosis with M1 phenotypes. For example, antibiotics induced dysbiosis with reduced Firmicutes and Bacteroidetes and decreased faecal concentrations of short chain fatty acids (SCFAs) have been associated with the accumulation of pro-inflammatory macrophages [68]. In contrast, Clostridium butyricum directly induced IL-10 production by intestinal macrophages in inflamed mucosa and triggered polarisation of the macrophages into the anti-inflammatory phenotype through the TLR-2/MyD88 pathway [69]. In addition,Bacteroides fragilis and Clostridia class, Fusobacterium nucleatum induce M2 polarization [70]. Lactobacillus intestinalis and Lactobacillus johnsonii drive macrophage to M2 phenotype and resolve mercury induced injury and intestinal permeability in vitro [71]. Lactobacillus johnsonii alleviates colitis via promoting M2 macrophages [72]. Mytilus coruscus reduced pro-inflammatory cytokines from macrophages in vitro and increased the abundance of some probiotics like Anaerotruncus, Lactobacillus, Desulfovibrio, Alistipe, Odoribacter, and Enterorhabdus in the colon and improved intestinal barrier integrity in vivo [73]. In another study, microbiota were observed to drive macrophage polarization towards the M2 phenotype and subsequently promote stem cell differentiation [74]. Interestingly, an in vivo study demonstrated the depletion of macrophages alters bacterial gut microbiota by promoting fungal overgrowth [75]. In another study, gut microbiota was shown to drive macrophage-dependent intestinal stem cell self-renewal mechanisms [76]. Moreover, microbial metabolites also have been studied in intestinal epithelial barrier repair via modulating macrophages. For example, butyrate, docosahexaenoic acid and other SCFAs reduce inflammation and help repair the intestinal barrier by driving M2 macrophage polarization [77] [78] [79]. In addition, bacterial components such as LPS and flagellin are reported to modulate and activate M2 macrophages represented by IL-3 and TGF-b signaling [80]. Macrophages infected by F. nucleatum upregulate IDO (Indoleamina 2,3-diossigenasi) on the cell surface, suggesting an additional mechanism whereby F. nucleatum might trigger macrophage-driven immunosuppression [81]. These studies suggest an explicit association of macrophages and gut microbiota and a careful modulation of microbiota composition might trigger a favorable macrophage phenotype to treat different disease conditions. Therefore, identifying the key mechanisms of gut microbiota and their products in regulation of macrophage phenotypes in the intestine needs further investigation for the development of an effective therapeutic approach for treating gut leakage and its associated diseases.