Abstract
Interactions between mucosal tissues and commensal microbes control appropriate host immune responses and inflammation, but very little is known about these interactions. Here we show that the depletion of resident bacteria using antibiotics (Abx) causes oral and gut immunopathology during oropharyngeal candidiasis (OPC) infection. Antibiotic treatment causes reduction in the frequency of Foxp3+ regulatory cells (Tregs) and IL-17A producers, with a concomitant increase in oral tissue pathology. While C. albicans (CA) is usually controlled in the oral cavity, antibiotic treatment led to CA dependent oral and gut inflammation. A combination of short chain fatty acids (SCFA) controlled the pathology in Abx treated mice, correlating to an increase in the frequency of Foxp3+, IL-17A+, and Foxp3+IL-17A+ double positive (Treg17) cells in tongue and oral draining lymph nodes. However, SCFA treatment did not fully reverse the gut inflammation suggesting that resident microbiota have SCFA independent homeostatic mechanisms in gut mucosa. We also found that SCFA potently induce Foxp3 and IL-17A expression in CD4+ T cells, depending on the cytokine milieu in vitro. Depletion of Tregs alone in FDTR mice recapitulated oral inflammation in CA infected mice, showing that Abx mediated reduction of Tregs was involved in infection induced pathology. SCFA did not control inflammation in Treg depleted mice in CA infected FDTR mice, showing that Foxp3+ T cell induction was required for the protective effect mediated by SCFA. Taken together, our data reveal that SCFA derived from resident bacteria play a critical role in controlling immunopathology by regulating T cell cytokines during mucosal infections. This study has broader implications on protective effects of resident microbiota in regulating pathological infections.
Highlights
Dysbiosis of resident microbes is unequivocally associated with immune-related disorders and opportunistic and pathogenic infections (Gallo and Nakatsuji, 2011; Abt et al, 2012; Flint et al, 2012; Hill et al, 2012; Abt and Artis, 2013; Hill and Artis, 2013; Kamada et al, 2013a,b; Spasova and Surh, 2014)
When cells stimulated under iTreg conditions were examined, we found that short chain fatty acids (SCFA), especially butyrate induces Foxp3 expression, only moderately (Figure 4C, lower panel, X-axis)
As in whole lymphoid organ cell suspension cultures, we found that SCFA significantly heightened both the frequency and geometric MFI of IL-17A expression in CD4+ cells under Th17 polarization conditions (Figures 4E,F, upper panels, Supplementary Figure S5)
Summary
Dysbiosis of resident microbes is unequivocally associated with immune-related disorders and opportunistic and pathogenic infections (Gallo and Nakatsuji, 2011; Abt et al, 2012; Flint et al, 2012; Hill et al, 2012; Abt and Artis, 2013; Hill and Artis, 2013; Kamada et al, 2013a,b; Spasova and Surh, 2014). Resident microbiota derived short chain fatty acids (SCFA) are shown to induce Foxp expression in CD4+ T cells, and promote function of Foxp3+Tregs and IL-10 producing Tregs in intestinal lamina propria (Round et al, 2011; Arpaia et al, 2013; Atarashi et al, 2013; Smith et al, 2013). Anti-inflammatory effects of SCFAs are known to be partly by inhibition of histone deacetylase (HDAC) activity (Vinolo et al, 2011) Supporting this mechanism, even chemical HDAC inhibitors promote Treg functions, and have beneficial effects on allograft survival and autoimmune diseases (Beier et al, 2011; Edwards and Pender, 2011; Arpaia et al, 2013)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
