W223 - Short-chain Fatty Acids Foster Bile Acid-metabolizing Microbiome Which Ameliorate Allergic Inflammation of the Airways via fxr/tgr5 Signaling

Chiao-Juno Chiu – PostDoc, Department of Medical Research and Graduate Institute of Clinical Medicine, School of Medicine, National Taiwan University, Taiwan; Min-Ting Huang – Msc, Department of Medical Research and Graduate Institute of Clinical Medicine, School of Medicine, National Taiwan University, Taiwan; Hsiao-Li Chuang – Researcher, National Laboratory Animal Center, Taiwan; Yen-Te Huang – Researcher, National Laboratory Animal Center, Taiwan

Abstract Text: We previously found that short-chain fatty acids (SCFAs) significantly reduced asthma severity through sequential induction of the immune-regulatory cells, Mac1+Ly6G+Ly6Clo granulocytic myeloid-derived suppressor cells (PMN-MDSCs) and Tregs.
Additionally, mice supplemented with SCFAs harbored increased Clostridiales and decreased Bacteroidales. The altered gut microbiome was associated with a distinct bile acid metabolomic profile which can be attributed to the unique function of a SCFA-enriched microbial taxon, Clostridium scindens. C. scindens is unique for its expression of the 7 alpha-dehydroxylase, an indispensable enzyme biotransforming unconjugated primary to secondary bile acids. We found pharmacological activation of either of the FxR or TGR5 bile acid receptor induced signals that expanded PMN-MDSCs and Tregs and mitigated the severity of allergic airway diseases.
We hypothesize that C. scindens protects against allergic inflammation of the airways through FXR and TGR5 signaling and forms a feed-forward loop in SCFA-elicited immune regulation. To investigate the effect of C. scindens in prevention and treatment of allergic airway disease, we generated the GN12 mice, the BALB/c counterparts of the sDMDMm2 mice harboring OligoMM12, a consortium of 12 representative gut microbial species which specifically lacks 7α-dehydroxylase activity. We found GN12 mice colonized with C. scindens (GN12-CS) had more PMN-MDSCs and Tregs and developed significantly less severe allergic disease than GN12 mice.
The present study provides a proof of principle that distinct microbes (C. scindens) exploit their metabolites (bile acids) to form a feed-forward loop within the mucosal microenvironment that shapes host’s response towards mucosal allergen sensitization and modulates inflammatory processes of the airways.