The Novel Roles of Dusp6 in Gut Barrier Modulation and Microbiome Shaping in a Mouse Colitis Model

Abstract

Abstract Gut microbiota dysbiosis and barrier integrity are important contributors to overall health and many diseases. Our study demonstrated that dual-specificity phosphatase 6 (Dusp6)-depletion is a novel modulator that enhances baseline gut barrier integrity. We found that Dusp6-knockout mice were more resistant to dextran sulfate sodium (DSS)-induced colitis and had enhanced intrinsic colonic tight-junctions and elongated microvilli before exposure to DSS. Our FMT in germ-free mice and co-housing experiments found that the Dusp6-knockout-derived gut microbiota contribute substantially to colitis resistance in mice. Further gut microbiome analysis showed that Dusp6-knockout mice harbored fewer pathobiont facultative anaerobes and more obligate anaerobes than wild-type mice after DSS treatment. Through multi-omics analysis, we found that epithelial barrier integrity and hypoxic and oxygen homeostasis regulation related pathways were more enriched in DUSP6-depleted Caco-2 cells and with a cultivation-based approach, we reported 11 new mouse gut microbiome members. Finally using microbe-phenotype triangulation and mono-colonization of germ-free mice, we found that the newly discovered Duncaniella species contributed to the colitis protection. In sum, identifying functioning gut microbiota members that shape host physiology and disease susceptibility will be vital to the advance of microbiota-based therapeutics. This work was supported by the following grants: IM-108-PP-04 from NHRI and 106-2628-B-400-001-MY3, 106-2923-B-400-001-MY3, 108-2321-B-400-011-, 109-2327-B-400-001-, 109-2320-B-400-008-MY3, 110-2327-B-400-005- from MOST.