Vitamin D receptor regulates mucosal immune responses to Clostridium difficile infection

Viladomiu, M., R. Hontecillas, M. Pedragosa, P. Michalak, K. Michalak, P. Lu and J. Bassaganya-Riera (2013) Vitamin D receptor regulates mucosal immune responses to Clostridium difficile infection, American Association of Immunologists Annual Meeting, Honolulu HI

Clostridium difficile is an anaerobic bacterium that has re-emerged as a facultative pathogen and can cause diarrhea, colitis or even death. Vitamin D deficiency contributes to a 5-fold increase in healthcare costs during C. difficile infection (CDI). We investigated the role of vitamin D signaling during CDI by using vitamin D receptor (VDR) -/- and wild-type (WT) mice. The loss of VDR increased disease activity, weight loss, and the severity of colonic inflammatory lesions following CDI. RNAseq analyses showed upregulation of sentrin/SUMO-specific proteases (SENPs), downregulation of phosphatidylinositol 3-kinase regulatory subunit and cAMP-specific 3’5’-cyclic phophodiesterase in colons of VDR-/- mice. SENPs mediate deSUMOylation reactions that can affect both the transcriptional activity of nuclear receptors such as VDR and peroxisome proliferator-activated receptor (PPAR) γ as well as their ability to antagonize NF-kB activity. These results provide a mechanistic basis for the upregulation of IFNγ, IL-6, IL-17 and IL-1β in colons of VDR-/- mice infected with C. difficile. In addition, miR-760-5p was donw-regulated in VDR-/- mice and upregulated in WT mice after CDI. Of note, miR-760 has 128 mRNA targets, including lanthionine synthetase component C-like 2 (LANCL2), which is upstream of PPARγ. We provide novel molecular evidence in vivo suggesting novel mechanisms involving LANCL2 and PPARγ by which vitamin D regulates C. difficile-associated disease and immunopathology.