Impacts of microbial derived short chain fatty acids in regulating immune activation at the female reproductive tract via epigenetic mechanisms Abu Bakar Siddik1, Chih-Yu Chen2, Chris Grant2, Garrett Westmacott2, T. Blake Ball1,2, Ruey-Chyi Su1,2,* 1University of Manitoba, Medical Microbiology & Infectious Diseases; 2National HIV and Retrovirology Laboratory, JC Wilt Infectious Diseases Research Centre, Winnipeg, Manitoba, Canada *Corresponding author.
Epithelia are physical barriers, as well as key regulators of mucosal immunity. Soluble mucosal factors such as short chain fatty acids (SCFAs) in the vaginal fluids (VF) can alter the epigenetic regulation of immunologic genes via inhibition of cellular histone deacetylase (HDAC) activities. The role of HDAC is to deacetylase histone which consequently wrapped the DNA tightly with the histone core. So the inhibition of HDAC cause keeping DNA in open conformation which eventually become favourable for gene expression. This study explores the impact of SCFAs in regulating the transcription of immunologic genes in epithelial cells derived from the female reproductive tract (FRT). To define the effects of sodium butyrate (NaB), one of the vaginal SCFAs, on the expression of anti- and pro-inflammatory mediators, and to identify cellular proteins that are specifically affected by exposure to NaB. The vaginal epithelial cell line 'Vk2' was pre-treated with NaB at non-toxic concentrations prior to stimulation with Toll-like-receptor (TLR) agonists. Cellular RNA was quantitated with RT-qPCR, and cellular proteins were analyzed for post-translational modifications (i.e. acetylation, methylation, and phosphorylation) using proteomic profiling. NaB (5mM) significantly enhanced transcription of the pro-inflammatory cytokines IL-6 and TNFα, and only TNFα transcript levels rose in response to TLR-1, -2, -3, -5, and -6 stimulation. A change in the profile of phosphorylated proteins was also observed following NaB-treatment in the absence of TLR stimulation. Proteins that lost phosphorylation in NaB-treated Vk2 cells were implicated in cell-cell adhesion and mRNA splicing. This suggests that changes in cytokine/chemokine expression may be affected at transcription or post-transcription. In addition, NaB may affect epithelial barrier function by altering protein phosphorylation.
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