Date of Award
Joan C. Edwards School of Medicine
Type of Degree
Dr. Alip Borthakur, Committee Chairperson
Dr. Richard Egleton, Committee Member
Inflammatory bowel disease (IBD) is a medical condition characterized by chronic inflammation of the intestinal epithelium. Krüppel-like factor 4 (KLF4), a zinc finger transcription factor, is vital for maintaining intestinal epithelial homeostasis. KLF4 promotes differentiation of goblet cells that generate the protective mucus layer. Reduced goblet cell number and defective mucus layer are associated with IBD. Shortchain fatty acids (SCFA) are known to play an important role in the maintenance of a strong and healthy intestinal epithelial layer and also in goblet cell differentiation. However, whether the positive effects of SCFAs on goblet cells are mediated, at least partly, via upregulation of KLF4 is not known. Current studies were designed to investigate if KLF4 expression is altered in inflammation and the role of SCFA in modulating KLF4 expression. We utilized quantitative reverse transcriptase PCR and Western blot, respectively, to measure the mRNA and protein levels of KLF4. Our results showed a significant reduction in KLF4 expression in human intestinal Caco2 cells exposed to cytokines (TNF- α/IFN-γ 10 ng/ml, 24 h) and in a mouse model of dextran sulfate sodium (DSS)-induced colitis (3% DSS 7 days). Of the 3 key SCFAs (acetate, propionate, butyrate), incubation with propionate (2 mM 24 h) maximally upregulated KLF4 mRNA and protein expression in Caco2 and colonic goblet cell-like LS-174T cells. Also, propionate-induced KLF4 expression was abrogated in the presence of the PPAR-g antagonist GW9662, while the PPAR-g agonist pioglitazone mimicked and synergized the effects of propionate on KLF4 expression, suggesting the role of PPAR-g in mediating propionate effects on KLF4. Propionate enhancement of KLF4 could be of importance in correcting goblet cell hypoplasia in IBD.
Inflammatory bowel disease -- Research.
Cells -- Research.
Forslund, Ylva, "Potential counter regulatory effects of a gut microbiota metabolite in alleviating down-regulation Krüppel-like factor 4 in intestinal inflammation" (2021). Theses, Dissertations and Capstones. 1402.