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Gut Bacterial Metabolite Propionate Upregulates Intestinal Epithelial Kruppel‐like Factor 4 Expression via a PPAR‐γ ‐dependent Mechanism
Author(s) -
Priyamvada Shubha,
Anbazhagan Arivarasu,
Chatterjee Ishita,
Alrefai Waddah,
Dudeja Pradeep,
Borthakur Alip
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.854.4
Subject(s) - klf4 , goblet cell , butyrate , intestinal mucosa , propionate , mucin 2 , chemistry , microbiology and biotechnology , endocrinology , medicine , biology , transcription factor , biochemistry , epithelium , gene expression , gene , sox2 , genetics , fermentation
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 and KLF4 null mice showed decreased goblet cells. Reduced goblet cell number and defective mucus layer are associated with inflammatory bowel diseases (IBD). However, whether KLF4 expression is altered in inflammation is not known. Further, gut bacterial metabolite short chain fatty acids (SCFA) have been shown to modulate goblet cell differentiation and mucus synthesis, but their impact on KLF4 expression is not studied in detail. Our current studies showed significant reduction (~50‐80%) of KLF4 expression in human intestinal Caco2 cells exposed to cytokines (IFN‐γ 30 ng/ml, 24 h) and in mouse model of 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 as well as in mouse ileal organoids. The PPAR‐γ antagonist GW9662 abrogated propionate effects on KLF4 expression, whereas PPAR‐γ agonist pioglitazone showed synergistic effects. The histone deacytylase (HDAC) inhibitor tricostatin A (TSA) alone or in combination with propionate showed no effects on KLF4 expression. Our data showed propionate enhancement of gut epithelial KLF4 expression via a PPAR‐γ‐dependent mechanism, independent of its HDAC‐inhibitory activity. Propionate enhancement of KLF4 could be of importance in correcting goblet cell hypoplasia in IBD. (Gates Foundation/NIDDK/VA)