Short-chain fatty acids (SCFAs) are products from the intestinal microbiota mainly produced by the fermentation of dietary fibers. SCFAs are found at high concentrations in the colon in where they play a fundamental energetic role in the epithelial cells, show important immunomodulatory effects, as well as they help to maintain the intestinal homeostasis through the regulation of the proliferation/apoptosis of intestinal epithelial cells (IECs) and the production of host defense peptides, both effects that seem to be involved with the stabilization of the ± subunit of the hypoxia-inducible factor 1 (HIF-1). Recent studies have related the energetic role of SCFAs with the increased (indirect) activation of HIF-1± in the IECs, even though they did not consider their other mechanisms of action. With that, the goal of this project is to investigate the participation and the importance of HIF-1 in the effects of the SCFAs produced under physiological conditions (diets with different amounts of fiber) in the IECs, as well as to elucidate the possible mechanism of direct interaction between the SCFAs and HIF-1. For that, we will use in vivo models (tissue-specific knockout animals for HIF-1 and/or Vhl) and in vitro models (intestinal organoids), in which we will perform molecular analysis including Western blotting, immunofluorescence, RT-PCR, metagenomics of 16S RNA, mass spectrometry, RNA sequencing, immunoprecipitation of chromatin with sequencing (ChIP-Seq), analysis of HDAC inhibitors and immunohistological analysis of the intestine after a model of inducible colitis by C. difficile.
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