Microbial-derived metabolites and known functions on intestinal epithelial barrier function. Cell A depicts known response to the short-chain fatty acid butyrate. Once taken through apical membrane transporters, butyrate function as both an HDAC inhibitor and HIF stabilizer to promote expression of tight junction-associated proteins, including synaptopodin (SYNPO) and claudin-1 (CLDN1), resulting in enhanced epithelial barrier function. Cell B shows epithelial responses to the microbial tryptophan derivative indole. Once inside cells, indole(s) associate with the arylhydrocarbon receptor (AHR) to activate transcriptional induction of the interleukin-10 receptor (IL-10R), which upon activation, results in the loss of “leaky” claudin-2 (CLDN2), thereby promoting epithelial barrier function. Cell C represents the most recent observations that various microbial-derived purines (esp. hypoxanthine, Hpx) are recycled via purine salvage to be used as an energy source. Increases in intracellular ATP are associated with enhanced mucus secretion to promote enhanced epithelial barrier function.