α-Defensin 5 gene expression is regulated by gut microbial metabolites

Abstract

α-Defensin 5 is important to both maintenance of a gut microbiota and host immunity. While previous reports have shown that gut bacteria are able to upregulate α-defensin 5 through Toll-like receptor signaling, we demonstrate here that α-defensin 5 expression can also be regulated by microbial metabolites. Among these, lactate appeared to significantly suppress α-defensin 5 gene transcription. Actually, fractions of <3 kD compounds obtained from the ceca of SPF mice were suppressed α-defensin 5 gene transcription at specific concentrations. Our results also suggest that cecal content may include as yet unidentified factors that can enhance α-defensin 5 expression. Our data point to a novel function for the gut microbial metabolites in controlling the expression of antimicrobial peptides in the intestine.

Human Defensin-5 Blocks Ethanol and Colitis-Induced Dysbiosis, Tight Junction Disruption and Inflammation in Mouse Intestine

“…However, in the small intestine they are released into the intestinal lumen, which are likely to be delivered into the colonic lumen. Expression of α-defensins are known to be down regulated in Crohn’s disease 5 and by intestinal microbial metabolites such as lactate 18 . In the present study, our data show for the first time, that chronic EtOH feeding down regulates the expression of Defa4 , Defa5 and Defa6 genes in mouse ileum.…”

Does an Apple a Day Also Keep the Microbes Away? The Interplay Between Diet, Microbiota, and Host Defense Peptides at the Intestinal Mucosal Barrier

“…Furthermore, by using a human-derived reporter cancer cell line, Sugi et al investigated the transcription of Defa5 after challenge with the bacterial ligands LPS, the synthetic lipopeptide P3CSK4 or with the bacterial metabolites acetate, lactate, butyrate, and propionate. Among these molecules, lactate strongly suppressed the transcription of Defa5 while propionate and butyrate were suppressive only at a high concentration (9 mM) (198). However, this intestinal cell line represents absorptive epithelial cells, and their defensin expression capacities are lower when compared to Paneth cells.…”

“…Accordingly, using mousederived small intestinal organoids, Farin et al showed that Paneth cell degranulation did not occur after stimulation with bacterial agents, but rather after direct induction with IFN-γ or a supernatant derived from stimulated iNKT cull culture (138). Similarly, the SCFA butyrate was shown to directly enhance the production of Defa1 in isolated crypts from the small intestine (165), but it is unclear whether Paneth cells could be stimulated by this fermentation product in the small intestine in vivo, where the concentration of butyrate is relatively low (165,198). Furthermore, by using a human-derived reporter cancer cell line, Sugi et al investigated the transcription of Defa5 after challenge with the bacterial ligands LPS, the synthetic lipopeptide P3CSK4 or with the bacterial metabolites acetate, lactate, butyrate, and propionate.…”

“…However, this intestinal cell line represents absorptive epithelial cells, and their defensin expression capacities are lower when compared to Paneth cells. Nevertheless, lactate was found in high concentrations in the small intestine, suggesting it could suppress the transcription of Defa5 in vivo and thereby prevent the release of pyrogenic molecules and the probable aberrant activation of inflammation (198). In addition to SCFA-mediated HDP regulation, microbialderived tryptophan catabolites (e.g., indole or indole-3-aldehyde) can bind the aryl hydrocarbon receptor (AhR) and activate IL-22 secretion (199).…”

Guardians of the Gut: Enteric Defensins

“…Novel discoveries have been made with regard to the structure, functional diversity, and effect on host microbiota of these peptides (Sugi et al, 2017; Zhang, 2017). Many of these discoveries point to a much greater role for defensins in host health and immunity than previously thought.…”