Regulation of antimicrobial peptide gene expression by nutrients and by-products of microbial metabolism

Abstract

Background: Antimicrobial peptides (AMPs) are synthesized and secreted by immune and epithelial cells that are constantly exposed to environmental microbes. AMPs are essential for barrier defense, and deficiencies lead to increased susceptibility to infection. In addition to their ability to disrupt the integrity of bacterial, viral and fungal membranes, AMPs bind lipopolysaccharides, act as chemoattractants for immune cells and bind to cellular receptors and modulate the expression of cytokines and chemokines. These additional biological activities may explain the role of AMPs in inflammatory diseases and cancer. Modulating the endogenous expression of AMPs offers potential therapeutic treatments for infection and disease.

Methods: The present review examines the published data from both in vitro and in vivo studies reporting the effects of nutrients and by-products of microbial metabolism on the expression of antimicrobial peptide genes in order to highlight an emerging appreciation for the role of dietary compounds in modulating the innate immune response.

Results: Vitamins A and D, dietary histone deacetylases and by-products of intestinal microbial metabolism (butyrate and secondary bile acids) have been found to regulate the expression of AMPs in humans. Vitamin D deficiency correlates with increased susceptibility to infection, and supplementation studies indicate an improvement in defense against infection. Animal and human clinical studies with butyrate indicate that increasing expression of AMPs in the colon protects against infection.

Conclusion: These findings suggest that diet and/or consumption of nutritional supplements may be used to improve and/or modulate immune function. In addition, by-products of gut microbe metabolism could be important for communicating with intestinal epithelial and immune cells, thus affecting the expression of AMPs. This interaction may help establish a mucosal barrier to prevent invasion of the intestinal epithelium by either mutualistic or pathogenic microorganisms.

Fig. 1

Regulation of AMP gene expression through the VDR or FXR pathways. a Vitamin D-pathway-dependent TLR activation of CAMP gene expression. TLR-signaling activates NF-κB binding and induces VDR and CYP27B1 expression, the enzyme that catalyzes the conversion of 25(OH)D to 1,25(OH)₂D. The expression of the vitamin D receptor (VDR) is increased. In the presence of locally high levels of 1,25(OH)₂D, ligand-bound VDR:RXR heterodimers translocate into the nucleus and bind to the VDRE in the promoter of the human CAMP gene inducing its expression. b Vitamin D-mediated regulation of the human DEFB4 gene. (1) Direct induction: TLR stimulation activates the vitamin D pathway as described in a. Also it up-regulates the expression of IL-1β and IL-1R1 and down-regulates the expression of IL-1R antagonist (IL-1RA). IL-1R1 activates the NF-κB transcription factor that binds to the promoter proximal NF-κB binding site in the DEFB4 gene and induces HBD-2 expression together with the VDR:RXR heterodimer that binds to the VDRE in the promoter of DEFB4 gene. Indirect induction: In the presence of 1,25(OH)₂D₃, the VDR:RXR heterodimer binds to the VDRE in the NOD2 gene promoter and induces the expression of the NOD2 protein. Activation of NOD2 by its agonist muramyl dipeptide stimulates the NF-κB transcription factor that binds to the promoter proximal NF-κB binding site in the DEFB4 gene to induce its expression. c Regulation of human CAMP gene expression by vitamin D and bile salts in biliary cells. (1) 1,25(OH)₂D₃ activates the VDR:RXR heterodimer that then binds to the VDRE in the CAMP gene promoter; (2) UDCA activates the ERK1/2 signaling pathway that, in turn, induces VDR protein expression and induction of CAMP gene expression in the presence of 1,25(OH)₂D₃; and (3) CDCA binds to the FXR:RXR heterodimer that binds to the VDRE in the CAMP gene promoter