Dietary Nutrients Mediate Intestinal Host Defense Peptide Expression

Abstract

The intestinal tract is the shared locus of intestinal epithelial cells, immune cells, nutrient digestion and absorption, and microbial survival. The gut in animals faces continuous challenges in communicating with the external environment. Threats from endogenous imbalance and exogenous feeds, especially pathogens, could trigger a disorder of homeostasis, leading to intestinal disease and even systematic disease risk. As a part of the intestinal protective barrier, endogenous host defense peptides (HDPs) play multiple beneficial physiological roles in the gut mucosa. Moreover, enhancing endogenous HDPs is being developed as a new strategy for resisting pathogens and commensal microbes, and to maintain intestinal health and reduce antibiotic use. In recent years, multiple nutrients such as branched-chain amino acids, SCFAs, lactose, zinc, and cholecalciferol (vitamin D3) have been reported to significantly increase HDP expression. Nutritional intervention has received more attention and is viewed as a promising means to defend against pathogenic infections and intestinal inflammation. The present review focuses on current discoveries surrounding HDP expression and nutritional regulation of mechanisms in the gut. Our aim is to provide a comprehensive overview, referable tactics, and novel opinions.

Keywords: antibiotic alternative; gut; host defense peptides; inflammation; nutrients; pathogens.

FIGURE 1

Multiple enterocytes and phagocytes synthesize and secrete HDPs in the intestine. The HDPs in the intestine can attach to and kill bacteria. Simultaneously, HDPs can enhance innate and adaptive immune functions to reduce inflammatory reactions and enhance antimicrobial capacity, can kill cancer cells, and can repair damage to intestinal tissues. HDP, host defense peptide.

FIGURE 2

Multiple amino acids and fatty acids upregulate HDP expression in the gut. The BCAAs enhance HDP expression by the Sirt1–ERK1/2–90RSK and GPCR–MAPK pathways. Arg significantly enhances HDP expression and may be mediated by the NO signal or mTOR pathway. Trp may enhance HDP expression by the mTOR pathway. SCFAs, MCFAs, and LCFAs can all contribute to HDP expression and SCFAs affect the HDP expression conducted by directly influencing histone acetylation and the GPCR–MAPK signal pathway. BCAA, branched-chain amino acid; ERK, extracellular regulated protein kinase; GPCR, G protein-coupled receptor; HAT, histone acetyltransferase; HDAC, histone deacetylase; HDP, host defense peptide; JNK, c-Jun N-terminal kinase; LCFA, long-chain fatty acid; MAPK, mitogen-activated protein kinase; MCFA, medium-chain fatty acid; mTOR, mammalian target of rapamycin; Sirt1, sirtuin-1; 90RSK, 90-kDa ribosomal S6 kinase.

FIGURE 3

Multiple trace elements and vitamins enhance HDP expression in intestinal mucosa. Zinc contributes to HDP expression by the ERK1/2 and p38 MAPK pathways. Lactoferrin can increase intestinal HDP expression, but the study about its mechanism of action is limited. Cholecalciferol (vitamin D₃) and its metabolite 1,25-dihydroxycholecalciferol [1,25(OH)₂-D₃] and vitamin B-3 increase histone acetylation levels to enhance transcription of HDP genes. Vitamin D₃ and 1,25(OH)₂-D₃ regulate increased histone acetylation level via the VDR. Vitamin A can contribute to HDP expression by activating the retinoic acid response element. Niacin can restrain the activity of class III HDACs and increase C/EBPε to enhance antibacterial capacity. GPCR109A also mediates the regulation of niacin. C/EBPε, CCAAT/enhancer binding protein ε; ERK, extracellular regulated protein kinase; GPCR109A, G protein-coupled receptor 109A; HAT, histone acetyltransferase; HDAC, histone deacetylase; HDP, host defense peptide; p38 MAPK, p38 mitogen-activated protein kinase; VDR, vitamin D receptor.