Antimicrobial peptide D3

Inflammatory bowel disease (IBD) is a chronic inflammation of the gastrointestinal tract (GIT), including Crohn's disease (CD) and ulcerative colitis (UC), which differ in the location and lesion extensions. Both diseases are associated with microbiota dysbiosis, with a reduced population of butyrate-producing species, abnormal inflammatory response, and micronutrient deficiency (e.g., vitamin D hypovitaminosis). Vitamin D (VitD) is involved in immune cell differentiation, gut microbiota modulation, gene transcription, and barrier integrity. Vitamin D receptor (VDR) regulates the biological actions of the active VitD (1α,25-dihydroxyvitamin D3), and is involved in the genetic, environmental, immune, and microbial aspects of IBD. VitD deficiency is correlated with disease activity and its administration targeting a concentration of 30 ng/mL may have the potential to reduce disease activity. Moreover, VDR regulates functions of T cells and Paneth cells and modulates release of antimicrobial peptides in gut microbiota-host interactions. Meanwhile, beneficial microbial metabolites, e.g., butyrate, upregulate the VDR signaling. In this review, we summarize the clinical progress and mechanism studies on VitD/VDR related to gut microbiota modulation in IBD. We also discuss epigenetics in IBD and the probiotic regulation of VDR. Furthermore, we discuss the existing challenges and future directions. There is a lack of well-designed clinical trials exploring the appropriate dose and the influence of gender, age, ethnicity, genetics, microbiome, and metabolic disorders in IBD subtypes. To move forward, we need well-designed therapeutic studies to examine whether enhanced vitamin D will restore functions of VDR and microbiome in inhibiting chronic inflammation.

Introduction: Most children with serious infection diseases suffer from malnutrition. Vitamin D participates in the immune response through endogenous antimicrobial peptides (AMPs) regulation. The aim of this study is to investigate the expression of 25-hydroxyvitamin D3 [25(OH)D3], AMPs [LL-37 and human β-defensin 2 (HBD-2)] in the children with pertussis. Methodology: Serum levels of 25(OH)D3, LL-37, and HBD-2 were detected in 116 children with pertussis aged at 1-12 months (67 males and 49 females). Fifty healthy infants at similar age were employed as normal controls. Results: The serum 25(OH)D3 levels in the children with mild (27.30 ± 5.98 ng/ml) and severe (24.40 ± 6.27 ng/ml) pertussis were significantly lower than that in the healthy group (30.16 ± 5.13 ng/ml; p <0.01). The vitamin D deficiency rates in children with mild (55.9%) and severe (78.12%) pertussis were significantly higher than that in the control group (34%; p < 0.01). The serum levels of LL-37 and HBD-2 were significantly higher in pertussis patients. Spearman rank correlation analysis did not show any correlation of 25-(OH)D3 with LL-37 or HBD-2. Conclusions: Most children with pertussis had vitamin D deficiency accompanied by elevated serum LL-37 and HBD-2 levels. However, the average level of 25(OH)D3 at 26.50 ng/ml in the infants with pertussis may not affect the immuno-regulatory ability; thus, the infants with pertussis still maintained a higher level of AMPs (LL-37 and HBD-2) against pertussis infection.

Helicobacter pylori (H. pylori) is a common human pathogenic bacterium. Once infected, it is difficult for the host to clear this organism using the innate immune system. Increased antibiotic resistance further makes it challenging for effective eradication. However, the mechanisms of immune evasion still remain obscure, and novel strategies should be developed to efficiently eliminate H. pylori infection in stomachs. Here we uncovered desirable anti-H. pylori effect of vitamin D3 both in vitro and in vivo, even against antibiotic-resistant strains. We showed that H. pylori can invade into the gastric epithelium where they became sequestered and survived in autophagosomes with impaired lysosomal acidification. Vitamin D3 treatment caused a restored lysosomal degradation function by activating the PDIA3 receptor, thereby promoting the nuclear translocation of PDIA3-STAT3 protein complex and the subsequent upregulation of MCOLN3 channels, resulting in an enhanced Ca2+ release from lysosomes and normalized lysosomal acidification. The recovered lysosomal degradation function drives H. pylori to be eliminated through the autolysosomal pathway. These findings provide a novel pathogenic mechanism on how H. pylori can survive in the gastric epithelium, and a unique pathway for vitamin D3 to reactivate the autolysosomal degradation function, which is critical for the antibacterial action of vitamin D3 both in cells and in animals, and perhaps further in humans.