Salivary antimicrobial peptides histatin-5, beta defensins, human neutrophilic peptides, LL-37, and calprotectin in severe dental caries, with a focus on early childhood caries: a systematic review and meta-analysis.

This systematic review and meta-analysis was performed to collect evidence on the association between salivary antimicrobial peptides (AMPs) and severe dental caries, with a focus on Early Childhood caries (ECC). Findings regarding AMPs can assess their potential as biomarkers for disease susceptibility and progression. A comprehensive search of PubMed, Scopus, and ClinicalKey was conducted up to 2025. Studies reporting salivary AMP concentrations in caries-affected and caries-free individuals were included. Risk of bias was assessed using ROBINS-I, and certainty of evidence was evaluated with GRADE. Random-effects meta-analyses were performed to calculate standardized mean differences (SMDs) and correlation coefficients. The AMPs evaluated were histatin-5 (HST-5), human β-defensin-1 (hBD-1), β-defensin-2 (hBD-2), β-defensin-3 (hBD-3), human neutrophil peptides 1-3 (HNP1-3), LL-37, and calprotectin. Using PRISMA guidelines, twelve studies were selected. Histatin-5 (HST-5) was depleted consistently in severe caries (SMD - 20.63; p < 0.01) and severe early childhood caries (ECC) compared to milder disease (SMD - 18.19; p < 0.01). Human β-defensin-1 (SMD - 2.87; p = 0.13) and Human β-defensin-3 (SMD - 0.16; p = 0.47) showed inconsistent and/or insignificant associations. Human β-defensin-2 (hBD-2) was significantly higher in children with ECC versus caries-free controls (SMD 1.65; p = 0.01), with moderate-certainty of evidence. Human neutrophil peptides (HNP1-3) were lower in severe ECC compared to mild disease (SMD - 0.63; p = 0.03), although the certainty was not as much as histatins and hBD-2. LL-37 (SMD - 0.60; p = 0.08) and calprotectin (effect size 0.986; p = 0.812) level associations were of low certainty evidence. Heterogeneity was noticed across most analyses (I² frequently > 80%). Our major findings were that salivary histatin-5 depletion and hBD-2 elevation show consistent associations with caries severity, and may serve as potential biomarkers. For other AMPs assessed, there was insufficient evidence. Robust longitudinal studies of AMPs with standard methodologies are needed to further our knowledge and provide evidence-based recommendations for clinical management.