Biomarkers common for inflammatory periodontal disease and depression: A systematic review

Abstract

Background: Dysregulated immune response arising in the periphery can induce depressive symptoms through neuroimmune interactions. Inflammatory oral pathology can be a potent inducer of chronic neuroimmune response relevant to depression. We aimed to synthesize available evidence for the association between inflammatory periodontal diseases (IPD) and major depression (MD) in relation to a broad range of biomarkers.

Methods: Medline, Embase, PsycInfo, Cochrane Library, Web of Science and Scopus databases were searched from inception until January 27, 2022. Search terms included subject headings and synonyms for inflammatory periodontal disease and depression. Studies that reported data on both depression and inflammatory periodontal disease as categories along with measurement of a biomarker were considered. Two reviewers independently selected the articles for inclusion, extracted data and assessed the quality of each study. The protocol for this study was registered with PROSPERO, CRD42021215524.

Results: Twenty-eight studies were included in the final review-eleven cross-sectional studies, seven case-control studies, and six prospective cohort studies conducted in humans; the remaining four were experimental animal studies. Eighteen studies including all animal studies reported a positive association between depression and periodontal disease; one study reported a negative association and another nine studies found no such associations. Twenty studies reported mixed associations between IPD and biomarkers (i.e, salivary, serum, urine or gingival crevicular fluid cortisol, C reactive protein, cytokines, etc.). Biomarkers related to depression were gingival crevicular fluid cortisol, interleukin 6 (IL-6), Il-1β, immunoglobulin G against Bacterioides forsythus; root canal lipopolysaccharides; blood IL-6, IL-1β, cortisol, advanced oxidation protein products, nitric oxide metabolites, lipid hydroperoxides and trapping antioxidant parameter; whereas five studies found no associations between depression and a biomarker. Although animal studies showed interaction of immune, inflammatory and neurotrophic biomarkers in the relationship between depression and periodontal disease, human studies showed mixed findings. In most studies, there were risks of bias due to the sample selection and assessment protocol. Study heterogeneity and limited number of comparable studies reporting on shared biomarkers precluded a meta-analysis.

Conclusion: Immune-inflammatory contribution to depression was evident in the context of inflammatory periodontal diseases, but whether biomarkers mediate the associations between IPD and MD needs to be tested through methodologically rigorous studies aiming specifically at this hypothesis.

Keywords: Biomarker; Depression; Neuroimmune; Periodontitis; Systematic review.

Fig. 1

Schematic showing biomarkers as putative connecting links between inflammatory periodontal disease and depression. Comorbidity between depression and inflammatory periodontal diseases can be explained in terms of psychological, social, pharmacological and biological, including genetic factors. The bidirectional associations are potentially mediated by a range of inflammatory biomarkers such as cytokines, chemokines, cytotoxic products of metabolic pathways, stress biomarkers, products of oral/gut microbiome, osteoclastogenic factors and epigenetic regulators. Factors responsible for inciting periodontal and depression pathologies may originate from oral microbes, periostial tissue as well as the central nervous system and systemic circulation. CRP: C-reactive protein, HMGB1: high mobility group box 1, IL: interleukin, TNF-α: tumor necrosis factor alpha, TLR: Toll-like receptor, NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells, Th1 cells: T Helper 1 Cells, Treg: Regulatory T cells, LPS: lipopolysaccharide, ncRNA: non-codingRNA, LBX2-AS1: LBX2 Antisense RNA 1, ANRIL: Antisense Noncoding RNA in the INK4 Locus.

Fig. 2

Preferred Reporting Items for Systematic Reviews and Meta-analysis flow diagram for the current study.