Metabolomics in endotoxemia and oral infections

Chronic oral infectious diseases, such as periodontitis and periapical lesions, as well as tooth loss, have been linked to systemic inflammation, cardiovascular diseases, diabetes, and all-cause mortality. Gram-negative bacterial lipopolysaccharide (LPS), a major virulence factor primarily originating from gut microbiota but also from oral pathogens, contributes to elevated plasma LPS levels, a condition known as endotoxemia. LPS activates the immune system, triggering the secretion of proinflammatory cytokines and exacerbating the pathogenesis of several cardiometabolic diseases. Metabolomics, the comprehensive study of small molecules in biological systems, has identified various metabolites influenced by inflammation and implicated in cardiometabolic diseases. This thesis aimed to investigate the systemic manifestations of local inflammation in the oral cavity by analyzing associations of common oral diseases, missing teeth, and endotoxemia with circulating metabolites. According to our hypothesis, oral inflammation adversely affects the systemic metabolome and thereby increases the risk for cardiometabolic diseases. The study employed four Finnish study populations: FINRISK-97 (n=6,159), Health-2000 (n=6,197), FinnTwin16 (n=554), and Parogene (n=465). A total of 157 serum metabolite measures were quantified using nuclear magnetic resonance (NMR) spectroscopy in all cohorts. Circulating endotoxin levels were determined in FINRISK-97, Parogene, and FinnTwin16. Clinical and radiographic oral examinations were performed in Parogene and Health-2000, while tooth count was recorded in FINRISK-97. In Health-2000, 3,371 subjects gave blood samples 11 years after baseline, and 1,186 of them underwent repeated oral examinations. Associations between metabolites, endotoxemia, and oral health parameters were analyzed using linear regression, with meta-analyses combining results across the cohorts. Additionally, we examined the relationship between baseline oral health, 11-year tooth loss, and metabolic changes over the follow-up period. Endotoxemia was associated with 149 metabolites, including increased very- low-density (VLDL) and low-density lipoproteins (LDL), and small triglyceride-rich high-density lipoprotein (HDL) particles. We also observed associations with decreased degree of fatty acid unsaturation and reduced proportions of polyunsaturated omega-3 and omega-6 fatty acids. Additionally, a strong positive association emerged between endotoxemia and GlycA, an inflammatory biomarker. Among periodontitis markers, deepened periodontal pockets, the combination of periodontal pockets and bleeding on probing (BOP), and periodontal inflammatory burden index were linked to 93, 88, and 77 metabolites, respectively. Root canal fillings (RCFs) were associated with 47 metabolites, inadequate RCFs with 27, and caries with 8. Additionally, baseline caries and BOP predicted changes in 30 and 8 metabolites, respectively, over the follow-up period. The number of teeth was associated with 60 metabolites and predicted changes in 43, whereas no associations were observed between tooth loss during the 11-year follow-up and metabolites. Similar to endotoxemia, oral health parameters were linked to metabolic signatures featuring increased VLDL and LDL levels, smaller HDL particle size, and a fatty acid profile enriched in saturated and monounsaturated fatty acids. The metabolites associated with endotoxemia included multiple features linked to inflammation and exacerbated cardiometabolic disease risk. Among chronic oral conditions, particularly periodontitis and missing teeth were associated with similar features. These findings suggest that poor oral health may perpetuate chronic systemic inflammation, underscoring its potential public health implications given the widespread prevalence of oral diseases.

Grantor dc:publisher

Helsingin yliopisto

Year dc:date.issued

2025

Author dc:creator

• Halme, Anne-Mari

• hammaslääketiede

Statement dc:rights

• This publication is copyrighted. You may download, display and print it for Your own personal use. Commercial use is prohibited.
• Julkaisu on tekijänoikeussäännösten alainen. Teosta voi lukea ja tulostaa henkilökohtaista käyttöä varten. Käyttö kaupallisiin tarkoituksiin on kielletty.
• Publikationen är skyddad av upphovsrätten. Den får läsas och skrivas ut för personligt bruk. Användning i kommersiellt syfte är förbjuden.

Language dc:language.iso

eng

Handle dc:identifier.uri

http://hdl.handle.net/10138/593522

OAI record oai:identifier

https://helda.helsinki.fi/server/oai/request?verb=GetRecord&metadataPrefix=dim&identifier=oai%3Ahelda.helsinki.fi%3A10138%2F593522