Dysbiosis of Oral Microbiota and Metabolite Profiles Associated with Type 2 Diabetes Mellitus

Abstract

Several previous studies have shown that oral microbial disorders may be closely related to the occurrence and development of type 2 diabetes mellitus (T2DM). However, whether the function of oral microorganisms and their metabolites have changed in patients with T2DM who have not suffered from any oral diseases has not been reported. We performed metagenomic analyses and nontargeted metabolic analysis of saliva and supragingival plaque samples from patients with T2DM who have not suffered any oral diseases and normal controls. We found that periodontal pathogens such as Porphyromonas gingivalis and Prevotella melaninogenica were significantly enriched, while the abundances of dental caries pathogens such as Streptococcus mutans and Streptococcus sobrinus were not significantly different in patients with T2DM compared to those in normal controls. Metabolomic analyses showed that the salivary levels of cadaverine and L-(+)-leucine of patients with T2DM were significantly higher than those of normal controls, while the supragingival plaque levels of N-acetyldopamine and 3,4-dimethylbenzoic acid in patients with T2DM were significantly higher than those in the normal controls. Additionally, we identified the types of oral microorganisms related to the changes in the levels of circulating metabolites, and the oral microorganisms were involved in the dysregulation of harmful metabolites such as cadaverine and n, n-dimethylarginine. Overall, our study first described the changes in the composition of oral microorganisms and their metabolites in patients with T2DM who have not suffered any oral diseases, which will provide a direct basis for finding oral biomarkers for early warning of oral diseases in T2DM. IMPORTANCE The incidence of oral diseases in type 2 diabetic patients might increase, and the severity might also be more serious. At present, the relationship between oral microorganisms and type 2 diabetes mellitus (T2DM) has become a hot topic in systemic health research. However, whether the function of oral microorganisms and their metabolites have changed in patients with T2DM who have not suffered from any oral diseases has not been reported. We found that even if the oral condition of T2DM is healthy, their oral microbes and metabolites have changed, thus increasing the risk of periodontal disease. Our study first described the changes in the composition of oral microorganisms and their metabolites in T2DM who have not suffered any oral diseases and revealed the correlation between oral microorganisms and their metabolites, which will provide a direct basis for finding oral biomarkers for early warning of oral diseases in patients with T2DM.

Keywords: metabolomic; metagenomic; oral diseases; oral microbiome; type 2 diabetes mellitus.

FIG 1

Diversity analysis and taxonomic signatures of saliva and supragingival plaque microorganisms at the species level in the T2DM group and healthy control group. (A) Diversity analysis of saliva samples. (B) Diversity analysis of supragingival plaque samples. (C) ANOSIM of saliva samples. (D) ANOSIM of supragingival plaque samples. (E) LEfSe analysis of saliva samples. (F) LEfSe analysis of supragingival plaque samples. TS refers to the saliva samples of T2DM group. TP refers to the supragingival plaque samples of T2DM group. CS refers to the saliva samples of control group. CP refers to the supragingival plaque samples of control group.

FIG 2

Taxonomic profiles of the microbial communities at the genus level and species level in each sample. (A) T2DM salivary bacteria at the genus level; (B) Control salivary bacteria at the genus level; (C) T2DM supragingival plaque bacteria at the species level; (D) Control supragingival plaque bacteria at the species level. TS refers to the saliva samples of T2DM group. TP refers to the supragingival plaque samples of T2DM group. CS refers to the saliva samples of control group. CP refers to the supragingival plaque samples of control group.

FIG 3

Multivariate analysis of serum metabolites. (A) PCA of saliva (POS); (B) PCA of saliva (NEG); (C) PCA of supragingival plaque (POS); (D) PCA of supragingival plaque (NEG); (E) OPLS-DA of saliva (POS); (F) OPLS-DA of saliva (NEG); (G) OPLS-DA of supragingival plaque (POS); (H) OPLS-DA of supragingival plaque (NEG). TS refers to the saliva samples of T2DM group. TP refers to the supragingival plaque samples of T2DM group. CS refers to the saliva samples of control group. CP refers to the supragingival plaque samples of control group.

FIG 4

Analysis of differentially abundant metabolites. (A) Metabolites of saliva (POS); (B) Metabolites of saliva (NEG); (C) Metabolites of supragingival plaque (POS); (D) Metabolites of supragingival plaque (NEG); (E) Metabolites of saliva (POS); (F) Metabolites of saliva (NEG); (G) Metabolites of supragingival plaque (POS); (H) Metabolites of supragingival plaque (NEG). (A–D) The x axis represents log₂ (Fold Change); y axis represents the negative logarithmic conversion of the P-value of the difference test between the two groups (-log₁₀ P-value). E~H: x axis enrichment factor (Rich Factor) is the number of differential metabolites annotated to the pathway divided by all identified metabolites annotated to the pathway. y axis represents pathways. 1 = Vitamin digestion and absorption; 2 = Tryptophan metabolism; 3 = Taste transduction; 4 = Pyrimidine metabolism; 5 = Protein digestion and absorption; 6 = Prostate cancer; 7 = Pathways in cancer; 8 = Neomycin, kanamycin and gentamicin biosynthesis; 9 = Biotin metabolism; 10 = Valine, leucine and isoleucine biosynthesis; 11 = Purine metabolism; 12 = mTOR signaling pathway; 13 = Metabolic pathways; 14 = HIF − 1 signaling pathway; 15 = Antifolate resistance; 16 = ABC transporters; 17 = Tyrosine metabolism; 18 = Longevity regulating pathway; 19 = Dopaminergic synapse; 20 = AMPK signaling pathway; 21 = Thyroid hormone synthesis; 22 = Starch and sucrose metabolism; 23 = Prolactin signaling pathway; 24 = Phenylalanine metabolism; 25 = Insulin secretion; 26 = Insulin resistance; 27 = Inositol phosphate metabolism; 28 = Galactose metabolism; 29 = Central carbon metabolism in cancer; 30 = Carbohydrate digestion and absorption.