ABSTRACT
Periodontal infection induces systemic inflammation; therefore, aggravating diabetes. Orally administered periodontal pathogens may directly alter the gut microbiota. We orally treated obese db/db diabetes mice using Porphyromonas gingivalis (Pg). We screened for Pg-specific peptides in the intestinal fecal specimens and examined whether Pg localization influenced the intestinal microbiota profile, in turn altering the levels of the gut metabolites. We evaluated whether the deterioration in fasting hyperglycemia was related to the changes in the intrahepatic glucose metabolism, using proteome and metabolome analyses. Oral Pg treatment aggravated both fasting and postprandial hyperglycemia (P < 0.05), with a significant (P < 0.01) increase in dental alveolar bone resorption. Pg-specific peptides were identified in fecal specimens following oral Pg treatment. The intestinal Pg profoundly altered the gut microbiome profiles at the phylum, family, and genus levels; Prevotella exhibited the largest increase in abundance. In addition, Pg-treatment significantly altered intestinal metabolite levels. Fasting hyperglycemia was associated with the increase in the levels of gluconeogenesis-related enzymes and metabolites without changes in the expression of proinflammatory cytokines and insulin resistance. Oral Pg administration induced gut microbiota changes, leading to entero-hepatic metabolic derangements, thus aggravating hyperglycemia in an obese type 2 diabetes mouse model.
Subject(s)
Diabetes Mellitus, Type 2/complications , Dysbiosis/complications , Dysbiosis/microbiology , Gastrointestinal Microbiome , Metabolic Diseases/etiology , Metabolic Diseases/metabolism , Porphyromonas gingivalis/physiology , Animals , Biological Therapy , Biomarkers , Blood Glucose , Culture Media, Conditioned/metabolism , Culture Media, Conditioned/pharmacology , Diabetes Mellitus, Type 2/metabolism , Disease Models, Animal , Energy Metabolism , Fasting , Insulin/blood , Mice , Peptides/metabolism , Peptides/pharmacology , Periodontitis/complications , Periodontitis/metabolism , Periodontitis/microbiology , Periodontitis/therapyABSTRACT
Transforming growth factor beta (TGF-ß) is a multi-functional growth factor expressed in many tissues and organs. Genetic animal models have revealed the critical functions of TGF-ß in craniofacial development, including the teeth and periodontal tissue. However, the physiological function of TGF-ß in the periodontal ligament (PDL) has not been fully elucidated. In this study, we examined the roles of TGF-ß in the cytodifferentiation of PDL cells using a TGF-ß receptor kinase inhibitor, SB431542. Mouse PDL cell clones (MPDL22) were cultured in calcification-inducing medium with or without SB431542 in the presence or absence of various growth factors, such as bone morphogenetic protein (BMP)-2, TGF-ß and fibroblast growth factor (FGF)-2. SB431542 dramatically enhanced the BMP-2-dependent calcification of MPDL22 cells and accelerated the expression of ossification genes alkaline phosphatase (ALPase) and Runt-related transcription factor (Runx) 2 during early osteoblastic differentiation. SB431542 did not promote MPDL22 calcification without BMP-2 stimulation. The cell growth rate and collagen synthesis during the late stage of MPDL22 culture were retarded by SB431542. Quantitative reverse transcription polymerase chain reaction analysis revealed that the expressions of Smurf1 and Smad6, which are negative feedback components in the TGF-ß/BMP signaling pathway, were downregulated in MPDL22 cells with SB431542 treatment. These results suggest that an endogenous signal from TGF-ß negatively regulates the early commitment and cytodifferentiation of PDL cells into hard tissue-forming cells. A synthetic drug that regulates endogenous TGF-ß signals may be efficacious for developing periodontal regenerative therapies.