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Polymicrobial Oral Infection with Four Periodontal Bacteria Orchestrates a Distinct Inflammatory Response and Atherosclerosis in ApoE Mice.

Chukkapalli SS, Velsko IM, Rivera-Kweh MF, Zheng D, Lucas AR, Kesavalu L - PLoS ONE (2015)

Bottom Line: Periodontal microbiome infection is associated with significant decreases in Apoa1, Apob, Birc3, Fga, FgB genes that are associated with atherosclerosis.Periodontal infection for 12 weeks had modified levels of inflammatory molecules, with decreased Fas ligand, IL-13, SDF-1 and increased chemokine RANTES.In contrast, 24 weeks of infection induced new changes in other inflammatory molecules with reduced KC, MCSF, enhancing GM-CSF, IFNγ, IL-1β, IL-13, IL-4, IL-13, lymphotactin, RANTES, and also an increase in select inflammatory molecules.

View Article: PubMed Central - PubMed

Affiliation: Department of Periodontology, College of Dentistry, University of Florida, Gainesville, Florida, United States of America.

ABSTRACT
Periodontal disease (PD) develops from a synergy of complex subgingival oral microbiome, and is linked to systemic inflammatory atherosclerotic vascular disease (ASVD). To investigate how a polybacterial microbiome infection influences atherosclerotic plaque progression, we infected the oral cavity of ApoE mice with a polybacterial consortium of 4 well-characterized periodontal pathogens, Porphyromonas gingivalis, Treponema denticola, Tannerealla forsythia and Fusobacterium nucleatum, that have been identified in human atherosclerotic plaque by DNA screening. We assessed periodontal disease characteristics, hematogenous dissemination of bacteria, peripheral T cell response, serum inflammatory cytokines, atherosclerosis risk factors, atherosclerotic plaque development, and alteration of aortic gene expression. Polybacterial infections have established gingival colonization in ApoE hyperlipidemic mice and displayed invasive characteristics with hematogenous dissemination into cardiovascular tissues such as the heart and aorta. Polybacterial infection induced significantly higher levels of serum risk factors oxidized LDL (p < 0.05), nitric oxide (p < 0.01), altered lipid profiles (cholesterol, triglycerides, Chylomicrons, VLDL) (p < 0.05) as well as accelerated aortic plaque formation in ApoE mice (p < 0.05). Periodontal microbiome infection is associated with significant decreases in Apoa1, Apob, Birc3, Fga, FgB genes that are associated with atherosclerosis. Periodontal infection for 12 weeks had modified levels of inflammatory molecules, with decreased Fas ligand, IL-13, SDF-1 and increased chemokine RANTES. In contrast, 24 weeks of infection induced new changes in other inflammatory molecules with reduced KC, MCSF, enhancing GM-CSF, IFNγ, IL-1β, IL-13, IL-4, IL-13, lymphotactin, RANTES, and also an increase in select inflammatory molecules. This study demonstrates unique differences in the host immune response to a polybacterial periodontal infection with atherosclerotic lesion progression in a mouse model.

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Polybacterial infection enhances atherogenic potential of infected ApoE-/- mice.(A). Total serum cholesterol and total serum triglycerides are significantly elevated in infected mice. (B). Chylomicrons and VLDL are significantly elevated in infected mice. (C). Acute inflammatory marker SAA is not significantly elevated in infected mice. (D). Oxidized LDL is significantly elevated in infected mice. (E). Serum nitric oxide is significantly decreased in infected mice. Chol—cholesterol, Trigly—triglycerides, CM—chylomicrons, VLDL—very low-density lipoprotein, LDL—low density lipoprotein, HDL—high density lipoprotein, Cn—control, Ply—poly infection, Pg–P. gingivalis infection, Td–T. denticola infection, Tf–T. forsythia infection, Fn–F. nucleatum infection, OxyLDL—oxidized LDL. n = 6, * p < 0.05, ** p < 0.01.
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pone.0143291.g004: Polybacterial infection enhances atherogenic potential of infected ApoE-/- mice.(A). Total serum cholesterol and total serum triglycerides are significantly elevated in infected mice. (B). Chylomicrons and VLDL are significantly elevated in infected mice. (C). Acute inflammatory marker SAA is not significantly elevated in infected mice. (D). Oxidized LDL is significantly elevated in infected mice. (E). Serum nitric oxide is significantly decreased in infected mice. Chol—cholesterol, Trigly—triglycerides, CM—chylomicrons, VLDL—very low-density lipoprotein, LDL—low density lipoprotein, HDL—high density lipoprotein, Cn—control, Ply—poly infection, Pg–P. gingivalis infection, Td–T. denticola infection, Tf–T. forsythia infection, Fn–F. nucleatum infection, OxyLDL—oxidized LDL. n = 6, * p < 0.05, ** p < 0.01.

Mentions: The serum lipid profiles, SAA, NO and oxyLDL of twenty-four week-infected (n = 6) and sham-infected (n = 6) mice were assessed to determine if bacterial infection altered known risk factors for atherosclerosis. Serum lipid profile analysis indicated a significant (p < 0.05) increase in total serum cholesterol and triglycerides of infected mice (Fig 4A), indicating they are more prone to develop atherosclerosis. Additionally, chylomicron and LDL particles were significantly (p < 0.05) elevated in infected mice relative to sham-infected mice (Fig 4B), indicating that infection alters the lipid profile to a more pro-atherogenic state. Serum amyloid A is used as a non-specific inflammatory serum risk marker for atherosclerosis in humans; however, the SAA concentration of infected mice was not significantly elevated relative to controls (Fig 4C). Oxidized LDL, a risk factor for atherosclerosis development, was significantly (p < 0.05) elevated in polybacterial-infected mice relative to sham-infected mice (Fig 4D), further supporting that periodontal infection alters lipid transport and metabolism with potential increased risk for atherosclerosis progression. Serum NO was significantly decreased (p < 0.01) in polybacterial-infected mice (Fig 4E), indicating endothelial dysfunction, which is known to be an initiating factor for atherosclerotic plaque progression. These findings indicate that infection may lead to dyslipidemia and endothelial dysfunction, which predisposes the aortic vessel to atherosclerotic plaque formation.


Polymicrobial Oral Infection with Four Periodontal Bacteria Orchestrates a Distinct Inflammatory Response and Atherosclerosis in ApoE Mice.

Chukkapalli SS, Velsko IM, Rivera-Kweh MF, Zheng D, Lucas AR, Kesavalu L - PLoS ONE (2015)

Polybacterial infection enhances atherogenic potential of infected ApoE-/- mice.(A). Total serum cholesterol and total serum triglycerides are significantly elevated in infected mice. (B). Chylomicrons and VLDL are significantly elevated in infected mice. (C). Acute inflammatory marker SAA is not significantly elevated in infected mice. (D). Oxidized LDL is significantly elevated in infected mice. (E). Serum nitric oxide is significantly decreased in infected mice. Chol—cholesterol, Trigly—triglycerides, CM—chylomicrons, VLDL—very low-density lipoprotein, LDL—low density lipoprotein, HDL—high density lipoprotein, Cn—control, Ply—poly infection, Pg–P. gingivalis infection, Td–T. denticola infection, Tf–T. forsythia infection, Fn–F. nucleatum infection, OxyLDL—oxidized LDL. n = 6, * p < 0.05, ** p < 0.01.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4664240&req=5

pone.0143291.g004: Polybacterial infection enhances atherogenic potential of infected ApoE-/- mice.(A). Total serum cholesterol and total serum triglycerides are significantly elevated in infected mice. (B). Chylomicrons and VLDL are significantly elevated in infected mice. (C). Acute inflammatory marker SAA is not significantly elevated in infected mice. (D). Oxidized LDL is significantly elevated in infected mice. (E). Serum nitric oxide is significantly decreased in infected mice. Chol—cholesterol, Trigly—triglycerides, CM—chylomicrons, VLDL—very low-density lipoprotein, LDL—low density lipoprotein, HDL—high density lipoprotein, Cn—control, Ply—poly infection, Pg–P. gingivalis infection, Td–T. denticola infection, Tf–T. forsythia infection, Fn–F. nucleatum infection, OxyLDL—oxidized LDL. n = 6, * p < 0.05, ** p < 0.01.
Mentions: The serum lipid profiles, SAA, NO and oxyLDL of twenty-four week-infected (n = 6) and sham-infected (n = 6) mice were assessed to determine if bacterial infection altered known risk factors for atherosclerosis. Serum lipid profile analysis indicated a significant (p < 0.05) increase in total serum cholesterol and triglycerides of infected mice (Fig 4A), indicating they are more prone to develop atherosclerosis. Additionally, chylomicron and LDL particles were significantly (p < 0.05) elevated in infected mice relative to sham-infected mice (Fig 4B), indicating that infection alters the lipid profile to a more pro-atherogenic state. Serum amyloid A is used as a non-specific inflammatory serum risk marker for atherosclerosis in humans; however, the SAA concentration of infected mice was not significantly elevated relative to controls (Fig 4C). Oxidized LDL, a risk factor for atherosclerosis development, was significantly (p < 0.05) elevated in polybacterial-infected mice relative to sham-infected mice (Fig 4D), further supporting that periodontal infection alters lipid transport and metabolism with potential increased risk for atherosclerosis progression. Serum NO was significantly decreased (p < 0.01) in polybacterial-infected mice (Fig 4E), indicating endothelial dysfunction, which is known to be an initiating factor for atherosclerotic plaque progression. These findings indicate that infection may lead to dyslipidemia and endothelial dysfunction, which predisposes the aortic vessel to atherosclerotic plaque formation.

Bottom Line: Periodontal microbiome infection is associated with significant decreases in Apoa1, Apob, Birc3, Fga, FgB genes that are associated with atherosclerosis.Periodontal infection for 12 weeks had modified levels of inflammatory molecules, with decreased Fas ligand, IL-13, SDF-1 and increased chemokine RANTES.In contrast, 24 weeks of infection induced new changes in other inflammatory molecules with reduced KC, MCSF, enhancing GM-CSF, IFNγ, IL-1β, IL-13, IL-4, IL-13, lymphotactin, RANTES, and also an increase in select inflammatory molecules.

View Article: PubMed Central - PubMed

Affiliation: Department of Periodontology, College of Dentistry, University of Florida, Gainesville, Florida, United States of America.

ABSTRACT
Periodontal disease (PD) develops from a synergy of complex subgingival oral microbiome, and is linked to systemic inflammatory atherosclerotic vascular disease (ASVD). To investigate how a polybacterial microbiome infection influences atherosclerotic plaque progression, we infected the oral cavity of ApoE mice with a polybacterial consortium of 4 well-characterized periodontal pathogens, Porphyromonas gingivalis, Treponema denticola, Tannerealla forsythia and Fusobacterium nucleatum, that have been identified in human atherosclerotic plaque by DNA screening. We assessed periodontal disease characteristics, hematogenous dissemination of bacteria, peripheral T cell response, serum inflammatory cytokines, atherosclerosis risk factors, atherosclerotic plaque development, and alteration of aortic gene expression. Polybacterial infections have established gingival colonization in ApoE hyperlipidemic mice and displayed invasive characteristics with hematogenous dissemination into cardiovascular tissues such as the heart and aorta. Polybacterial infection induced significantly higher levels of serum risk factors oxidized LDL (p < 0.05), nitric oxide (p < 0.01), altered lipid profiles (cholesterol, triglycerides, Chylomicrons, VLDL) (p < 0.05) as well as accelerated aortic plaque formation in ApoE mice (p < 0.05). Periodontal microbiome infection is associated with significant decreases in Apoa1, Apob, Birc3, Fga, FgB genes that are associated with atherosclerosis. Periodontal infection for 12 weeks had modified levels of inflammatory molecules, with decreased Fas ligand, IL-13, SDF-1 and increased chemokine RANTES. In contrast, 24 weeks of infection induced new changes in other inflammatory molecules with reduced KC, MCSF, enhancing GM-CSF, IFNγ, IL-1β, IL-13, IL-4, IL-13, lymphotactin, RANTES, and also an increase in select inflammatory molecules. This study demonstrates unique differences in the host immune response to a polybacterial periodontal infection with atherosclerotic lesion progression in a mouse model.

Show MeSH
Related in: MedlinePlus