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Infection with Porphyromonas gingivalis exacerbates endothelial injury in obese mice.

ABSTRACT: BACKGROUND:A number of studies have revealed a link between chronic periodontitis and cardiovascular disease in obese patients. However, there is little information about the influence of periodontitis-associated bacteria, Porphyromonas gingivalis (Pg), on pathogenesis of atherosclerosis in obesity. METHODS:In vivo experiment: C57BL/6J mice were fed with a high-fat diet (HFD) or normal chow diet (CD), as a control. Pg was infected from the pulp chamber. At 6 weeks post-infection, histological and immunohistochemical analysis of aortal tissues was performed. In vitro experiment: hTERT-immortalized human umbilical vein endothelial cells (HuhT1) were used to assess the effect of Pg/Pg-LPS on free fatty acid (FFA) induced endothelial cells apoptosis and regulation of cytokine gene expression. RESULTS:Weaker staining of CD31 and increased numbers of TUNEL positive cells in aortal tissue of HFD mice indicated endothelial injury. Pg infection exacerbated the endothelial injury. Immunohistochemically, Pg was detected deep in the smooth muscle of the aorta, and the number of Pg cells in the aortal wall was higher in HFD mice than in CD mice. Moreover, in vitro, FFA treatment induced apoptosis in HuhT1 cells and exposure to Pg-LPS increased this effect. In addition, Pg and Pg-LPS both attenuated cytokine production in HuhT1 cells stimulated by palmitate. CONCLUSIONS:Dental infection of Pg may contribute to pathogenesis of atherosclerosis by accelerating FFA-induced endothelial injury.

SUBMITTER: Ao M

PROVIDER: S-EPMC4204882 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Infection with Porphyromonas gingivalis exacerbates endothelial injury in obese mice.

Ao Min M Miyauchi Mutsumi M Inubushi Toshihiro T Kitagawa Masae M Furusho Hisako H Ando Toshinori T Ayuningtyas Nurina Febriyanti NF Nagasaki Atsuhiro A Ishihara Kazuyuki K Tahara Hidetoshi H Kozai Katsuyuki K Takata Takashi T

PloS one 20141021 10

<h4>Background</h4>A number of studies have revealed a link between chronic periodontitis and cardiovascular disease in obese patients. However, there is little information about the influence of periodontitis-associated bacteria, Porphyromonas gingivalis (Pg), on pathogenesis of atherosclerosis in obesity.<h4>Methods</h4>In vivo experiment: C57BL/6J mice were fed with a high-fat diet (HFD) or normal chow diet (CD), as a control. Pg was infected from the pulp chamber. At 6 weeks post-infection, ...[more]

PMID: 25334003

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Project description:BackgroundEpidemiological studies have revealed a link between dental infection and preterm birth or low birth weight (PTB/LBW), however, the underlying mechanisms remain unclear. Progress in understanding the associated mechanisms has been limited in part by lack of an animal model for chronic infection-induced PTB/LBW, mimicking pregnancy under conditions of periodontitis. We aimed to establish a mouse model of chronic periodontitis in order to investigate the link between periodontitis and PTB/LBW.MethodsTo establish chronic inflammation beginning with dental infection, we surgically opened mouse (female, 8 weeks old) 1st molar pulp chambers and directly infected with w83 strain Porphyromonas gingivalis (P.g.), a keystone periodontal pathogen. Mating was initiated at 6 wks post-infection, by which time dental granuloma tissue had developed and live P.g. was cultured from extracted tooth root, which serves as a persistent source of P.g. The gestational day (gd) and birth weight were recorded during for P.g.-infected and control mice, and serum and placental tissues were collected at gd 15 to evaluate the systemic and local conditions during pregnancy.ResultsDental infection with P.g. significantly increased circulating TNF-α (2.5-fold), IL-17 (2-fold), IL-6 (2-fold) and IL-1β (2-fold). The P.g.-infected group delivered at gd 18.25 vs. gd 20.45 in the non-infected control (NC) group (p < 0.01), and pups exhibited LBW compared to controls (p < 0.01). P.g. was localized to placental tissues by immunohistochemistry and PCR, and defects in placental tissues of P.g. infected mice included premature rupture of membrane, placental detachment, degenerative changes in trophoblasts and endothelial cells, including necrotic areas. P.g. infection caused significantly increased numbers of polymorphonuclear leukocytes (PMNLs) and macrophages in placental tissues, associated with increased local expression of pro-inflammatory mediators including TNF-α and COX-2. Further placental tissue damage was indicated in P.g. infected mice by decreased CD-31 in endothelial cells, increased expression of 8OHdG, an indicator of oxidative DNA damage, and cleaved caspase-3, a marker of apoptosis. In vitro, P.g. lipopolysaccharide significantly increased expression of COX-2, IL-8 and TNF-α, in HTR-8 trophoblasts in an NF-κB-dependent fashion.ConclusionsOur novel mouse model supports previous epidemiological studies signifying dental infection as predisposing factor for PTB/LBW. We demonstrate PTB and LBW in infected mice, translocation of P.g to placental tissues, increased circulating and local pro-inflammatory markers, and the capability of P.g. LPS to directly induce cytokine production in trophoblasts, in vitro. These findings further underscore the importance of local and systemic infections and inflammation during pregnancy and suggest that prevention and/or elimination of dental infections such as marginal or periapical periodontitis before pregnancy may have a beneficial effect on PTB/LBW.

Project description:Porphyromonas gingivalis, a keystone periodontal pathogen, has emerged as a risk factor for systemic chronic diseases, including non-alcoholic fatty liver disease (NAFLD). To clarify the mechanism by which this pathogen induces such diseases, we simultaneously analyzed the transcriptome of intracellular P. gingivalis and infected host cells via dual RNA sequencing. Pathway analysis was also performed to determine the differentially expressed genes in the infected cells. Further, the infection-induced notable expression of P. gingivalis livk and livh genes, which participate in branched-chain amino acid (BCAA) transfer, was also analyzed. Furthermore, given that the results of recent studies have associated NAFLD progression with elevated serum BCAA levels, which reportedly, are upregulated by P. gingivalis, we hypothesized that this pathogen may induce increases in serum BCAA levels and exacerbate liver injury via livh/livk. To verify this hypothesis, we constructed P. gingivalis livh/livk-deficient strains (Δlivk, Δlivh) and established a high-fat diet (HFD)-fed murine model infected with P. gingivalis. Thereafter, the kinetic growth and exopolysaccharide (EPS) production rates as well as the invasion efficiency and in vivo colonization of the mutant strains were compared with those of the parental strain. The serum BCAA and fasting glucose levels of the mice infected with either the wild-type or mutant strains, as well as their liver function were also further investigated. It was observed that P. gingivalis infection enhanced serum BCAA levels and aggravated liver injury in the HFD-fed mice. Additionally, livh deletion had no effect on bacterial growth, EPS production, invasion efficiency, and in vivo colonization, whereas the Δlivk strain showed a slight decrease in invasion efficiency and in vivo colonization. More importantly, however, both the Δlivk and Δlivh strains showed impaired ability to upregulate serum BCAA levels or exacerbate liver injury in HFD-fed mice. Overall, these results suggested that P. gingivalis possibly aggravates NAFLD progression in HFD-fed mice by increasing serum BCAA levels, and this effect showed dependency on the bacterial BCAA transport system.

Dataset Information

Infection with Porphyromonas gingivalis exacerbates endothelial injury in obese mice.

Publications

Infection with Porphyromonas gingivalis exacerbates endothelial injury in obese mice.

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