Journal of Gastroenterology

, Volume 48, Issue 11, pp 1259–1270 | Cite as

Dental infection of Porphyromonas gingivalis exacerbates high fat diet-induced steatohepatitis in mice

  • Hisako Furusho
  • Mutsumi Miyauchi
  • Hideyuki Hyogo
  • Toshihiro Inubushi
  • Min Ao
  • Kazuhisa Ouhara
  • Junzou Hisatune
  • Hidemi Kurihara
  • Motoyuki Sugai
  • C. Nelson Hayes
  • Takashi Nakahara
  • Hiroshi Aikata
  • Shoichi Takahashi
  • Kazuaki Chayama
  • Takashi Takata
Original Article—Liver, Pancreas, and Biliary Tract

Abstract

Background

We investigated the effects of dental infection with Porphyromonas gingivalis (P.g.), an important periodontal pathogen, on NASH progression, by feeding mice a high fat diet (HFD)and examining P.g. infection in the liver of NASH patients.

Methods

C57BL/6J mice were fed either chow-diet (CD) or HFD for 12 weeks, and then half of the mice in each group were infected with P.g. from the pulp chamber (HFD-P.g.(−), HFD-P.g.(+), CD-P.g.(−) and CD-P.g.(+)). Histological and immunohistochemical examinations, measurement of serum lipopolysaccharide (LPS) levels and ELISA for cytokines in the liver were performed. We then studied the effects of LPS from P.g. (P.g.-LPS) on palmitate-induced steatotic hepatocytes in vitro, and performed immunohistochemical detection of P.g. in liver biopsy specimens of NASH patients.

Results

Serum levels of LPS are upregulated in P.g.(+) groups. Steatosis of the liver developed in HFD groups, and foci of Mac2-positive macrophages were prominent in HFD-P.g.(+). P.g. was detected in Kupffer cells and hepatocytes. Interestingly, areas of fibrosis with proliferation of hepatic stellate cells and collagen formation were only observed in HFD-P.g.(+). In steatotic hepatocytes, expression of TLR2, one of the P.g.-LPS receptors, was upregulated. P.g.-LPS further increased mRNA levels of palmitate-induced inflammasome and proinflammatory cytokines in steatotic hepatocytes. We demonstrated for the first time that P.g. existed in the liver of NASH patients with advanced fibrosis.

Conclusions

Dental infection of P.g. may play an important role in NASH progression through upregulation of the P.g.-LPS-TLR2 pathway and activation of inflammasomes. Therefore, preventing and/or eliminating P.g. infection by dental therapy may have a beneficial impact on management of NASH.

Keywords

NASH Dental infection P. gingivalis Fibrosis TLRs 

Abbreviations

NAFLD

Non-alcoholic fatty liver disease

NASH

Non-alcoholic steatohepatitis

FFA

Free fatty acid

LPS

Lipopolysaccharides

P.g.

Porphyromonas gingivalis

HFD

High fat diet

CD

Chow diet

H&E

Hematoxylin and Eosin

α-SMA

α-smooth muscle actin

TLR

Toll-like receptor

NLRP3

Nod-like receptor 3

Casp-1

Caspase-1

Notes

Acknowledgments

The authors thank Ryo Matsuda, Mao Muroi and Shinnichi Sakamoto for their support of this project. We are also grateful to Professor Kazuyuki Ishihara (Tokyo Dental College) for providing P.g.-specific polyclonal antibodies and Prof. Hidetoshi Tahara (Hiroshima University) for providing Hc3716-hTERT cells.

Conflict of interest

The authors declare that they have no conflict of interest.

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Copyright information

© Springer Japan 2013

Authors and Affiliations

  • Hisako Furusho
    • 1
  • Mutsumi Miyauchi
    • 1
  • Hideyuki Hyogo
    • 2
  • Toshihiro Inubushi
    • 1
  • Min Ao
    • 1
    • 3
  • Kazuhisa Ouhara
    • 4
  • Junzou Hisatune
    • 5
  • Hidemi Kurihara
    • 4
  • Motoyuki Sugai
    • 5
  • C. Nelson Hayes
    • 2
  • Takashi Nakahara
    • 2
  • Hiroshi Aikata
    • 2
  • Shoichi Takahashi
    • 2
  • Kazuaki Chayama
    • 2
  • Takashi Takata
    • 1
  1. 1.Department of Oral and Maxillofacial Pathobiology, Basic Life Sciences, Institute of Biomedical and Health SciencesHiroshima UniversityHiroshimaJapan
  2. 2.Department of Medicine and Molecular Science, Graduate School of Biomedical SciencesHiroshima UniversityHiroshimaJapan
  3. 3.Department of Pediatric Dentistry, Applied Life Sciences, Institute of Biomedical and Health SciencesHiroshima UniversityHiroshimaJapan
  4. 4.Department of Periodontal Medicine, Applied Life Sciences, Institute of Biomedical and Health SciencesHiroshima UniversityHiroshimaJapan
  5. 5.Department of Bacteriology, Basic Life Sciences, Institute of Biomedical and Health SciencesHiroshima UniversityHiroshimaJapan

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