Role of <i>Porphyromonas gingivalis</i> in the pathogenesis of non-alcoholic fatty liver disease_West China Medical Journal

Authors：

LI Danting ¹ , LING Xiongjian ² ,  HUANG Yan ¹

1. Health Management Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China;
2. China Dental Implantology Center, West China University of Medical Sciences, Chengdu, Sichuan 610041, P. R. China;

Corresponding author：

HUANG Yan, Email: huangyanhy513@163.com

Keywords：

Non-alcoholic fatty liver disease; Porphyromonas gingivalis; Pathogenesis

DOI：

10.7507/1002-0179.201912046

Video：

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Non-alcoholic fatty liver disease (NAFLD) is one of the major chronic liver diseases that endanger human health. It is characterized by hepatic steatosis and absence of other causes of hepatic fat accumulation, such as alcohol abuse. The incidence of NAFLD is increasing year by year. However, the pathogenesis is still undefined. Porphyromonas gingivalis is a major periodontal pathogen of various periodontal disease. Apart from affecting periodontal health, Porphyromonas gingivalis is also related to the incidence of many systemic diseases. In recent years, Porphyromonas gingivalis is considered to be a risk factor of NAFLD. In this paper, the relationship between NAFLD and Porphyromonas gingivalis, as well as the possible pathogenesis are discussed.

Citation： LI Danting, LING Xiongjian, HUANG Yan. Role of Porphyromonas gingivalis in the pathogenesis of non-alcoholic fatty liver disease. West China Medical Journal, 2021, 36(6): 826-830. doi: 10.7507/1002-0179.201912046 Copy

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2.	Angulo P. Nonalcoholic fatty liver disease. N Engl J Med, 2002, 346(16): 1221-1231.
3.	Alakhali MS, Al-Maweri SA, Al-Shamiri HM, et al. The potential association between periodontitis and non-alcoholic fatty liver disease: a systematic review. Clin Oral Investig, 2018, 22(9): 2965-2974.
4.	Marchesini G, Bugianesi E, Forlani G, et al. Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome. Hepatology, 2003, 37(4): 917-923.
5.	Abdelmalek MF, Diehl AM. Nonalcoholic fatty liver disease as a complication of insulin resistance. Med Clin North Am, 2007, 91(6): 1125-1149, ix.
6.	Byrne CD, Targher G. NAFLD: a multisystem disease. J Hepatol, 2015, 62(Suppl 1): S47-S64.
7.	Nakahara T, Hyogo H, Ono A, et al. Involvement of Porphyromonas gingivalis in the progression of non-alcoholic fatty liver disease. J Gastroenterol, 2018, 53(2): 269-280.
8.	Yoneda M, Naka S, Nakano K, et al. Involvement of a periodontal pathogen, Porphyromonas gingivalis on the pathogenesis of non-alcoholic fatty liver disease. BMC Gastroenterol, 2012, 12: 16.
9.	Seymour GJ, Ford PJ, Cullinan MP, et al. Relationship between periodontal infections and systemic disease. Clin Microbiol Infect, 2007, 13(Suppl 4): 3-10.
10.	Pizzo G, Guiglia R, Lo Russo L, et al. Dentistry and internal medicine: from the focal infection theory to the periodontal medicine concept. Eur J Intern Med, 2010, 21(6): 496-502.
11.	Wada K, Kamisaki Y. Roles of oral bacteria in cardiovascular diseases--from molecular mechanisms to clinical cases: involvement of Porphyromonas gingivalis in the development of human aortic aneurysm. J Pharmacol Sci, 2010, 113(2): 115-119.
12.	Bhandari S, Gupta E, Abdul MKM, et al. Association of Porphyromonas gingivalis serum antibody levels and non-alcoholic fatty liver disease (NAFLD): an NHANES study. Am J Gastroenterol, 2017, 112: S559-S559.
13.	Fujita M, Kuraji R, Ito H, et al. Histological effects and pharmacokinetics of lipopolysaccharide derived from Porphyromonas gingivalis on rat maxilla and liver concerning with progression into non-alcoholic steatohepatitis. J Periodontol, 2018, 89(9): 1101-1111.
14.	Enersen M, Nakano K, Amano A. Porphyromonas gingivalis fimbriae. J Oral Microbiol, 2013: 5.
15.	Nakagawa I, Amano A, Kimura RK, et al. Distribution and molecular characterization of Porphyromonas gingivalis carrying a new type of fimA gene. J Clin Microbiol, 2000, 38(5): 1909-1914.
16.	Nakagawa I, Amano A, Ohara-Nemoto Y, et al. Identification of a new variant of fimA gene of Porphyromonas gingivalis and its distribution in adults and disabled populations with periodontitis. J Periodontal Res, 2002, 37(6): 425-432.
17.	Amano A, Nakagawa I, Kataoka K, et al. Distribution of Porphyromonas gingivalis strains with fimA genotypes in periodontitis patients. J Clin Microbiol, 1999, 37(5): 1426-1430.
18.	Nakano K, Inaba H, Nomura R, et al. Distribution of Porphyromonas gingivalis fimA genotypes in cardiovascular specimens from Japanese patients. Oral Microbiol Immunol, 2008, 23(2): 170-172.
19.	Amano A, Kuboniwa M, Nakagawa I, et al. Prevalence of specific genotypes of Porphyromonas gingivalis fimA and periodontal health status. J Dent Res, 2000, 79(9): 1664-1668.
20.	Forner L, Larsen T, Kilian M, et al. Incidence of bacteremia after chewing, tooth brushing and scaling in individuals with periodontal inflammation. J Clin Periodontol, 2006, 33(6): 401-407.
21.	Furusho H, Miyauchi M, Hyogo H, et al. Dental infection of Porphyromonas gingivalis exacerbates high fat diet-induced steatohepatitis in mice. J Gastroenterol, 2013, 48(11): 1259-1270.
22.	Kuraji R, Ito H, Fujita M, et al. Porphyromonas gingivalis induced periodontitis exacerbates progression of non-alcoholic steatohepatitis in rats. Clin Exp Dent Res, 2016, 2(3): 216-225.
23.	Ding LY, Liang LZ, Zhao YX, et al. Porphyromonas gingivalis-derived lipopolysaccharide causes excessive hepatic lipid accumulation via activating NF-κB and JNK signaling pathways. Oral Dis, 2019, 25(7): 1789-1797.
24.	Arimatsu K, Yamada H, Miyazawa H, et al. Oral pathobiont induces systemic inflammation and metabolic changes associated with alteration of gut microbiota. Sci Rep, 2014, 4: 4828.
25.	Sasaki N, Katagiri S, Komazaki R, et al. Endotoxemia by porphyromonas gingivalis injection aggravates non-alcoholic fatty liver disease, disrupts glucose/lipid metabolism, and alters gut microbiota in mice. Front Microbiol, 2018, 9: 2470.
26.	Lim MY, You HJ, Yoon HS, et al. The effect of heritability and host genetics on the gut microbiota and metabolic syndrome. Gut, 2017, 66(6): 1031-1038.
27.	Shen F, Zheng RD, Sun XQ, et al. Gut microbiota dysbiosis in patients with non-alcoholic fatty liver disease. Hepatobiliary Pancreat Dis Int, 2017, 16(4): 375-381.
28.	Aron-Wisnewsky J, Gaborit B, Dutour A, et al. Gut microbiota and non-alcoholic fatty liver disease: new insights. Clin Microbiol Infect, 2013, 19(4): 338-348.
29.	de Faria Ghetti F, Oliveira DG, de Oliveira JM, et al. Influence of gut microbiota on the development and progression of nonalcoholic steatohepatitis. Eur J Nutr, 2018, 57(3): 861-876.
30.	Gordon S. Alternative activation of macrophages. Nat Rev Immunol, 2003, 3(1): 23-35.
31.	Yu S, Ding L, Liang D, et al. Porphyromonas gingivalis inhibits M2 activation of macrophages by suppressingα-ketoglutarate production in mice. Mol Oral Microbiol, 2018, 33(5): 388-395.
32.	Odegaard JI, Chawla A. Alternative macrophage activation and metabolism. Annu Rev Pathol, 2011, 6: 275-297.
33.	Sica A, Invernizzi P, Mantovani A. Macrophage plasticity and polarization in liver homeostasis and pathology. Hepatology, 2014, 59(5): 2034-2042.
34.	Wan J, Benkdane M, Teixeira-Clerc F, et al. M2 kupffer cells promote M1 kupffer cell apoptosis: a protective mechanism against alcoholic and nonalcoholic fatty liver disease. Hepatology, 2014, 59(1): 130-142.
35.	Liu K, Zhao E, Ilyas G, et al. Impaired macrophage autophagy increases the immune response in obese mice by promoting proinflammatory macrophage polarization. Autophagy, 2015, 11(2): 271-284.
36.	Czaja MJ. Functions of autophagy in hepatic and pancreatic physiology and disease. Gastroenterology, 2011, 140(7): 1895-1908.
37.	González-Rodríguez A, Mayoral R, Agra N, et al. Impaired autophagic flux is associated with increased endoplasmic reticulum stress during the development of NAFLD. Cell Death Dis, 2014, 5(4): e1179.
38.	Singh R, Kaushik S, Wang Y, et al. Autophagy regulates lipid metabolism. Nature, 2009, 458(7242): 1131-1135.
39.	Tong W, Ju L, Qiu M, et al. Liraglutide ameliorates non-alcoholic fatty liver disease by enhancing mitochondrial architecture and promoting autophagy through the SIRT1/SIRT3-FOXO3a pathway. Hepatol Res, 2016, 46(9): 933-943.
40.	Rodrigues PH, Bélanger M, Dunn W Jr, et al. Porphyromonas gingivalis and the autophagic pathway: an innate immune interaction?. Front Biosci, 2008, 13: 178-187.
41.	Zaitsu Y, Iwatake M, Sato K, et al. Lipid droplets affect elimination of Porphyromonas gingivalis in HepG2 cells by altering the autophagy-lysosome system. Microbes Infect, 2016, 18(9): 565-571.

1. Eslam M, Valenti L, Romeo S. Genetics and epigenetics of NAFLD and NASH: clinical impact. J Hepatol, 2018, 68(2): 268-279.
2. Angulo P. Nonalcoholic fatty liver disease. N Engl J Med, 2002, 346(16): 1221-1231.
3. Alakhali MS, Al-Maweri SA, Al-Shamiri HM, et al. The potential association between periodontitis and non-alcoholic fatty liver disease: a systematic review. Clin Oral Investig, 2018, 22(9): 2965-2974.
4. Marchesini G, Bugianesi E, Forlani G, et al. Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome. Hepatology, 2003, 37(4): 917-923.
5. Abdelmalek MF, Diehl AM. Nonalcoholic fatty liver disease as a complication of insulin resistance. Med Clin North Am, 2007, 91(6): 1125-1149, ix.
6. Byrne CD, Targher G. NAFLD: a multisystem disease. J Hepatol, 2015, 62(Suppl 1): S47-S64.
7. Nakahara T, Hyogo H, Ono A, et al. Involvement of Porphyromonas gingivalis in the progression of non-alcoholic fatty liver disease. J Gastroenterol, 2018, 53(2): 269-280.
8. Yoneda M, Naka S, Nakano K, et al. Involvement of a periodontal pathogen, Porphyromonas gingivalis on the pathogenesis of non-alcoholic fatty liver disease. BMC Gastroenterol, 2012, 12: 16.
9. Seymour GJ, Ford PJ, Cullinan MP, et al. Relationship between periodontal infections and systemic disease. Clin Microbiol Infect, 2007, 13(Suppl 4): 3-10.
10. Pizzo G, Guiglia R, Lo Russo L, et al. Dentistry and internal medicine: from the focal infection theory to the periodontal medicine concept. Eur J Intern Med, 2010, 21(6): 496-502.
11. Wada K, Kamisaki Y. Roles of oral bacteria in cardiovascular diseases--from molecular mechanisms to clinical cases: involvement of Porphyromonas gingivalis in the development of human aortic aneurysm. J Pharmacol Sci, 2010, 113(2): 115-119.
12. Bhandari S, Gupta E, Abdul MKM, et al. Association of Porphyromonas gingivalis serum antibody levels and non-alcoholic fatty liver disease (NAFLD): an NHANES study. Am J Gastroenterol, 2017, 112: S559-S559.
13. Fujita M, Kuraji R, Ito H, et al. Histological effects and pharmacokinetics of lipopolysaccharide derived from Porphyromonas gingivalis on rat maxilla and liver concerning with progression into non-alcoholic steatohepatitis. J Periodontol, 2018, 89(9): 1101-1111.
14. Enersen M, Nakano K, Amano A. Porphyromonas gingivalis fimbriae. J Oral Microbiol, 2013: 5.
15. Nakagawa I, Amano A, Kimura RK, et al. Distribution and molecular characterization of Porphyromonas gingivalis carrying a new type of fimA gene. J Clin Microbiol, 2000, 38(5): 1909-1914.
16. Nakagawa I, Amano A, Ohara-Nemoto Y, et al. Identification of a new variant of fimA gene of Porphyromonas gingivalis and its distribution in adults and disabled populations with periodontitis. J Periodontal Res, 2002, 37(6): 425-432.
17. Amano A, Nakagawa I, Kataoka K, et al. Distribution of Porphyromonas gingivalis strains with fimA genotypes in periodontitis patients. J Clin Microbiol, 1999, 37(5): 1426-1430.
18. Nakano K, Inaba H, Nomura R, et al. Distribution of Porphyromonas gingivalis fimA genotypes in cardiovascular specimens from Japanese patients. Oral Microbiol Immunol, 2008, 23(2): 170-172.
19. Amano A, Kuboniwa M, Nakagawa I, et al. Prevalence of specific genotypes of Porphyromonas gingivalis fimA and periodontal health status. J Dent Res, 2000, 79(9): 1664-1668.
20. Forner L, Larsen T, Kilian M, et al. Incidence of bacteremia after chewing, tooth brushing and scaling in individuals with periodontal inflammation. J Clin Periodontol, 2006, 33(6): 401-407.
21. Furusho H, Miyauchi M, Hyogo H, et al. Dental infection of Porphyromonas gingivalis exacerbates high fat diet-induced steatohepatitis in mice. J Gastroenterol, 2013, 48(11): 1259-1270.
22. Kuraji R, Ito H, Fujita M, et al. Porphyromonas gingivalis induced periodontitis exacerbates progression of non-alcoholic steatohepatitis in rats. Clin Exp Dent Res, 2016, 2(3): 216-225.
23. Ding LY, Liang LZ, Zhao YX, et al. Porphyromonas gingivalis-derived lipopolysaccharide causes excessive hepatic lipid accumulation via activating NF-κB and JNK signaling pathways. Oral Dis, 2019, 25(7): 1789-1797.
24. Arimatsu K, Yamada H, Miyazawa H, et al. Oral pathobiont induces systemic inflammation and metabolic changes associated with alteration of gut microbiota. Sci Rep, 2014, 4: 4828.
25. Sasaki N, Katagiri S, Komazaki R, et al. Endotoxemia by porphyromonas gingivalis injection aggravates non-alcoholic fatty liver disease, disrupts glucose/lipid metabolism, and alters gut microbiota in mice. Front Microbiol, 2018, 9: 2470.
26. Lim MY, You HJ, Yoon HS, et al. The effect of heritability and host genetics on the gut microbiota and metabolic syndrome. Gut, 2017, 66(6): 1031-1038.
27. Shen F, Zheng RD, Sun XQ, et al. Gut microbiota dysbiosis in patients with non-alcoholic fatty liver disease. Hepatobiliary Pancreat Dis Int, 2017, 16(4): 375-381.
28. Aron-Wisnewsky J, Gaborit B, Dutour A, et al. Gut microbiota and non-alcoholic fatty liver disease: new insights. Clin Microbiol Infect, 2013, 19(4): 338-348.
29. de Faria Ghetti F, Oliveira DG, de Oliveira JM, et al. Influence of gut microbiota on the development and progression of nonalcoholic steatohepatitis. Eur J Nutr, 2018, 57(3): 861-876.
30. Gordon S. Alternative activation of macrophages. Nat Rev Immunol, 2003, 3(1): 23-35.
31. Yu S, Ding L, Liang D, et al. Porphyromonas gingivalis inhibits M2 activation of macrophages by suppressingα-ketoglutarate production in mice. Mol Oral Microbiol, 2018, 33(5): 388-395.
32. Odegaard JI, Chawla A. Alternative macrophage activation and metabolism. Annu Rev Pathol, 2011, 6: 275-297.
33. Sica A, Invernizzi P, Mantovani A. Macrophage plasticity and polarization in liver homeostasis and pathology. Hepatology, 2014, 59(5): 2034-2042.
34. Wan J, Benkdane M, Teixeira-Clerc F, et al. M2 kupffer cells promote M1 kupffer cell apoptosis: a protective mechanism against alcoholic and nonalcoholic fatty liver disease. Hepatology, 2014, 59(1): 130-142.
35. Liu K, Zhao E, Ilyas G, et al. Impaired macrophage autophagy increases the immune response in obese mice by promoting proinflammatory macrophage polarization. Autophagy, 2015, 11(2): 271-284.
36. Czaja MJ. Functions of autophagy in hepatic and pancreatic physiology and disease. Gastroenterology, 2011, 140(7): 1895-1908.
37. González-Rodríguez A, Mayoral R, Agra N, et al. Impaired autophagic flux is associated with increased endoplasmic reticulum stress during the development of NAFLD. Cell Death Dis, 2014, 5(4): e1179.
38. Singh R, Kaushik S, Wang Y, et al. Autophagy regulates lipid metabolism. Nature, 2009, 458(7242): 1131-1135.
39. Tong W, Ju L, Qiu M, et al. Liraglutide ameliorates non-alcoholic fatty liver disease by enhancing mitochondrial architecture and promoting autophagy through the SIRT1/SIRT3-FOXO3a pathway. Hepatol Res, 2016, 46(9): 933-943.
40. Rodrigues PH, Bélanger M, Dunn W Jr, et al. Porphyromonas gingivalis and the autophagic pathway: an innate immune interaction?. Front Biosci, 2008, 13: 178-187.
41. Zaitsu Y, Iwatake M, Sato K, et al. Lipid droplets affect elimination of Porphyromonas gingivalis in HepG2 cells by altering the autophagy-lysosome system. Microbes Infect, 2016, 18(9): 565-571.

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Role of Porphyromonas gingivalis in the pathogenesis of non-alcoholic fatty liver disease

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