Periodontitis and Metabolic Dysfunction-Associated Fatty Liver Disease: From Oral Dysbiosis to Hepatic Metabolic Dysregulation

WANG Min, CHEN Rixin, KE Xiaojing, GU Yaya, ZHANG Yangheng, YAN Fuhua

Abstract

Periodontitis and metabolic dysfunction-associated fatty liver disease (MAFLD) are both highly prevalent chronic diseases that impose a significant global burden. Recent studies have revealed a close association between them. This article systematically reviews the epidemiological link between periodontitis and MAFLD, as well as their potential underlying mechanisms. Regarding the investigation of underlying mechanisms, the article focuses on two primary pathways. Firstly, the classical hematogenous transmission pathway, in which periodontal pathogens and their mediated inflammatory responses affect the liver through the systemic circulation; secondly, the recently proposed “oral-gut-liver axis” pathway, in which periodontitis alters the oral microbiota, subsequently disrupting gut microbiota and intestinal barrier function, ultimately leading to hepatic metabolic dysregulation. These studies offer new perspectives for understanding the complex relationship between these diseases and provide potential novel strategies for the prevention and treatment of MAFLD.

 

Keywords: Periodontitis, Metabolic dysfunction-associated fatty liver disease, Oral-gut-liver axis, Review

 

Full Text:

PDF


References


GBD 2021 Oral Disorders Collaborators. Trends in the global, regional, and national burden of oral conditions from 1990 to 2021: a systematic analysis for the Global Burden of Disease Study 2021. Lancet, 2025, 405(10482): 897-910. doi: 10.1016/s0140-6736(24)02811-3.

HERRERA D, SANZ M, SHAPIRA L, et al. Association between periodontal diseases and cardiovascular diseases, diabetes and respiratory diseases: Consensus report of the Joint Workshop by the European Federation of Periodontology (EFP) and the European arm of the World Organization of Family Doctors (WONCA Europe). J Clin Periodontol, 2023, 50(6): 819-841. doi: 10.1111/jcpe.13807.

HAGSTRÖM H, SHANG Y, HEGMAR H, et al. Natural history and progression of metabolic dysfunction-associated steatotic liver disease. Lancet Gastroenterol Hepatol, 2024, 9(10): 944-956. doi: 10.1016/s2468-1253(24)00193-6.

Chinese Society of Hepatology, Chinese Medical Association. Guidelines for the prevention and treatment of metabolic dysfunction-associated (non-alcoholic) fatty liver disease (Version 2024). Chinese Journal of Hepatology, 2024, 32(5): 418-434. doi: 10.3760/cma.j.cn501113-20240327-00163.

DEVARBHAVI H, ASRANI S K, ARAB J P, et al. Global burden of liver disease: 2023 update. J Hepatol, 2023, 79(2): 516-537. doi: 10.1016/j.jhep. 2023.03.017.

KUNATH B J, DE RUDDER C, LACZNY C C, et al. The oral-gut microbiome axis in health and disease. Nat Rev Microbiol, 2024, 22(12): 791-805. doi: 10.1038/s41579-024-01075-5.

PABST O, HORNEF M W, SCHAAP F G, et al. Gut-liver axis: barriers and functional circuits. Nat Rev Gastroenterol Hepatol, 2023, 20(7): 447-461. doi: 10.1038/s41575-023-00771-6.

ALBUQUERQUE-SOUZA E, SAHINGUR S E. Periodontitis, chronic liver diseases, and the emerging oral-gut-liver axis. Periodontol 2000, 2022, 89(1): 125-141. doi: 10.1111/prd.12427.

SAITO T, SHIMAZAKI Y, KOGA T, et al. Relationship between periodontitis and hepatic condition in Japanese women. J Int Acad Periodontol, 2006, 8(3): 89-95.

QIAO F, FU K, ZHANG Q, et al. The association between missing teeth and non-alcoholic fatty liver disease in adults. J Clin Periodontol, 2018, 45(8): 941-951. doi: 10.1111/jcpe.12929.

IWASAKI T, HIROSE A, AZUMA T, et al. Correlation between ultrasound-diagnosed non-alcoholic fatty liver and periodontal condition in a cross-sectional study in Japan. Sci Rep, 2018, 8(1): 7496. doi: 10.1038/s41598-018-25857-z.

WEINTRAUB J A, LOPEZ MITNIK G, DYE B A. Oral Diseases Associated with Nonalcoholic Fatty Liver Disease in the United States. J Dent Res, 2019, 98(11): 1219-1226. doi: 10.1177/0022034519866442.

AKINKUGBE A A, SLADE G D, BARRITT A S, et al. Periodontitis and Non-alcoholic Fatty Liver Disease, a population-based cohort investigation in the Study of Health in Pomerania. J Clin Periodontol, 2017, 44(11): 1077-1087. doi: 10.1111/jcpe.12800.

HELENIUS-HIETALA J, SUOMINEN A L, RUOKONEN H, et al. Periodontitis is associated with incident chronic liver disease-A population-based cohort study. Liver Int, 2019, 39(3): 583-591. doi: 10. 1111/liv.13985.

KUROE K, FURUTA M, TAKEUCHI K, et al. Association between periodontitis and fibrotic progression of non-alcoholic fatty liver among Japanese adults. J Clin Periodontol, 2021, 48(3): 368-377. doi: 10.1111/jcpe.13415.

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. doi: 10.1186/1471-230x-12-16.

BAJAJ J S, MATIN P, WHITE M B, et al. Periodontal therapy favorably modulates the oral-gut-hepatic axis in cirrhosis. Am J Physiol Gastrointest Liver Physiol, 2018, 315(5): G824-G837. doi: 10.1152/ajpgi. 00230.2018.

CURTIS M A, DIAZ P I, VAN DYKE T E. The role of the microbiota in periodontal disease. Periodontol 2000, 2020, 83(1): 14-25. doi: 10.1111/prd.12296.

HAJISHENGALLIS G. Periodontitis: from microbial immune subversion to systemic inflammation. Nat Rev Immunol, 2015, 15(1): 30-44. doi: 10. 1038/nri3785.

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. doi: 10.1007/s00535-012-0738-1.

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. doi: 10.1007/s00535-017-1368-4.

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. doi: 10. 1002/jper.17-0678.

GUILLIAMS M, SCOTT C L. Liver macrophages in health and disease. Immunity, 2022, 55(9): 1515-1529. doi: 10.1016/j.immuni.2022.08.002.

DING L Y, LIANG L Z, ZHAO Y X, 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. doi: 10.1111/odi.13153.

LUEDDE T, SCHWABE R F. NF-κB in the liver--linking injury, fibrosis and hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol, 2011, 8(2): 108-118. doi: 10.1038/nrgastro.2010.213.

NAGASAKI A, SAKAMOTO S, CHEA C, et al. Odontogenic infection by Porphyromonas gingivalis exacerbates fibrosis in NASH via hepatic stellate cell activation. Sci Rep, 2020, 10(1): 4134. doi: 10.1038/s41598-020-60904-8.

HAJISHENGALLIS G, CHAVAKIS T. Local and systemic mechanisms linking periodontal disease and inflammatory comorbidities. Nat Rev Immunol, 2021, 21(7): 426-440. doi: 10.1038/s41577-020-00488-6.

BOUTAGA K, SAVELKOUL P H, WINKEL E G, et al. Comparison of subgingival bacterial sampling with oral lavage for detection and quantification of periodontal pathogens by real-time polymerase chain reaction. J Periodontol, 2007, 78(1): 79-86. doi: 10.1902/jop.2007.060078.

Von TROIL-LINDÉN B, TORKKO H, ALALUUSUA S, et al. Salivary levels of suspected periodontal pathogens in relation to periodontal status and treatment. J Dent Res, 1995, 74(11): 1789-1795. doi: 10.1177/ 00220345950740111201.

SENDER R, FUCHS S, MILO R. Revised Estimates for the Number of Human and Bacteria Cells in the Body. PLoS Biol, 2016, 14(8): e1002533. doi: 10.1371/journal.pbio.1002533.

BAO J, LI L, ZHANG Y, et al. Periodontitis may induce gut microbiota dysbiosis via salivary microbiota. Int J Oral Sci, 2022, 14(1): 32. doi: 10. 1038/s41368-022-00183-3.

LU J, ZHANG S, HUANG Y, et al. Periodontitis-related salivary microbiota aggravates Alzheimer's disease via gut-brain axis crosstalk. Gut Microbes, 2022, 14(1): 2126272. doi: 10.1080/19490976.2022. 2126272.

QIAN J, LU J, CHENG S, et al. Periodontitis salivary microbiota exacerbates colitis-induced anxiety-like behavior via gut microbiota. NPJ Biofilms Microbiomes, 2023, 9(1): 93. doi: 10.1038/s41522-023-00462-9. aggravates bone loss in ovariectomized rats. Front Cell Infect Microbiol, 2022, 12: 983608. doi: 10.3389/fcimb.2022.983608.

CHOPYK D M, GRAKOUI A. Contribution of the Intestinal Microbiome and Gut Barrier to Hepatic Disorders. Gastroenterology, 2020, 159(3): 849-863. doi: 10.1053/j.gastro.2020.04.077.

KURAJI R, YE C, ZHAO C, et al. Nisin lantibiotic prevents NAFLD liver steatosis and mitochondrial oxidative stress following periodontal disease by abrogating oral, gut and liver dysbiosis. NPJ Biofilms Microbiomes, 2024, 10(1): 3. doi: 10.1038/s41522-024-00476-x.

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. doi: 10.1038/srep04828.

QIAN J, LU J, HUANG Y, et al. Periodontitis Salivary Microbiota Worsens Colitis. J Dent Res, 2022, 101(5): 559-568. doi: 10.1177/ 00220345211049781.

WANG M, LI L, QIAN J, et al. Periodontitis salivary microbiota exacerbates nonalcoholic fatty liver disease in high-fat diet-induced obese mice. iScience, 2023, 26(4): 106346. doi: 10.1016/j.isci.2023.106346.

MIELE L, VALENZA V, La TORRE G, et al. Increased intestinal permeability and tight junction alterations in nonalcoholic fatty liver disease. Hepatology, 2009, 49(6): 1877-1887. doi: 10.1002/hep.22848.

ALBILLOS A, De GOTTARDI A, RESCIGNO M. The gut-liver axis in liver disease: Pathophysiological basis for therapy. J Hepatol, 2020, 72(3): 558-577. doi: 10.1016/j.jhep.2019.10.003.

SOPPERT J, BRANDT E F, HEUSSEN N M, et al. Blood Endotoxin Levels as Biomarker of Nonalcoholic Fatty Liver Disease: A Systematic Review and Meta-analysis. Clin Gastroenterol Hepatol, 2023, 21(11): 2746-2758. doi: 10.1016/j.cgh.2022.11.030.

AN L, WIRTH U, KOCH D, et al. The Role of Gut-Derived Lipopolysaccharides and the Intestinal Barrier in Fatty Liver Diseases. J Gastrointest Surg, 2022, 26(3): 671-683. doi: 10.1007/s11605-021-05188-7.

DING C, SHEN Z, XU R, et al. Exosomes derived from periodontitis induce hepatic steatosis through the SCD-1/AMPK signaling pathway. Biochim Biophys Acta Mol Basis Dis, 2024, 1870(7): 167343. doi: 10.1016/j.bbadis.2024.167343.

HAI S, LI X, XIE E, et al. Intestinal IL-33 promotes microbiota-derived trimethylamine N -oxide synthesis and drives metabolic dysfunction-associated steatotic liver disease progression by exerting dual regulation on HIF-1α. Hepatology, 2025, 82(1): 184-198. doi: 10.1097/hep. 0000000000000985.

MüNTE E, HARTMANN P. The Role of Short-Chain Fatty Acids in Metabolic Dysfunction-Associated Steatotic Liver Disease and Other Metabolic Diseases. Biomolecules, 2025, 15(4): 46. doi: 10.3390/biom15040469.

JIAO N, BAKER SS, CHAPA-RODRIGUEZ A, et al. Suppressed hepatic bile acid signalling despite elevated production of primary and secondary bile acids in NAFLD. Gut, 2018, 67(10): 1881-1891. doi: 10.1136/gutjnl-2017-314307.

CHEN R, QIAN J, WANG Q, et al. Periodontitis exacerbates metabolic dysfunction-associated steatotic liver disease via the gut microbiota-derived tryptophan metabolism-AHR axis in obesity. EBioMedicine, 2025, 122: 106037. doi: 10.1016/j.ebiom.2025.106037.

GAGGINI M, CARLI F, ROSSO C, et al. Altered amino acid concentrations in NAFLD: Impact of obesity and insulin resistance. Hepatology, 2018, 67(1): 145-158. doi: 10.1002/hep.29465.

GRZYCH G, VONGHIA L, BOUT M A, et al. Plasma BCAA Changes in Patients With NAFLD Are Sex Dependent. J Clin Endocrinol Metab, 2020, 105(7): dgaa175. doi: 10.1210/clinem/dgaa175.


Refbacks

  • There are currently no refbacks.