Periodontal disease has been reported to induce gut microbiome dysbiosis and contribute to the onset and progression of liver disease ^1,2. The gut dysbiosis increases hepatotoxic factors, such as lipopolysaccharides, ethanol, and volatile organic compounds, and further increases intestinal permeability by disrupting intercellular tight junctions in the intestinal wall, thereby promoting the translocation of intestinal bacteria and their by-products to the liver.

In particularly, nonalcoholic fatty liver disease (NAFLD), a hepatic phenotype of the metabolic syndrome, is closely associated with periodontal disease ^3-5. NAFLD is characterized by hepatic lipid deposition in the absence of secondary predisposing factors, such as a habitual drinking history, viral infection, or autoimmune disease. Some cases of NAFLD may develop into more severe and progressive nonalcoholic steatohepatitis (NASH) and even end-stage liver disease, such as cirrhosis and hepatocellular carcinoma.

In this regard, microbiota-targeted therapy using probiotics and bacteriocins may be an effective approach to prevent liver diseases, such as NAFLD/NASH by shifting not only oral dysbiosis associated with periodontal disease but also shifting intestinal dysbiosis to a healthy state ⁶. In this study, nisin, a bacteriocin produced by Lactococcus lactis, was orally administered to a mouse model of polymicrobial periodontal disease ^7-9 to investigate the effects of nisin on gut dysbiosis and liver disease.

The results showed that nisin significantly shifted the oral, gut and liver microbiome to a new composition commensurate with health, while preventing toxic inflammation in the small intestine associated with reduced structural integrity of the villi, and increased hepatic exposure to bacteria, and accumulation of lipids and malondialdehyde in the liver. Validation by RNA Seq analysis confirmed significant infection-related changes in several genes involved in mitochondrial dysregulation, oxidative phosphorylation, and metal/iron binding, and their recovery after nisin treatment. This is the first demonstration of the preventive effects of nisin, bacteriocins, and probiotics, particularly in periodontitis-induced intestinal dysbiosis and fatty liver disease.

In 2023, a new term, metabolic dysfunction-associated steatotic liver disease (MASLD) / metabolic steatohepatitis (MASH) ¹⁰, was proposed to replace NAFLD/NASH and its definition includes at least one of five cardiovascular metabolic risk factors (overweight, hypertension, hypercholesterolemia, smoking habits, and diabetes). In other words, the definition of MASLD is not just a name change, but a strengthening of the traditional bidirectional link between NAFLD and metabolic disease. Similarly, it is a well-known fact that periodontal disease has smoking as its greatest environmental risk factor and exacerbates metabolic diseases, such as diabetes, obesity, and coronary vascular disease, which is an important coincidence with the pathogenesis of MASLD.

Furthermore, recent studies have reported that the liver from patients with gut dysbiosis and MASLD, as in the elderly and post-cardiac arrest donors, is a marginal organ that increases the risk of poor prognosis after liver resection or liver transplantation, the main treatment modalities for liver disease. Thereby, the detailed pathomechanisms of hepatic ischemia-reperfusion injury and post-transplant rejection in these operations are not known, but periodontal disease may be a potential risk factor for these hepatotoxic events as well.

These facts suggests the need for a potential disease definition of periodontal disease-related-MASLD/MASH and may support the utility of the microbiome-targeted therapy.

Read the paper here:

Kuraji R, Ye C, Zhao C, Gao L, Martinez A, Miyashita Y, Radaic A, Kamarajan P, Le C, Zhan L, Range H, Sunohara M, Numabe Y, Kapila YL. Nisin lantibiotic prevents NAFLD liver steatosis and mitochondrial oxidative stress following periodontal disease by abrogating oral, gut and liver dysbiosis. NPJ Biofilms Microbiomes. 2024 Jan 17;10(1):3. doi: 10.1038/s41522-024-00476-x. PMID: 38233485; PMCID: PMC10794237.

https://www.nature.com/articles/s41522-024-00476-x

Ref

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2. Kuraji, R., Shiba, T., Dong, T. S., Numabe, Y. & Kapila, Y. L. Periodontal treatment and microbiome-targeted therapy in management of periodontitis-related nonalcoholic fatty liver disease with oral and gut dysbiosis. World J. Gastroenterol. 29, 967-996 (2023).
3. Kuraji, R., Hashimoto, S., Ito, H. & Numabe, Y. Development and Usage of Mouth Gag for Oral Experiments in the Mouse. Nihon Shishubyo Gakkai Kaishi (Journal of the Japanese Society of Periodontology) 58, 148-154 (2016).
4. Kuraji, R., Fujita, M., Ito, H., Hashimoto, S. & Numabe, Y. Effects of experimental periodontitis on the metabolic system in rats with diet-induced obesity (DIO): an analysis of serum biochemical parameters. Odontology 106, 162-170 (2018).
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8. Gao, L. et al. Nisin probiotic prevents inflammatory bone loss while promoting reparative proliferation and a healthy microbiome. NPJ Biofilms Microbiomes 8, 45 (2022).
9. Zhao, C. et al. Nisin a probiotic bacteriocin mitigates brain microbiome dysbiosis and Alzheimer's disease-like neuroinflammation triggered by periodontal disease. J. Neuroinflammation 20, 228 (2023).
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