Nisin lantibiotic prevents NAFLD liver steatosis and mitochondrial oxidative stress following periodontal disease by abrogating oral, gut and liver dysbiosis

Abstract

Oral microbiome dysbiosis mediates chronic periodontal disease, gut microbial dysbiosis, and mucosal barrier disfunction that leads to steatohepatitis via the enterohepatic circulation. Improving this dysbiosis towards health may improve liver disease. Treatment with antibiotics and probiotics have been used to modulate the microbial, immunological, and clinical landscape of periodontal disease with some success. The aim of the present investigation was to evaluate the potential for nisin, an antimicrobial peptide produced by Lactococcus lactis, to counteract the periodontitis-associated gut dysbiosis and to modulate the glycolipid-metabolism and inflammation in the liver. Periodontal pathogens, namely Porphyromonas gingivalis, Treponema denticola, Tannerella forsythia and Fusobacterium nucleatum, were administrated topically onto the oral cavity to establish polymicrobial periodontal disease in mice. In the context of disease, nisin treatment significantly shifted the microbiome towards a new composition, commensurate with health while preventing the harmful inflammation in the small intestine concomitant with decreased villi structural integrity, and heightened hepatic exposure to bacteria and lipid and malondialdehyde accumulation in the liver. Validation with RNA Seq analyses, confirmed the significant infection-related alteration of several genes involved in mitochondrial dysregulation, oxidative phosphorylation, and metal/iron binding and their restitution following nisin treatment. In support of these in vivo findings indicating that periodontopathogens induce gastrointestinal and liver distant organ lesions, human autopsy specimens demonstrated a correlation between tooth loss and severity of liver disease. Nisin’s ability to shift the gut and liver microbiome towards a new state commensurate with health while mitigating enteritis, represents a novel approach to treating NAFLD-steatohepatitis-associated periodontal disease.

Updated mechanisms of MASLD pathogenesis

“…Notably, oral health, such as periodontitis, has been theorized to be linked to the development of MASLD [ 126 ]. In addition, emerging evidence suggests a relationship between oral and gut microorganisms [ 127 , 128 ]. The oral-gut-liver axis concept has been proposed, portraying periodontal treatment as a potential treatment and prevention strategy for MASLD [ 129 ].…”

Role of Nonalcoholic Fatty Liver Disease in Periodontitis: A Bidirectional Relationship

“…P. gingivalis provokes intestinal microenvironmental disorder and increases the permeability of the intestinal wall, thus facilitating the direct passage of pathogenic microbes and their metabolites to the bloodstream and hepatic tissues [ 125 - 127 ]. Thus, periodontal pathogenic microbes and their metabolites in hepatic tissue instigate hepatic inflammation and the progression of fatty liver disease [ 19 , 82 , 103 , 128 ].…”

“…Dysbiosis of the oral microbiota gives rise to a probability of pathogenic infection among internal organs through gut microbiota dysbiosis [ 16 - 18 ]. It arouses poor mucosal wall physiology, leading to steatohepatitis through the enterohepatic circulation [ 19 ]. Another study revealed that the oral microbiome has supervisory authority over the gut microbiome [ 17 ].…”