Oral Pathobiont-Induced Changes in Gut Microbiota Aggravate the Pathology of Nonalcoholic Fatty Liver Disease in Mice

Abstract

Background & AimsPeriodontitis increases the risk of nonalcoholic fatty liver disease (NAFLD); however, the underlying mechanisms are unclear. Here, we show that gut dysbiosis induced by oral administration of Porphyromonas gingivalis, a representative periodontopathic bacterium, is involved in the aggravation of NAFLD pathology.MethodsC57BL/6N mice were administered either vehicle, P. gingivalis, or Prevotella intermedia, another periodontopathic bacterium with weaker periodontal pathogenicity, followed by feeding on a choline-deficient, l-amino acid-defined, high-fat diet with 60 kcal% fat and 0.1% methionine (CDAHFD60). The gut microbial communities were analyzed by pyrosequencing the 16S ribosomal RNA genes. Metagenomic analysis was used to determine the relative abundance of the Kyoto Encyclopedia of Genes and Genomes pathways encoded in the gut microbiota. Serum metabolites were analyzed using nuclear magnetic resonance-based metabolomics coupled with multivariate statistical analyses. Hepatic gene expression profiles were analyzed via DNA microarray and quantitative polymerase chain reaction.ResultsCDAHFD60 feeding induced hepatic steatosis, and in combination with bacterial administration, it further aggravated NAFLD pathology, thereby increasing fibrosis. Gene expression analysis of liver samples revealed that genes involved in NAFLD pathology were perturbed, and the two bacteria induced distinct expression profiles. This might be due to quantitative and qualitative differences in the influx of bacterial products in the gut because the serum endotoxin levels, compositions of the gut microbiota, and serum metabolite profiles induced by the ingested P. intermedia and P. gingivalis were different.ConclusionsSwallowed periodontopathic bacteria aggravate NAFLD pathology, likely due to dysregulation of gene expression by inducing gut dysbiosis and subsequent influx of gut bacteria and/or bacterial products.

Correlation Analysis of Gut Microbiota and Serum Metabolome With Porphyromonas gingivalis-Induced Metabolic Disorders

“…Given that the oral mucosa and colonic mucosa are physically connected, oral bacteria could be ingested and translocated to the lower digestive tract, and a possible mechanism of the “mouth-gut axis” has been proposed in the pathogenesis of periodontitis-associated MetS. Notably, a few studies conducted recently demonstrated that oral administration of periodontal pathogens, mainly P. gingivalis , could cause a variety of MetS-related disorders, including increased BMI, insulin resistance, circulatory inflammatory states, and alterations of intestinal permeability and microbiota ( Blasco-Baque et al., 2017 ; Tsuzuno et al., 2021 ; Yamazaki et al., 2021 ). However, little research has focused on the alteration of gut microbiota-derived metabolites.…”

Novel Insight into the Mechanisms of the Bidirectional Relationship between Diabetes and Periodontitis

“…A recent study has proven that transmission and subsequent colonization of the gut by oral bacteria is a common event in healthy subjects [ 142 ]. In periodontitis, swallowed periodontal bacteria can induce gut dysbiosis [ 58 , 143 ] and this is another possible mechanism linking periodontitis and DM [ 138 ].…”

“…P. gingivalis-induced gut dysbiosis was paralleled by downregulation of tight junction proteins (TJP-1, occluding) [ 115 , 144 , 145 ], likely leading to enhanced gut permeability and favoring endotoxemia. Of interest, oral administration of P. gingivalis induced changes in the gut microbiota prior to the development of systemic inflammation, suggesting that periodontitis-induced gut dysbiosis may cause endotoxemia, leading then to systemic inflammation and insulin resistance [ 143 ].…”

Exploration of Shared Gene Signatures and Molecular Mechanisms Between Periodontitis and Nonalcoholic Fatty Liver Disease

“…From the beginning, periodontitis has contributed to the development of NAFLD owing to systemic inflammation and oxidative stress on the basis of vitro study ( Tomofuji et al, 2007 ). Then, Porphyromonas gingivalis, the main pathogenic bacteria of periodontitis, resulted in the development of NAFLD, above which academic discussion had continued ever since ( Furusho et al, 2013 ; Nagasaki et al, 2021 ; Yamazaki et al, 2021 ). Epidemiological investigation reported that NAFLD incidence was increasing with the combination of periodontitis, which could increase the risk of progression to liver fibrosis as well ( Akinkugbe et al, 2017a ; Akinkugbe et al, 2017b ; Iwasaki et al, 2018 ; Suominen et al, 2019 ; Kuroe et al, 2021 ).…”