Gut microbiota may mediate the impact of chronic apical periodontitis on atherosclerosis in apolipoprotein E‐deficient mice

Abstract

Aim: There are growing evidences linking chronic apical periodontitis (CAP) to atherosclerosis. Gut microbiota is found to be involved in the development of atherosclerosis. Recent studies have shown that CAP could change the diversity and composition of the gut microbiota. It was therefore, we hypothesized that gut microbiota and its metabolites could mediate the impact of CAP on atherosclerosis.Methodology: Twenty-four 5-week-old lipoprotein E knockout (apoE −/− ) mice were randomly divided into four groups: the CAP group, Con group, Co-CAP (cohoused with CAP) and Co-Con (cohoused with Con) group. In the CAP group, sterile cotton wool containing P. gingivalis was placed into the exposed pulp chamber, followed by coronal resin-based composite restoration of the bilateral maxillary first and second molars. In the Con group, a sham operation was performed. Biweekly, mice in the CAP group were anaesthetised to check the sealing of coronal access. Meanwhile, the animals in the Con group were anaesthetised. The cohousing approach was used to introduce gut microbiota from the CAP and Con groups into the Co-CAP and Co-Con groups, respectively. Alterations in the abundance and diversity of the gut microbiota were detected using 16S rRNA sequencing, Oil-red O staining was used to demonstrate the extent of lesions, and serum levels of trimethylamine Noxide (TMAO), and immunohistochemistry of flavin-containing monooxygenase 3 (FMO3) in liver were used to assess TMAO-related metabolic alterations.Results: Alterations of alpha and beta diversity were shown both in the CAP and the Co-CAP groups. Moreover, the percentage of atherosclerotic lesion area increased in the CAP and Co-CAP groups (p < .05). Linear discriminant analysis effect size (LEfSe) at the family level found the increases of Lachnospiraceae and Ruminococcaceae (p < .05), which were positively correlated with serum TMAO levels (p < .05). In the redundancy analysis technique (RDA), serum levels of TMAO were positively associated with the atherosclerotic lesions. Co-occurrence analysis revealed that the relative abundances of Lachnospiraceae and Porphyromonadacae were positively correlated with both the percentage of lesion area and TMAO level (p < .05).

Unveiling the Oral-Gut Connection: Chronic Periodontal Infection Accelerates Atherosclerosis via Gut Microbiota Dysbiosis and Altered Metabolites in apoE-/- Mice on a High-Fat Diet

“…High levels of serum TCDCA induced by aging activate TMAO-associated signaling pathways via hepatic FXR. 33 Previous experiments also found increased serum levels of TMAO in mice from CAP group, 23 suggesting that CAP may in uence the development of atherosclerosis by modulating the gut microbiota metabolism of bile acids and affecting serum TMAO levels. This nding is consistent with metabolite set enrichment, which revealed an alteration in primary bile acid synthesis in the CAP group (Fig.…”

“…10 Notably, fecal microbiota transplantation with altered gut microbiota as an independent variable, also exacerbated the degree of atherosclerosis in apoE −/− mice, suggesting a causal link between gut microbiota and atherosclerosis. 23 Nevertheless, the precise mechanisms through which gut microbiota contribute to the development of atherosclerosis require further exploration. Based on this study's ndings, it is possible that CAP impacts atherosclerosis by modulating the gut microbiota metabolites and intestinal permeability.…”

Unveiling the oral-gut connection: chronic apical periodontitis accelerates atherosclerosis via gut microbiota dysbiosis and altered metabolites in apoE−/− Mice on a high-fat diet

“…High levels of serum TCDCA induced by aging activate TMAO-associated signaling pathways via hepatic FXR. 34 Previous experiments also revealed increased serum levels of TMAO in mice in the CAP group, 25 suggesting that CAP may influence the development of atherosclerosis by modulating the metabolism of bile acids in the gut microbiota and affecting the serum TMAO concentration. These findings are consistent with those of the metabolite set enrichment analysis, which revealed an alteration in primary bile acid synthesis in the CAP group (Fig.…”

“… 12 Notably, FMT with an altered gut microbiota as an independent variable also exacerbated the degree of atherosclerosis in apoE −/− mice, suggesting a causal link between the gut microbiota and atherosclerosis. 25 However, the specific mechanisms through which the gut microbiota contributes to the development of atherosclerosis require further exploration. Based on the findings of the present study, it is possible that CAP impacts atherosclerosis by modulating gut microbiota metabolites and intestinal permeability.…”

The Roles of Periodontal Bacteria in Atherosclerosis

“…Specifically, they observed significant differences in the abundance of 37 taxa, wherein an increase in the relative abundance of Firmicutes , Chloroflexi , and Cyanobacteria , along with a decrease in Bacteroidetes , correlated with the progression of AS ( p < 0.05) [ 222 ]. In the context of chronic apical periodontitis, ApoE -/- mice exhibited elevated serum levels of trimethylamine N-oxide (TMAO), a gut-derived metabolite that indicates the risk of cardiovascular events [ 223 ]. Co-occurrence analysis demonstrated a significant positive correlation ( p < 0.05) between the relative abundances of Lachnospiraceae and Porphyromonadaceae with both the percentage of lesion area and TMAO levels, suggesting that chronic apical periodontitis exacerbates atherosclerotic lesions by modulating the gut microbiota and its metabolites [ 223 ].…”