Resolvin E1 Reverses Experimental Periodontitis and Dysbiosis

Abstract

Periodontitis is a biofilm-induced inflammatory disease characterized by dysbiosis of the commensal periodontal microbiota. It is unclear how natural regulation of inflammation affects the periodontal biofilm. Promoters of active resolution of inflammation including Resolvin E1 (RvE1) effectively treat inflammatory periodontitis in animal models. The goals of this study were 1) to compare periodontal tissue gene expression in different clinical conditions, 2) to determine the impact of local inflammation on the composition of subgingival bacteria, and 3) to understand how inflammation impacts these changes. Two clinically-relevant experiments were performed in rats: prevention and treatment of ligature-induced periodontitis with RvE1 topical treatment. The gingival transcriptome was evaluated by RNA-seq sequencing of mRNA. The composition of the subgingival microbiota was characterized by 16S rDNA sequencing. Periodontitis was assessed by bone morphometric measurements and histomorphometry of block sections. H&E and, tartrate resistant acid phosphatase staining were used to characterize and quantify inflammatory changes. RvE1 treatment prevented bone loss in ligature induced periodontitis. Osteoclast density and inflammatory cell infiltration in the RvE1 groups were lower than those in the placebo group. RvE1 treatment reduced expression of inflammation-related genes returning the expression profile to one more similar to health. Treatment of established periodontitis with RvE1 reversed bone loss, reversed inflammatory gene expression and reduced osteoclast density. Assessment of the rat subgingival microbiota after RvE1 treatment revealed marked changes in both prevention and treatment experiments. The data suggest that modulation of local inflammation has a major role in shaping the composition of the subgingival microbiota.

Pro-resolving mediators in the regulation of periodontal disease

“…The important principles demonstrated by these studies are that resolvins and lipoxins act to modulate the inflammatory response essentially aborting and reversing the chronic phase, promoting more rapid resolution, and that elimination of inflammation in a healing lesion promotes tissue regeneration. In small animals, these findings are not limited to the rabbit, but have been reproduced in mice and rats as well (54, 95). …”

“…It has been demonstrated that there is dysbiosis of the oral microbiome associated with periodontitis (9), but the temporal sequence of onset of each and the interplay between bacteria and inflammation is just beginning to be described (54, 55). …”

“…, without mechanical or antimicrobial therapy. In a subsequent study by Lee and co-workers, the temporal dynamics of inflammation-induced dysbiosis of the periodontal microbiota and the impact of RvE1 were examined in rat periodontitis (54). Periodontitis was induced in rats using ligature placement alone to observe naturally occurring dysbiosis of the rat microbiome associated with progressive periodontitis, rather than adding a human pathogen to induce disease.…”

“…Animals models of periodontal disease have been used to demonstrate regeneration of periodontal tissues mediated by lipoxins and resolvins, endogenous regulators if inflammation (8, 54, 94). The capacity for regeneration in small animals is greater than in large animals and man.…”

“…The complexity of the microbiome (alpha diversity) and the bacterial biomass was also reduced (data not shown). (Adapted from Lee et al 2016 (54)).…”