Periodontitis-induced oral microbiome alterations provide clues on how periodontitis exacerbates colitis

Abstract

Aim: To evaluate whether and how microbiota-derived metabolites associated with periodontitis aggravate colitis in mice.

Materials and methods: A mouse model of periodontitis and colitis was constructed. Unbiased transcriptomic analyses of the colon were performed to explore important pathways through which periodontitis exacerbated colitis. Oral and gut bacteria were analysed using 16S rRNA sequencing. Gas chromatography-mass spectrometry was used to observe the alterations of oral and gut metabolites. Isolated intestinal lamina propria lymphocytes were analysed by flow cytometry. Inflammasome pathway was detected using qRT-PCR, Western blotting or ELISA.

Results: Periodontitis activated the colonic inflammasome pathway and altered the gut microbial composition and metabolite profiles in mice with colitis. Notably, periodontitis induced increase of the faecal metabolite isoleucine (Ile) which was synthesized by microbiota and plants. Moreover, periodontitis upregulated the Ile levels in saliva, but not in serum, indicating that Ile might be an oral pathobiont-synthesizing metabolite that transited from the oral cavity to the gut. Ile triggered the inflammasome pathway, upregulated the number of inflammatory IL-1β^high MHCII^high Ly6C^high monocytes in colonic lamina propria, and exacerbated colitis. Further studies found that the Ile metabolite acetyl-coenzyme A positively regulated NLRP3 inflammasome by KAT5-mediated acetylation of NLRP3.

Conclusions: Our study revealed that alteration in periodontitis-induced microbial metabolites deteriorated colitis in a mouse model and that this was associated with Ile production.

Keywords: NLRP3 inflammasome; colitis; isoleucine; monocytes; periodontitis.