Intestinal Translocation of LiveDrives Insulin Resistance.

Abstract

Periodontitis has been emphasized as a risk factor of insulin resistance-related systemic diseases. Accumulating evidence has suggested a possible "oral-gut axis" linking oral infection and extraoral diseases, but it remains unclear whether periodontal pathogens can survive the barriers of the digestive tract and how they play their pathogenic roles. The present study established a periodontitis mouse model through oral ligature plusinoculation and demonstrated that periodontitis aggravated diet-induced obesity and insulin resistance, while also causingenrichment in the intestine. Metabolic labeling strategy validated thatcould translocate to the gastrointestinal tract in a viable state. Oral administration of livingelicited insulin resistance, while administration of pasteurizedhad no such effect. Combination analysis of metagenome sequencing and nontargeted metabolomics suggested that the tryptophan metabolism pathway, specifically indole and its derivatives, was involved in the pathogenesis of insulin resistance caused by oral administration of living. Moreover, liquid chromatography-high-resolution mass spectrometry analysis confirmed that the aryl hydrocarbon receptor (AhR) ligands, mainly indole acetic acid, tryptamine, and indole-3-aldehyde, were reduced in diet-induced obese mice with periodontitis, leading to inactivation of AhR signaling. Supplementation with Ficz (6-formylindolo (3,2-b) carbazole), an AhR agonist, alleviated periodontitis-associated insulin resistance, in which the restoration of gut barrier function might play an important role. Collectively, these findings reveal that the oral-gut translocation of viableworks as a fuel linking periodontitis and insulin resistance, in which reduction of AhR ligands and inactivation of AhR signaling are involved. This study provides novel insight into the role of the oral-gut axis in the pathogenesis of periodontitis-associated comorbidities.