Intestinal Ralstonia pickettii augments glucose intolerance in obesity.

Shanthadevi D Udayappan,Willem M De Vos,Suzan Van Der Meij,Hilde Herrema,Fredrik Bäckhed,Bart A Van Wagensveld,Anne Vrieze,Guido J Bakker,Steven Aalvink,Kristien E Bouter,Stefan R Havik,Max Nieuwdorp,Clara Belzer,Göran Bergström,Julia J Witjes,Albert K Groen,Noor De Sonnaville,Patrice D Cani,Alice Chaplin,Hans G.h.j Heilig ,Erik S.g Stroes ,F Holleman ,Petia Kovatcheva‐Datchary ,J B L Hoekstra ,Daniël H Van Raalte ,Geesje M Dallinga‐Thie

doi:10.1371/journal.pone.0181693

Abstract

An altered intestinal microbiota composition has been implicated in the pathogenesis of metabolic disease including obesity and type 2 diabetes mellitus (T2DM). Low grade inflammation, potentially initiated by the intestinal microbiota, has been suggested to be a driving force in the development of insulin resistance in obesity. Here, we report that bacterial DNA is present in mesenteric adipose tissue of obese but otherwise healthy human subjects. Pyrosequencing of bacterial 16S rRNA genes revealed that DNA from the Gram-negative species Ralstonia was most prevalent. Interestingly, fecal abundance of Ralstonia pickettii was increased in obese subjects with pre-diabetes and T2DM. To assess if R. pickettii was causally involved in development of obesity and T2DM, we performed a proof-of-concept study in diet-induced obese (DIO) mice. Compared to vehicle-treated control mice, R. pickettii-treated DIO mice had reduced glucose tolerance. In addition, circulating levels of endotoxin were increased in R. pickettii-treated mice. In conclusion, this study suggests that intestinal Ralstonia is increased in obese human subjects with T2DM and reciprocally worsens glucose tolerance in DIO mice.

Highlights

The worldwide epidemic of obesity, which is a major risk factor for insulin resistance, drives the development of common medical conditions such as type 2 diabetes mellitus (T2DM), dyslipidaemia and cardiovascular disease [1]
Bacterial 16S rDNA was PCR amplified from DNA isolated from human mesenteric visceral adipose tissue biopsies, whereas PCR amplification from omental or subcutaneous adipose tissue biopsies barely yielded any 16S rDNA amplicons
Considering emerging data in the field suggesting that endotoxin derived from Gram-negative bacteria is involved in metabolic endotoxemia and reduced glucose tolerance [9, 14, 16], for this project we focused on the role of Ralstonia in glucose homeostasis

Summary

Introduction

The worldwide epidemic of obesity, which is a major risk factor for insulin resistance, drives the development of common medical conditions such as type 2 diabetes mellitus (T2DM), dyslipidaemia and cardiovascular disease [1]. The development of obesity and T2DM is complex and is driven by both environmental and genetic factors [2]. Obesity-induced inflammatory changes in white adipose tissue have been postulated to play a crucial part in the pathophysiology of obesity and T2DM. Mesenteric visceral adipose tissue inflammation is linked to insulin resistance reflected in reduced plasma adiponectin levels, which are associated with development of insulin resistance [4] and macrophage influx [5]. Insulin resistance correlates with upregulation of visceral adipose genes involved in innate immunity and inflammation [5]

Methods

Results

Conclusion