Changes in Gut Microbiota Control Metabolic Endotoxemia-Induced Inflammation in High-Fat Diet–Induced Obesity and Diabetes in Mice

Abstract

OBJECTIVE-Diabetes and obesity are characterized by a low-grade inflammation whose molecular origin is unknown. We previously determined, first, that metabolic endotoxemia controls the inflammatory tone, body weight gain, and diabetes, and second, that high-fat feeding modulates gut microbiota and the plasma concentration of lipopolysaccharide (LPS), i.e., metabolic endotoxemia. Therefore, it remained to demonstrate whether changes in gut microbiota control the occurrence of metabolic diseases. RESEARCH DESIGN AND METHODS-We changed gut microbiota by means of antibiotic treatment to demonstrate, first, that changes in gut microbiota could be responsible for the control of metabolic endotoxemia, the low-grade inflammation, obesity, and type 2 diabetes and, second, to provide some mechanisms responsible for such effect.RESULTS-We found that changes of gut microbiota induced by an antibiotic treatment reduced metabolic endotoxemia and the cecal content of LPS in both high-fat-fed and ob/ob mice. This effect was correlated with reduced glucose intolerance, body weight gain, fat mass development, lower inflammation, oxidative stress, and macrophage infiltration marker mRNA expression in visceral adipose tissue. Importantly, high-fat feeding strongly increased intestinal permeability and reduced the expression of genes coding for proteins of the tight junctions. Furthermore, the absence of CD14 in ob/ob CD14 Ϫ/Ϫ mutant mice mimicked the metabolic and inflammatory effects of antibiotics.CONCLUSIONS-This new finding demonstrates that changes in gut microbiota controls metabolic endotoxemia, inflammation, and associated disorders by a mechanism that could increase intestinal permeability. It would thus be useful to develop strategies for changing gut microbiota to control, intestinal permeability, metabolic endotoxemia, and associated disorders.

Coenzyme Q10 supplementation lowers hepatic oxidative stress and inflammation associated with diet-induced obesity in mice

“…We know that HF feeding is responsible for the development of obesity and leads to insulin resistance within a few weeks in mice [8]. Here we confirm that the HF diet-induced obesity and glucose intolerance are independent of lipid peroxidation, since the level of tissue lipid peroxides are paradoxically strongly blunted due to a high vitamin E content of the HF…”

“…The lack of massive lipid accumulation might be explained by the fact that the sampling was performed at a late post-absorptive state (six hours after food removal). Moreover, the increase in mRNA HFF mice also present an altered glucose response, already generated through HF diet given independently on fructose administration [8]. Interestingly, this HFF models also drives inflammation in the liver tissue as shown by the higher COX2, CRP, IL6, TNFα and STAMP2 mRNA levels.…”

“…Plasma insulin was measured on 5µl of plasma collected from tail blood at 0 and 15 min using an ELISA kit (Mercodia, Upssala, Sweden). The insulin-resistance index was obtained by multiplication of the area under the curve of glucose between 0 and 15 min after glucose administration and the area under the curve of insulin between 0 and 15 min after glucose administration; its unit is mM*pM*min 2 - [8,[30][31][32]. The area under the curve was calculated from basal glycemia Page 7 of 42 A c c e p t e d M a n u s c r i p t 7 up to 120 minutes after the glucose administration, with no correction of the area by the basal value.…”

“…It has been shown that a high fat (HF) diet promotes endotoxemia and thereby increases proinflammatory cytokines production, namely in the liver [7,8]. Upon obesity, proinflammatory cytokines and oxidative stress have been shown to drive metabolic disturbances, such as insulin resistance and activation of immune system in the liver, in the adipose tissue and in the muscle [5,6,9].…”

L’altération de la perméabilité intestinale : chaînon manquant entre dysbiose et inflammation au cours de l’obésité ?

“…Chez l'homme, les modifications de perméabilité intestinale et ses liens avec le microbiote et l'inflammation au cours de l'obésité sont encore peu documentés mais ces études sont en plein essor. < dique ont montré que le changement de composition du microbiote et l'inflammation systémique étaient effectivement associés à une alté-ration de la perméabilité intestinale et de la sensibilité à l'insuline [8]. Cependant, les altérations de la perméabilité intestinale et ses liens potentiels avec l'inflammation et le microbiote intestinal restent à explorer dans l'obésité humaine.…”