Modulation of gut microbiota by antibiotics improves insulin signalling in high-fat fed mice

Carvalho, Bruno M.; Guadagnini, Dioze; Tsukumo, Daniela Miti Lemos; Schenka, André Almeida; Latuf-Filho, Paulo; Vassallo, José; Dias, Juliano César; Kubota, Lauro T.; Carvalheira, José Barreto Campello; Saad, Mário José Abdalla

doi:10.1007/s00125-012-2648-4

Cited by 272 publications

(228 citation statements)

References 44 publications

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“…In addition, as previously reported [19] , we also observed a systemic repression of inflammation by antibiotic treatment. A striking observation in this study was that antibiotic treatment exerted a dramatic effect in improving glucose intolerance in HFD-fed mice, which was comparable to that of metformin.…”

Section: Discussionsupporting

confidence: 91%

“…In concert with the role of gut bacteria and LPS on the regulation of host inflammation and insulin sensitivity, antibiotic treatment aiming to reduce gut-derived LPS [19] exerted similar effects to metformin in attenuating oxidative stress, activating the Nrf2 system and reducing PTEN expression. In addition, as previously reported [19] , we also observed a systemic repression of inflammation by antibiotic treatment.…”

Section: Discussionmentioning

confidence: 99%

“…In the LPS (Sigma-Aldrich, Shanghai, China) injection experiments, HFDfed mice were divided into HFD, HFD plus metformin (HM) and HFD plus metformin with LPS (HML) groups. Before giving the mice drinking water with metformin, LPS (50 μg· kg -1 ·d -1 ) was subcutaneously injected into mice for 5 d, and they were then treated with metformin as described above for an additional 10 d. We also performed these experiments on a [19] . These mice were then treated without (HA) or with metformin (HMA) in their drinking water for 4 weeks, as described above.…”

Section: Methodsmentioning

confidence: 99%

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Metformin exerts glucose-lowering action in high-fat fed mice via attenuating endotoxemia and enhancing insulin signaling

et al. 2016

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Aim: Accumulating evidence shows that lipopolysaccharides (LPS) derived from gut gram-negative bacteria can be absorbed, leading to endotoxemia that triggers systemic inflammation and insulin resistance. In this study we examined whether metformin attenuated endotoxemia, thus improving insulin signaling in high-fat diet fed mice. Methods: Mice were fed a high-fat diet for 18 weeks to induce insulin resistance. One group of the mice was treated with oral metformin (100 mg·kg -1 ·d -1 ) for 4 weeks. Another group was treated with LPS (50 μg·kg -1 ·d -1 , sc) for 5 days followed by the oral metformin for 10 d. Other two groups received a combination of antibiotics for 7 d or a combination of antibiotics for 7 d followed by the oral metformin for 4 weeks, respectively. Glucose metabolism and insulin signaling in liver and muscle were evaluated, the abundance of gut bacteria, gut permeability and serum LPS levels were measured. Results: In high-fat fed mice, metformin restored the tight junction protein occludin-1 levels in gut, reversed the elevated gut permeability and serum LPS levels, and increased the abundance of beneficial bacteria Lactobacillus and Akkermansia muciniphila. Metformin also increased PKB Ser473 and AMPK T172 phosphorylation, decreased MDA contents and redox-sensitive PTEN protein levels, activated the anti-oxidative Nrf2 system, and increased IκBα in liver and muscle of the mice. Treatment with exogenous LPS abolished the beneficial effects of metformin on glucose metabolism, insulin signaling and oxidative stress in liver and muscle of the mice. Treatment with antibiotics alone produced similar effects as metformin did. Furthermore, the beneficial effects of antibiotics were addictive to those of metformin. Conclusion: Metformin administration attenuates endotoxemia and enhances insulin signaling in high-fat fed mice, which contributes to its anti-diabetic effects.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Metformin exerts glucose-lowering action in high-fat fed mice via attenuating endotoxemia and enhancing insulin signaling

et al. 2016

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“…Decreased insulin sensivity following 1 week of vancomycin treatment was observed in humans following changes in gut microbiota and bile acids (34), whereas a retrospective study has reported increased adiposity following antibiotic treatment with vancomycin for infectious endocarditis (58). In contrast to these observations, exposure to antibiotics in early life among children of overweight mothers has been associated with a decreased risk of overweight in childhood (52) and studies of ob/ob, high-fat diet-fed and insulin-resistant mice have demonstrated improved glucose tolerance following antibiotic treatment (22,59). Collectively, these studies may suggest that exposure to antibiotics early in life on one hand has the potential to disturb a healthy gut microbiota but, on the other hand, also has the potential to modify a disturbed microbiota towards a healthier state.…”

Section: Type 2 Diabetes and Gut Microbiota: A Word Of Cautionmentioning

confidence: 99%

MECHANISMS IN ENDOCRINOLOGY: Gut microbiota in patients with type 2 diabetes mellitus

Allin

Nielsen

Pedersen

2015

European Journal of Endocrinology

201

136

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Perturbations of the composition and function of the gut microbiota have been associated with metabolic disorders including obesity, insulin resistance and type 2 diabetes. Studies on mice have demonstrated several underlying mechanisms including host signalling through bacterial lipopolysaccharides derived from the outer membranes of Gram-negative bacteria, bacterial fermentation of dietary fibres to short-chain fatty acids and bacterial modulation of bile acids. On top of this, an increased permeability of the intestinal epithelium may lead to increased absorption of macromolecules from the intestinal content resulting in systemic immune responses, low-grade inflammation and altered signalling pathways influencing lipid and glucose metabolism. While mechanistic studies on mice collectively support a causal role of the gut microbiota in metabolic diseases, the majority of studies in humans are correlative of nature and thus hinder causal inferences. Importantly, several factors known to influence the risk of type 2 diabetes, e.g. diet and age, have also been linked to alterations in the gut microbiota complicating the interpretation of correlative studies. However, based upon the available evidence, it is hypothesised that the gut microbiota may mediate or modulate the influence of lifestyle factors triggering development of type 2 diabetes. Thus, the aim of this review is to critically discuss the potential role of the gut microbiota in the pathophysiology and pathogenesis of type 2 diabetes.

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“…Moreover, mice treated with a high-fat diet, were observed to present a reduction in intestinal permeability and in serum LPS levels, in addition to a decrease in the inflammation of adipose tissue and macrophage infiltration, after the modification of gut microbiota using antibiotics (49)(50)(51)(52)(53).…”

Section: Induction Of Subclinical Inflammationmentioning

confidence: 99%

Translational research into gut microbiota: new horizons on obesity treatment: updated 2014

Tsukumo

Carvalho

Carvalho-Filho

et al. 2015

Arch. Endocrinol. Metab.

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Obesity is currently a pandemic of worldwide proportions affecting millions of people. Recent stu dies have proposed the hypothesis that mechanisms not directly related to the human genome could be involved in the genesis of obesity, due to the fact that, when a population undergoes the same nutritional stress, not all individuals present weight gain related to the diet or become hyperglycemic. The human intestine is colonized by millions of bacteria which form the intestinal flora, known as gut flora. Studies show that lean and overweight human may present a difference in the composition of their intestinal flora; these studies suggest that the intestinal flora could be involved in the development of obesity. Several mechanisms explain the correlation between intestinal flora and obesity. The intestinal flora would increase the energetic extraction of non-digestible polysaccharides. In addition, the lipopolysaccharide from intestinal flora bacteria could trigger a chronic sub-clinical inflammatory process, leading to obesity and diabetes. Another mechanism through which the intestinal flora could lead to obesity would be through the regulation of genes of the host involved in energy storage and expenditure. In the past five years data coming from different sources established causal effects between intestinal microbiota and obesity/insulin resistance, and it is clear that this area will open new avenues of therapeutic to obesity, insulin resistance and DM2. Arch Endocrinol Metab. 2015;59(2):154-60

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Modulation of gut microbiota by antibiotics improves insulin signalling in high-fat fed mice

Cited by 272 publications

References 44 publications

Metformin exerts glucose-lowering action in high-fat fed mice via attenuating endotoxemia and enhancing insulin signaling

Metformin exerts glucose-lowering action in high-fat fed mice via attenuating endotoxemia and enhancing insulin signaling

MECHANISMS IN ENDOCRINOLOGY: Gut microbiota in patients with type 2 diabetes mellitus

Translational research into gut microbiota: new horizons on obesity treatment: updated 2014

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