Metformin alters the gut microbiome of individuals with treatment-naive type 2 diabetes, contributing to the therapeutic effects of the drug

Wu, Hao; Esteve, Eduardo; Tremaroli, Valentina; Khan, Muhammad Idrees; Caesar, Robert; Mannerås-Holm, Louise; Ståhlman, Marcus; Olsson, Lisa; Sérino, Matteo; Planas-Fèlix, Mercè; Xifra, Gemma; Mercader, Josep M.; Torrents, David; Burcelin, Rémy; Ricart, Wifredo; Perkins, Rosie; Fernández‐Real, José Manuel; Bäckhed, Fredrik

doi:10.1038/nm.4345

Cited by 1,202 publications

(1,279 citation statements)

References 71 publications

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“…Studies have proposed various mechanisms of action for metformin to reduce gluconeogenesis in the liver (5) or via affecting the gut microbiota (30), reporting mainly indirect effects of metformin through various pathways involved in the metabolic control. Thus far, only Madiraju et al (6) and this study have revealed tissue-specific, direct cellular targets of metformin, mtGPD in liver, and SHIP2 in muscle and kidney, contributing to the effect of metformin to reduce gluconeogenesis and increase glucose uptake, respectively.…”

Section: Discussionmentioning

confidence: 99%

Metformin increases glucose uptake and acts renoprotectively by reducing SHIP2 activity

Polianskyte-Prause¹,

Tolvanen²,

Lindfors³

et al. 2018

FASEB j.

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Metformin, the first-line drug to treat type 2 diabetes (T2D), inhibits mitochondrial glycerolphosphate dehydrogenase in the liver to suppress gluconeogenesis. However, the direct target and the underlying mechanisms by which metformin increases glucose uptake in peripheral tissues remain uncharacterized. Lipid phosphatase Src homology 2 domain-containing inositol-5-phosphatase 2 (SHIP2) is upregulated in diabetic rodent models and suppresses insulin signaling by reducing Akt activation, leading to insulin resistance and diminished glucose uptake. Here, we demonstrate that metformin directly binds to and reduces the catalytic activity of the recombinant SHIP2 phosphatase domain in vitro. Metformin inhibits SHIP2 in cultured cells and in skeletal muscle and kidney of db/db mice. In SHIP2-overexpressing myotubes, metformin ameliorates reduced glucose uptake by slowing down glucose transporter 4 endocytosis. SHIP2 overexpression reduces Akt activity and enhances podocyte apoptosis, and both are restored to normal levels by metformin. SHIP2 activity is elevated in glomeruli of patients with T2D receiving nonmetformin medication, but not in patients receiving metformin, compared with people without diabetes. Furthermore, podocyte loss in kidneys of metformin-treated T2D patients is reduced compared with patients receiving nonmetformin medication. Our data unravel a novel molecular mechanism by which metformin enhances glucose uptake and acts renoprotectively by reducing SHIP2 activity.—Polianskyte-Prause, Z., Tolvanen, T. A., Lindfors, S., Dumont, V., Van, M., Wang, H., Dash, S. N., Berg, M., Naams, J.-B., Hautala, L. C., Nisen, H., Mirtti, T., Groop, P.-H., Wähälä, K., Tienari, J., Lehtonen, S. Metformin increases glucose uptake and acts renoprotectively by reducing SHIP2 activity.

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Section: Discussionmentioning

confidence: 99%

Metformin increases glucose uptake and acts renoprotectively by reducing SHIP2 activity

Polianskyte-Prause¹,

Tolvanen²,

Lindfors³

et al. 2018

FASEB j.

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“…143 In a recent RCT of 40 patients with type 2 diabetes, metformin altered the composition of gut microbiota by increasing the abundance of Escherichia and Bifidobacterium and decreasing the abundance of Intestinibacter, thereby increasing production of SCFAs. 144 …”

Section: Othersmentioning

confidence: 99%

Environmental Factors, Gut Microbiota, and Colorectal Cancer Prevention

Song

Chan

2019

Clinical Gastroenterology and Hepatology

207

157

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The substantial burden of colorectal cancer and increasing trend in young adults highlight the importance of lifestyle modification as a complement to screening for colorectal cancer prevention. Several dietary and lifestyle factors have been implicated in the development of colorectal cancer, possibly through the intricate metabolic and inflammatory mechanisms. Likewise, as a key metabolic and immune regulator, the gut microbiota has been recognized to play an important role in colorectal tumorigenesis. Increasing data support that environmental factors are crucial determinants for the gut microbial composition and function, whose alterations induce changes in the host gene expression, metabolic regulation, and local and systemic immune response, thereby influencing cancer development. Here, we review the epidemiologic and mechanistic evidence regarding the links between diet and lifestyle and the gut microbiota in the development of colorectal cancer. We focus on factors for which substantial data support their importance for colorectal cancer and their potential role in the gut microbiota, including overweight and obesity, physical activity, dietary patterns, fiber, red and processed meat, marine omega-3 fatty acid, alcohol, and smoking. We also briefly describe other colorectal cancer-preventive factors for which the links with the gut microbiota have been suggested but remain to be mechanistically characterized, including vitamin D status, dairy consumption, and metformin use. Given limitations in available evidence, we highlight the need for further investigations in the relationship between environmental factors, gut microbiota, and colorectal cancer, which may lead to development and clinical translation of potential microbiota-based strategies for cancer prevention.

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“…There is convincing evidence [19,20] that metformin exposure induces significant changes in human intestinal microbiota (for example, decreases in abundance of Intestinibacter), and in the gut metabolome (for example, increased butyrate production). These observations stemmed from efforts to confirm and extend prior research (for examples, [21][22][23]) concerning relationships between microbiota composition, obesity and diabetes.…”

Section: Metformin and Gut Microbiotamentioning

confidence: 99%

The effects of metformin on gut microbiota and the immune system as research frontiers

Pollak

2017

Diabetologia

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Recent studies have revealed that metformin influences gut microbiota and the immune system although neither is a classic target of the drug. This research has revealed complexity not previously appreciated, and opened new research directions. The extent to which immunomodulatory effects and actions on the microbiota are related to each other and account for effects on host energy metabolism remains to be determined. These sites of action may be relevant not only to the efficacy of metformin for its established use in type 2 diabetes, but also to proposed novel indications in oncology and other diseases.

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Metformin alters the gut microbiome of individuals with treatment-naive type 2 diabetes, contributing to the therapeutic effects of the drug

Cited by 1,202 publications

References 71 publications

Metformin increases glucose uptake and acts renoprotectively by reducing SHIP2 activity

Metformin increases glucose uptake and acts renoprotectively by reducing SHIP2 activity

Environmental Factors, Gut Microbiota, and Colorectal Cancer Prevention

The effects of metformin on gut microbiota and the immune system as research frontiers

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