High Accumulation of Metformin in Colonic Tissue of Subjects With Diabetes or the Metabolic Syndrome

Paleari, Laura; Burhenne, Jürgen; Weiß, Johanna; Foersch, Sebastian; Roth, Wilfried; Parodi, A. Ferretto; Gnant, Michael; Bachleitner‐Hofmann, Thomas; Scherer, Dominique; Ulrich, Cornelia M.; Štabuc, Borut; Puntoni, Matteo; Coccia, G.; Petrera, Marilena; Haefeli, Walter E.; DeCensi, Andrea

doi:10.1053/j.gastro.2017.12.040

Cited by 31 publications

(24 citation statements)

References 9 publications

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“…First, a research published in 2018 screened the impact of more than 1000 non-antibiotic drugs including metformin on gut bacteria [47] . The authors found that metformin would inhibit F. nucleatum at a colon concentration of 1.5 mM, which is considered a safe dose for humans as metformin concentrates approximately 150-fold higher than in plasma [56] . Second, before the start of our animal experiments, we have performed growth curve of both F. nucleatum and ETBF with and without metformin.…”

Section: Discussionmentioning

confidence: 99%

Metformin elicits antitumour effect by modulation of the gut microbiota and rescues Fusobacterium nucleatum-induced colorectal tumourigenesis

et al. 2020

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Background The effect of metformin on gut microbiota has been reported, but whether metformin can suppress colorectal cancer (CRC) by affecting gut microbiota composition and rescue F. nucleatum -induced tumourigenicity remains unclear. Methods To identify microbiota associated with both CRC occurrence and metformin treatment, first, we reanalyzed the gut microbiome of our previous data on two human cohorts of normal and CRC individuals. Subsequently, we summarized microbiota altered by metformin from published literatures. Several taxa, including Fusobacterium , were associated with both CRC occurrence and metformin treatment. We investigated the effect of metformin on APC Min/+ mice given with or without F. nucleatum . 16S rRNA gene sequencing was performed. Findings We summarized 131 genera altered by metformin from 18 published literatures . Five genera reported to be changed by metformin, including Bacteroides, Streptococcus, Achromobacter, Alistipes and Fusobacterium , were associated with CRC in both of our human cohorts. Metformin relieved the symptoms caused by F. nucleatum administration in APC Min/+ mice, and showed promise in suppressing intestinal tumour formation and rescuing F. nucleatum -induced tumourigenicity. Administration of F. nucleatum and/or metformin had effect on gut microbiome structure, composition and functions of APC Min/+ mice. Interpretation This study pioneers in predicting critical CRC-associated taxa contributing to the antitumour effect of metformin, and correlating gut microbiome with the antitumour effect of metformin in experimental animals. We presented a basis for future investigations into metformin's potential effect on suppressing F. nucleatum -induced tumor formation in vivo . Funding This work was supported by grants from the National Natural Science Foundation of China (31701250).

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Section: Discussionmentioning

confidence: 99%

Metformin elicits antitumour effect by modulation of the gut microbiota and rescues Fusobacterium nucleatum-induced colorectal tumourigenesis

et al. 2020

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“…However, as reviewed here, both AMPK-dependent and AMPK-independent pathways have been proposed to explain the glucose-lowering and anti-tumor effect of metformin ( Figures 1 , 2 ). Besides, although the liver is considered as the primary site of metformin pharmacodynamics, the gut is also recognized an important site for its anti-diabetic and anti-tumor effects ( Duca et al, 2015 ; Paleari et al, 2018 ). In addition, recent studies demonstrated that metformin might affect metabolite profiles in patients with type 2 diabetes or tumor cells ( Zhang et al, 2014 ; He et al, 2015 ; Xu et al, 2015 ).…”

Section: Discussionmentioning

confidence: 99%

Molecular Mechanisms of Metformin for Diabetes and Cancer Treatment

Zhang

et al. 2018

Front. Physiol.

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Metformin has been the first-line drug treatment for hyperglycemia and insulin resistance for over 50 years. However, the molecular basis of its therapeutic role remained incompletely understood. Recent advances demonstrate that metformin could exert its glucose-lowering effect by multiple mechanisms, including activation of 5′-AMP-activated protein kinase, decreasing production of cyclic AMP, suppressing mitochondrial complex I of the electron transport chain, targeting glycerophosphate dehydrogenase, and altering the gut microbiome. In addition, epidemiological and clinical observation studies suggest that metformin reduced cancer risk in patients with type 2 diabetes and improved survival outcome of human cancers. Experimental studies have shown that this drug can inhibit cancer cell viability, growth, and proliferation through inhibiting mTORC1 signaling and mitochondrial complex I, suggesting that it may be a promising drug candidate for malignancy. Here, we summarize recent progress in studies of metformin in type 2 diabetes and tumorigenesis, which provides novel insight on the therapeutic development of human diseases.

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“…140 Mechanistically, metformin has been shown to reduce cellular proliferative activity through activation of AMP-activated protein kinase, 141 protect against immune evasion of tumors by countering the functional exhaustion of tumor infiltrating lymphocytes, 142 and accumulate in colonic tissue in a considerable concentration (approximately 150-fold higher than in plasma). 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

223

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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High Accumulation of Metformin in Colonic Tissue of Subjects With Diabetes or the Metabolic Syndrome

Cited by 31 publications

References 9 publications

Metformin elicits antitumour effect by modulation of the gut microbiota and rescues Fusobacterium nucleatum-induced colorectal tumourigenesis

Metformin elicits antitumour effect by modulation of the gut microbiota and rescues Fusobacterium nucleatum-induced colorectal tumourigenesis

Molecular Mechanisms of Metformin for Diabetes and Cancer Treatment

Environmental Factors, Gut Microbiota, and Colorectal Cancer Prevention

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