Metformin-induced reductions in tumor growth involves modulation of the gut microbiome

Broadfield, Lindsay A.; Saigal, Amna; Szamosi, Jake C.; Hammill, Joanne A.; Bezverbnaya, Ksenia; Wang, Dongdong; Gautam, Jaya; Tsakiridis, Evangelina; Pastena, Fiorella Di; McNicol, Jamie D.; Wu, Jianhan; Syed, Saad; Lally, James; Raphenya, Amogelang R.; Blouin, Marie-José; Pollak, Michael; Sacconi, Andrea; Blandino, Giovanni; McArthur, Andrew G; Schertzer, Jonathan D.; Surette, Michael G.; Collins, Stephen M.; Bramson, Jonathan L.; Muti, Paola; Tsakiridis, Theodoros; Steinberg, Gregory R.

doi:10.1016/j.molmet.2022.101498

Cited by 29 publications

(26 citation statements)

References 56 publications

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“…Of interest, sex-related differences were reported for metformin-induced changes in gut microbiota composition and function in HFD-fed mice, indicating the relevance of interactions between sex hormones and the microbiota 116 . Importantly, metformin-induced changes in the diversity of the gut microbiota are linked to oral, but not intraperitoneal, metformin delivery in mice 117 . Metformin-induced changes in gut microbiota diversity of HFD-fed mice were associated with reduced microbiota encroachment into the mucus layer, which is a driver of low-grade inflammation 118 .…”

Section: Metformin and Microbiota Interactionsmentioning

confidence: 99%

Metformin: update on mechanisms of action and repurposing potential

2023

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Currently, metformin is the first-line medication to treat type 2 diabetes mellitus (T2DM) in most guidelines and is used daily by >200 million patients. Surprisingly, the mechanisms underlying its therapeutic action are complex and are still not fully understood. Early evidence highlighted the liver as the major organ involved in the effect of metformin on reducing blood levels of glucose. However, increasing evidence points towards other sites of action that might also have an important role, including the gastrointestinal tract, the gut microbial communities and the tissue-resident immune cells. At the molecular level, it seems that the mechanisms of action vary depending on the dose of metformin used and duration of treatment. Initial studies have shown that metformin targets hepatic mitochondria; however, the identification of a novel target at low concentrations of metformin at the lysosome surface might reveal a new mechanism of action. Based on the efficacy and safety records in T2DM, attention has been given to the repurposing of metformin as part of adjunct therapy for the treatment of cancer, age-related diseases, inflammatory diseases and COVID-19. In this Review, we highlight the latest advances in our understanding of the mechanisms of action of metformin and discuss potential emerging novel therapeutic uses.

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Section: Metformin and Microbiota Interactionsmentioning

confidence: 99%

Metformin: update on mechanisms of action and repurposing potential

2023

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“…Transfer of faeces from obese mice treated with metformin into untreated mice inhibited tumour growth independently of changes in body mass, blood glucose or serum insulin. The study authors proposed that metformin treatment led to a proportionate increase in short-chain fatty acid-producing microbes and faecal transfer then led to reprogramming of tumour metabolism specifically changes in lipid homoeostasis [41]. To date, these approaches have been unexplored in the clinic.…”

Section: Future Directions: Is Further Clinical Investigation Of Metf...mentioning

confidence: 99%

Is it still worth pursuing the repurposing of metformin as a cancer therapeutic?

Lord

Harris

2023

Br J Cancer

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Over the past 15 years, there has been great interest in the potential to repurpose the diabetes drug, metformin, as a cancer treatment. However, despite considerable efforts being made to investigate its efficacy in a number of large randomised clinical trials in different tumour types, results have been disappointing to date. This perspective article summarises how interest initially developed in the oncological potential of metformin and the diverse clinical programme of work to date including our contribution to establishing the intra-tumoral pharmacodynamic effects of metformin in the clinic. We also discuss the lessons that can be learnt from this experience and whether a further clinical investigation of metformin in cancer is warranted.

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“…In the light of these findings, in vivo investigations of the effects of fiber-rich diet on immune responses defined by network analysis showed that species of the Ruminococcaceae family are fiber-fermenting bacteria producing significant amounts of SCFAs that can contribute to the accumulation of T cells in the tumor, such as CD4 + T cells, inducible T cell co-stimulator (ICOS) + T cells, and CD8 + T cells, and engage pathways of T cell activation which mediate their anti-tumor effects [ 30 ]. In line with these data, another study by Broadfield et al showed that SCFA-producing Ruminococcaceae as well as Lachnospiraceae and Alistipes are increased following oral administration of metformin (Met) in high-fat diet (HFD)-fed mice, resulting in suppressed growth of MC38 murine colon cancer cells [ 31 ]. In addition, these findings were validated by transferring fecal microbiota (FMT) from HFD-Met fed mice to drug naïve, conventional HFD-fed mice, leading to decreased tumor proliferation following expansion in circulating butyrate and propionate.…”

Section: Positive and Negative Impact Of The Gut Microbiota On T Cell...mentioning

confidence: 96%

Potential links between the microbiota and T cell immunity determine the tumor cell fate

et al. 2023

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The central role of the microbiota as a pivotal factor regulating anti-tumor immune responses has recently been appreciated. Increasing evidence has put a spotlight on the connection of microbiota to T cells, by showing impaired effector and/or memory responses in germ-free (GF) mice or in the presence of dysbiotic communities, and association with tumor growth and overall survival (OS). These observations also have significant implications for anti-tumor therapy and vaccination, suggesting that the communication between T cells and the microbiota involves soluble mediators (microbiota-derived metabolites) that influence various functions of T cells. In addition, there is growing appreciation of the role of bacterial translocation into the peritumoral milieu from the intestinal tract, as well as of locally developed tumor microbial communities, spatially separated from the gut microbiota, in shaping the tumor microbiome. Collectively, these findings have added new support to the idea that tonic inputs mirroring the existence of tumor microbiome could regulate the function of tumor-infiltrating T cells and tissue-resident memory T (TRM) cells. In this review, we focus on recent advances and aspects of these active areas of investigation and provide a comprehensive overview of the unique mechanisms that play a pivotal role in the regulation of anti-tumor immunity by the microbiota, some of which could be of particular relevance for addressing problems caused by tumor heterogeneity. It is our hope that this review will provide a theoretical foundation for future investigations in this area.

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Metformin-induced reductions in tumor growth involves modulation of the gut microbiome

Cited by 29 publications

References 56 publications

Metformin: update on mechanisms of action and repurposing potential

Metformin: update on mechanisms of action and repurposing potential

Is it still worth pursuing the repurposing of metformin as a cancer therapeutic?

Potential links between the microbiota and T cell immunity determine the tumor cell fate

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