Metformin on gut microbiota and the immune system

Metformin is well known for being used as the first line of treatment to manage type 2 diabetes. Its effectiveness comes from the compound guanidine which in 1918 was shown to lower blood glucose. The first report of the use of metformin to treat diabetes was in 1957 by the French physician Jean Sterne. It was first used intro clinical practice in Europe in the 1950s and then it became known and used in North America in the 1990s. While its primary mechanism of action involves reducing glucose production in the liver and increasing the sensitivity of muscle cells to insulin recent studies have shown that metformin also has some action in the gut microbiota and the immune system.

The mechanism of action of metformin is well known and has been extensively studied through the years. Research in both animals and humans has indicated that metformin can lead to changes in the abundance of certain bacterial species and shifts in microbial diversity. These changes can have implications for metabolic health and may contribute to some of the effects of metformin beyond its direct impact on insulin sensitivity. One of the most studied mechanisms is focused on inhibiting respiratory complex I of the electron transport chain, having consequences for ATP-requiring reactions, arising from activation of AMP-activated protein kinase which reprograms cellular energy metabolism leading to a maximized ATP production,

There’s evidence that metformin exposure induces changes in the gut microbiota and in the gut metabolome, although its exact mechanism is still undefined; but as there is a relationship between the immune system, the microbiota, and energy metabolism it is something worth studying. In a certain kind of bacteria Caenorhabditis elegans metformin showed to increase its lifespan may be produced by the effects of the drug on folate metabolism within bacteria.

Some other ways in which metformin contributes to the gut microbiome are:

  1. Bacterial Composition: Metformin has been associated with alterations in the relative abundance of specific bacterial species in the gut. Some studies have shown an increase in beneficial bacteria such as Akkermansia muciniphila, which is associated with improved metabolic health.
  2. Microbial Diversity: Metformin use has been linked to changes in microbial diversity. A decrease in microbial diversity is often observed in conditions like obesity and type 2 diabetes, and metformin might help maintain or restore a more diverse microbiome.
  3. Short-Chain Fatty Acid Production: Metformin-induced changes in the gut microbiome can influence the production of short-chain fatty acids (SCFAs). SCFAs are metabolites produced by certain gut bacteria during the fermentation of dietary fibers. They play a role in gut health, energy metabolism, and immune regulation.
  4. Metabolism and Inflammation: Changes in the gut microbiome caused by metformin might impact metabolic pathways and inflammation in the body. Some of the effects of metformin on insulin sensitivity and glucose regulation could be mediated through interactions with the gut microbiome.

Also, a study done by Pollak M, describes that in the field of immunometabolism has shown that AMPK influences T cell effector responses.  Therefore, the prior body of evidence that metformin inhibits oxidative phosphorylation, leading to AMPK activation, provides a plausible basis for the effects of the drug on immune function and, in tumor immunology, there exist examples of enhanced immune function because of metformin exposure including tuberculosis suggesting anti-inflammatory action too. Concluding that the effects of metformin on the microbiome and immune system may be relevant to propose novel indications, for example in oncology and aging as it can have also systemic action in various cell lineages as the ones of the immune system or neoplastic tissues.

It’s important to note that the impact of metformin on the gut microbiome can vary from person to person, and not everyone who takes metformin will experience significant changes in their microbiome. Additionally, research in this area is still ongoing, and there is much more to learn about the complex interactions between metformin, the gut microbiome, and overall health.

Reference:Michael Pollak, , The effects of metformin on gut microbiota and the immune system as research frontiers, https://link.springer.com/article/10.1007/s00125-017-4352-x

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