Metformin and gut microbiota: a complex relationship

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Recent studies suggest that metformin’s therapeutic effects could be partly related to its interaction with the gut microbiota. The same could also be true of its gastrointestinal adverse effects.

 

Gastrointestinal adverse events (GIAEs) are frequently reported in patients with type 2 diabetes mellitus (T2DM) treated with metformin and appear to be the main cause of treatment withdrawal (about 5% of patients). An exploratory study carried out by a Latvian team recently brought to light changes in gut microbiota in 18 healthy volunteers receiving metformin. Two main changes were observed: decrease in flora diversity 24 hours after the beginning of the treatment and increase of opportunistic bacteria correlated to the severity of GIAEs.  

Immediate bacterial depletion

Eighteen healthy volunteers received metformin 850 mg b.i.d. for 7 days. The diversity of their gut microbiota was analyzed before the treatment, after 24 hours, and on Day 7. GIAEs were reported and participants were divided into 3 groups. Although limited by the low power of the study, the results indicate bacterial depletion and decreased bacterial diversity after 24 hours, as well as reversal to baseline conditions on Day 7. In parallel with this, the level of opportunistic pathogens from Escherichia-Shigella genera decreases significantly between 24 hours and Day 7.

A pre-treatment marker?

The team hypothesized that the decrease in gut microbiota diversity is a driver of the proliferation of Escherichia-Shigella enterobacteria that could lead to or worsen dysbiosis-related GIAEs. It should be noted that the group with no GIAE had undetectable levels of Escherichia-Shigella before the treatment, unlike the two groups who had GIAEs. The authors suggest that a pre-treatment test should be conducted in patients with diabetes mellitus who are candidates for metformin treatment in order to identify those who are at risk of suffering from GIAEs and consequently follow the adequate therapeutic strategy (low starting dose, extended release formulation).

Beneficial change in the microbiota

The analysis also showed a significant decrease in both families (Peptostreptococcaceae et Clostridiaceae_1) on Day 7, while the increase of either of these species has been associated in several studies to multiple pathologies (colorectal cancer, NASH…). According to the authors, the decrease in these “adverse” species might be involved in the therapeutic effect of metformin. Additional studies are needed to confirm these results (adding a placebo group to the design) and shed light on the mechanism of action of metformin in the gut microbiota.

 

Sources:

Association of metformin administration with gut microbiome dysbiosis in healthy volunteers ; Ilze Elbere, Ineta Kalnina and col. ; PLOS ONE ; September 27, 2018