The antidiabetic drug metformin aids bacteria in hijacking vitamin B12 from the environment through RcdA

Abstract

Years of use of the antidiabetic drug metformin has long been associated with the risk of vitamin B12 (B12) deficiency in type 2 diabetes (T2D) patients, although the underlying mechanisms are unclear. Accumulating evidence has shown that metformin may exert beneficial effects by altering the metabolism of the gut microbiota, but whether it induces human B12 deficiency via modulation of bacterial activity remains poorly understood. Here, we show that both metformin and the other biguanide drug phenformin markedly elevate the accumulation of B12 in E. coli. By functional and genomic analysis, we demonstrate that both biguanides can significantly increase the expression of B12 transporter genes, and depletions of vital ones, such as tonB, nearly completely abolish the drugs’ effect on bacterial B12 accumulation. Via high-throughput screens in E. coli and C. elegans, we reveal that the TetR-type transcription factor RcdA is required for biguanide-mediated promotion of B12 accumulation and the expressions of B12 transporter genes in bacteria. Together, our study unveils that the antidiabetic drug metformin helps bacteria gather B12 from the environment by increasing the expressions of B12 transporter genes in an RcdA-dependent manner, which may theoretically reduce the B12 supply to T2D patients taking the drug over time.

Nutrition at the Intersection between Gut Microbiota Eubiosis and Effective Management of Type 2 Diabetes

“…Further, treatment with metformin, currently the first-line treatment of T2DM, has been shown to cause vitamin B12 deficiency [ 241 ]. A recent study showed that metformin can assist gut microbiota in contributing to this deficiency [ 242 ]. Using functional and genomic analyses via high-throughput screens for E. coli and C. elegans, it was shown that metformin helps bacteria gather B12 from the environment by increasing the expressions of B12 transporter genes, thus reducing the B12 supply to T2D patients taking the drug over time [ 242 ].…”

“…A recent study showed that metformin can assist gut microbiota in contributing to this deficiency [ 242 ]. Using functional and genomic analyses via high-throughput screens for E. coli and C. elegans, it was shown that metformin helps bacteria gather B12 from the environment by increasing the expressions of B12 transporter genes, thus reducing the B12 supply to T2D patients taking the drug over time [ 242 ]. It is important to note that vitamin B12 deficiency can further exacerbate the sequelae of T2DM such as peripheral neuropathy and even macrovascular complications in patients with the condition [ 243 ].…”

Nutrition at the Intersection between Gut Microbiota Eubiosis and Effective Management of Type 2 Diabetes

“…Further, treatment with metformin, currently the first-line treatment of T2DM, has been shown to cause vitamin B12 deficiency [241]. Recent study showed that metformin can assist gut microbiota in contributing to this deficiency [242]. Using functional and genomic analyses via high-throughput screens in E. coli and C. elegans it was shown that metformin helps bacteria gather B12 from the environment by increasing the expressions of B12 transporter genes thus reducing the B12 supply to T2D patients taking the drug over time [242].…”

“…Recent study showed that metformin can assist gut microbiota in contributing to this deficiency [242]. Using functional and genomic analyses via high-throughput screens in E. coli and C. elegans it was shown that metformin helps bacteria gather B12 from the environment by increasing the expressions of B12 transporter genes thus reducing the B12 supply to T2D patients taking the drug over time [242]. It is important to note that Vitamin B12 deficiency can further exacerbate sequelae of T2DM such as peripheral neuropathy and even macrovascular complications in patients with the condition [243].…”

Effect of metformin on vitamin B12 and homocysteine levels among Sudanese with type 2 diabetes mellitus

“…Hyperhomocysteinemia and dementia are associated with VitB12 de ciency [12] . The potential reasons for VitB12 de ciency include malnutrition; malabsorption; genetic changes in the way that VitB12 is transported in the blood, cellular uptake, or metabolic route [13] ; autoimmune diseases or pernicious anemia [9] ; and some medications such as proton pump inhibitors [14] and metformin [15] .…”