What is already known on this topic
The gut microbiota can affect the efficacy of several drugs, including metformin, a common medication for the treatment of type 2 diabetes. Previous studies have shown that the microbial metabolite imidazole propionate, which is elevated in people with type 2 diabetes, can impair glucose tolerance. But whether imidazole propionate also contributes to how well individuals respond to metformin is unknown.
What this research adds
Researchers have shown that microbial-derived imidazole propionate is elevated in people with type 2 diabetes who were treated with the anti-diabetic drug metformin. In mice, imidazole propionate interacts with metformin-induced signaling pathways, reducing the glucose-lowering response to metformin and making the drug less effective.
The findings show that microbial metabolites can influence the activity of metformin. Understanding the mechanisms behind this interaction could help to improve individual responses to metformin and develop personalized treatments for type 2 diabetes.
Gut bacteria could make the anti-diabetic drug metformin less effective, researchers have found.
The study, published in Cell Metabolism, identified one of the mechanisms through which the microbiota or its products affect drug responses. The findings could help to improve individual responses to metformin and develop personalized treatments for type 2 diabetes, the researchers say.
“Our findings show clearly how important the interaction between gut microbiota and diet is to understand our metabolism in health and disease,” says study lead author Fredrik Bäckhed at the University of Gothenburg. “The result also shows that gut bacteria from different individuals can lead to the production of completely different substances that may have very specific effects in the body,” Bäckhed says.
Previous studies from the same team have shown that the microbial metabolite imidazole propionate, which is elevated in people with type 2 diabetes, can impair glucose tolerance. But whether imidazole propionate also contributes to how well individuals respond to metformin is unknown.
To investigate whether this microbial metabolite is associated with the clinical outcome of metformin treatment, researchers led by Bäckhed and Ara Koh analyzed imidazole propionate levels in people with type 2 diabetes who were taking metformin.
Impairing response to metformin
The researchers found that the levels of imidazole propionate were higher in people treated with metformin who had high blood glucose compared to those with lower blood glucose.
An analysis of stool samples showed that, unlike the microbiota of healthy people, that of individuals with type 2 diabetes produced imidazole propionate in the presence of histidine, an amino acid that is mainly derived from the diet.
Working in mice, the team found that imidazole propionate affected a signaling pathway that is associated with metabolic diseases such as obesity and cardiovascular disease. The interaction between imidazole propionate and metformin-induced signaling pathways reduced the glucose-lowering response to metformin.
The findings suggest that the gut microbiota of people with type 2 diabetes can metabolize diet-derived histidine, leading to the formation of imidazole propionate. Imidazole propionate can impair the cells’ ability to respond to insulin, making the drug less effective.
Bäckhed cautions that imidazole propionate does not cause all cases of type 2 diabetes, “but our working hypothesis is that there are subpopulations of patients who might benefit from changing their diet or altering their gut microbiota to reduce the levels of imidazole propionate.”
The findings could provide opportunities for identifying personalized treatments for people with type 2 diabetes: for example, reducing the amount of bacterial-derived imidazole propionate may be a new way of treating the condition, the researchers say.