Effect of Metformin on Metabolic Improvement and Gut Microbiota

Abstract

bMetformin is commonly used as the first line of medication for the treatment of metabolic syndromes, such as obesity and type 2 diabetes (T2D). Recently, metformin-induced changes in the gut microbiota have been reported; however, the relationship between metformin treatment and the gut microbiota remains unclear. In this study, the composition of the gut microbiota was investigated using a mouse model of high-fat-diet (HFD)-induced obesity with and without metformin treatment. As expected, metformin treatment improved markers of metabolic disorders, including serum glucose levels, body weight, and total cholesterol levels. Moreover, Akkermansia muciniphila (12.44% ؎ 5.26%) and Clostridium cocleatum (0.10% ؎ 0.09%) abundances increased significantly after metformin treatment of mice on the HFD. The relative abundance of A. muciniphila in the fecal microbiota was also found to increase in brain heart infusion (BHI) medium supplemented with metformin in vitro. In addition to the changes in the microbiota associated with metformin treatment, when other influences were controlled for, a total of 18 KEGG metabolic pathways (including those for sphingolipid and fatty acid metabolism) were significantly upregulated in the gut microbiota during metformin treatment of mice on an HFD. Our results demonstrate that the gut microbiota and their metabolic pathways are influenced by metformin treatment. Metformin is a common antidiabetic agent in the biguanide class and is known to suppress glucose production in the liver, increase insulin sensitivity, and enhance peripheral glucose uptake in hepatic and skeletal muscle (1). The metformin-induced increase in AMP-activated protein kinase (AMPK) plays an important role in energy balance and glucose metabolism; the cellular AMP/ATP ratio is maintained by increasing ATP consumption and decreasing ATP production, which is associated with AMPK activation (2, 3). Recent studies also reported that metformin regulates hepatic gluconeogenesis and improves hyperglycemia independently of the AMPK pathway (4), which suggests that metformin-induced improvement of metabolic disorders is associated with the energy state of the body.The gut microbiota is known to play an important role in harvesting energy from food, metabolic processes, and immune modulation. The composition of the gut microbiota is significantly associated with obesity, type 2 diabetes (T2D), and metabolic syndromes (5-7). Dysbiosis of the gut microbiota is also associated with other diseases, such as inflammatory bowel disease (IBD) (8), cardiovascular disease (9), and autism (10). Recently, metformininduced changes in the abundance of Akkermansia muciniphila were shown to be associated with metabolic improvement (11). Another study reported that treatment with A. muciniphila, which was identified from enterotype gut microbiota, improved metabolic disorders (12). However, other gut microbiota and metabolic pathways related to metformin treatment remain uncharacterized. In addition, the effect of diet and metformin treatmen...

Metformin exerts glucose-lowering action in high-fat fed mice via attenuating endotoxemia and enhancing insulin signaling

“…In addition, metformin increases blood levels of GLP-1, an insulin sensitizing hormone, by promoting its secretion through a gut bacteria-related mechanism [15] . Metformin has also been shown to upregulate certain probiotics, such as A muciniphila and lactobacillus, and importantly, this modulation was associated with the beneficial effects of metformin on gut barrier function and glucose metabolism [14,16] . Because metformin modulates the composition of gut bacteria and enhances gut barrier function, we inferred that the alteration of the gut bacteria community by metformin may reduce LPS absorption by reducing its absorption via protecting gut integrity.…”

“…Interestingly, recent studies indicate that the modulatory effect of metformin on the gut microbiota is related to its anti-inflammatory and anti-obesity as well as its therapeutic efficacy on glucose metabolism [14][15][16] . For example, feeding a HFD to mice leads to a reduction in the probiotic Akkermansia muciniphila (A muciniphila) in the gut, which is important in maintaining the integrity of the gut barrier and insulin sensitivity [16] , while metformin has recently been shown to reverse this reduction [14][15][16] .…”

“…Interestingly, recent studies indicate that the modulatory effect of metformin on the gut microbiota is related to its anti-inflammatory and anti-obesity as well as its therapeutic efficacy on glucose metabolism [14][15][16] . For example, feeding a HFD to mice leads to a reduction in the probiotic Akkermansia muciniphila (A muciniphila) in the gut, which is important in maintaining the integrity of the gut barrier and insulin sensitivity [16] , while metformin has recently been shown to reverse this reduction [14][15][16] . Because increased gut permeability has been reported in HFD-fed mice, which can enhance gut bacteria-derived LPS absorption and lead to endotoxemia [17,18] , we proposed that metformin could protect gut-barrier function through reversing abnormal alterations of the gut microbiota and, therefore, reduce LPS-induced inflammation and its detrimental effects on insulin action.…”

Gut microorganisms as promising targets for the management of type 2 diabetes

“…A few months later, Lee et al confirmed that metformin treatment induces an increase in the A. muciniphila population and demonstrated a negative correlation between glycaemia and A. muciniphila abundance. Interestingly, co-incubation of metformin and mouse stool samples led to an enrichment in A. muciniphila [51], suggesting that metformin directly interacts with the gut microbiota to foster the growth of A. muciniphila.…”

Metformin: Hype or Hope for Cancer

“…62 Metformin increases the abundance of Akkermansia, a mucus-degrading gram-negative bacteria in the gut, which is associated with restoration of reduced regulatory T cells and amelioration of low-grade tissue inflammation in the adipose tissue of obese animals. 63 This effect of metformin on intestines probably causes anti-aging and anti-cancerous effects and life span extension, the effects which need verification.…”