An increase in theAkkermansiaspp. population induced by metformin treatment improves glucose homeostasis in diet-induced obese mice

Abstract

Background Recent evidence indicates that the composition of the gut microbiota contributes to the development of metabolic disorders by affecting the physiology and metabolism of the host. Metformin is one of the most widely prescribed type 2 diabetes (T2D) therapeutic agents. Objective To determine whether the antidiabetic effect of metformin is related to alterations of intestinal microbial composition. Design C57BL/6 mice, fed either a normal-chow diet or a high-fat diet (HFD), were treated with metformin for 6 weeks. The effect of metformin on the composition of the gut microbiota was assessed by analysing 16S rRNA gene sequences with 454 pyrosequencing. Adipose tissue inflammation was examined by flow cytometric analysis of the immune cells present in visceral adipose tissue (VAT). Results Metformin treatment significantly improved the glycaemic profile of HFD-fed mice. HFD-fed mice treated with metformin showed a higher abundance of the mucin-degrading bacterium Akkermansia than HFD-fed control mice. In addition, the number of mucin-producing goblet cells was significantly increased by metformin treatment (p<0.0001). Oral administration of Akkermansia muciniphila to HFD-fed mice without metformin significantly enhanced glucose tolerance and attenuated adipose tissue inflammation by inducing Foxp3 regulatory T cells (Tregs) in the VAT. Conclusions Modulation of the gut microbiota (by an increase in the Akkermansia spp. population) may contribute to the antidiabetic effects of metformin, thereby providing a new mechanism for the therapeutic effect of metformin in patients with T2D. This suggests that pharmacological manipulation of the gut microbiota in favour of Akkermansia may be a potential treatment for T2D.

Prenatal androgen exposure causes hypertension and gut microbiota dysbiosis

“…After treatment with Metformin, the gut microbiota of patients with PCOS became enriched with Akkermansia , bacteria that may be associated with glucose homeostasis. 127 These gram-negative bacteria are associated with increased production of the bacterial metabolite, lipopolysaccharide (LPS) and induce T cell-mediated immune responses. 128 …”

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.…”

Autophagy deficiency in myeloid cells increases susceptibility to obesity-induced diabetes and experimental colitis

“…6,10,52 While the detailed molecular mechanism of lipid-induced inflammasome activation remains to be investigated, mitochondrial dysfunction induced by fatty acids in combination with LPS likely plays an important role in inflammasome activation, which was exemplified by the markedly decreased NAD C :NADH ratio and increased mitochondrial ROS content, consistent with previous papers. 12,24 An in vivo source of TLR (toll-like receptor) ligands which are essential for efficient stimulation of inflammasome in addition to lipid, could be a low-level endotoxin owing to altered intestinal barrier function 53,54 or AHSG (a-2-HS-glycoprotein) that can activate TLR in complex with lipids. 55 All these results suggest that inflammasome activation due to lipid or obesity could be a crucial event in obesity-induced insulin resistance by enhancing the release of IL1B as an effector molecule of insulin resistance, which can be exacerbated by autophagy deficiency of myeloid cells.…”