Gut microbiota: A new therapeutic target for diabetic cardiomyopathy

Figures

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  FIGURE 1. Gut microbiota and bile acids (BAs). In the gut, BAs are a detergent required for the formation of mixed micelles, dissolution, and digestion. BAs regulate metabolic homeostasis by activating BA receptors, such as G protein-coupled bile acid receptor 1 (TGR5), which are expressed in the intestinal tract, heart, liver, kidney, and other organs. Primary bile acids, such as cholic acid and chenodesoxycholic acid, could be converted into secondary BAs, including deoxycholic acid and lithocholic acid, under the regulation of gut microbiota.

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  FIGURE 2. Insulin mechanisms in cardiac glucose regulation. 1) Insulin resistance may occur when cardiomyocytes are exposed to high glucose. 2) The phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway stimulates the translocation of glucose transporter type 4 (GLUT4) to the membrane, thereby resulting in glucose uptake to cells of the heart. However, in a knockout model of the cardiac insulin receptor, cardiac glucose uptake is reduced, resulting in mitochondrial dysfunction, and increased cardiac reactive oxygen species (ROS) production. 3) Mitochondrial dysfunction occurs when the PPARγ coactivator 1α (PGC-1α)/AMP-activated protein kinase (AMPK) signaling pathway is impaired. 4) The level of autophagy may be reduced when the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin1 (mTORC1) pathway is activated.

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  FIGURE 3. M1 and M2 in DCM. When reactive oxygen species (ROS) is increased, monocytes/macrophages can polarize into a pro-inflammatory M1 phenotype, promoting the occurrence of diabetic cardiomyopathy (DCM). In diabetic heart tissue, the pro-inflammatory polarization of M2 macrophages is inhibited, while the pro-inflammatory polarization of M1 macrophages is upregulated. M1, classically activated macrophages; M2, alternatively activate anti-inflammatory macrophages.

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  FIGURE 4. Gut microbiota in diabetic cardiomyopathy. Gut microbiota and its metabolites can affect the development of host cell autophagy, the inflammatory response, oxidative stress, apoptosis, pyroptosis, and insulin resistance through the short-chain fatty acids (SCFAs) metabolic pathway, bile acid (BA) metabolism, and the trimethylamine N-oxide (TMAO) metabolic, mitogen-activated protein kinase (MAPK), and PI3K/Akt/mTOR pathways, among others. PI3K:phosphatidylinositol 3-kinase; Akt, protein kinase B, mTORC: mammalian target of rapamycin.