Bacterial imidazole propionate: the bridge between gut microbiota and type 2 diabetes

Gut microbial metabolites and metabolic diseases

More and more studies have shown that changes in the composition and function of the gut microbiome are closely related to obesity, diabetes, and cardiovascular disease, and that different individuals have different metabolic responses to a certain diet, and differences in the microbiome are also one of the reasons [1]. On the one hand, microbial metabolites can improve metabolism, such as short URL fatty acids, a metabolite produced by bacterial fermentation of dietary fiber, which not only participate in energy metabolism, but also participate in the improvement of diseases such as obesity, diabetes and colitis [2]; on the other hand, certain microbial metabolites are also involved in the occurrence and development of diseases. For example, recent studies have identified trimethylamine N-oxide as a microbial-dependent metabolite, which is involved in the occurrence of arteriosclerosis in mouse models and is also associated with cardiovascular disease in humans [3]; in addition, branched-chain amino acids, glutamates, and amino acid-derived uremic toxins are also considered to be potentially harmful microbial-regulated metabolites [4].

Association of imidazolium propionate with type 2 diabetes

As early as 1972, it was found that patients with intestinal diseases secrete more imidazole propionate [5], which attracted attention to the relationship between this compound and disease. A recent paper published in Cell entitled Microbially Produced Imidazole Propionate Impairs Insulin Signaling through mTORC1 [6] pointed out that imidazole propionate is an amino acid-derived bacterial metabolite that may be involved in the development of type 2 diabetes.

Bacterial metabolites in the gut can reach the liver through the hepatic portal vein, and then enter the whole body circulation. Scientists from Sweden compared the hepatic portal blood and peripheral blood of 5 people with type 2 diabetes and 10 people without the disease in obese people. They found that in the samples of diabetic patients, there were significantly increased levels of four amino acid-derived metabolites (dopamine sulfate, glutamate, imidazolpropionate, and N-acetyl putrescine), among which imidazolpropionate is an intestinal bacterial metabolite. The scientists further expanded the scope of their investigation and found that the level of imidazolpropionate was positively correlated with the level of sugar tolerance by examining 649 volunteers. Using an in vitro intestinal emulator to culture intestinal flora, the researchers also confirmed that the intestinal flora of patients with type 2 diabetes does produce high levels of imidazole propionate.

Production mechanism of imidazole propionate

Both bacteria and mammals can degrade histidine into urinic propionate or glutamate through different pathways [7]. The authors experimentally verified that the intestinal flora of patients with type 2 diabetes produces imidazolate through the alanine-urinic propionate pathway, and that the key reductase involved in this metabolic pathway is a homologue with "Y" and "M" but no "H". The authors further pointed out that the imidazolate-producing strains are more distributed in the intestines of patients with type 2 diabetes.

Molecular mechanism of imidazole propionate affecting sugar metabolism

Using an animal model, the researchers found that injecting imidazolpropionate into mice increased sugar tolerance and significantly increased the expression of key rate-limiting gluconeogenase G6pase and Pepck genes in the liver. However, the effect of imidazolpropionate on sugar metabolism does not directly affect insulin, but also affects insulin signal transduction at the level of insulin receptor substrate (IRS). After further exploration of the mechanism, the researchers pointed out that imidazolpropionate activates mTORC1 (mechenistic target of complex 1, rapamycin complex 1) by activating p38γ MAPK and promoting phosphorylation of p62. Activation of mTORC1 can cause downstream S6K1 phosphorylation, which in turn mediates S636/S639 phosphorylation of IRS1 and accelerates IRS degradation. Type 2 diabetic patients have higher levels of p62 and S6K1 phosphorylation in the liver, which further confirms the molecular mechanism revealed by in vitro experiments.

Research Significance and Prospects

This study of the mechanism of action of imidazole propionate established a link between gut microbiota, overactivation of mTORC1, and human health. The author finally pointed out that the therapeutic targets identified by imidazole drugs in the human body are diverse, which suggests that the signaling pathway of imidazole propionate action may not be single. Therefore, in-depth understanding of the signaling pathway triggered by imidazole propionate can find therapeutic targets for microbial metabolic diseases.

References

1. Cotillard, A., Kennedy, S.P., Kong, L.C., Prifti, E., Pons, N., Le Chatelier, E., Almeida, M., Quinquis, B., Levenez, F., Galleron, N., et al.; ANR MicroObes consortium (2013). Dietary intervention impact on gut microbial gene richness. Nature 500, 585 - 588

2. Koh, A., De Vadder, F., Kovatcheva-Datchary, P., and Ba ̈ ckhed, F. (2016). From dietary fibers to host physiology: short-chain fatty acids as key bacterial metabolites. Cell 165, 1332 - 1345.

4. Kikuchi, M., Ueno, M., Itoh, Y., Suda, W., and Hattori, M. (2017). Uremic toxinproducing gut microbiota in rats with chronic kidney disease. Nephron 135, 51 - 60.

5. Van der Heiden, C., Wadman, S.K., de Bree, P.K., and Wauters, E.A. (1972). Increased urinary imidazolepropionic acid, N-acetylhistamine and other imidazole compounds in patients with intestinal disorders. Clin. Chim. Acta 39, 201 - 214.

6. Koh A, Molinaro A, Ståhlman M, Khan MT, Schmidt C, Mannerås-Holm L, Wu H, Carreras A, Jeong H, Olofsson LE, Bergh PO, Gerdes V, Hartstra A, de Brauw M, Perkins R, Nieuwdorp M, Bergström G, Bäckhed F. (2016). Microbially Produced Imidazole Propionate Impairs Insulin Signaling through mTORC1. Cell. 175, 947-961.

7. Bender, R.A. (2012). Regulation of the histidine utilization (hut) system in bacteria. Microbiol. Mol. Biol. Rev. 76, 565 - 584.