Microbially Produced Imidazole Propionate Impairs Insulin Signaling through mTORC1

Abstract

Graphical Abstract Highlights d Imidazole propionate levels are increased in subjects with type 2 diabetes (T2D) d Imidazole propionate is produced from histidine by T2Dassociated bacteria d Imidazole propionate impairs glucose tolerance and insulin signaling d Imidazole propionate inhibits IRS via activation of p38g/p62/ mTORC1In Brief Imidazole propionate, a metabolite produced by the gut microbiota, is elevated in type 2 diabetes and can directly impair glucose tolerance and insulin signaling. SUMMARYInteractions between the gut microbiota, diet, and the host potentially contribute to the development of metabolic diseases. Here, we identify imidazole propionate as a microbially produced histidinederived metabolite that is present at higher concentrations in subjects with versus without type 2 diabetes. We show that imidazole propionate is produced from histidine in a gut simulator at higher concentrations when using fecal microbiota from subjects with versus without type 2 diabetes and that it impairs glucose tolerance when administered to mice. We further show that imidazole propionate impairs insulin signaling at the level of insulin receptor substrate through the activation of p38g MAPK, which promotes p62 phosphorylation and, subsequently, activation of mechanistic target of rapamycin complex 1 (mTORC1). We also demonstrate increased activation of p62 and mTORC1 in liver from subjects with type 2 diabetes. Our findings indicate that the microbial metabolite imidazole propionate may contribute to the pathogenesis of type 2 diabetes. 948 Cell 175, 947-961, November 1, 2018 (legend continued on next page) 950 Cell 175, 947-961,

The role of the gut microbiota in development, function and disorders of the central nervous system and the enteric nervous system

“…It can be produced from tyrosine by the microbial enzyme p ‐hydroxyphenylacetate decarboxylase . Imidazole propionate is yet another microbially produced amino acid‐derived metabolite; histidine is metabolised to urocanate, which is further metabolised by bacteria expressing the enzyme urocanate reductase to imidazole propionate . The plasma levels of imidazole propionate vary substantially between individuals, with higher levels in type 2 diabetic subjects compared to control subjects, and the metabolite has been shown to impair insulin signalling .…”

“…Imidazole propionate is yet another microbially produced amino acid‐derived metabolite; histidine is metabolised to urocanate, which is further metabolised by bacteria expressing the enzyme urocanate reductase to imidazole propionate . The plasma levels of imidazole propionate vary substantially between individuals, with higher levels in type 2 diabetic subjects compared to control subjects, and the metabolite has been shown to impair insulin signalling . Thus, these amino acid‐derived metabolites can affect the physiology of the host and results suggest that they modulate CNS development and function, as discussed in more detail below.…”

Measurement of gut microbial metabolites in cardiometabolic health and translational research

“…Using these technologies, a broad coverage of various classes of small molecules, including carbohydrates, lipids, amino acids, biogenic amines, and many other organic acids, in clinical samples can be quantified and annotated . Untargeted metabolomics approaches have been increasingly used to explore disease‐associated metabolites from case–control studies . The identified disease–metabolite correlations can then be confirmed by a validation cohort.…”

“…TMAO is now generally regarded as an independent risk factor for CVD as well as a therapeutic target for the development of interventional approaches . By adopting a similar approach, Bäckhed et al discovered that imidazole propionate, which is generated from the gut microbial metabolism of histidine, is an etiological compound for the development of type II diabetes . Moreover, potentially beneficial compounds for disease prevention and control could also be discovered from metabolome research targeting microbial metabolites.…”

“…Accumulating evidence suggests that microbiota‐derived small molecules could be key messengers conveyed from gut microbes to other parts of the human body . These small bioactive molecules, such as short‐chain fatty acids (SCFAs), trimethylamine N ‐oxide (TMAO), imidazole propionate, conjugated linoleic acid, and s‐equol, are derived mainly from the gut microbiota metabolism of dietary components such as dietary fibers, amino acids, fatty acids, and phytochemicals . Studies have suggested that gut microbiota‐derived metabolites play key roles in health maintenance and disease progression .…”