3By studying metabolites used and produced by gut microorganisms, IMS researchers have identified bacterial species that could prevent onset of diabe-tes in high-risk individuals.Lipid metabolitesHydrophilic metabolites100Transcriptome14,614(N= 306)Study participantsJapanese, age 20-75No treatment for diabetesNo treatment for intestinal diseasesNo prior use of antibiotics in two weeksClinical phenotypesInsulin resistance (IR) Metabolic syndrome (MetS)Clinical data4116S (Species)482635Predicted genes6,458,217Lipid metabolites2,654CytokinesHydrophilic metabolites19510HostMicrobiotaDiabetes is a growing problem worldwide. The chronic nature of the disease makes it not only challenging but also expensive to treat. One solution could be to prevent disease onset in the first place, particularly in the rising number of individuals with high-risk conditions such as insulin resis-tance and metabolic syndrome.Although a number of culprits have been implicated in diabetes and diabetes-related conditions, a particularly enigmatic one is the gut microbiome. “We know the micro-biome is involved,” said Hiroshi Ohno, Team Leader of the Laboratory for Intestinal Ecosystem at IMS. “The missing link is the mechanism.”To fill this gap, Ohno’s team collaborated with multiple laboratories across IMS to conduct a comprehensive multi-omics study centered on metabolomics. “The goal was to identify bacteria-derived metabolites that could be mediat-ing the interaction between microorganisms and patho-genesis,” Ohno noted.In their paper published in Nature, the team first con-ducted metabolomics of fecal samples from 306 individuals who underwent a complete medical checkup at the Uni-versity of Tokyo Hospital. Focusing on participants with insulin resistance or metabolic syndrome, the researchers found higher levels of monosaccharides in the feces of these individuals compared to those without these pre-diabetic conditions.High levels of monosaccharides were also correlated with cytokines, suggesting that individuals with insulin re-sistance had low-grade inflammation. Further analysis un-expectedly revealed that the well-known anti-inflammatory cytokine IL-10 could be acting as an intermediate mediator between high monosaccharide levels and insulin resistance. Ohno notes that although this finding is somewhat contro-versial, the link between IL-10 and insulin resistance is not new, and could suggest that IL-10 acts as an inflammatory signal under certain conditions.The researchers focused their attention on finding a link between pre-diabetic conditions, metabolite concentration, and bacterial species, and in doing so discovered that distinct groups of bacteria were associated with insulin resistance. Specifically, bacteria in the Lachnospiraceae family tended to be found in participants with insulin resistance and high levels of fecal monosaccharides. In contrast, bacteria of the order Bacteroidales tended to be linked to those without in-sulin resistance and low levels of monosaccharides.Bacterial culture experiments confirmed these relation-ships and provided additional mechanistic insight. Bacteria in the Eubacteriales order, such as Lachnospiraceae, pro-duced monosaccharides, increasing overall levels in the gut and the risk of insulin resistance. Meanwhile, Bacteroidales bacteria consumed monosaccharides, explaining their as-sociation with a lower risk of insulin resistance.To test the therapeutic potential of their findings, the team administered Bacteroidales bacteria to mice with obe-sity and diabetes. These experiments confirmed that the treatment can effectively ameliorate insulin resistance and obesity. The researchers are now conducting further pre-clinical studies to test the safety of administering Bacteroida-les bacteria to animals before moving onto human trials.In addition, Ohno notes that reducing bacteria that raise levels of monosaccharides in the gut could be an alternative strategy for improving pre-diabetic conditions. The team is testing this theory by examining whether targeted removal of Lachnospiraceae bacteria in mice could halt progression to diabetes.Figure: A comprehensive multi-omics approach centered on metabolomics identifies key bacte-rial species with a role in pre-diabetic conditionsMetabolomics was conducted on fecal samples from 306 participants with or without insulin resistance or meta-bolic syndrome to identify metabolites associated with these conditions. Together with metagenomic studies of the gut microbiome, these analyses revealed potential therapeutic bacterial species that could halt pre-diabetes. Reproduced from Extended Data Fig. 1 with permission from the Nature and licensed under CC BY 3.0 DEED.Original paper:Takeuchi T, Kubota T, Nakanishi Y, Tsugawa H, Suda W, Kwon AT, Yazaki J, Ikeda K, Nemoto S, Mochizuki Y, Kitami T, Yugi K, Mizuno Y, Yamamichi N, Yamazaki T, Takamoto I, Kubota N, Kadowaki T, Arner E, Carninci P, Ohara O, Arita M, Hattori M, Koyasu S, Ohno H. Gut mi-crobial carbohydrate metabolism contributes to insulin resistance. Nature 621, 389-395 (2023)Hiroshi OhnoMining the metabolome to prevent diabetes
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