Recent studies have highlighted the role of gut microbiota in the pathogenesis of cardiometabolic diseases. In particular, microbially produced metabolites have been shown to affect the host metabolism, however, their impacts on metabolic diseases have not been fully elucidated. For instance, the findings from an obese mouse model have suggested that polysaccharide fermentation could serve as the additional energy sources, yet the effects on human pathology has not been reported. To address this question, we applied a multi-omics strategy, which integrated gut microbiome analyses with multi-platform metabolomic techniques. We sampled from 306 Japanese males and females with obesity (49.7%) and prediabetes (32.7%). Fecal microbiome was analyzed by 16S rRNA amplicon and metagenomic shot-gun sequencings, while fecal hydrophilic and lipid metabolites were measured using GC-MS and LC-MS-based platforms respectively, and were clustered by their co-expression profiles. We found that three out of 19 fecal hydrophilic clusters and three out of 86 lipid clusters were significantly associated with insulin resistance (IR) defined by HOMA-IR. Notably, the identified fecal hydrophilic clusters were classified as sugar derivatives such as monosaccharides and disaccharides. These metabolites were indeed increased in not only the fecal contents but also the plasma samples of IR group. In addition, microbes belonging to genera Dorea and Coprococcus, which are known to degrade polysaccharides, were abundant in the IR group, and were highly correlated with fecal sugar derivatives, while other microbes such as Alistipes showed negative correlation. Finally, we confirmed that the oral administration of a Dorea strain to HFD-fed mice exacerbated obesity and IR compared with Alistipes administration. Collectively, we report a novel mechanistic insight into the effects of gut microbes on metabolic diseases, where microbial fermentation of polysaccharides and its derivatives impact the host metabolism.


T. Takeuchi: None. Y. Nakanishi: None. K. Ikeda: None. H. Tsugawa: None. W. Suda: None. Y. Mizuno: None. N. Yamamichi: None. M. Arita: None. M. Hattori: None. N. Kubota: None. T. Kubota: None. T. Kadowaki: Research Support; Self; Astellas Pharma Inc., Daiichi Sankyo, Mitsubishi Tanabe Pharma Corporation, MSD Corporation, Novartis Pharma K.K., Novo Nordisk Pharma Ltd., Ono Pharmaceutical Co., Ltd., Sanofi, Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Company Limited. Speaker’s Bureau; Self; Abbott, Astellas Pharma Inc., AstraZeneca K.K., Boehringer Ingelheim Pharmaceuticals, Inc., Cosmic Corporation, Daiichi Sankyo, Eli Lilly Japan K.K., FUJIFILM, Kowa Company, Ltd., Kyowa Hakko Kirin Co., Ltd., Medscape Education, Medtronic, Mitsubishi Tanabe Pharma Corporation, MSD Corporation, NIPRO Medical Corporation, Novartis Pharma K.K., Novo Nordisk Pharma Ltd., Ono Pharmaceutical Co., Ltd., Sanofi, Sanwa Kagaku Kenkyusho, Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited, Terumo Medical Corporation. Other Relationship; Self; Asahi Mutual Life Insurance. S. Koyasu: None. H. Ohno: None.

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