Gut microbial carbohydrate metabolism contributes to insulin resistance

Tadashi Takeuchi, Tetsuya Kubota (), Yumiko Nakanishi, Hiroshi Tsugawa, Wataru Suda, Andrew Tae-Jun Kwon, Junshi Yazaki, Kazutaka Ikeda, Shino Nemoto, Yoshiki Mochizuki, Toshimori Kitami, Katsuyuki Yugi, Yoshiko Mizuno, Nobutake Yamamichi, Tsutomu Yamazaki, Iseki Takamoto, Naoto Kubota, Takashi Kadowaki, Erik Arner, Piero Carninci, Osamu Ohara, Makoto Arita, Masahira Hattori, Shigeo Koyasu and Hiroshi Ohno ()
Additional contact information
Tadashi Takeuchi: RIKEN Center for Integrative Medical Sciences (IMS)
Tetsuya Kubota: RIKEN Center for Integrative Medical Sciences (IMS)
Yumiko Nakanishi: RIKEN Center for Integrative Medical Sciences (IMS)
Hiroshi Tsugawa: RIKEN Center for Sustainable Resource Science (CSRS)
Wataru Suda: RIKEN Center for Integrative Medical Sciences (IMS)
Andrew Tae-Jun Kwon: RIKEN Center for Integrative Medical Sciences (IMS)
Junshi Yazaki: RIKEN Center for Integrative Medical Sciences (IMS)
Kazutaka Ikeda: RIKEN Center for Integrative Medical Sciences (IMS)
Shino Nemoto: RIKEN Center for Integrative Medical Sciences (IMS)
Yoshiki Mochizuki: RIKEN Center for Integrative Medical Sciences (IMS)
Toshimori Kitami: RIKEN Center for Integrative Medical Sciences (IMS)
Katsuyuki Yugi: RIKEN Center for Integrative Medical Sciences (IMS)
Yoshiko Mizuno: The University of Tokyo
Nobutake Yamamichi: The University of Tokyo Hospital
Tsutomu Yamazaki: International University of Health and Welfare
Iseki Takamoto: The University of Tokyo
Naoto Kubota: The University of Tokyo
Takashi Kadowaki: The University of Tokyo
Erik Arner: RIKEN Center for Integrative Medical Sciences (IMS)
Piero Carninci: RIKEN Center for Integrative Medical Sciences (IMS)
Osamu Ohara: RIKEN Center for Integrative Medical Sciences (IMS)
Makoto Arita: RIKEN Center for Integrative Medical Sciences (IMS)
Masahira Hattori: RIKEN Center for Integrative Medical Sciences (IMS)
Shigeo Koyasu: RIKEN Center for Integrative Medical Sciences (IMS)
Hiroshi Ohno: RIKEN Center for Integrative Medical Sciences (IMS)

Nature, 2023, vol. 621, issue 7978, 389-395

Abstract: Abstract Insulin resistance is the primary pathophysiology underlying metabolic syndrome and type 2 diabetes1,2. Previous metagenomic studies have described the characteristics of gut microbiota and their roles in metabolizing major nutrients in insulin resistance3–9. In particular, carbohydrate metabolism of commensals has been proposed to contribute up to 10% of the host’s overall energy extraction10, thereby playing a role in the pathogenesis of obesity and prediabetes3,4,6. Nevertheless, the underlying mechanism remains unclear. Here we investigate this relationship using a comprehensive multi-omics strategy in humans. We combine unbiased faecal metabolomics with metagenomics, host metabolomics and transcriptomics data to profile the involvement of the microbiome in insulin resistance. These data reveal that faecal carbohydrates, particularly host-accessible monosaccharides, are increased in individuals with insulin resistance and are associated with microbial carbohydrate metabolisms and host inflammatory cytokines. We identify gut bacteria associated with insulin resistance and insulin sensitivity that show a distinct pattern of carbohydrate metabolism, and demonstrate that insulin-sensitivity-associated bacteria ameliorate host phenotypes of insulin resistance in a mouse model. Our study, which provides a comprehensive view of the host–microorganism relationships in insulin resistance, reveals the impact of carbohydrate metabolism by microbiota, suggesting a potential therapeutic target for ameliorating insulin resistance.

Date: 2023
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DOI: 10.1038/s41586-023-06466-x

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