Novel bile acid biosynthetic pathways are enriched in the microbiome of centenarians

Yuko Sato, Koji Atarashi, Damian R. Plichta, Yasumichi Arai, Satoshi Sasajima, Sean M. Kearney, Wataru Suda, Kozue Takeshita, Takahiro Sasaki, Shoki Okamoto, Ashwin N. Skelly, Yuki Okamura, Hera Vlamakis, Youxian Li, Takeshi Tanoue, Hajime Takei, Hiroshi Nittono, Seiko Narushima, Junichiro Irie, Hiroshi Itoh, Kyoji Moriya, Yuki Sugiura, Makoto Suematsu, Nobuko Moritoki, Shinsuke Shibata, Dan R. Littman, Michael A. Fischbach, Yoshifumi Uwamino, Takashi Inoue, Akira Honda, Masahira Hattori, Tsuyoshi Murai, Ramnik J. Xavier (), Nobuyoshi Hirose and Kenya Honda ()
Additional contact information
Yuko Sato: Keio University School of Medicine
Koji Atarashi: Keio University School of Medicine
Damian R. Plichta: Broad Institute of MIT and Harvard
Yasumichi Arai: Keio University School of Medicine
Satoshi Sasajima: Keio University School of Medicine
Sean M. Kearney: Keio University School of Medicine
Wataru Suda: RIKEN Center for Integrative Medical Sciences
Kozue Takeshita: Keio University School of Medicine
Takahiro Sasaki: Health Sciences University of Hokkaido
Shoki Okamoto: Keio University School of Medicine
Ashwin N. Skelly: Keio University School of Medicine
Yuki Okamura: Keio University School of Medicine
Hera Vlamakis: Broad Institute of MIT and Harvard
Youxian Li: RIKEN Center for Integrative Medical Sciences
Takeshi Tanoue: Keio University School of Medicine
Hajime Takei: Junshin Clinic Bile Acid Institute
Hiroshi Nittono: Junshin Clinic Bile Acid Institute
Seiko Narushima: Keio University School of Medicine
Junichiro Irie: Keio University School of Medicine
Hiroshi Itoh: Keio University School of Medicine
Kyoji Moriya: The University of Tokyo
Yuki Sugiura: Keio University School of Medicine
Makoto Suematsu: Keio University School of Medicine
Nobuko Moritoki: Keio University School of Medicine
Shinsuke Shibata: Keio University School of Medicine
Dan R. Littman: New York University School of Medicine
Michael A. Fischbach: Stanford University
Yoshifumi Uwamino: Keio University School of Medicine
Takashi Inoue: Central Institute for Experimental Animals
Akira Honda: Tokyo Medical University Ibaraki Medical Center
Masahira Hattori: RIKEN Center for Integrative Medical Sciences
Tsuyoshi Murai: Health Sciences University of Hokkaido
Ramnik J. Xavier: Broad Institute of MIT and Harvard
Nobuyoshi Hirose: Keio University School of Medicine
Kenya Honda: Keio University School of Medicine

Nature, 2021, vol. 599, issue 7885, 458-464

Abstract: Abstract Centenarians have a decreased susceptibility to ageing-associated illnesses, chronic inflammation and infectious diseases1–3. Here we show that centenarians have a distinct gut microbiome that is enriched in microorganisms that are capable of generating unique secondary bile acids, including various isoforms of lithocholic acid (LCA): iso-, 3-oxo-, allo-, 3-oxoallo- and isoallolithocholic acid. Among these bile acids, the biosynthetic pathway for isoalloLCA had not been described previously. By screening 68 bacterial isolates from the faecal microbiota of a centenarian, we identified Odoribacteraceae strains as effective producers of isoalloLCA both in vitro and in vivo. Furthermore, we found that the enzymes 5α-reductase (5AR) and 3β-hydroxysteroid dehydrogenase (3β-HSDH) were responsible for the production of isoalloLCA. IsoalloLCA exerted potent antimicrobial effects against Gram-positive (but not Gram-negative) multidrug-resistant pathogens, including Clostridioides difficile and Enterococcus faecium. These findings suggest that the metabolism of specific bile acids may be involved in reducing the risk of infection with pathobionts, thereby potentially contributing to the maintenance of intestinal homeostasis.

Date: 2021
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DOI: 10.1038/s41586-021-03832-5

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