Novel bile acid biosynthetic pathways are enriched in the microbiome of centenarians PMID: 34325466

Target-related Cytokines

2026-09-23

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

Nature. 2021 Nov;599(7885):458-464. doi: 10.1038/s41586-021-03832-5.

Yuko Sato ^# ¹ ² ³ , Koji Atarashi ^# ¹ ² ³ , Damian R Plichta ^# ⁴ , Yasumichi Arai ⁵ , Satoshi Sasajima ¹ ³ , Sean M Kearney ¹ ² , Wataru Suda ² , Kozue Takeshita ¹ ³ , Takahiro Sasaki ⁶ , Shoki Okamoto ¹ , Ashwin N Skelly ¹ , Yuki Okamura ¹ , Hera Vlamakis ⁴ , Youxian Li ² , Takeshi Tanoue ¹ ² ³ , Hajime Takei ⁷ , Hiroshi Nittono ⁷ , Seiko Narushima ¹ ² , Junichiro Irie ⁸ , Hiroshi Itoh ⁸ , Kyoji Moriya ⁹ , Yuki Sugiura ¹⁰ , Makoto Suematsu ¹⁰ , Nobuko Moritoki ¹¹ , Shinsuke Shibata ¹¹ , Dan R Littman ¹² ¹³ , Michael A Fischbach ¹⁴ , Yoshifumi Uwamino ¹⁵ , Takashi Inoue ¹⁶ , Akira Honda ¹⁷ , Masahira Hattori ² ¹⁸ , Tsuyoshi Murai ⁶ , Ramnik J Xavier ¹⁹ ²⁰ ²¹ , Nobuyoshi Hirose ⁵ , Kenya Honda ²² ²³ ²⁴

Affiliations

1. Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo, Japan.
2. RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
3. JSR-Keio University Medical and Chemical Innovation Center, Tokyo, Japan.
4. Infectious Disease and Microbiome Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
5. Centre for Supercentenarian Medical Research, Keio University School of Medicine, Tokyo, Japan.
6. School of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Hokkaido, Japan.
7. Junshin Clinic Bile Acid Institute, Tokyo, Japan.
8. Department of Internal Medicine, Division of Endocrinology, Metabolism and Nephrology, Keio University School of Medicine, Tokyo, Japan.
9. Department of Infection Control and Prevention, The University of Tokyo, Tokyo, Japan.
10. Department of Biochemistry, Keio University School of Medicine, Tokyo, Japan.
11. Electron Microscope Laboratory, Keio University School of Medicine, Tokyo, Japan.
12. The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, NY, USA.
13. Howard Hughes Medical Institute, New York, NY, USA.
14. Department of Bioengineering, Stanford University, Stanford, CA, USA.
15. Department of Laboratory Medicine, Keio University School of Medicine, Tokyo, Japan.
16. Department of Marmoset Biology and Medicine, Central Institute for Experimental Animals, Kawasaki, Japan.
17. Division of Gastroenterology and Hepatology, Tokyo Medical University Ibaraki Medical Center, Ibaraki, Japan.
18. Graduate School of Advanced Science and Engineering, Waseda University, Tokyo, Japan.
19. Infectious Disease and Microbiome Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA. [email protected].
20. Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA, USA. [email protected].
21. Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA. [email protected].
22. Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo, Japan. [email protected].
23. RIKEN Center for Integrative Medical Sciences, Yokohama, Japan. [email protected].
24. JSR-Keio University Medical and Chemical Innovation Center, Tokyo, Japan. [email protected].
# Contributed equally.

Abstract

Centenarians have a decreased susceptibility to ageing-associated illnesses, chronic inflammation and infectious diseases^1-3. 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.