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

• Published in: Nature (London) Vol. 599; no. 7885; pp. 458 - 464
• Main Authors: Sato, Yuko, Atarashi, Koji, Plichta, Damian R., Arai, Yasumichi, Sasajima, Satoshi, Kearney, Sean M., Suda, Wataru, Takeshita, Kozue, Sasaki, Takahiro, Okamoto, Shoki, Skelly, Ashwin N., Okamura, Yuki, Vlamakis, Hera, Li, Youxian, Tanoue, Takeshi, Takei, Hajime, Nittono, Hiroshi, Narushima, Seiko, Irie, Junichiro, Itoh, Hiroshi, Moriya, Kyoji, Sugiura, Yuki, Suematsu, Makoto, Moritoki, Nobuko, Shibata, Shinsuke, Littman, Dan R., Fischbach, Michael A., Uwamino, Yoshifumi, Inoue, Takashi, Honda, Akira, Hattori, Masahira, Murai, Tsuyoshi, Xavier, Ramnik J., Hirose, Nobuyoshi, Honda, Kenya
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 18-11-2021; Nature Publishing Group
• Subjects: 101/28; 101/58; 3-Hydroxysteroid Dehydrogenases - metabolism; 45/22; 45/23; 631/326/22/1434; 631/326/2565/2134; 64/60; Acids; Age; Aged, 80 and over; Aging; Animals; Anti-Bacterial Agents - biosynthesis; Anti-Bacterial Agents - metabolism; Antiinfectives and antibacterials; Bacteria - classification; Bacteria - enzymology; Bacteria - isolation & purification; Bacteria - metabolism; Bile; Bile acids; Biosynthesis; Biosynthetic Pathways; Centenarians; Cholestenone 5 alpha-Reductase - metabolism; Chronic illnesses; Dehydrogenases; Enzymes; Feces - chemistry; Feces - microbiology; Female; Gastrointestinal Microbiome; Geriatrics; Gram-Positive Bacteria - metabolism; Health risks; Homeostasis; Humanities and Social Sciences; Humans; Hydroxysteroids; Inflammation; Inflammatory bowel disease; Intestinal microflora; Isoforms; Lithocholic Acid - analogs & derivatives; Lithocholic Acid - biosynthesis; Lithocholic Acid - metabolism; Male; Metabolites; Mice; Microbiomes; Microbiota; Microbiota (Symbiotic organisms); Microorganisms; multidisciplinary; Multidrug resistance; Oldest old people; Physiological aspects; Physiological research; Reductases; Science; Science (multidisciplinary); Symbiosis; Japan
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-021-03832-5

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.
The microbiota of centenarians (aged 100 years and older) comprise gut microorganisms that are capable of generating unique secondary bile acids, including isoallolithocholic acid, a bile acid with potent antimicrobial effects against Gram-positive—but not Gram-negative—multidrug-resistant pathogens.