Novel bile acid biosynthetic pathways are enriched in the microbiome of centenarians
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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.
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The Odoribacter genus is strongly associated with bile acids and short-chain fatty acids.
“This certain bacterial genus was strongly associated with the bile acids (BAs) and short-chain fatty acids (SCFAs) (Chen et al. 2025; Sato et al. 2021).”
From Odoribacter laneus protects intestinal barrier by bile acid-FXR axis in acute pancreatitis (2026) · cites this paper as Sato et al. 2021
In “Effects of isoalloLCA on the commensal gut microbiota” (page not provided), the paper reports positive correlations between Odoribacter laneus and three bile acids. It does not report an association between Odoribacter and short-chain fatty acids, so only the bile-acid part is supported. (LLM, conf=0.88)
Experimental — accuracy not yet measuredGenomes of Odoribacter contain the essential enzymes 5AR and 3β-HSDH required for secondary bile acid synthesis.
“The genomes of Odoribacter contain the essential enzymes (5AR and 3β-HSDH) required for secondary bile acid (SBA) synthesis (Sato et al. 2021).”
From Odoribacter laneus protects intestinal barrier by bile acid-FXR axis in acute pancreatitis (2026) · cites this paper as Sato et al. 2021
In “5AR- and 3β-HSDH-mediated transformation of 3-oxoΔ4-LCA to isoalloLCA” (page not given), the paper identifies an Odoribacteraceae St21 isolate carrying genes for 5AR and 3β-HSDH and links them to isoalloLCA production. It does not establish that Odoribacter genomes generally carry these genes or that the enzymes are required for secondary bile acid synthesis broadly. (LLM, conf=0.86)
Experimental — accuracy not yet measuredCertain secondary bile acids serve significant biological functions, including regulation of host metabolism, immunity, and resistance against intestinal pathogen expansion.
“Nevertheless, it is noteworthy that certain secondary BAs serve significant biological functions, including the regulation of host metabolism, immunity, and resistance against intestinal pathogen expansion.21,360–364”
From Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases (2024) · cites this paper as [21]
Specific secondary bile acids produced by Alistipes putredinis and Odoribacter splanchnicus are more prevalent in centenarians and contribute to intestinal homeostasis.
“specific secondary bile acids (including isoallolithocholic acid) produced by distinct gut species (such as Alistipes putredinis and Odoribacter splanchnicus) are more prevalent in centenarian individuals and reportedly contribute to intestinal homeostasis22.”
From Gut OncoMicrobiome Signatures (GOMS) as next-generation biomarkers for cancer immunotherapy (2023) · cites this paper as [22]
The gut microbiota of centenarians is enriched in bacteria capable of generating unique secondary bile acids with potent effects against pathogens such as Clostridioides difficile and Enterococcus faecium.
“The gut microbiota of centenarians is also enriched in bacteria capable of generating unique secondary bile acids with potent effects against pathogens such as Clostridioides difficile and Enterococcus faecium.”
From Meta-hallmarks of aging and cancer (2023) · cites this paper as [92]
Previous research highlighted the involvement of R. gnavus in bile acid metabolism, particularly the production of iso-bile acids, which were elevated in Japanese centenarians.
“Previous research also highlighted the involvement of R. gnavus in bile acid metabolism, 44 particularly the production of iso-bile acids, which were elevated in Japanese centenarians. 45”
From Global genetic diversity of human gut microbiome species is related to geographic location and host health (2025) · cites this paper as [45]
Studies in the past decade have demonstrated that gut microbiome composition changes with age, that exceptionally long-lived individuals have a different microbiome composition from average older adults, and that certain microorganisms and the metabolites they produce are beneficial to human health.
“Studies in the past decade have demonstrated that gut microbiome composition changes with age, that exceptionally long-lived individuals have a different microbiome composition from average older adults131–133, and that certain microorganisms131,134,135 and the metabolites they produce132,134,136 are beneficial to human health.”
From Measuring biological age using omics data (2022) · cites this paper as [136]
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Self-citationAndreu-Sánchez, S., Blanco-Míguez, A., Wang, D., Golzato, D., Manghi, P., Heidrich, V., Fackelmann, G., Zhernakova, D. V., Kurilshikov, A., Valles-Colomer, M., et al. (2025) · Cell · doi:10.1016/j.cell.2025.04.014 · Cited by 81 · see citing works
Chen, J., Levy, A., Tian, A.-L., Huang, X., Cai, G., Fidelle, M., Rauber, C., Ly, P., Pizzato, E., Sitterle, L., et al. (2025) · Cancer Cell · doi:10.1016/j.ccell.2025.02.010 · Cited by 67 · see citing works
Toward a health-associated core keystone index for the human gut microbiome
Goel, A., Shete, O., Goswami, S., Samal, A., C.B., L., Kedia, S., Ahuja, V., O’Toole, P. W., Shanahan, F., & Ghosh, T. S. (2025) · Cell Reports · doi:10.1016/j.celrep.2025.115378 · Cited by 37 · see citing works
Phan, J., Nair, D., Jain, S., Montagne, T., Flores, D. V., Nguyen, A., Dietsche, S., Gombar, S., & Cotter, P. (2021) · mSystems · doi:10.1128/msystems.01215-21 · Cited by 33 · see citing works
Gut Microbiota–Related Biomarkers in Immuno-Oncology
Silva, C. A. C., Fidelle, M., Almonte, A. A., Derosa, L., & Zitvogel, L. (2025) · Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-061124-102218 · Cited by 22 · see citing works
Odoribacter laneus protects intestinal barrier by bile acid-FXR axis in acute pancreatitis
Gu, R., Li, J., Qi, J., Sun, R., Wu, H., & Jin, B. (2026) · AMB Express · doi:10.1186/s13568-026-02071-z · Cited by 2 · see citing works
“The genomes of Odoribacter contain the essential enzymes (5AR and 3β-HSDH) required for secondary bile acid (SBA) synthesis (Sato et al. 2021).”
Influential
- Authors
- Sato, Y., Atarashi, K., Plichta, D. R., Arai, Y., Sasajima, S., Kearney, S. M., Suda, W., Takeshita, K., Sasaki, T., Okamoto, S., Skelly, A. N., Okamura, Y., Vlamakis, H., Li, Y., Tanoue, T., Takei, H., Nittono, H., Narushima, S., Irie, J., Itoh, H., Moriya, K., Sugiura, Y., Suematsu, M., Moritoki, N., Shibata, S., Littman, D. R., Fischbach, M. A., Uwamino, Y., Inoue, T., Honda, A., Hattori, M., Murai, T., Xavier, R. J., Hirose, N., & Honda, K.
- Affiliations
- Keio University (JP)
- Broad Institute (US)
- RIKEN Center for Integrative Medical Sciences (JP)
- Health Sciences University of Hokkaido (JP)
- The University of Tokyo (JP)
- Howard Hughes Medical Institute (US)
- Stanford University (US)
- Central Institute for Experimental Animals (JP)
- Tokyo Medical University Ibaraki Medical Center (JP)
- Waseda University (JP)
- Corresponding author
- Xavier, Ramnik J.
- Honda, Kenya
- ORCID
- Sato, Yuko
- Atarashi, Koji
- Plichta, Damian R.
- Arai, Yasumichi
- Kearney, Sean M.
- Suda, Wataru
- Sasaki, Takahiro
- 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
- Xavier, Ramnik J.
- Honda, Kenya
- Venue
- Nature
- Published
- 2021-07-29
- Volume
- 599
- Issue
- 7885
- Pages
- 458-464
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W3184541229
- Cited by
- 632
- References
- 53
- Citations by year
- 2026: 113 · 2025: 126 · 2024: 174 · 2023: 99 · 2022: 94 · 2021: 24
- FWCI
- 31.13
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Locations
- Nature (publishedVersion)
- Research Square (acceptedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Naito Foundation
- Takeda Science Foundation
- Japan Agency for Medical Research and Development (20gm0010003h0005)
- Broad Institute
- Keio University
- Japan Society for the Promotion of Science (20H05627, 21K18270, 21K08584, 18H03055, 20H00535, No: 20H05627)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK043351)
- Research Complex Program (JP15667051)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Steroid Chemistry and Biochemistry
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Keywords
- centenarians, gut microbiota, secondary bile acids, lithocholic acid, bile acid synthesis, 5α-reductase, 3β-hydroxysteroid dehydrogenase, antimicrobial activity, multidrug-resistant pathogens, Clostridium difficile, Enterococcus faecium, pathobionts, intestinal homeostasis, aging
- MeSH terms
- Gastrointestinal Microbiome, Centenarians, Aged, 80 and over, Animals, Anti-Bacterial Agents, Bacteria, Feces, Female, Gram-Positive Bacteria, Humans, Lithocholic Acid, Male, Symbiosis, 3-Hydroxysteroid Dehydrogenases, Cholestenone 5 alpha-Reductase, Mice, Biosynthetic Pathways
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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