Gut Microbiota Mediate the Metabolism of Colonic Prostaglandins

  • Res Sq. 2026 Feb 20:rs.3.rs-8856024. doi: 10.21203/rs.3.rs-8856024/v1.
Nan Jing  1  2 ,  Guodong Cao  3 ,  Han Qiao  3 ,  Matthew L Edin  4 ,  Katherine Z Sanidad  5  6 ,  Yige Wang  1  2 ,  Eleanor Zhu  7 ,  Jianzhong Ge  8 ,  Jun Yang  9 ,  Fred B Lih  4 ,  Emma Luu  7 ,  Augustine Arredondo  7 ,  Lauren E Hutchinson  10 ,  Quancai Sun  2  11 ,  Jianan Zhang  12 ,  Vladimir Yeliseyev  13 ,  Jonathan C P Steele  14 ,  Richard K Phipps  14 ,  Stephen K Wrigley  14 ,  Tetsuo Kokubun  14 ,  Ravi N Manohar  14 ,  Emily Hopkins  14 ,  Yi Wang  8 ,  Ginger L Milne  15 ,  Sunny Hei Wong  16 ,  Andreas J Bäumler  17 ,  Justin B Siegel  7  18  19 ,  Matthew R Redinbo  10 ,  Melody Y Zeng  5  6 ,  Darryl C Zeldin  4 ,  Zongwei Cai  3  20 ,  Guodong Zhang  1  2  12
Affiliations
  • 1. Department of Nutrition, University of California, Davis, CA, USA.
  • 2. Department of Food Science and Technology, National University of Singapore, Singapore.
  • 3. State Key Laboratory of Environmental and Biological Analysis, Department of Chemistry, Hong Kong Baptist University, Hong Kong, SAR, China.
  • 4. Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, Durham, NC, USA.
  • 5. Gale and Ira Drukier Institute for Children's Health, Weill Cornell Medicine, New York, NY, USA.
  • 6. Department of Pediatrics, Weill Cornell Medicine, New York, NY, USA.
  • 7. Genome Center, University of California, Davis, CA, USA.
  • 8. Biological and Agricultural Engineering, University of California, Davis, CA, USA.
  • 9. Department of Entomology and Nematology, University of California, Davis, CA, USA.
  • 10. Departments of Chemistry, Biochemistry, Microbiology and Genomics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • 11. Department of Health, Nutrition, and Food Sciences, Florida State University, Tallahassee, FL, USA.
  • 12. Department of Food Science, University of Massachusetts, Amherst, MA, USA.
  • 13. Massachusetts Host-Microbiota Center, Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA.
  • 14. Hypha Discovery Limited, Abingdon, United Kingdom.
  • 15. Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
  • 16. Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore.
  • 17. Department of Medical Microbiology and Immunology, University of California, Davis, CA, USA.
  • 18. Department of Chemistry, University of California, Davis, CA, USA.
  • 19. Department of Biochemistry and Molecular Medicine, University of California, Davis, CA, USA.
  • 20. Eastern Institute of Technology, Ningbo, Zhejiang, China.
PMID: 41756457 DOI: 10.21203/rs.3.rs-8856024/v1
Abstract

Prostaglandins (PGs) are endogenous lipid signaling molecules that regulate diverse physiological and pathological processes, and their biosynthetic pathways are targets of widely used drugs such as aspirin and Other nonsteroidal anti-inflammatory drugs (NSAIDs)1-7. However, previous research of PG biosynthesis has focused on host metabolic pathways; as such, the contribution of gut microbiota remains unknown1. Here, we demonstrate a colonic pathway in which gut microbes directly participate in PG metabolism, thereby regulating intestinal PG levels and their biological effects. Comparison of germ-free and conventionally raised mice reveals that the gut microbiota markedly increase gut levels of multiple PGs. This effect is driven by Bacterial β-glucuronidases (GUS), which hydrolyze host-derived PG glucuronides - less active or inactive conjugates - to regenerate bioactive, free-form PGs. Administration of purified GUS enzyme or mono-colonization with wild-type or GUS-deficient bacteria in germ-free mice demonstrates the critical role for microbial GUS in regulating intestinal PG levels and downstream biological responses. Together, these findings reveal a previously unrecognized function of the gut microbiota in PG metabolism and highlight microbial pathways as potential targets for modulating colonic PG signaling to prevent or treat gastrointestinal disease.

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