Circulating androgen regulation by androgen-catabolizing gut bacteria in male mouse gut

ABSTRACT

Abnormally high circulating androgen levels have been considered a causative factor for benign prostatic hypertrophy and prostate cancer in men. Recent animal studies on gut microbiome suggested that gut bacteria are involved in sex steroid metabolism; however, the underlying mechanisms and bacterial taxa remain elusive. Denitrifying betaproteobacteria Thauera spp. are metabolically versatile and often distributed in the animal gut. Thauera sp. strain GDN1 is an unusual betaproteobacterium capable of catabolizing androgen under both aerobic and anaerobic conditions. We administered C57BL/6 mice (aged 7 weeks) with strain GDN1 through oral gavage. The strain GDN1 administration caused a minor increase in the relative abundance of Thauera (≤0.1%); however, it has profound effects on the host physiology and gut bacterial community. The results of our ELISA assay and metabolite profile analysis indicated an approximately 50% reduction in serum androgen levels in the strain GDN1-administered male mice. Moreover, androgenic ring-cleaved metabolites were detected in the fecal extracts of the strain GDN1-administered mice. Furthermore, our RT – qPCR results revealed the expression of the androgen catabolism genes in the gut of the strain GDN1-administered mice. We found that the administered strain GDN1 regulated mouse serum androgen levels, possibly because it blocked androgen recycling through enterohepatic circulation. This study discovered that sex steroids serve as a carbon source of gut bacteria; moreover, host circulating androgen levels may be regulated by androgen-catabolizing gut bacteria. Our data thus indicate the possible applicability of androgen-catabolic gut bacteria as potent probiotics in alternative therapy of hyperandrogenism.

GRAPHICAL ABSTRACT

KEYWORDS:

• Androgen
• gut microbe
• hyperandrogenism
• mouse
• sex steroids
• testosterone catabolism
• thauera

Acknowledgments

We thank the Small Molecule Metabolomics core facility sponsored by the Institute of Plant and Microbial Biology (IPMB), Academia Sinica for UPLC–HRMS analysis.

Authors’ contributions

T.-H.H., C.-H.C., M.-J.C., and Y.-R.C. designed research; T.-H.H., C.-H.C., Y.-L.C., G.-J.B.-M., T.-Y.W., P.-T.L., C.-W.L., Y.-L.L., P.-H.C., and Y.-L.T. performed research; P.-H.W., T.-H.L., and C.-J.S. contributed new reagents/analytic tools; C.-H.C., Y.-L.C., M.-J.C. and Y.-R.C. analyzed data; and T.-H.H., P.-H.W. and Y.-R.C. wrote the paper.

Disclosure statement

No potential conflict of interest was reported by the authors.

Data availability statement

Oligonucleotide primers used in this study are listed in Table S2. Nucleotide sequences of the 16S rRNA and androgen catabolism genes of strain GDN1 are shown in Appendices S1–S3. Transcriptomic data of the strain GDN1 are available in Dataset S1. Genome sequence of the strain GDN1 (accession no. CP097870) has been deposited in the National Center for Biotechnology Information (NCBI) Genome database. The transcriptomes of the strain GDN1 have been deposited in the NCBI SRA database under BioProject ID PRJNA838737 [accession numbers: SRR19418054~ SRR19418057]. The fecal bacterial 16S rRNA sequencing datasets have been deposited in the NCBI SRA database under BioProject ID PRJNA838737 [accession numbers: SRR19913488~SRR19913535].

Supplementary data

Supplemental data for this article can be accessed online at https://doi.org/10.1080/19490976.2023.2183685

Additional information

Funding

This study was supported by the Ministry of Science and Technology of Taiwan (MOST 110-2311-B-001-033-MY3, 109-2314-B-002-125-MY3, 110-2811-B-002-562, and 110-2222-E-008-002) and Academia Sinica Career Development Award (AS-CDA-110-L13). We thank the Small Molecule Metabolomics core facility sponsored by the Institute of Plant and Microbial Biology (IPMB), Academia Sinica for UPLC–HRMS analysis.