Biology subjects

Tseng, Y.-L.

Publications and source records attributed to Tseng, Y.-L..

3 recordsLinked to original sources

bioRxiv2024

Multi-Omics Mapping of Gut Microbiota's Role in Progesterone Metabolism

5-neurosteroids such as allopregnanolone and isopregnanolone play critical roles in neurological health and mood regulation, yet current therapeutic production faces significant limitations. We demonstrate that specific gut microbes represent a previously unrecognized source of bioavailable 5-neurosteroids that reach the central nervous system via the gut-brain axis. Through integrated metabolomic and genomic analyses of progesterone-amended fecal cultures, we identified Holdemania as a major producer of isopregnanolone via microbial steroid 5-reductase (BaiJ type 2) and 3{beta}-hydroxysteroid dehydrogenase/reductase. Phylogenetic analysis revealed that BaiJ-like sequences cluster predominantly within Firmicutes, with Holdemania species forming a distinct clade. In female C57BL/6 mice administered progesterone and H. filiformis, 5-neurosteroids including isopregnanolone predominated in gut tissues while allopregnanolone was the major hepatic neurosteroid. Critically, using stable isotope tracing with [3,4-{superscript 1}3C2]progesterone, we detected {superscript 1}3C-labeled isopregnanolone in brain tissue, providing direct evidence for gut-to-brain transport of microbiota-derived neurosteroids. High-fat diet significantly enhanced brain 5-neurosteroid accumulation. Global meta-analysis reveals reduced Holdemania abundance in PCOS patients (n = 346) compared to healthy women (n = 321). These findings identify gut microbiota as pharmacologically relevant neurosteroid producers and position H. filiformis as a promising probiotic candidate for enhancing endogenous neurosteroid production to treat mood disorders and other neuropsychiatric conditions. HighlightsO_LIHoldemania was identified as a major producer of 5-neurosteroids, particularly isopregnanolone, in the intestinal tract C_LIO_LIHoldemania 5-reductase (BaiJ type 2) belongs to a distinct phylogenetic clade compared to characterized Clostridium BaiJ (type 1) C_LIO_LI5-neurosteroids occurred predominantly in the cecum of female mice administered H. filiformis, progesterone, and high-fat diet C_LIO_LI{superscript 1}3C-labeled 5-neurosteroids were detected in brain tissue of female mice orally administered [3,4-{superscript 1}3C2]progesterone and H. filiformis, demonstrating gut-to-brain transport C_LIO_LIGut microbes such as H. filiformis represent promising probiotic candidates for enhancing 5-neurosteroid production and circulation via the gut-brain axis C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=146 HEIGHT=200 SRC="FIGDIR/small/628284v3_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@1b85caaorg.highwire.dtl.DTLVardef@cbb352org.highwire.dtl.DTLVardef@169f7fcorg.highwire.dtl.DTLVardef@17c638_HPS_FORMAT_FIGEXP M_FIG C_FIG

microbiology↗

bioRxiv2024

Clostridium innocuum, an opportunistic gut pathogen, inactivates host gut progesterone and arrests ovarian follicular development

HighlightsO_LIWe identified Clostridium innocuum as a key player in gut progesterone metabolism. C_LIO_LIProgesterone is converted into epipregnanolone with negligible progestogenic activity. C_LIO_LIWe identified the enzyme and mechanisms of microbial epipregnanolone production. C_LIO_LIC. innocuum caused decreased serum progesterone and follicular arrest in female mice. C_LIO_LIC. innocuum is a causal factor of progesterone resistance in women taking progesterone. C_LI O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=93 SRC="FIGDIR/small/585140v1_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@14cceaborg.highwire.dtl.DTLVardef@1946432org.highwire.dtl.DTLVardef@13e46d2org.highwire.dtl.DTLVardef@19b9a25_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical AbstractC_FLOATNO C_FIG In briefChen et al. identified Clostridium innocuum as a major species involved in gut progesterone metabolism, with epipregnanolone as the main product, and elucidated the molecular mechanisms. C. innocuum inactivates gut progesterone in female mice, leading to decreased circulating progesterone levels. C. innocuum is also a causal factor of follicular arrest. Levels of progesterone, an endogenous female hormone, increase after ovulation; progesterone is crucial in the luteal phase to maintain successful pregnancy and prevent early miscarriage. Both endogenous and exogenous progesterone are recycled between the liver and gut; thus, the gut microbiota regulate host progesterone levels by inhibiting enterohepatic progesterone circulation. Our data indicated Clostridium innocuum as a major species involved in gut progesterone metabolism in women with infertility. C. innocuum converts progesterone into the neurosteroid epipregnanolone (with negligible progestogenic activity). We purified and characterized the corresponding enzyme, namely NADPH-dependent 5{beta}-dihydroprogesterone reductase, which is highly oxygen sensitive and whose corresponding genes are prevalent in C. innocuum. Moreover, C. innocuum-administered female C57BL/6 mice (aged 7 weeks) exhibited decreased serum progesterone levels ([~]35%). Clostridium-specific antibiotics (metronidazole) restored low serum progesterone levels in these mice. Furthermore, prolonged C. innocuum administration (12 weeks) arrested ovarian follicular development in female mice. Cytological and histological analyses indicated that C. innocuum may cause luteal phase insufficiency and affect menstrual regularity. Our findings suggest C. innocuum as a causal factor of progesterone resistance in women taking progesterone.

microbiology↗

bioRxiv2022

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

Abnormally high circulating androgen levels have been considered a causative factor for benign prostatic hypertrophy and prostate cancer. Recent studies suggested that gut bacteria can alter sex steroid profile of host; however, the underlying mechanisms and bacterial taxa remain elusive. Thauera sp. strain GDN1 is an unusual betaproteobacterium capable of aerobic and anaerobic androgen catabolism in environmental conditions (37{degrees}C) resembling the mammalian gut. The strain GDN1 administration to C57BL/6J mice through oral gavage profoundly affected gut bacterial community, along with an approximately 50% reduction in serum androgen level in male mice. Our RT-qPCR results revealed the differential expression of aerobic and anaerobic androgen catabolic genes in the mouse ileum (microaerobic) and caecum (anaerobic), respectively. Furthermore, androgenic ring-cleaved metabolites were detected in the mouse fecal extract. This study discovered that androgen serves as a carbon source of gut microbes and that androgen-catabolizing gut bacteria can modulate host circulating androgen levels. HighlightsO_LIThauera sp. strain GDN1 administration through oral gavage regulated mouse serum androgen levels. C_LIO_LIThe biochemical, genetic, and metabolite profile analyses revealed the occurrence of bacterial androgen catabolism in the mouse gut. C_LIO_LIAndrogen catabolism proceeds through the O2-dependent and O2-independent catabolic pathways in mouse ileum and caecum, respectively. C_LIO_LIA possibility to harness Thauera sp. strain GDN1 as a functional probiotic to treat hyperandrogenism. C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=89 SRC="FIGDIR/small/500890v1_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@515126org.highwire.dtl.DTLVardef@a696faorg.highwire.dtl.DTLVardef@1020beforg.highwire.dtl.DTLVardef@15da175_HPS_FORMAT_FIGEXP M_FIG C_FIG In briefHsiao et al. found that oral administration of androgen-catabolizing Thauera species regulated mouse serum androgen level. They characterized the gut microbe-mediated androgen catabolism through genetic and biochemical analyses. Their discovery portends a possibility of harnessing androgen-catabolic gut bacteria as functional probiotics to treat hyperandrogenism.

microbiology↗