Biology subjects

Lai, Y.-L.

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

7 recordsLinked to original sources

bioRxiv2025

Multi-omics integration uncovers host-microbiota crosstalk underlying sexual differentiation in the shortfin eel Anguilla bicolor pacifica

The global decline in anguillid eel populations has intensified interest in understanding their biology for conservation and aquaculture. While host-gut microbiota interactions are well-characterized in homeotherms, these relationships remain poorly understood in poikilotherms during sexual differentiation. We examined gut microbiota dynamics across developmental stages in the shortfin eel Anguilla bicolor pacifica, which exhibits early sexual differentiation and a relatively short life cycle. Glass eels were cultivated in controlled freshwater conditions for three years, with sampling at key stages: glass eel, elver, sex-undetermined eel, and sex-determined eel. Full-length 16S rRNA gene sequencing revealed significant compositional shifts during development, with higher bacterial richness in adults versus younger eels. Early stages were dominated by Pseudomonadota, while sex-determined adults showed increased Deinococcota abundance. Network analysis identified Deinococcus, Sphingomonas, and Variovorax as key genera in sex-determined eels, with positive correlations between anti-Mullerian hormone gene expression and these taxa. We isolated 66 gut bacterial strains capable of metabolizing sex hormones under microaerobic conditions. These isolates, representing 22 genera across four phyla, demonstrated diverse metabolic capabilities from partial oxidation to complete steroid mineralization. Multiple strains achieved complete estradiol degradation as single isolates--a rare metabolic capability of environmental microorganisms. Comparative genomic analysis revealed widespread steroid-metabolizing genes, with Deinococcus species showing previously unreported hormone degradation capabilities. Our multi-omics analysis demonstrates that gut microbiota composition and function are intimately linked to eel sexual development, suggesting bidirectional host-microbe interactions influencing reproductive physiology. These findings advance understanding of host-microbiota interactions in aquatic vertebrates and provide implications for eel aquaculture and conservation.

microbiology↗

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

Aromatase-independent estrogenesis: Wood-Ljungdahl pathway likely contributed to the emergence of estrogens in the biosphere

Androgen and estrogen, key sex hormones, were long thought to be exclusively produced by vertebrates. The O2-dependent aromatase that converts androgen to estrogen (estrogenesis) has never been identified in any prokaryotes. Here, we report the discovery of anaerobic estrogenesis in a Peptococcaceae bacterium (strain TUW77) isolated from the gut of the great blue-spotted mudskipper (Boleophthalmus pectinirostris). This strain exhibits unprecedented testosterone fermentation pathways, transforming testosterone into estrogens and androstanediol under anaerobic conditions. Physiological experiments revealed that strain TUW77 grows exclusively on testosterone, utilizing the androgenic C-19 methyl group as both the carbon source and electron donor. The genomic analysis identified three copies of a polycistronic gene cluster, abeABC (anaerobic bacterial estrogenesis), encoding components of a classic cobalamin-dependent methyltransferase system. These genes, highly expressed under testosterone-fed conditions, show up to 57% protein identity to the characterized EmtAB from denitrifying Denitratisoma spp., known for methylating estrogen into androgen (the reverse reaction). Tiered transcriptomic and proteomic analyses suggest that the removed C-19 methyl group is completely oxidized to CO2 via the oxidative Wood-Ljungdahl pathway, while the reducing equivalents (NADH) fully reduce remaining testosterone to androstanediol. Consistently, the addition of anthraquinone-2,6-disulfonate, an extracellular electron acceptor, to testosterone-fed TUW77 cultures enabled complete testosterone conversion into estrogen without androstanediol accumulation (anaerobic testosterone oxidation). This discovery of aromatase-independent estrogenesis in anaerobic bacteria suggests that the ancient Wood-Ljungdahl pathway may have contributed to the emergence of estrogens in the early biosphere. SignificanceUsing a testosterone-grown anaerobic bacterium as a model organism, we characterized this unusual anaerobic estrogenesis at the molecular level. Our findings challenge the long-held belief that estrogen production is exclusive to aromatase-containing vertebrates, expanding our understanding of steroid hormone biosynthesis across domains of life. The involvement of ancient strictly anaerobic Peptococcaceae members and the Wood-Ljungdahl pathway suggests that bacterial estrogenesis may predate O2-dependent estrogenesis in vertebrates. Furthermore, the identification of estrogen-producing bacteria in animal guts opens new avenues for potential microbiome-based hypoestrogenism therapies to supplement estrogen in menopausal or ovariectomized females, offering an innovative alternative to current hormone replacement strategies.

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

MicroRNA-4776-5p acts as a radiosensitizer and predicts the prognosis of patients with head and neck cancer receiving radiotherapy

Head and neck cancer is the leading cancer worldwide. Radiation therapy plays important role of treatment for head and neck cancer. MicroRNAs have been shown to be related to tumor progression and radiosensitivity. However, the mechanisms are still largely unknown and evidence are still limited. In the current study, we sought to identify the miRNA related the radiosensitivity of head and neck tumor cell, which leading to the disappointed prognosis of patients with head and neck cancer receiving radiation therapy. The miRNA expression profiles and clinical information of patients with head and neck cancer were obtained from The Cancer Genome Atlas. The identification of miRNA was carried out through an integrated bioinformatics analysis. The miRNA identified in previous approach was validated through in vitro and in vivo studies. MiR-4776-5p was finally identified as the role of radio-sensitizer and predicts the prognosis of patients with head and neck cancer receiving radiotherapy. 11 of 16 genes targeted by the miR-4776-5p have been discovered to regulate the mechanisms related to radiosensitivity using functional annotation.

cancer biology↗

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↗

bioRxiv2021

Integrated multi-omics investigations reveal the key role of synergistic microbial networks in removing plasticizer di-(2-ethylhexyl) phthalate from estuarine sediments

Di-(2-ethylhexyl) phthalate (DEHP) is the most widely used plasticizer worldwide with an annual global production of over eight million tons. Because of its improper disposal, endocrine-disrupting DEHP often accumulates in estuarine sediments in industrialized countries at sub-millimolar levels, resulting in adverse effects on both ecosystems and human beings. The microbial degraders and biodegradation pathways of DEHP in O2-limited estuarine sediments remain elusive. Here, we employed an integrated meta-omics approach to identify the DEHP degradation pathway and major degraders in this ecosystem. Estuarine sediments were treated with DEHP or its derived metabolites, o-phthalic acid and benzoic acid. The rate of DEHP degradation in denitrifying mesocosms was two times slower than that of o-phthalic acid, suggesting that side-chain hydrolysis of DEHP is the rate-limiting step of anaerobic DEHP degradation. On the basis of microbial community structures, functional gene expression, and metabolite profile analysis, we proposed that DEHP biodegradation in estuarine sediments is mainly achieved through synergistic networks between denitrifying proteobacteria. Acidovorax and Sedimenticola are the major degraders of DEHP side-chains; the resulting o-phthalic acid is mainly degraded by Aestuariibacter through the UbiD-dependent benzoyl-CoA pathway. We isolated and characterized Acidovorax sp. strain 210-6 and its extracellular hydrolase, which hydrolyzes both alkyl side-chains of DEHP. Interestingly, genes encoding DEHP/MEHP hydrolase and phthaloyl-CoA decarboxylase--key enzymes for side-chain hydrolysis and o-phthalic acid degradation, respectively--are flanked by transposases in these proteobacterial genomes, indicating that DEHP degradation capacity is likely transferred horizontally in microbial communities. ImportanceXenobiotic phthalate esters (PAE) have been produced on a considerably large scale for only 70 years. The occurrence of endocrine-disrupting di-(2-ethylhexyl) phthalate (DEHP) in environments has raised public concern, and estuarine sediments are major DEHP reservoirs. Our multi-omics analyses indicated that complete DEHP degradation in O2-limited estuarine sediments depends on synergistic microbial networks between diverse denitrifying proteobacteria and uncultured candidates. Our data also suggest that the side-chain hydrolysis of DEHP, rather than o-phthalic acid activation, is the rate-limiting step in DEHP biodegradation within O2-limited estuarine sediments. Therefore, deciphering the bacterial ecophysiology and related biochemical mechanisms can help facilitate the practice of bioremediation in O2-limited environments. Furthermore, the DEHP hydrolase genes of active DEHP degraders can be used as molecular markers to monitor environmental DEHP degradation. Finally, future studies on the directed evolution of identified DEHP/MEHP hydrolase would bring a more catalytically efficient DEHP/MEHP hydrolase into practice.

microbiology↗