Biology subjects
Publications and source records attributed to Chou, C.-H..
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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
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.
Infection with West Nile Virus (WNV) can drive a wide range of responses, from asymptomatic to flu-like symptoms/fever or severe cases of encephalitis and death. To identify cellular and molecular signatures distinguishing WNV severity, we employed systems profiling of peripheral blood from asymptomatic and severely ill individuals infected with WNV. We interrogated immune responses longitudinally from acute infection through convalescence at 3 months and 1 year employing multiplexed single cell protein and transcriptional profiling (CyTOF and Seq-Well) complemented with matched serum proteomics and metabolomics. At the acute time point, we detected both an elevated proportion of pro-inflammatory markers in innate immune cell types and reduced frequency of regulatory T cell activity in participants with severe infection compared to those with asymptomatic infection. Single-cell transcriptomics of paired samples revealed that asymptomatic donors had higher expression of genes associated with innate immune pathways, in particular anti-inflammatory CD16+ monocytes at the acute time point. A multi-omics analysis identified factors--beyond those from individual analyses--that distinguished immune state trajectory between severity groups. Here we highlighted the potential of systems immunology using multiple cell-type and cell-state-specific analyses to identify correlates of infection severity and host cellular activity contributing to an effective anti-viral response.
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.
To understand the genetic basis in governing phosphorus (P) acquisition, we performed genome-wide association studies (GWAS) on a diversity panel of Arabidopsis thaliana by two primary determinants of P acquisition, phosphate (Pi)-uptake activity and PHOSPHATE TRANSPORTER 1 (PHT1) protein abundance. Association mapping revealed a shared significant peak on chromosome 5 (Chr5) where the PHT1;1/2/3 genes reside, suggesting a strong correlation between the regulation of Pi-uptake activity and PHT1 protein abundance. Genes encoding transcription factors, kinases, and a metalloprotease associated with both traits were also identified. Conditional GWAS followed by statistical analysis of genotype-dependent expression of PHT1;1 and transcription activity assays revealed an epistatic interaction between PHT1;1 and MYB DOMAIN PROTEIN 52 (MYB52) on Chr1. Analyses of F1 hybrids generated by crossing two subgroups of natural accessions carrying specific SNPs associated with PHT1;1 and MYB52 further revealed the strong effects of potential variants on PHT1;1 expression and Pi uptake activity. Notably, the soil P contents in A. thaliana habitats were found to coincide with PHT1;1 haplotype, underscoring how fine-tuning of the activity of P acquisition by natural variants allows plants to adapt to their environments. This study sheds light on the complex regulation of P acquisition and offers a framework to systematically assess the effectiveness of GWAS approaches in the study of quantitative traits. One sentence summaryStepwise GWAS analyses reveal insights into the genetic basis in regulating phosphorus acquisition and associations between the phosphate transporter PHT1;1 haplotype and Arabidopsis habitats.
This study investigates how DNA methyltransferase 3b (DNMT3b) dysfunction causes genome instability. We showed that in DNMT3b deficient cells, R-loops contribute to prominent {gamma}H2AX signal, which was mapped to repetitive satellite sequences including centromere regions. By ChIP and DRIP analyses, our data revealed that centromeric R-loops in DNMT3b deficient cells are removed by XPG/XPF, thus generating DNA breaks in centromeres to increase mitotic aberration. In immunodeficiency-centromeric instability-facial anomalies (ICF) patient cells carrying the loss-of-function mutation at DNMT3b, knockdown of XPG/XPF in ICF cells also reduces DNA breaks in centromere while bringing up centromeric R-loop to the level similar to that in wild-type cells. These results suggest that DNMT3b has a critical function in preventing XPG/XPF-mediated cleavages at centromeric R-loop sites. Finally, we showed the involvement of non-homologous end-joining repair at centromeric sites in ICF cells. Thus, DNA cleavages at centromeric R-loops with error-prone repair undermine centromere stability in ICF cells.
Gut microbiota has been demonstrated to be involved in intestinal nutrition, defense, and immunity, as well as participating in disease progression. This study was to investigate gut microbiota changes in chickens challenged with netB-positive Clostridium perfringens strain 1 (CP1) and/or the predisposing Eimeria species (Eimeria). In addition, the effects of lauric acid, a medium-chain fatty acid (MCFA), on NE reduction and modulation of microbiota were evaluated. The results demonstrated that microbial communities in the jejunum were distinct from those in the cecum, and the microbial community change was more significant in jejunum. Challenge of CP1 in conjunction with Eimeria significantly reduced species diversity in jejunal microbiota, but cecal microbiota remained stable. In the jejunum, CP1 challenge increased the abundance of the genera of Clostridium sensu stricto 1, Escherichia Shigella, and Weissella, but significantly decreased the population of Lactobacillus. Eimeria infection on its own was unable to promote NE, demonstrating decrements of Clostridium sensu stricto 1 and Lactobacillus. Co-infection with CP1 and Eimeria reproduced the majority of NE lesions with significant increment of Clostridium sensu stricto 1 and reduction in Lactobacillus. The changes of these two taxa increased the severity of NE lesions. Further analyses of metagenomeSeq, STAMP, and LEfSe showed significant overgrowth of Clostridium sensu stricto 1 was associated with NE and Eimeria infection than C. perfringens challenge alone. The supplementation of lauric acid did not reduce NE incidence and severity but decreased the relative abundance of Escherichia Shigella. In conclusion, significant overgrowth of Clostridium sensu stricto 1 in the jejunm is the major microbiota contributory to NE. Controlling proliferation of this taxon in the jejunum should be the niche for developing effective strategies against NE.