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Biology subjects

Zhai, L.

Publications and source records attributed to Zhai, L..

At least 19 recordsLinked to original sources

Climate Warming Patterns Predict Potential Residency Shifts

Introduction and Aim: Future climate instability creates obstacles for organisms across taxa, especially in areas that experience higher stochasticity. Wetland wading bird populations are a prime example of this scenario, as the hydrologic cycles that drive population success in these habitats depend heavily on the predictability of wet and dry periods. When fluctuations in wet and dry periods shift excessively, populations may be forced to relocate or shift migration routes. Our goal is to predict if worsening environmental conditions could drive increases in facultative migration and subsequent residency shifts Location: State of Florida, USA. Methods: We developed an individual-based movement model motivated by wading birds in southern Florida to determine if this concept of climate-driven range or residency shift is likely to occur in the future. To further interpret the outputs of this individual-based model, we compared habitat suitability for the American wood stork across Southeast of the United States between 2010 and 2025, 2055 and 2085. Results: Our IBM model predicted that a northward residency shift is predicted to occur given the environmental scenario of harsher fluctuation via climate instability in the Everglades. Moreover, our findings suggest that wood storks with partial and/or facultative migration may be more likely to adapt to these fluctuations. Our suitability maps showed spatially heterogeneous responses, with notable increases in northern Georgia, and the Carolinas, and consistent declines in northern Florida, indicating a gradual northward shift in suitable breeding habitat. Main Conclusions: Conserving networks of suitable wetlands across broader spatial scales, may be critical for facilitating movement and persistence under hydrologic instability. Mechanistic models such as the one presented in this study can help anticipate these shifts and inform proactive conservation planning. This model can also be adapted to fit similar wetland systems, or other landscapes with various population and movement phenotypes present.

ecology↗

Deconvolution of multiplexed peptidoform mass spectra enables high-resolution profiling of complex protein modification patterns

Combinatorial patterns of post-translational modifications (PTMs), like the histone code, play critical roles in regulating protein functionality. However, in bottom-up proteomics, isobaric modification peptidoforms (IMPs) frequently co-elute and co-fragment during liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS), resulting in multiplexed mass spectra that cannot be properly analyzed by conventional protein identification and quantification methods. Existing solutions are either limited to highly narrow scenarios or unavailable for public use. Here, we introduce PTMdecoder, a robust and versatile software tool for discriminating and quantifying IMPs by deconvoluting their multiplexed MS/MS spectra and ion chromatograms without requiring a spectral library of individual peptidoforms. Tested on 34 samples of synthesized IMPs, PTMdecoder achieved an overall sensitivity of 95.7% for IMP identification and root mean square errors mostly <0.05 for quantification. In human histone samples, it detected and quantified 36.7-44.8% more IMPs than conventional methods, providing a higher-resolution view of histone modification patterns.

bioinformatics↗

Metabolic modulation of intratumoral cholesterol with gut microbiota for the treatment of colorectal cancer

Excess cholesterol is positively correlated with colorectal cancer (CRC). Current therapeutic strategies for modulating cholesterol levels in CRC are limited and often come with complications. Here, we demonstrated that microbiome shunting of intestinal cholesterol to anticancer metabolites is a safe and applicable therapeutic approach for CRC. By screening major microbial metabolic products of cholesterol, we found that 4-cholesten-3-one (4-C-3) was selectively depleted in fecal samples and tumor tissues of patients with CRC. 4-C-3 exhibits strong antitumor effects on human CRC cell lines, patient-derived organoids, and patient-derived xenograft (PDX) models. Mechanistically, 4-C-3 suppresses CRC tumorigenesis by dually targeting the epidermal growth factor receptor (EGFR) and Kirsten rat sarcoma viral oncogene homologue (KRAS). 4-C-3 directly binds to EGFR, blocking its signal transduction by inhibiting the binding of EGFR ligands. Additionally, 4-C-3 inhibits oncogenic KRAS variants, such as KRASG12D, by suppressing nucleotide exchange activity and effector engagement. By targeting both EGFR and KRAS, 4-C-3 reduces primary resistance to anti-EGFR therapies caused by KRAS mutations in CRC. As a proof-of-concept study, we showed that delivery of 4-C-3 by Oscillibacter ruminantium, a 4-C-3- producing commensal bacterium that is reduced in CRC patients, or a nonpathogenic Escherichia coli strain engineered to specifically convert intestinal cholesterol into 4-C-3, removed intratumoral cholesterol and led to rapid tumor regression in multiple models of CRC. These results suggest that microbial therapies for restoring intestinal cholesterol homeostasis represent a new therapeutic avenue for CRC.

cancer biology↗

Exploring Population Differences in the Human Gut Microbiome: from Microbial Abundance to Single Nucleotide Polymorphisms

The human gut microbiota exhibits significant diversity across populations, influenced by factors such as geography, diet, and lifestyle, particularly between the Han Chinese and non-Chinese populations. While previous studies have predominantly focused on the taxonomic abundance of the gut microbiome, the impact of single nucleotide polymorphisms (SNPs) in driving population-specific differences remains largely underexplored. In this study, we systematically investigated gut microbial differences between the Han Chinese and non-Chinese populations using the Human Gut Microbiome Reference Genome Catalog (HGMRGC). HGMRGC includes 271,480 non-redundant genomes from 5,785 prokaryotic species, which was generated by metagenomic sequencing data from 9,320 publicly available samples across 22 countries and 3,584 newly sequenced samples from Han Chinese individuals across 29 provinces and regions in China. We observed geography was the primary driver of microbial variation of abundance and SNPs. We identified 625 novel population-specific genome clusters from HGMRGC with functional differences in carbohydrate utilization and 126 species exhibiting distinct prevalence related to vitamin biosynthesis, antibiotic resistance, and carbohydrate metabolism. Beta diversity analysis highlighted significant inter-population differences in both microbial abundance and SNPs, while alpha diversity analysis revealed that non-Chinese populations exhibited higher diversity in microbial abundance, and Han Chinese populations displayed greater diversity in SNPs. These results provide valuable insights into population-specific microbial diversity, laying the groundwork for future research on its functional and health implications.

microbiology↗

Visible-Light-Controlled Residue-Selective Cross-Linking for Deciphering Protein Complexes and Dynamic Protein-Protein Interactions in Live Cells

Cross-linking mass spectrometry (XL-MS) has emerged as an attractive technology for investigating protein complexes and protein-protein interactions (PPIs). However, commonly used cross-linking strategies present significant challenges for precise analysis of protein complexes and dynamic PPIs in native biological environments. Here we present the visible-light-controlled lysine-selective cross-linking (VL-XL) strategy for in-depth analysis of protein complexes and dynamic PPIs both in vitro and in live cells, building on light-induced primary amines and o-nitrobenzyl alcohols cyclization (PANAC) chemistry. We demonstrate that the VL-XL strategy effectively explores the dynamic dimerization of PD-L1 stimulated by exogenous modulators. Moreover, the VL-XL strategy successfully profiles the time-resolved EGF-stimulated EGFR interactome, providing valuable insights into the regulatory mechanisms of EGFR signaling and intracellular trafficking. Importantly, the VL-XL strategy efficiently deciphers the molecular glue (MG) induced dynamic PPIs and substrate profile of MG degrader, opening an innovative avenue for identifying neo-substrates. By harnessing the advantages of temporal controllability, good biocompatibility, and lysine selectivity, the VL-XL method simplifies MS data analysis and facilitates the acquisition of accurate structural information of protein complexes and the elucidation of elusive PPIs in live cells. Overall, the VL-XL strategy expands the XL-MS toolbox, and realizes in-depth analysis of protein complexes and dynamic PPIs, which will inspire innovative solutions for protein interactomes research and structural systems biology.

biochemistry↗

Rational Design and Optimization of a Potent IDO1 Proteolysis Targeting Chimera (PROTAC)

Indoleamine 2,3-dioxygenase 1 (IDO1) is a potently immunosuppressive protein that inhibits antitumor immunity through both tryptophan metabolism and non-enzymatic functions. Pharmacological therapies targeting IDO1 enzyme activity have generally failed to improve the overall survival of patients with cancer. Developing new therapeutic agents that are capable of neutralizing both enzyme-and non-enzyme-derived immunosuppressive IDO1 effects is therefore of high interest. We previously described the development of a novel Proteolysis Targeting Chimera (PROTAC), NU223612, that degrades IDO1 in cultured human glioblastoma (GBM) cells, as well as in well-established brain tumors, in vivo. In this study, we rationally optimized the composition, rigidity, and linker orientation of the PROTAC structure to create NU227326, which degrades IDO1 with a DC50 of 5 nM in human GBM cells. Mechanistic studies showed that IDO1 degradation occurred through the ubiquitin-proteasome system and was sustained for at least 2 days, supporting NU227326 as a highly potent IDO1 PROTAC suitable for further studies in GBM and other human cancers.

biochemistry↗

Glutamine availability regulates cDC subsets in tissue

AbstractProliferating tumor cells take up glutamine for anabolic processes engendering glutamine deficiency in the tumor microenvironment. How this might impact immune cells is not well understood. Using multiple mouse models of soft tissue sarcomas, glutamine antagonists, as well as genetic and pharmacological inhibition of glutamine utilization, we found that the number and frequency of conventional dendritic cells (cDC) is dependent on microenvironmental glutamine levels. cDCs comprise two distinct subsets - cDC1 and cDC2, with the former subset playing a critical role in antigen cross-presentation and tumor immunity. While both subsets show dependence on Glutamine, cDC1s are particularly sensitive. Notably, glutamine antagonism did not reduce the frequency of DC precursors but decreased proliferation and survival of cDC1s. Further studies suggest a role of the nutrient sensing mTOR signaling pathway in this process. Taken together, these findings uncover glutamine dependence of cDC1s that is coopted by tumors to escape immune responses. One Sentence SummaryType 1 conventional dendritic cells require glutamine to maintain their number in non-lymphoid tissue. SignificanceImmune evasion is a key hallmark of cancer; however, the underlying pathways are diverse, tumor-specific and not fully elucidated. Many tumor cells avidly import glutamine to support their anabolic needs, creating a glutamine-deficient tumor microenvironment (TME). Herein, using mouse models of soft tissue sarcomas, we show that glutamine depletion in TME leads to reduced type 1 conventional dendritic cells - a cell type that is critical for adaptive immune responses. This work is a paradigm for how tumor cell metabolism can regulate anti-tumor immune responses and will be foundational to future efforts targeting glutamine metabolism for cancer immunotherapy.

immunology↗

Cell Type Specific Responses of the Endoplasmic Reticulum Dynamics to Environmental Stress

To overcome the challenge of balancing imaging speecd and resolution, which currently limits the accurate identification of structural and dynamic changes in the study of endoplasmic reticulum (ER) in plant cells. This research employs structured illumination microscopy techniques to achieve super-resolution real-time imaging of the ER in live Arabidopsis materials. Additionally, a self-supervised denoising framework (Blind2Unblind) was optimized to further enhance the signal-to-noise ratio of rapid microscopic imaging. Based on the images with high quality, a method for quantitative analysis of ER structures using time-lapse images is developed. Moreover, detections of changes in ER structures under environmental stress are conducted to verify the effectiveness of the method. Moreover, correlation analyses of various parameters indicate a significant positive correlation between the area and length of tubular ER with the number of growth tips and tricellular junctions, while the area of ER cisternae and bulk flow exhibits a significant negative correlation with the area and length of tubules. The super-resolution imaging and dynamic analysis method developed in this study will provide new technical approaches for further elucidating the function and regulatory mechanisms of the plant ER.

plant biology↗

SHP2-triggered endothelium activation fuels estradiol-independent endometrial sterile inflammation

Endometrial hyperplasia (EH) is a common gynecological disease primarily driven by excess estrogen. How endometrial sterile inflammation regulates EH remains unclear. First, we found the upregulation of SHP2 in endometrial endothelial cells from patients with EH by scRNA-Seq. SHP2 promoted inflammatory activation of endothelial cells, which promoted macrophage transendothelial migration. Subsequently, IL1{beta} and TNF from macrophages gave a feedforward loop to enhance endothelial cell activation and result in more IGF1 secretion, thereby sustaining sterile endometrial inflammation and facilitating endometrial epithelial cell proliferation even after estradiol withdrawal. Mechanistically, results of bulk RNA-Seq and phosphoproteomic analyses showed that endothelial SHP2 dephosphorylated RIPK1Y380 after estradiol stimulation. This event promoted activator protein 1 (AP-1) activation, instigating inflammation and increased CXCL10, CXCL13, COX2 and IGF1 secretion. Furthermore, targeting SHP2 by SHP099 or endothelial-specific SHP2 deletion alleviated EH progression in mice. Collectively, our findings demonstrate that SHP2 mediates the transition of endothelial activation, from estradiol-driven short inflammation to macrophage-amplified continuous sterile inflammation. Targeting chronic sterile inflammation mediated by endothelial cell activation is a promising strategy for non-hormonal intervention in EH.

molecular biology↗

Engineered dsRNA-protein nanoparticles for effective long-distance transport, delivery and gene silencing in plants

Long-distance transport of exogenous biologically active RNA molecules in higher plants has not been reported. Here, we report that cationized bovine serum albumin (cBSA) avidly binds double-stranded beta-glucuronidase RNA (dsGUS RNA) to form nucleic acid-protein nanocomplexes. Using tobacco and poplar plants, we have shown effective uptake and long-distance transport of cBSA/dsGUS RNA nanocomplexes from basal ends of leaf petioles to leaf blades as well as from basal ends of shoots to their apexes and apical leaves. We have further demonstrated that the cBSA/dsGUS RNA nanocomplexes are highly effective in silencing both conditionally inducible DR5-GUS gene and constitutively active 35S-GUS gene in leaf, shoot and shoot meristem tissues. This cBSA/dsRNA delivery technology may provide a convenient, fast, and inexpensive tool for characterizing gene functions in plants, and potentially for in planta gene-editing.

molecular biology↗

The histone lysine demethylase KDM5C fine-tunes gene expression to regulate dendritic cell heterogeneity and function

The functional and phenotypic heterogeneity of dendritic cells (DCs) plays a crucial role in facilitating the development of diverse immune responses that are essential for providing host protection. We found that KDM5C, a histone lysine demethylase of the KDM5 family regulates several aspects of conventional DC (cDC) and plasmacytoid DC (pDC) population heterogeneity and function. Using mice conditionally deficient in KDM5C in DCs, we found that loss of KDM5C results in an increase in Ly6C- pDCs compared to Ly6C+ pDCs. We found that Ly6C- pDCs, compared to Ly6C+ pDCs, have increased expression of cell cycle genes, decreased expression of activation markers and limited ability to produce type I interferon (IFN). Both KDM5C-deficient Ly6C- and Ly6C+ pDCs have increased expression of activation markers, however, are dysfunctional and have limited ability to produce type I IFN. For conventional cDCs, KDM5C deficiency resulted in increased proportions of cDC2Bs (CLEC12A+, ESAM-) and cDC1s, which was partly dependent on type I IFN and pDCs. Using ATAC-seq, RNA-seq, and CUT&RUN for histone marks, we found that KDM5C regulates epigenetic programming of cDC1. In the absence of KDM5C, we found an increased expression of inflammatory markers, consistent with our previous results in bone marrow-derived DCs. However, we also found a decrease in mitochondrial metabolism genes and altered expression of cDC lineage-specific genes. In response to Listeria infection, KDM5C-conditionally deficient mice mounted reduced CD8+ T cell responses, indicating that KDM5C expression in DCs is necessary for their function. Thus, KDM5C is a key regulator of DC heterogeneity by modulating the balance of DC subsets and serves as a critical driver of the epigenetic programming and functional properties of DCs.

immunology↗

The histone demethylase KDM5C controls female bone mass by promoting energy metabolism in osteoclasts

Women experience osteoporosis at higher rates than men. Aside from hormones, the mechanisms driving sex-dependent bone mass regulation are not well-understood. Here, we demonstrate that the X-linked H3K4me2/3 demethylase KDM5C regulates sex-specific bone mass. Loss of KDM5C in hematopoietic stem cells or bone marrow monocytes (BMM) increases bone mass in female but not male mice. Mechanistically, loss of KDM5C impairs the bioenergetic metabolism resulting in impaired osteoclastogenesis. Treatment with the KDM5 inhibitor reduces osteoclastogenesis and energy metabolism of both female mice and human monocytes. Our report details a novel sex-dependent mechanism for bone homeostasis, connecting epigenetic regulation to osteoclast metabolism, and positions KDM5C as a target for future treatment of osteoporosis in women. One-Sentence SummaryKDM5C, an X-linked epigenetic regulator, controls female bone homeostasis by promoting energy metabolism in osteoclasts.

cell biology↗

Surf4 deficiency reduces intestinal lipid absorption and secretion and decreases metabolism in mice

BackgroundPostprandial dyslipidemia is a causative risk factor for cardiovascular disease. The majority of absorbed dietary lipids are packaged into chylomicron and then delivered to circulation. Previous studies showed that Surfeit4 (Surf4) mediates very low-density lipoprotein secretion from hepatocytes. Silencing hepatic Surf4 markedly reduces the development of atherosclerosis in different mouse models of atherosclerosis without causing hepatic steatosis. However, the role of Surf4 in chylomicron secretion is unknown. MethodsWe developed inducible intestinal-specific Surf4 knockdown mice (Surf4IKO) using Vil1Cre-ERT2 and Surf4flox mice. Metabolic cages were used to monitor mouse metabolism. Enzymatic kits were employed to measure serum and tissue lipid levels. The expression of target genes was detected by qRT-PCR and Western Blot. Transmission electron microscopy and radiolabeled oleic acid were used to assess the structure of enterocytes and intestinal lipid absorption and secretion, respectively. Proteomics was performed to determine changes in protein expression in serum and jejunum. ResultsSurf4IKO mice, especially male Surf4IKO mice, displayed significant body weight loss, increased mortality, and reduced metabolism. Surf4IKO mice exhibited lipid accumulation in enterocytes and impaired fat absorption and secretion. Lipid droplets and small lipid vacuoles were accumulated in the cytosol and the endoplasmic reticulum lumen of the enterocytes of Surf4IKO mice, respectively. Surf4 colocalized with apoB and co-immunoprecipitated with apoB48 in differentiated Caco-2 cells. Intestinal Surf4 deficiency also significantly reduced serum triglyceride, cholesterol and free fatty acid levels in mice. Proteomics data revealed that diverse pathways were altered in Surf4IKO mice. In addition, Surf4IKO mice had mild liver damage, decreased liver size and weight, and reduced hepatic triglyceride levels. ConclusionOur findings demonstrate that intestinal Surf4 plays an essential role in lipid absorption and chylomicron secretion and suggest that the therapeutic use of Surf4 inhibition requires highly cell/tissue-specific targeting. HighlightsO_LIIntestinal Surf4 deficiency reduces chylomicron secretion. C_LIO_LILack of intestinal Surf4 reduces absorption of dietary lipids. C_LIO_LISilencing intestinal Surf4 reduces serum lipid levels. C_LIO_LIIntestinal Surf4 deficiency leads to lipid accumulation in intestinal villi. C_LIO_LIIntestinal Surf4 is essential for dietary lipid absorption and secretion. C_LI

physiology↗

Single-cell transcriptomics reveal distinct subsets of activated dendritic cells in the tumor microenvironment

Dendritic cells (DCs) are rare in tumors where their heterogeneity remains unclear. To overcome the limitations of surface marker-based analyses, we utilized DC-reporter mice (Zbtb46GFP/+) to isolate tissue and tumor DCs and performed single-cell RNA sequencing (scRNA-seq). The known DC subsets were conserved across tissues, albeit at different frequencies. Activated and mature DCs formed a distinct cluster in both healthy and tumor tissues and displayed the hallmark DC migratory program (migratory DCs). We also identified a distinct subset of activated DCs in tumors that did not induce the migratory program, instead displaying signatures of interferon exposure (interferon-DCs or IFN-DCs). IFN-DCs were proficient in antigen-presentation, supported T cell proliferation, and expressed high levels of T cell-attracting chemokines. IFN-DCs further comprised of IFN1- and IFN2-DCs that were generated from CD11b+ DCs in response to type I or type II interferons respectively. We also identified IFN-DCs in scRNA-seq of human tumor-infiltrating leukocytes. These findings illustrate DC heterogeneity in tumors and suggest the existence of an interferon regulated division of labor among activated DCs whereby the migratory DCs drive T cell priming in draining lymph nodes while the sessile IFN-DCs help recruit T cells and regulate their function in the tumor microenvironment. One Sentence SummaryTumors harbor an interferon-regulated activated sessile subset of dendritic cells.

immunology↗

Rho of plant GTPase MxROP1 regulates Fe deficiency responses by targeting Zinc Ribbon 3 in apple rootstock

Small G protein is a multifunctional molecular switch that can regulate plant growth, development and responses to the environment. However, how Rho-related GTPase of plants (ROPs) regulates the response to Fe deficiency has not been well clarified. Here, we found that Fe deficiency induced MxROP1 in Malus xiaojinensis at both the transcriptional and translational levels. The overexpression of MxROP1, MxROP1DN (inactive form) and MxROP1CA (active form) in apple roots increased the activity of ferric chelate reductase and the ability to acidify the rhizosphere, and lines that overexpressed MxROP1DN exhibited the strongest reaction to enhance Fe uptake. Yeast two-hybrid library screening indicated that MxROP1 interacted with ZR3.1, a DNL zinc finger protein that negatively regulates Fe deficiency responses. We further identified their interaction in vitro and in vivo using pull-down and bimolecular fluorescence complementation assays, respectively, and MxROP1DN-MxZR3.1 interacted the most strongly. Furthermore, MxROP1 negatively affected the stability of MxZR3.1 protein in vitro as shown by a cell semi-degradation assay, and the application of MG132 inhibited the degradation of MxZR3.1-HIS proteins. This indicated that MxROP1 caused the degradation of MxZR3.1 protein through the 26S proteasome pathway. Similar results were found in OE-MxROP1+OE-MxZR3.1 transgenic apple callus compared with those in the OE-MxZR3.1 callus. We also demonstrated that MxZR3.1 interacted with MxbHLH39, a known positive transcription factor and core component of Fe deficiency, and MxROP1 affected the interaction of MxZR3.1-MxbHLH39 using a competitive binding assay. This illuminated one MxROP1-MxZR3.1-MxbHLH39 pathway that maintains Fe homeostasis in M. xiaojinensis.

plant biology↗

A cell-permeant nanobody-based degrader that induces fetal hemoglobin

Proximity-based strategies to degrade proteins have enormous therapeutic potential in medicine, but the technologies are limited to proteins for which small molecule ligands exist. The identification of such ligands for therapeutically relevant but "undruggable" proteins remains challenging. Herein, we employed yeast surface display of synthetic nanobodies to identify a protein ligand selective for BCL11A, a critical repressor of fetal globin gene transcription. Fusion of the nanobody to a cell-permeant miniature protein and an E3 adaptor creates a degrader that depletes cellular BCL11A in erythroid precursor cells, thereby inducing the expression of fetal hemoglobin, a modifier of clinical severity of sickle cell disease and {beta}-thalassemia. This work establishes a new paradigm for the targeted degradation of previously intractable proteins using cell-permeant nanobody-based degraders. One sentence summaryA cell-permeant, protein-based degrader is used for the induction of fetal hemoglobin.

biochemistry↗

Structural insights into bacterial sterol transport

Sterol lipids are widely present in eukaryotes and play essential roles in signaling and modulating membrane fluidity. Although rare, some bacteria also produce sterols, but their function in bacteria is not known. Moreover, many more species, including pathogens and commensal microbes, acquire or modify sterols from eukaryotic hosts through poorly understood molecular mechanisms. The aerobic methanotroph Methylococcus capsulatus was the first bacterium shown to synthesize sterols, producing a mixture of C-4 methylated sterols that are distinct from those observed in eukaryotes. C-4 methylated sterols are synthesized in the cytosol and localized to the outer membrane, suggesting that a bacterial sterol transport machinery exists. Until now, the identity of such machinery remained a mystery. In this study, we identified three novel proteins that may be the first examples of transporters for bacterial sterol lipids. The proteins, which all belong to well-studied families of bacterial metabolite transporters, are predicted to reside in the inner membrane, periplasm, and outer membrane of M. capsulatus, and may work as a conduit to move modified sterols to the outer membrane. Quantitative analysis of ligand binding revealed their remarkable specificity for 4-methylsterols, and crystallographic structures coupled with docking and molecular dynamics simulations revealed the structural bases for substrate binding by two of the putative transporters. Their striking structural divergence from eukaryotic sterol transporters signals that they form a distinct sterol transport system within the bacterial domain. Finally, bioinformatics revealed the widespread presence of similar transporters in bacterial genomes, including in some pathogens that use host sterol lipids to construct their cell envelopes. The unique folds of these bacterial sterol binding proteins should now guide the discovery of other proteins that handle this essential metabolite.

biochemistry↗

Phenethylamine-producing gut bacteria induces diarrhea-predominant irritable bowel syndrome by increasing serotonin biosynthesis

Despite the strong association between gut microbial dysbiosis, serotonin (5-HT) dysregulation and diarrhea-predominant irritable bowel syndrome (IBS-D), the mechanism by which changes in the gut microbiota contribute to the pathogenesis of IBS-D, particularly the role of dysregulated 5-HT production, remains unclear. The present study identified Ruminococcus gnavus in the human gut microbiota as a key risk factor of IBS-D. R. gnavus was significantly enriched in IBS-D patients and exhibited positive correlation with serum 5- HT level and severity of diarrhea symptoms. We showed that R. gnavus induced diarrhea-like symptoms in mice by promoting microbial shunting of essential aromatic amino acids to aromatic trace amines including phenethylamine and tryptamine, thereby stimulating the biosynthesis of peripheral 5-HT, a potent stimulator for gastrointestinal transit. This study identify gut-microbial metabolism of dietary amino acids as a cause of IBS-D and lays a foundation for developing novel therapeutic target for the treatment of IBS-D. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/483096v1_ufig1.gif" ALT="Figure 1"> View larger version (38K): org.highwire.dtl.DTLVardef@48400aorg.highwire.dtl.DTLVardef@1645aedorg.highwire.dtl.DTLVardef@18d878dorg.highwire.dtl.DTLVardef@be4b30_HPS_FORMAT_FIGEXP M_FIG C_FIG

microbiology↗