Pub Date : 2025-01-16DOI: 10.1016/j.chembiol.2024.12.012
Judith Behnsen, Kerwyn Casey Huang, Matthew T. Sorbara, Meng C. Wang, Jun Yu, Melody Y. Zeng
The field of microbiome research has experienced remarkable growth, leading to unprecedented discoveries of the molecular mechanisms that dictate host-microbiota interactions and their crucial roles in human health. In this “chemical biology of the microbiome” focus issue from Cell Chemical Biology, this Voices piece asks researchers from a range of backgrounds to share their insights on the most exciting recent developments in the microbiome field.
{"title":"New opportunities in mechanistic and functional microbiome studies","authors":"Judith Behnsen, Kerwyn Casey Huang, Matthew T. Sorbara, Meng C. Wang, Jun Yu, Melody Y. Zeng","doi":"10.1016/j.chembiol.2024.12.012","DOIUrl":"10.1016/j.chembiol.2024.12.012","url":null,"abstract":"<div><div>The field of microbiome research has experienced remarkable growth, leading to unprecedented discoveries of the molecular mechanisms that dictate host-microbiota interactions and their crucial roles in human health. In this “chemical biology of the microbiome” focus issue from <em>Cell Chemical Biology</em>, this Voices piece asks researchers from a range of backgrounds to share their insights on the most exciting recent developments in the microbiome field.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 1","pages":"Pages 5-8"},"PeriodicalIF":6.6,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142986892","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-16DOI: 10.1016/j.chembiol.2024.12.009
Katerina Jones, Camila Bernardo de Brito, Mariana Xavier Byndloss
In an interview with Samantha Nelson, a scientific editor of Cell Chemical Biology, the authors of the review entitled “Metabolic tug-o-war: Microbial metabolism shapes colonization resistance against enteric pathogens” share their perspectives on the field and their lives as scientists.
在接受《细胞化学生物学》（Cell Chemical Biology）科学编辑萨曼莎-尼尔森（Samantha Nelson）的采访时，题为《新陈代谢拉锯战：微生物新陈代谢塑造了对肠道病原体的定植抗性》的综述作者分享了他们对这一领域的看法以及作为科学家的生活：微生物新陈代谢决定了对肠道病原体的定植抵抗力 "的评论文章的作者分享了他们对这一领域的看法以及他们作为科学家的生活。
{"title":"Meet the authors: Katerina Jones, Camila Bernardo de Brito, and Mariana Xavier Byndloss","authors":"Katerina Jones, Camila Bernardo de Brito, Mariana Xavier Byndloss","doi":"10.1016/j.chembiol.2024.12.009","DOIUrl":"10.1016/j.chembiol.2024.12.009","url":null,"abstract":"<div><div>In an interview with Samantha Nelson, a scientific editor of <em>Cell Chemical Biology</em>, the authors of the review entitled “<span><span>Metabolic tug-o-war: Microbial metabolism shapes colonization resistance against enteric pathogens</span><svg><path></path></svg></span>” share their perspectives on the field and their lives as scientists.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 1","pages":"Pages 3-4"},"PeriodicalIF":6.6,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142986931","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-16DOI: 10.1016/j.chembiol.2024.12.004
Christopher Whidbey
Microbiomes exist in ecological niches ranging from the ocean and soil to inside of larger organisms like plants and animals. Within these niches, microbes play key roles in biochemical processes that impact larger phenomena, such as biogeochemical cycling or health. By understanding of how these processes occur at the molecular level, it may be possible to develop new interventions to address global problems. The complexity of these systems poses challenges to more traditional techniques. Chemical biology can help overcome these challenges by providing tools that are broadly applicable and can obtain molecular-level information about complex systems. This primer is intended to serve as a brief introduction to chemical biology and microbiome science, to highlight some of the ways that these two disciplines complement each other, and to encourage dialog and collaboration between these fields.
{"title":"The right tool for the job: Chemical biology and microbiome science","authors":"Christopher Whidbey","doi":"10.1016/j.chembiol.2024.12.004","DOIUrl":"10.1016/j.chembiol.2024.12.004","url":null,"abstract":"<div><div>Microbiomes exist in ecological niches ranging from the ocean and soil to inside of larger organisms like plants and animals. Within these niches, microbes play key roles in biochemical processes that impact larger phenomena, such as biogeochemical cycling or health. By understanding of how these processes occur at the molecular level, it may be possible to develop new interventions to address global problems. The complexity of these systems poses challenges to more traditional techniques. Chemical biology can help overcome these challenges by providing tools that are broadly applicable and can obtain molecular-level information about complex systems. This primer is intended to serve as a brief introduction to chemical biology and microbiome science, to highlight some of the ways that these two disciplines complement each other, and to encourage dialog and collaboration between these fields.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 1","pages":"Pages 83-97"},"PeriodicalIF":6.6,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142929676","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-16DOI: 10.1016/j.chembiol.2024.07.011
Natavan Dudkina , Hyun Bong Park , Deguang Song , Abhishek Jain , Sajid A. Khan , Richard A. Flavell , Caroline H. Johnson , Noah W. Palm , Jason M. Crawford
Altered human aldo-keto reductase family 1 member C3 (AKR1C3) expression has been associated with poor prognosis in diverse cancers, ferroptosis resistance, and metabolic diseases. Despite its clinical significance, the endogenous biochemical roles of AKR1C3 remain incompletely defined. Using untargeted metabolomics, we identified a major transformation mediated by AKR1C3, in which a spermine oxidation product “sperminal” is reduced to “sperminol.” Sperminal causes DNA damage and activates the DNA double-strand break response, whereas sperminol induces autophagy in vitro. AKR1C3 also pulls down acyl-pyrones and pyrone-211 inhibits AKR1C3 activity. Through G protein-coupled receptor ligand screening, we determined that pyrone-211 is also a potent agonist of the semi-orphan receptor GPR84. Strikingly, mammalian fatty acid synthase produces acyl-pyrones in vitro, and this production is modulated by NADPH. Taken together, our studies support a regulatory role of AKR1C3 in an expanded polyamine pathway and a model linking fatty acid synthesis and NADPH levels to GPR84 signaling.
{"title":"Human AKR1C3 binds agonists of GPR84 and participates in an expanded polyamine pathway","authors":"Natavan Dudkina , Hyun Bong Park , Deguang Song , Abhishek Jain , Sajid A. Khan , Richard A. Flavell , Caroline H. Johnson , Noah W. Palm , Jason M. Crawford","doi":"10.1016/j.chembiol.2024.07.011","DOIUrl":"10.1016/j.chembiol.2024.07.011","url":null,"abstract":"<div><div>Altered human aldo-keto reductase family 1 member C3 (AKR1C3) expression has been associated with poor prognosis in diverse cancers, ferroptosis resistance, and metabolic diseases. Despite its clinical significance, the endogenous biochemical roles of AKR1C3 remain incompletely defined. Using untargeted metabolomics, we identified a major transformation mediated by AKR1C3, in which a spermine oxidation product “sperminal” is reduced to “sperminol.” Sperminal causes DNA damage and activates the DNA double-strand break response, whereas sperminol induces autophagy <em>in vitro</em>. AKR1C3 also pulls down acyl-pyrones and pyrone-211 inhibits AKR1C3 activity. Through G protein-coupled receptor ligand screening, we determined that pyrone-211 is also a potent agonist of the semi-orphan receptor GPR84. Strikingly, mammalian fatty acid synthase produces acyl-pyrones <em>in vitro</em>, and this production is modulated by NADPH. Taken together, our studies support a regulatory role of AKR1C3 in an expanded polyamine pathway and a model linking fatty acid synthesis and NADPH levels to GPR84 signaling.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 1","pages":"Pages 126-144.e18"},"PeriodicalIF":6.6,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142007975","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-16DOI: 10.1016/j.chembiol.2024.07.012
Eric M. Brown , Phuong N.U. Nguyen , Ramnik J. Xavier
The strong association of the human leukocyte antigen B∗27 alleles (HLA-B∗27) with spondyloarthritis and related rheumatic conditions has long fascinated researchers, yet the precise mechanisms underlying its pathogenicity remain elusive. Here, we review how interplay between the microbiome, the immune system, and the enigmatic HLA-B∗27 could trigger spondyloarthritis, with a focus on whether HLA-B∗27 presents an arthritogenic peptide. We propose mechanisms by which the unique biochemical characteristics of the HLA-B∗27 protein structure, particularly its peptide binding groove, could dictate its propensity to induce pathological T cell responses. We further provide new insights into how TRBV9+ CD8+ T cells are implicated in the disease process, as well as how the immunometabolism of T cells modulates tissue-specific inflammatory responses in spondyloarthritis. Finally, we present testable models and suggest approaches to this problem in future studies given recent advances in computational biology, chemical biology, structural biology, and small-molecule therapeutics.
人类白细胞抗原B∗27等位基因（HLA-B∗27）与脊柱关节炎及相关风湿病的密切关系一直令研究人员着迷，但其致病的确切机制却仍然难以捉摸。在这里，我们回顾了微生物组、免疫系统和神秘的 HLA-B∗27 之间的相互作用是如何诱发脊柱关节炎的，重点是 HLA-B∗27 是否会产生致关节炎肽。我们提出了 HLA-B∗27 蛋白结构的独特生化特性（尤其是其肽结合槽）可能决定其诱导病理 T 细胞反应倾向的机制。我们进一步提供了关于 TRBV9+ CD8+ T 细胞如何参与疾病过程以及 T 细胞的免疫代谢如何调节脊柱关节炎组织特异性炎症反应的新见解。最后，鉴于计算生物学、化学生物学、结构生物学和小分子疗法的最新进展，我们提出了可检验的模型，并建议在未来研究中解决这一问题的方法。
{"title":"Emerging biochemical, microbial and immunological evidence in the search for why HLA-B∗27 confers risk for spondyloarthritis","authors":"Eric M. Brown , Phuong N.U. Nguyen , Ramnik J. Xavier","doi":"10.1016/j.chembiol.2024.07.012","DOIUrl":"10.1016/j.chembiol.2024.07.012","url":null,"abstract":"<div><div>The strong association of the human leukocyte antigen B<sup>∗</sup>27 alleles (<em>HLA-B<sup>∗</sup>27</em>) with spondyloarthritis and related rheumatic conditions has long fascinated researchers, yet the precise mechanisms underlying its pathogenicity remain elusive. Here, we review how interplay between the microbiome, the immune system, and the enigmatic HLA-B<sup>∗</sup>27 could trigger spondyloarthritis, with a focus on whether HLA-B<sup>∗</sup>27 presents an arthritogenic peptide. We propose mechanisms by which the unique biochemical characteristics of the HLA-B<sup>∗</sup>27 protein structure, particularly its peptide binding groove, could dictate its propensity to induce pathological T cell responses. We further provide new insights into how TRBV9<sup>+</sup> CD8<sup>+</sup> T cells are implicated in the disease process, as well as how the immunometabolism of T cells modulates tissue-specific inflammatory responses in spondyloarthritis. Finally, we present testable models and suggest approaches to this problem in future studies given recent advances in computational biology, chemical biology, structural biology, and small-molecule therapeutics.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 1","pages":"Pages 12-24"},"PeriodicalIF":6.6,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142015826","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-16DOI: 10.1016/j.chembiol.2024.10.007
Marco Jochem , Anna Schrempf , Lina-Marie Wagner , Dmitri Segal , Jose Cisneros , Amanda Ng , Georg E. Winter , Jeroen Krijgsveld
Targeted protein degradation (TPD) has emerged as a powerful strategy to selectively eliminate cellular proteins using small-molecule degraders, offering therapeutic promise for targeting proteins that are otherwise undruggable. However, a remaining challenge is to unambiguously identify primary TPD targets that are distinct from secondary downstream effects in the proteome. Here we introduce an approach for selective analysis of protein degradation by mass spectrometry (DegMS) at proteomic scale, which derives its specificity from the exclusion of confounding effects of altered transcription and translation induced by target depletion. We show that the approach efficiently operates at the timescale of TPD (hours) and we demonstrate its utility by analyzing the cyclin K degraders dCeMM2 and dCeMM4, which induce widespread transcriptional downregulation, and the GSPT1 degrader CC-885, an inhibitor of protein translation. Additionally, we apply DegMS to characterize a previously uncharacterized degrader, and identify the zinc-finger protein FIZ1 as a degraded target.
{"title":"Degradome analysis to identify direct protein substrates of small-molecule degraders","authors":"Marco Jochem , Anna Schrempf , Lina-Marie Wagner , Dmitri Segal , Jose Cisneros , Amanda Ng , Georg E. Winter , Jeroen Krijgsveld","doi":"10.1016/j.chembiol.2024.10.007","DOIUrl":"10.1016/j.chembiol.2024.10.007","url":null,"abstract":"<div><div>Targeted protein degradation (TPD) has emerged as a powerful strategy to selectively eliminate cellular proteins using small-molecule degraders, offering therapeutic promise for targeting proteins that are otherwise undruggable. However, a remaining challenge is to unambiguously identify primary TPD targets that are distinct from secondary downstream effects in the proteome. Here we introduce an approach for selective analysis of protein degradation by mass spectrometry (DegMS) at proteomic scale, which derives its specificity from the exclusion of confounding effects of altered transcription and translation induced by target depletion. We show that the approach efficiently operates at the timescale of TPD (hours) and we demonstrate its utility by analyzing the cyclin K degraders dCeMM2 and dCeMM4, which induce widespread transcriptional downregulation, and the GSPT1 degrader CC-885, an inhibitor of protein translation. Additionally, we apply DegMS to characterize a previously uncharacterized degrader, and identify the zinc-finger protein FIZ1 as a degraded target.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 1","pages":"Pages 192-200.e6"},"PeriodicalIF":6.6,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142599577","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-16DOI: 10.1016/j.chembiol.2024.10.013
Olivia N. Rebeck , Miranda J. Wallace , Jerome Prusa , Jie Ning , Esse M. Evbuomwan , Sunaina Rengarajan , LeMoyne Habimana-Griffin , Suryang Kwak , David Zahrah , Jason Tung , James Liao , Bejan Mahmud , Skye R.S. Fishbein , Erick S. Ramirez Tovar , Rehan Mehta , Bin Wang , Mark G. Gorelik , Beth A. Helmink , Gautam Dantas
Engineered probiotics are an emerging platform for in situ delivery of therapeutics to the gut. Herein, we developed an orally administered, yeast-based therapeutic delivery system to deliver next-generation immune checkpoint inhibitor (ICI) proteins directly to gastrointestinal tumors. We engineered Saccharomyces cerevisiae var. boulardii (Sb), a probiotic yeast with high genetic tractability and innate anticancer activity, to secrete “miniature” antibody variants that target programmed death ligand 1 (Sb_haPD-1). When tested in an ICI-refractory colorectal cancer (CRC) mouse model, Sb_haPD-1 significantly reduced intestinal tumor burden and resulted in significant shifts to the immune cell profile and microbiome composition. This oral therapeutic platform is modular and highly customizable, opening new avenues of targeted drug delivery that can be applied to treat a myriad of gastrointestinal malignancies.
{"title":"A yeast-based oral therapeutic delivers immune checkpoint inhibitors to reduce intestinal tumor burden","authors":"Olivia N. Rebeck , Miranda J. Wallace , Jerome Prusa , Jie Ning , Esse M. Evbuomwan , Sunaina Rengarajan , LeMoyne Habimana-Griffin , Suryang Kwak , David Zahrah , Jason Tung , James Liao , Bejan Mahmud , Skye R.S. Fishbein , Erick S. Ramirez Tovar , Rehan Mehta , Bin Wang , Mark G. Gorelik , Beth A. Helmink , Gautam Dantas","doi":"10.1016/j.chembiol.2024.10.013","DOIUrl":"10.1016/j.chembiol.2024.10.013","url":null,"abstract":"<div><div>Engineered probiotics are an emerging platform for <em>in situ</em> delivery of therapeutics to the gut. Herein, we developed an orally administered, yeast-based therapeutic delivery system to deliver next-generation immune checkpoint inhibitor (ICI) proteins directly to gastrointestinal tumors. We engineered <em>Saccharomyces cerevisiae</em> var. <em>boulardii</em> (<em>Sb</em>), a probiotic yeast with high genetic tractability and innate anticancer activity, to secrete “miniature” antibody variants that target programmed death ligand 1 (<em>Sb</em>_haPD-1). When tested in an ICI-refractory colorectal cancer (CRC) mouse model, <em>Sb</em>_haPD-1 significantly reduced intestinal tumor burden and resulted in significant shifts to the immune cell profile and microbiome composition. This oral therapeutic platform is modular and highly customizable, opening new avenues of targeted drug delivery that can be applied to treat a myriad of gastrointestinal malignancies.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 1","pages":"Pages 98-110.e7"},"PeriodicalIF":6.6,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142673596","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-16DOI: 10.1016/j.chembiol.2024.12.005
Katerina Jones , Camila Bernardo de Brito , Mariana Xavier Byndloss
A widely recognized benefit of gut microbiota is that it provides colonization resistance against enteric pathogens. The gut microbiota and their products can protect the host from invading microbes directly via microbe-pathogen interactions and indirectly by host-microbiota interactions, which regulate immune system function. In contrast, enteric pathogens have evolved mechanisms to utilize microbiota-derived metabolites to overcome colonization resistance and increase their pathogenic potential. This review will focus on recent studies of metabolism-mediated mechanisms of colonization resistance and virulence strategies enteric pathogens use to overcome them, along with how induction of inflammation by pathogenic bacteria changes the landscape of the gut and enables alternative metabolic pathways. We will focus on how intestinal pathogens counteract the protective effects of microbiota-derived metabolites to illustrate the growing appreciation of how metabolic factors may serve as crucial virulence determinants and overcome colonization resistance.
{"title":"Metabolic tug-of-war: Microbial metabolism shapes colonization resistance against enteric pathogens","authors":"Katerina Jones , Camila Bernardo de Brito , Mariana Xavier Byndloss","doi":"10.1016/j.chembiol.2024.12.005","DOIUrl":"10.1016/j.chembiol.2024.12.005","url":null,"abstract":"<div><div>A widely recognized benefit of gut microbiota is that it provides colonization resistance against enteric pathogens. The gut microbiota and their products can protect the host from invading microbes directly via microbe-pathogen interactions and indirectly by host-microbiota interactions, which regulate immune system function. In contrast, enteric pathogens have evolved mechanisms to utilize microbiota-derived metabolites to overcome colonization resistance and increase their pathogenic potential. This review will focus on recent studies of metabolism-mediated mechanisms of colonization resistance and virulence strategies enteric pathogens use to overcome them, along with how induction of inflammation by pathogenic bacteria changes the landscape of the gut and enables alternative metabolic pathways. We will focus on how intestinal pathogens counteract the protective effects of microbiota-derived metabolites to illustrate the growing appreciation of how metabolic factors may serve as crucial virulence determinants and overcome colonization resistance.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 1","pages":"Pages 46-60"},"PeriodicalIF":6.6,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142986932","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-16DOI: 10.1016/j.chembiol.2024.08.014
Lara Kern , Ignacio Mastandrea , Anna Melekhova , Eran Elinav
Recent developments in microbiome research suggest that the gut microbiome may remotely modulate central and peripheral neuronal processes, ranging from early brain development to age-related changes. Dysbiotic microbiome configurations have been increasingly associated with neurological disorders, such as neurodegeneration, but causal understanding of these associations remains limited. Most mechanisms explaining how the microbiome may induce such remote neuronal effects involve microbially modulated metabolites that influx into the ‘sterile’ host. Some metabolites are able to cross the blood-brain barrier (BBB) to reach the central nervous system, where they can impact a variety of cells and processes. Alternatively, metabolites may directly signal to peripheral nerves to act as neurotransmitters or exert modulatory functions, or impact immune responses, which, in turn, modulate neuronal function and associated disease propensity. Herein, we review the current knowledge highlighting microbiome-modulated metabolite impacts on neuronal disease, while discussing unknowns, controversies and prospects impacting this rapidly evolving research field.
{"title":"Mechanisms by which microbiome-derived metabolites exert their impacts on neurodegeneration","authors":"Lara Kern , Ignacio Mastandrea , Anna Melekhova , Eran Elinav","doi":"10.1016/j.chembiol.2024.08.014","DOIUrl":"10.1016/j.chembiol.2024.08.014","url":null,"abstract":"<div><div>Recent developments in microbiome research suggest that the gut microbiome may remotely modulate central and peripheral neuronal processes, ranging from early brain development to age-related changes. Dysbiotic microbiome configurations have been increasingly associated with neurological disorders, such as neurodegeneration, but causal understanding of these associations remains limited. Most mechanisms explaining how the microbiome may induce such remote neuronal effects involve microbially modulated metabolites that influx into the ‘sterile’ host. Some metabolites are able to cross the blood-brain barrier (BBB) to reach the central nervous system, where they can impact a variety of cells and processes. Alternatively, metabolites may directly signal to peripheral nerves to act as neurotransmitters or exert modulatory functions, or impact immune responses, which, in turn, modulate neuronal function and associated disease propensity. Herein, we review the current knowledge highlighting microbiome-modulated metabolite impacts on neuronal disease, while discussing unknowns, controversies and prospects impacting this rapidly evolving research field.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 1","pages":"Pages 25-45"},"PeriodicalIF":6.6,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142317170","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-16DOI: 10.1016/j.chembiol.2024.05.009
Lin Han , Augustus Pendleton , Adarsh Singh , Raymond Xu , Samantha A. Scott , Jaymee A. Palma , Peter Diebold , Kien P. Malarney , Ilana L. Brito , Pamela V. Chang
The gut microbiome possesses numerous biochemical enzymes that biosynthesize metabolites that impact human health. Bile acids comprise a diverse collection of metabolites that have important roles in metabolism and immunity. The gut microbiota-associated enzyme that is responsible for the gateway reaction in bile acid metabolism is bile salt hydrolase (BSH), which controls the host’s overall bile acid pool. Despite the critical role of these enzymes, the ability to profile their activities and substrate preferences remains challenging due to the complexity of the gut microbiota, whose metaproteome includes an immense diversity of protein classes. Using a systems biochemistry approach employing activity-based probes, we have identified gut microbiota-associated BSHs that exhibit distinct substrate preferences, revealing that different microbes contribute to the diversity of the host bile acid pool. We envision that this chemoproteomic approach will reveal how secondary bile acid metabolism controlled by BSHs contributes to the etiology of various inflammatory diseases.
{"title":"Chemoproteomic profiling of substrate specificity in gut microbiota-associated bile salt hydrolases","authors":"Lin Han , Augustus Pendleton , Adarsh Singh , Raymond Xu , Samantha A. Scott , Jaymee A. Palma , Peter Diebold , Kien P. Malarney , Ilana L. Brito , Pamela V. Chang","doi":"10.1016/j.chembiol.2024.05.009","DOIUrl":"10.1016/j.chembiol.2024.05.009","url":null,"abstract":"<div><div><span><span>The gut microbiome<span> possesses numerous biochemical enzymes<span><span> that biosynthesize metabolites that impact human health. Bile acids comprise a diverse collection of metabolites that have important roles in metabolism and immunity. The gut microbiota-associated enzyme that is responsible for the gateway reaction in </span>bile acid metabolism<span><span> is bile salt </span>hydrolase (BSH), which controls the host’s overall bile acid pool. Despite the critical role of these enzymes, the ability to profile their activities and substrate preferences remains challenging due to the complexity of the </span></span></span></span>gut microbiota<span>, whose metaproteome includes an immense diversity of protein classes. Using a systems biochemistry approach employing activity-based probes, we have identified gut microbiota-associated BSHs that exhibit distinct substrate preferences, revealing that different microbes contribute to the diversity of the host bile acid pool. We envision that this chemoproteomic approach will reveal how secondary bile acid metabolism controlled by BSHs contributes to the etiology of various </span></span>inflammatory diseases.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 1","pages":"Pages 145-156.e9"},"PeriodicalIF":6.6,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141333824","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
扫码关注我们
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号