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1.
Cell Rep ; 43(4): 114042, 2024 Apr 23.
Article in English | MEDLINE | ID: mdl-38573858

ABSTRACT

Pathogenic infection elicits behaviors that promote recovery and survival of the host. After exposure to the pathogenic bacterium Pseudomonas aeruginosa PA14, the nematode Caenorhabditis elegans modifies its sensory preferences to avoid the pathogen. Here, we identify antagonistic neuromodulators that shape this acquired avoidance behavior. Using an unbiased cell-directed neuropeptide screen, we show that AVK neurons upregulate and release RF/RYamide FLP-1 neuropeptides during infection to drive pathogen avoidance. Manipulations that increase or decrease AVK activity accelerate or delay pathogen avoidance, respectively, implicating AVK in the dynamics of avoidance behavior. FLP-1 neuropeptides drive pathogen avoidance through the G protein-coupled receptor DMSR-7, as well as other receptors. DMSR-7 in turn acts in multiple neurons, including tyraminergic/octopaminergic neurons that receive convergent avoidance signals from the cytokine DAF-7/transforming growth factor ß. Neuromodulators shape pathogen avoidance through multiple mechanisms and targets, in agreement with the distributed neuromodulatory connectome of C. elegans.


Subject(s)
Caenorhabditis elegans Proteins , Caenorhabditis elegans , Neuropeptides , Pseudomonas aeruginosa , Animals , Caenorhabditis elegans/metabolism , Caenorhabditis elegans/microbiology , Neuropeptides/metabolism , Pseudomonas aeruginosa/metabolism , Caenorhabditis elegans Proteins/metabolism , Biogenic Monoamines/metabolism , Neurons/metabolism , Avoidance Learning/physiology , Receptors, G-Protein-Coupled/metabolism , Signal Transduction
2.
Nat Commun ; 15(1): 1520, 2024 Feb 19.
Article in English | MEDLINE | ID: mdl-38374083

ABSTRACT

Fatty acid desaturation is central to metazoan lipid metabolism and provides building blocks of membrane lipids and precursors of diverse signaling molecules. Nutritional conditions and associated microbiota regulate desaturase expression, but the underlying mechanisms have remained unclear. Here, we show that endogenous and microbiota-dependent small molecule signals promote lipid desaturation via the nuclear receptor NHR-49/PPARα in C. elegans. Untargeted metabolomics of a ß-oxidation mutant, acdh-11, in which expression of the stearoyl-CoA desaturase FAT-7/SCD1 is constitutively increased, revealed accumulation of a ß-cyclopropyl fatty acid, becyp#1, that potently activates fat-7 expression via NHR-49. Biosynthesis of becyp#1 is strictly dependent on expression of cyclopropane synthase by associated bacteria, e.g., E. coli. Screening for structurally related endogenous metabolites revealed a ß-methyl fatty acid, bemeth#1, which mimics the activity of microbiota-dependent becyp#1 but is derived from a methyltransferase, fcmt-1, that is conserved across Nematoda and likely originates from bacterial cyclopropane synthase via ancient horizontal gene transfer. Activation of fat-7 expression by these structurally similar metabolites is controlled by distinct mechanisms, as microbiota-dependent becyp#1 is metabolized by a dedicated ß-oxidation pathway, while the endogenous bemeth#1 is metabolized via α-oxidation. Collectively, we demonstrate that evolutionarily related biosynthetic pathways in metazoan host and associated microbiota converge on NHR-49/PPARα to regulate fat desaturation.


Subject(s)
Caenorhabditis elegans Proteins , Caenorhabditis elegans , Animals , Caenorhabditis elegans/metabolism , Caenorhabditis elegans Proteins/metabolism , PPAR alpha/metabolism , Escherichia coli/genetics , Escherichia coli/metabolism , Fatty Acids/metabolism , Cyclopropanes/metabolism
3.
Proc Natl Acad Sci U S A ; 121(5): e2307515121, 2024 Jan 30.
Article in English | MEDLINE | ID: mdl-38252833

ABSTRACT

Protein lipidation plays critical roles in regulating protein function and localization. However, the chemical diversity and specificity of fatty acyl group utilization have not been investigated using untargeted approaches, and it is unclear to what extent structures and biosynthetic origins of S-acyl moieties differ from N- and O-fatty acylation. Here, we show that fatty acylation patterns in Caenorhabditis elegans differ markedly between different amino acid residues. Hydroxylamine capture revealed predominant cysteine S-acylation with 15-methylhexadecanoic acid (isoC17:0), a monomethyl branched-chain fatty acid (mmBCFA) derived from endogenous leucine catabolism. In contrast, enzymatic protein hydrolysis showed that N-terminal glycine was acylated almost exclusively with straight-chain myristic acid, whereas lysine was acylated preferentially with two different mmBCFAs and serine was acylated promiscuously with a broad range of fatty acids, including eicosapentaenoic acid. Global profiling of fatty acylated proteins using a set of click chemistry-capable alkyne probes for branched- and straight-chain fatty acids uncovered 1,013 S-acylated proteins and 510 hydroxylamine-resistant N- or O-acylated proteins. Subsets of S-acylated proteins were labeled almost exclusively by either a branched-chain or a straight-chain probe, demonstrating acylation specificity at the protein level. Acylation specificity was confirmed for selected examples, including the S-acyltransferase DHHC-10. Last, homology searches for the identified acylated proteins revealed a high degree of conservation of acylation site patterns across metazoa. Our results show that protein fatty acylation patterns integrate distinct branches of lipid metabolism in a residue- and protein-specific manner, providing a basis for mechanistic studies at both the amino acid and protein levels.


Subject(s)
Amino Acids , Caenorhabditis elegans , Animals , Acylation , Fatty Acids , Hydroxylamine , Hydroxylamines
4.
Nat Cell Biol ; 26(1): 72-85, 2024 Jan.
Article in English | MEDLINE | ID: mdl-38168768

ABSTRACT

A growing body of evidence indicates that gut microbiota influence brain function and behaviour. However, the molecular basis of how gut bacteria modulate host nervous system function is largely unknown. Here we show that vitamin B12-producing bacteria that colonize the intestine can modulate excitatory cholinergic signalling and behaviour in the host Caenorhabditis elegans. Here we demonstrate that vitamin B12 reduces cholinergic signalling in the nervous system through rewiring of the methionine (Met)/S-adenosylmethionine cycle in the intestine. We identify a conserved metabolic crosstalk between the methionine/S-adenosylmethionine cycle and the choline-oxidation pathway. In addition, we show that metabolic rewiring of these pathways by vitamin B12 reduces cholinergic signalling by limiting the availability of free choline required by neurons to synthesize acetylcholine. Our study reveals a gut-brain communication pathway by which enteric bacteria modulate host behaviour and may affect neurological health.


Subject(s)
S-Adenosylmethionine , Vitamin B 12 , Animals , Vitamin B 12/metabolism , S-Adenosylmethionine/metabolism , Caenorhabditis elegans/metabolism , Choline/metabolism , Bacteria/metabolism , Methionine/metabolism , Vitamins/metabolism , Cholinergic Agents/metabolism
5.
bioRxiv ; 2023 Oct 24.
Article in English | MEDLINE | ID: mdl-37961151

ABSTRACT

Adenosine triphosphate (ATP) serves as an extracellular messenger that mediates diverse cell-to-cell communication. Compelling evidence supports that ATP is released from cells through pannexins, a family of heptameric large pore-forming channels. However, the activation mechanisms that trigger ATP release by pannexins remain poorly understood. Here, we discover lysophospholipids as endogenous pannexin activators, using activity-guided fractionation of mouse tissue extracts combined with untargeted metabolomics and electrophysiology. We show that lysophospholipids directly and reversibly activate pannexins in the absence of other proteins. Molecular docking, mutagenesis, and single-particle cryo-EM reconstructions suggest that lysophospholipids open pannexin channels by altering the conformation of the N-terminal domain. Our results provide a connection between lipid metabolism and ATP signaling, both of which play major roles in inflammation and neurotransmission. One-Sentence Summary: Untargeted metabolomics discovers a class of messenger lipids as endogenous activators of membrane channels important for inflammation and neurotransmission.

6.
bioRxiv ; 2023 Aug 31.
Article in English | MEDLINE | ID: mdl-37693574

ABSTRACT

Fatty acid desaturation is central to metazoan lipid metabolism and provides building blocks of membrane lipids and precursors of diverse signaling molecules. Nutritional conditions and associated microbiota regulate desaturase expression1-4, but the underlying mechanisms have remained unclear. Here, we show that endogenous and microbiota-dependent small molecule signals promote lipid desaturation via the nuclear receptor NHR-49/PPARα in C. elegans. Untargeted metabolomics of a ß-oxidation mutant, acdh-11, in which expression of the stearoyl-CoA desaturase FAT-7/SCD1 is constitutively increased, revealed accumulation of a ß-cyclopropyl fatty acid, becyp#1, that potently activates fat-7 expression via NHR-49. Biosynthesis of becyp#1 is strictly dependent on expression of cyclopropane synthase by associated bacteria, e.g., E. coli. Screening for structurally related endogenous metabolites revealed a ß-methyl fatty acid, bemeth#1, whose activity mimics that of microbiota-dependent becyp#1, but is derived from a methyltransferase, fcmt-1, that is conserved across Nematoda and likely originates from bacterial cyclopropane synthase via ancient horizontal gene transfer. Activation of fat-7 expression by these structurally similar metabolites is controlled by distinct mechanisms, as microbiota-dependent becyp#1 is metabolized by a dedicated ß-oxidation pathway, while the endogenous bemeth#1 is metabolized via α-oxidation. Collectively, we demonstrate that evolutionarily related biosynthetic pathways in metazoan host and associated microbiota converge on NHR-49/PPARα to regulate fat desaturation.

7.
Proc Natl Acad Sci U S A ; 120(26): e2221150120, 2023 06 27.
Article in English | MEDLINE | ID: mdl-37339205

ABSTRACT

From bacterial quorum sensing to human language, communication is essential for social interactions. Nematodes produce and sense pheromones to communicate among individuals and respond to environmental changes. These signals are encoded by different types and mixtures of ascarosides, whose modular structures further enhance the diversity of this nematode pheromone language. Interspecific and intraspecific differences in this ascaroside pheromone language have been described previously, but the genetic basis and molecular mechanisms underlying the variation remain largely unknown. Here, we analyzed natural variation in the production of 44 ascarosides across 95 wild Caenorhabditis elegans strains using high-performance liquid chromatography coupled to high-resolution mass spectrometry. We discovered wild strains defective in the production of specific subsets of ascarosides (e.g., the aggregation pheromone icas#9) or short- and medium-chain ascarosides, as well as inversely correlated patterns between the production of two major classes of ascarosides. We investigated genetic variants that are significantly associated with the natural differences in the composition of the pheromone bouquet, including rare genetic variants in key enzymes participating in ascaroside biosynthesis, such as the peroxisomal 3-ketoacyl-CoA thiolase, daf-22, and the carboxylesterase cest-3. Genome-wide association mappings revealed genomic loci harboring common variants that affect ascaroside profiles. Our study yields a valuable dataset for investigating the genetic mechanisms underlying the evolution of chemical communication.


Subject(s)
Caenorhabditis elegans , Nematoda , Animals , Humans , Caenorhabditis elegans/genetics , Pheromones/chemistry , Genome-Wide Association Study , Genetic Variation
8.
J Am Chem Soc ; 145(21): 11611-11621, 2023 05 31.
Article in English | MEDLINE | ID: mdl-37192367

ABSTRACT

Nucleosides are essential cornerstones of life, and nucleoside derivatives and synthetic analogues have important biomedical applications. Correspondingly, production of non-canonical nucleoside derivatives in animal model systems is of particular interest. Here, we report the discovery of diverse glucose-based nucleosides in Caenorhabditis elegans and related nematodes. Using a mass spectrometric screen based on all-ion fragmentation in combination with total synthesis, we show that C. elegans selectively glucosylates a series of modified purines but not the canonical purine and pyrimidine bases. Analogous to ribonucleosides, the resulting gluconucleosides exist as phosphorylated and non-phosphorylated forms. The phosphorylated gluconucleosides can be additionally decorated with diverse acyl moieties from amino acid catabolism. Syntheses of representative variants, facilitated by a novel 2'-O- to 3'-O-dibenzyl phosphoryl transesterification reaction, demonstrated selective incorporation of different nucleobases and acyl moieties. Using stable-isotope labeling, we further show that gluconucleosides incorporate modified nucleobases derived from RNA and possibly DNA breakdown, revealing extensive recycling of oligonucleotide catabolites. Gluconucleosides are conserved in other nematodes, and biosynthesis of specific subsets is increased in germline mutants and during aging. Bioassays indicate that gluconucleosides may function in stress response pathways.


Subject(s)
Nucleosides , Ribonucleosides , Animals , Caenorhabditis elegans , Oligonucleotides
9.
PLoS Biol ; 21(4): e3002057, 2023 04.
Article in English | MEDLINE | ID: mdl-37043428

ABSTRACT

In humans, mutations in D-2-hydroxyglutarate (D-2HG) dehydrogenase (D2HGDH) result in D-2HG accumulation, delayed development, seizures, and ataxia. While the mechanisms of 2HG-associated diseases have been studied extensively, the endogenous metabolism of D-2HG remains unclear in any organism. Here, we find that, in Caenorhabditis elegans, D-2HG is produced in the propionate shunt, which is transcriptionally activated when flux through the canonical, vitamin B12-dependent propionate breakdown pathway is perturbed. Loss of the D2HGDH ortholog, dhgd-1, results in embryonic lethality, mitochondrial defects, and the up-regulation of ketone body metabolism genes. Viability can be rescued by RNAi of hphd-1, which encodes the enzyme that produces D-2HG or by supplementing either vitamin B12 or the ketone bodies 3-hydroxybutyrate (3HB) and acetoacetate (AA). Altogether, our findings support a model in which C. elegans relies on ketone bodies for energy when vitamin B12 levels are low and in which a loss of dhgd-1 causes lethality by limiting ketone body production.


Subject(s)
Caenorhabditis elegans , Propionates , Humans , Animals , Caenorhabditis elegans/genetics , Caenorhabditis elegans/metabolism , Propionates/metabolism , Vitamin B 12 , Ketones
10.
Nat Commun ; 14(1): 320, 2023 01 19.
Article in English | MEDLINE | ID: mdl-36658169

ABSTRACT

Recent studies of animal metabolism have revealed large numbers of novel metabolites that are involved in all aspects of organismal biology, but it is unclear to what extent metabolomes differ between sexes. Here, using untargeted comparative metabolomics for the analysis of wildtype animals and sex determination mutants, we show that C. elegans hermaphrodites and males exhibit pervasive metabolomic differences. Several hundred small molecules are produced exclusively or in much larger amounts in one sex, including a host of previously unreported metabolites that incorporate building blocks from nucleoside, carbohydrate, lipid, and amino acid metabolism. A subset of male-enriched metabolites is specifically associated with the presence of a male germline, whereas enrichment of other compounds requires a male soma. Further, we show that one of the male germline-dependent metabolites, an unusual dipeptide incorporating N,N-dimethyltryptophan, increases food consumption, reduces lifespan, and accelerates the last stage of larval development in hermaphrodites. Our results serve as a foundation for mechanistic studies of how the genetic sex of soma and germline shape the C. elegans metabolome and provide a blueprint for the discovery of sex-dependent metabolites in other animals.


Subject(s)
Caenorhabditis elegans Proteins , Caenorhabditis elegans , Animals , Male , Caenorhabditis elegans/metabolism , Metabolome , Caenorhabditis elegans Proteins/metabolism , Metabolomics/methods , Longevity
11.
Nat Chem Biol ; 19(2): 141-150, 2023 02.
Article in English | MEDLINE | ID: mdl-36216995

ABSTRACT

The neurotransmitter serotonin plays a central role in animal behavior and physiology, and many of its functions are regulated via evolutionarily conserved biosynthesis and degradation pathways. Here we show that in Caenorhabditis elegans, serotonin is abundantly produced in nonneuronal tissues via phenylalanine hydroxylase, in addition to canonical biosynthesis via tryptophan hydroxylase in neurons. Combining CRISPR-Cas9 genome editing, comparative metabolomics and synthesis, we demonstrate that most serotonin in C. elegans is incorporated into N-acetylserotonin-derived glucosides, which are retained in the worm body and further modified via the carboxylesterase CEST-4. Expression patterns of CEST-4 suggest that serotonin or serotonin derivatives are transported between different tissues. Last, we show that bacterial indole production interacts with serotonin metabolism via CEST-4. Our results reveal a parallel pathway for serotonin biosynthesis in nonneuronal cell types and further indicate that serotonin-derived metabolites may serve distinct signaling functions and contribute to previously described serotonin-dependent phenotypes.


Subject(s)
Caenorhabditis elegans Proteins , Caenorhabditis elegans , Animals , Caenorhabditis elegans/metabolism , Serotonin , Caenorhabditis elegans Proteins/genetics , Caenorhabditis elegans Proteins/metabolism , Tryptophan Hydroxylase/genetics , Tryptophan Hydroxylase/metabolism , Behavior, Animal
13.
Nature ; 607(7919): 571-577, 2022 07.
Article in English | MEDLINE | ID: mdl-35794472

ABSTRACT

Individuals can exhibit differences in metabolism that are caused by the interplay of genetic background, nutritional input, microbiota and other environmental factors1-4. It is difficult to connect differences in metabolism to genomic variation and derive underlying molecular mechanisms in humans, owing to differences in diet and lifestyle, among others. Here we use the nematode Caenorhabditis elegans as a model to study inter-individual variation in metabolism. By comparing three wild strains and the commonly used N2 laboratory strain, we find differences in the abundances of both known metabolites and those that have not to our knowledge been previously described. The latter metabolites include conjugates between 3-hydroxypropionate (3HP) and several amino acids (3HP-AAs), which are much higher in abundance in one of the wild strains. 3HP is an intermediate in the propionate shunt pathway, which is activated when flux through the canonical, vitamin-B12-dependent propionate breakdown pathway is perturbed5. We show that increased accumulation of 3HP-AAs is caused by genetic variation in HPHD-1, for which 3HP is a substrate. Our results suggest that the production of 3HP-AAs represents a 'shunt-within-a-shunt' pathway to accommodate a reduction-of-function allele in hphd-1. This study provides a step towards the development of metabolic network models that capture individual-specific differences of metabolism and more closely represent the diversity that is found in entire species.


Subject(s)
Caenorhabditis elegans , Metabolic Networks and Pathways , Animals , Humans , Alcohol Oxidoreductases/genetics , Alcohol Oxidoreductases/metabolism , Amino Acids/metabolism , Caenorhabditis elegans/classification , Caenorhabditis elegans/enzymology , Caenorhabditis elegans/genetics , Caenorhabditis elegans/metabolism , Lactic Acid/analogs & derivatives , Lactic Acid/metabolism , Metabolic Networks and Pathways/genetics , Mitochondrial Proteins/genetics , Mitochondrial Proteins/metabolism , Models, Animal , Propionates/metabolism , Vitamin B 12/metabolism
14.
Nat Commun ; 13(1): 782, 2022 02 10.
Article in English | MEDLINE | ID: mdl-35145075

ABSTRACT

Untargeted metabolomics via high-resolution mass spectrometry can reveal more than 100,000 molecular features in a single sample, many of which may represent unidentified metabolites, posing significant challenges to data analysis. We here introduce Metaboseek, an open-source analysis platform designed for untargeted comparative metabolomics and demonstrate its utility by uncovering biosynthetic functions of a conserved fat metabolism pathway, α-oxidation, using C. elegans as a model. Metaboseek integrates modules for molecular feature detection, statistics, molecular formula prediction, and fragmentation analysis, which uncovers more than 200 previously uncharacterized α-oxidation-dependent metabolites in an untargeted comparison of wildtype and α-oxidation-defective hacl-1 mutants. The identified metabolites support the predicted enzymatic function of HACL-1 and reveal that α-oxidation participates in metabolism of endogenous ß-methyl-branched fatty acids and food-derived cyclopropane lipids. Our results showcase compound discovery and feature annotation at scale via untargeted comparative metabolomics applied to a conserved primary metabolic pathway and suggest a model for the metabolism of cyclopropane lipids.


Subject(s)
Caenorhabditis elegans/metabolism , Lipid Metabolism , Metabolic Networks and Pathways , Metabolomics/methods , Animals , Caenorhabditis elegans/genetics , Carbon-Carbon Lyases/genetics , Carbon-Carbon Lyases/metabolism , Fatty Acids/genetics , Fatty Acids/metabolism , Humans , Larva , Lipid Metabolism/genetics , Mass Spectrometry , Metabolic Networks and Pathways/genetics , Metabolome , Oxidation-Reduction
15.
J Am Chem Soc ; 143(36): 14676-14683, 2021 09 15.
Article in English | MEDLINE | ID: mdl-34460264

ABSTRACT

The recently discovered modular glucosides (MOGLs) form a large metabolite library derived from combinatorial assembly of moieties from amino acid, neurotransmitter, and lipid metabolism in the model organism C. elegans. Combining CRISPR-Cas9 genome editing, comparative metabolomics, and synthesis, we show that the carboxylesterase homologue Cel-CEST-1.2 is responsible for specific 2-O-acylation of diverse glucose scaffolds with a wide variety of building blocks, resulting in more than 150 different MOGLs. We further show that this biosynthetic role is conserved for the closest homologue of Cel-CEST-1.2 in the related nematode species C. briggsae, Cbr-CEST-2. Expression of Cel-cest-1.2 and MOGL biosynthesis are strongly induced by starvation conditions in C. elegans, one of the premier model systems for mechanisms connecting nutrition and physiology. Cel-cest-1.2-deletion results in early death of adult animals under starvation conditions, providing first insights into the biological functions of MOGLs.


Subject(s)
Caenorhabditis elegans Proteins/metabolism , Caenorhabditis elegans/metabolism , Carboxylic Ester Hydrolases/metabolism , Glucosides/biosynthesis , Starvation/metabolism , Acylation , Animals , Glucosides/chemistry , Metabolomics , ortho-Aminobenzoates/metabolism
16.
Mol Syst Biol ; 16(10): e9649, 2020 10.
Article in English | MEDLINE | ID: mdl-33022146

ABSTRACT

Metabolism is a highly compartmentalized process that provides building blocks for biomass generation during development, homeostasis, and wound healing, and energy to support cellular and organismal processes. In metazoans, different cells and tissues specialize in different aspects of metabolism. However, studying the compartmentalization of metabolism in different cell types in a whole animal and for a particular stage of life is difficult. Here, we present MEtabolic models Reconciled with Gene Expression (MERGE), a computational pipeline that we used to predict tissue-relevant metabolic function at the network, pathway, reaction, and metabolite levels based on single-cell RNA-sequencing (scRNA-seq) data from the nematode Caenorhabditis elegans. Our analysis recapitulated known tissue functions in C. elegans, captured metabolic properties that are shared with similar tissues in human, and provided predictions for novel metabolic functions. MERGE is versatile and applicable to other systems. We envision this work as a starting point for the development of metabolic network models for individual cells as scRNA-seq continues to provide higher-resolution gene expression data.


Subject(s)
Caenorhabditis elegans Proteins/metabolism , Caenorhabditis elegans/metabolism , Gene Expression Regulation/genetics , Transcriptome/genetics , Algorithms , Animals , Caenorhabditis elegans/genetics , Caenorhabditis elegans Proteins/genetics , Computational Biology , Computer Simulation , Gene Regulatory Networks , Gonads/metabolism , Intestinal Mucosa/metabolism , Metabolic Networks and Pathways , Neuroglia/metabolism , Organ Specificity/genetics , Organ Specificity/physiology , RNA-Seq , Single-Cell Analysis , Subcutaneous Tissue/metabolism
17.
J Am Chem Soc ; 142(43): 18449-18459, 2020 10 28.
Article in English | MEDLINE | ID: mdl-33053303

ABSTRACT

Untargeted metabolomics indicates that the number of unidentified small-molecule metabolites may exceed the number of protein-coding genes for many organisms, including humans, by orders of magnitude. Uncovering the underlying metabolic networks is essential for elucidating the physiological and ecological significance of these biogenic small molecules. Here we develop a click-chemistry-based enrichment strategy, DIMEN (deep interrogation of metabolism via enrichment), that we apply to investigate metabolism of the ascarosides, a family of signaling molecules in the model organism C. elegans. Using a single alkyne-modified metabolite and a solid-phase azide resin that installs a diagnostic moiety for MS/MS-based identification, DIMEN uncovered several hundred novel compounds originating from diverse biosynthetic transformations that reveal unexpected intersection with amino acid, carbohydrate, and energy metabolism. Many of the newly discovered transformations could not be identified or detected by conventional LC-MS analyses without enrichment, demonstrating the utility of DIMEN for deeply probing biochemical networks that generate extensive yet uncharacterized structure space.


Subject(s)
Caenorhabditis elegans/metabolism , Metabolome , Molecular Probes/chemistry , Animals , Chromatography, High Pressure Liquid , Click Chemistry , Signal Transduction , Tandem Mass Spectrometry
18.
Nat Chem Biol ; 16(10): 1039-1040, 2020 10.
Article in English | MEDLINE | ID: mdl-32943790
19.
Nature ; 583(7816): 415-420, 2020 07.
Article in English | MEDLINE | ID: mdl-32555456

ABSTRACT

Animals coexist in commensal, pathogenic or mutualistic relationships with complex communities of diverse organisms, including microorganisms1. Some bacteria produce bioactive neurotransmitters that have previously been proposed to modulate nervous system activity and behaviours of their hosts2,3. However, the mechanistic basis of this microbiota-brain signalling and its physiological relevance are largely unknown. Here we show that in Caenorhabditis elegans, the neuromodulator tyramine produced by commensal Providencia bacteria, which colonize the gut, bypasses the requirement for host tyramine biosynthesis and manipulates a host sensory decision. Bacterially produced tyramine is probably converted to octopamine by the host tyramine ß-hydroxylase enzyme. Octopamine, in turn, targets the OCTR-1 octopamine receptor on ASH nociceptive neurons to modulate an aversive olfactory response. We identify the genes that are required for tyramine biosynthesis in Providencia, and show that these genes are necessary for the modulation of host behaviour. We further find that C. elegans colonized by Providencia preferentially select these bacteria in food choice assays, and that this selection bias requires bacterially produced tyramine and host octopamine signalling. Our results demonstrate that a neurotransmitter produced by gut bacteria mimics the functions of the cognate host molecule to override host control of a sensory decision, and thereby promotes fitness of both the host and the microorganism.


Subject(s)
Caenorhabditis elegans/microbiology , Caenorhabditis elegans/physiology , Feeding Behavior/physiology , Intestines/microbiology , Neurotransmitter Agents/metabolism , Providencia/metabolism , Smell/physiology , Animals , Avoidance Learning/drug effects , Caenorhabditis elegans/drug effects , Caenorhabditis elegans Proteins/genetics , Caenorhabditis elegans Proteins/metabolism , Gastrointestinal Microbiome/physiology , Metabolomics , Mutation , Octanols/pharmacology , Octopamine/biosynthesis , Octopamine/metabolism , Providencia/enzymology , Providencia/physiology , Receptors, Biogenic Amine/metabolism , Receptors, G-Protein-Coupled/metabolism , Sensory Receptor Cells/metabolism , Smell/drug effects , Tyramine/biosynthesis , Tyramine/metabolism , Tyrosine Decarboxylase/deficiency , Tyrosine Decarboxylase/genetics
20.
Elife ; 82019 04 08.
Article in English | MEDLINE | ID: mdl-30958264

ABSTRACT

We find that variation in the dbt-1 gene underlies natural differences in Caenorhabditis elegans responses to the toxin arsenic. This gene encodes the E2 subunit of the branched-chain α-keto acid dehydrogenase (BCKDH) complex, a core component of branched-chain amino acid (BCAA) metabolism. We causally linked a non-synonymous variant in the conserved lipoyl domain of DBT-1 to differential arsenic responses. Using targeted metabolomics and chemical supplementation, we demonstrate that differences in responses to arsenic are caused by variation in iso-branched chain fatty acids. Additionally, we show that levels of branched chain fatty acids in human cells are perturbed by arsenic treatment. This finding has broad implications for arsenic toxicity and for arsenic-focused chemotherapeutics across human populations. Our study implicates the BCKDH complex and BCAA metabolism in arsenic responses, demonstrating the power of C. elegans natural genetic diversity to identify novel mechanisms by which environmental toxins affect organismal physiology. Editorial note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter).


Subject(s)
3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)/metabolism , Amino Acids, Branched-Chain/metabolism , Arsenic/toxicity , Biological Variation, Population , Caenorhabditis elegans/drug effects , Caenorhabditis elegans/metabolism , Animals , Caenorhabditis elegans/enzymology , Genetic Variation , HEK293 Cells , Humans
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