Abstract
Individuals can exhibit differences in metabolism that are caused by the interplay of genetic background, nutritional input, microbiota and other environmental factors1,2,3,4. 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.
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Data availability
The HPLC–MS/MS data generated during this study have been deposited in the MassIVE database under accession code MSV000087810 (https://doi.org/10.25345/C5C244). The raw sequencing reads for these samples are available from the NCBI Sequence Read Archive (project PRJNA669127). The metabolic network model with the added short chain fatty acid–amino acid conjugation reactions (pan-iCELv1.0) is available for download in SBML and JSON formats at the wormflux website (http://wormflux.umassmed.edu/download.php). Genotype data for C. elegans strains were acquired from the variant call format (VCF) file (release 20200815) available from the CeNDR (http://elegansvariation.org). Source data are provided with this paper.
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Acknowledgements
We thank members of the laboratories of A.J.M.W., E.C.A. and F.C.S, and T. Fazzio for discussion and critical reading of the manuscript. This work was supported by a grant from the National Institutes of Health DK115690 to E.C.A., F.C.S. and A.J.M.W.
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A.J.M.W., F.C.S. and E.C.A. conceived the study. Y.-U.L., O.P., B.W.F. and H.N. prepared C. elegans cultures. B.W.F. performed LC–MS experiments and analysed the LC–MS data with help from P.R.R. and A.R.K. O.P. performed GC–MS experiments and analysed the GC–MS data. G.Z. performed the RNA-seq experiments. G.Z. and L.S.Y. analysed the RNA-seq data. G.E.G. and M.W. performed 3HP toxicity assays. N.M.R. created genome-edited strains. G.Z. and B.W.F. analysed genomic variants. B.J.C. synthesized the authentic standards. T.A.C. and S.Z. collected new wild strains. L.S.Y. created pan-iCELv1.0 by adding new metabolites and reactions to iCEL1314. A.J.M.W., B.W.F., L.S.Y., F.C.S. and E.C.A. wrote the paper. All authors read, edited and approved the final manuscript.
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Extended data figures and tables
Extended Data Fig. 1 Genetic relatedness of the four C. elegans strains used in this study and experimental design.
a, Similarity matrix depicting the genetic relatedness of the four C. elegans strains used in this study. Pairwise similarities for strains were calculated based on 2,604,844 bi-allelic SNVs. See Methods for more details. b, C. elegans populations were synchronized either by bleaching or by settling in three biological replicates each, yielding six independent samples. Freeze-dried E. coli HB101 lysate powder was used as a food source to culture C. elegans. Animals and supernatant were collected as day 1 adults at the stage of the first egg laid and used for transcriptomic and metabolomic analyses. Created with BioRender.com. c, Photographs of all strains at the time of collection from each experiment. Scale bar, 250 μm.
Extended Data Fig. 2 iglu#93 is an indole glycoside produced by wild strains but not by the N2 reference strain.
a, Quantification of indole glycoside iglu#93 in exo-metabolome extracts of the four strains. Data represent six biologically independent experiments and bars indicate mean ± s.d. p-values calculated by unpaired, two-sided t-test with Welch correction. b, Major fragmentation reactions of m/z 498.1983 (negative ion mode) and resulting fragment ions representing free indole and indole glycoside. Fragmentation is consistent with a deoxy-dimethyl sugar moiety, such as di-O-methylfucose50. c, Proposed structure of iglu#93. Stereochemistry and exact substitution patterns are unknown. Source data are provided as a Source Data file.
Extended Data Fig. 3 Homologous series of hydroxy-fatty acids reduced in the N2 strain compared to wild strains.
a,b, Representative HPLC–MS (negative ion) EICs for m/z 213.1496 (a) and m/z 227.1653 (b) in the exo- and endo-metabolomes of the four strains, as indicated. Features highly differential between strains are highlighted with red arrows. Several additional isobaric species detected primarily in the exo-metabolomes do not vary significantly among the four strains. c, Quantification of singly unsaturated (N:1), mono-oxygenated (mN:1) fatty acids ranging from 11 to 15 carbons (m11:1 – m15:1) in exo- and endo-metabolome extracts, as indicated. Data represent six (exo) or five (endo) biologically independent experiments and bars indicate mean ± s.d., p-values calculated by unpaired, two-sided t-test with Welch correction. ns, not significant. Y-axis scaling is maintained across graphs, which are separated for clarity. d, Quantification of singly unsaturated fatty acids (11:1 – 15:1) in endo-metabolome extracts, as indicated. Data represent five biologically independent experiments and bars indicate mean ± s.d., p-values calculated by unpaired, two-sided t-test with Welch correction. ns, not significant. Source data are provided as a Source Data file.
Extended Data Fig. 4 Full MS/MS network.
MS/MS network generated from exo-metabolome extracts in negative ionization mode. A simplified version of the boxed region containing 3HP-AAs is shown in Fig. 2a. An estimated 70% of nodes represent unique metabolites in this network, culled by standard filtering methods and some additional manual curation, see Methods for more details.
Extended Data Fig. 5 3HP-AAs are more abundant in the exo-metabolome and are 13C3-enriched from 13C5-Val supplementation in hphd-1(ok3580) animals.
a, Quantification of 3HP-AAs in endo- and exo-metabolome extracts of the four strains. Data represent five or six biologically independent experiments for endo- or exo-metabolome quantification, respectively, and bars indicate mean ± s.d., p-values calculated by two-sided, unpaired t-test with Welch correction. ns, not significant. b, Major MS/MS fragmentation (negative ion mode) of 3HP-AAs and resulting fragment ions representing neutral loss of CH2O and free amino acids. Source data are provided as a Source Data file. c, EICs for 202.1085 and 205.1191, corresponding to C9H16NO4- and 13C3-C9H16NO4-, from exo-metabolome extracts of N2 and hphd-1(ok3580). Red dashed lines highlight metabolites with 13C3-enrichment that are also more abundant in hphd-1(ok3580), corresponding to 3HP-Ile and 3HP-Leu. Y-axis for 205.1191 EIC is scaled 40-fold to more clearly show traces for labelled features. Isotopic labelling is highlighted with green shading in the shown compound structures. d, EICs for 236.0928 and 239.1028, corresponding to C12H14NO4- and 13C3-C12H14NO4-, from exo-metabolome extracts of N2 and hphd-1(ok3580), as indicated. Red dashed line on the x-axis highlights metabolite with 13C3-enrichment that is also more abundant in hphd-1(ok3580), corresponding to 3HP-Phe. Y-axis for 239.1028 EIC is scaled 50-fold to more clearly show traces for labelled features. Isotopic labelling is highlighted with green shading in the shown compound structures.
Extended Data Fig. 6 13C6-Leu tracing distinguishes Leu- and Ile-conjugates that share identical MS/MS fragmentation.
a, Schematic of 13C6-Leu isotope-tracing experiment. Synchronized N2 and hphd-1(ok3580) animals were supplemented with Leu or 13C6-Leu and analysed for isotopic enrichment of metabolites of interest. b, EICs (negative ion mode) for m/z 202.1085 and 208.1291, corresponding to C9H16NO4- and 13C6-C9H16NO4-, from exo-metabolome extracts of N2 and hphd-1(ok3580). Red dashed lines highlight metabolites with 13C6-enrichment, corresponding to 3HP- and N-lactoyl Leu conjugates. Y-axis for m/z 208.1291 EIC is scaled 10-fold to more clearly show traces for labelled features. Isotopic labelling is highlighted with green shading in the shown compound structures. c, EIC for m/z 202.1085 (negative ion mode), corresponding to C9H16NO4-, from exo-metabolome extracts of N2 and the three wild strains. d, MS/MS fragmentation for metabolites A-F in (c). Metabolites A and B have near-identical MS/MS spectra, that differ significantly from the near-identical MS/MS spectra of metabolites C, D, E, and F. Based on isotopic labelling and MS/MS fragmentation data, A and B were assigned as 3HP-Ile and 3HP-Leu, respectively. The remaining four metabolites represent diastereomers of N-lactoyl-Ile and -Leu, with the later-eluting metabolite of each pair assigned as N-lactoyl-Leu based on isotopic enrichment (see panel b).
Extended Data Fig. 7 Isotope-tracing experiments aid the identification of N-propionyl-AAs.
a, EICs for m/z 172.0979 and 177.1147, corresponding to C8H14NO3- and 13C5-C8H14NO3-, from exo-metabolome extracts of N2 supplemented with Val or 13C5-Val. Red dashed line highlights metabolite with 13C5-enrichment, corresponding to N-propionyl-Val. EIC Y-axis for m/z 177.1147 is scaled 20-fold to more clearly show traces for labelled features. Isotopic labelling is highlighted by green shading in the structure of N-propionyl-Val. b, EICs for m/z 186.1136 and 192.1337, corresponding to C9H16NO3- and 13C6-C9H16NO3-, from exo-metabolome extracts of N2, supplemented with Leu or 13C6-Leu. Red dashed line highlights metabolite with 13C6-enrichment, corresponding to N-propionyl-Leu. Isotopic labelling is highlighted by green shading in the structure of N-propionyl-Leu. c, Major MS/MS fragmentation (negative ion mode) of N-propionyl-AAs and resulting fragment ions representing different amino acids. d, Quantification of N-propionyl-AAs from endo- and exo-metabolome extracts of the four strains. Data represent five or six biologically independent experiments for the endo- or exo-metabolomes, respectively, and bars indicate mean ± s.d. Y-axis scaling is maintained across graphs. e, Quantification of N-propionyl-AAs in exo-metabolome extracts of N2 and hphd-1(ok3580) animals. Data represent four biologically independent experiments and bars indicate mean ± s.d. f, Quantification of N-propionyl-AAs in exo-metabolome extracts of the DL238 strain fed the standard E. coli OP50 diet without or with supplementation of 64 nM vitamin B12, as indicated. Data represent three biologically independent experiments and bars means ± s.d. For d, e, and f, p-values calculated by two-sided, unpaired t-test with Welch correction. ns, not significant. Source data are provided as a Source Data file.
Extended Data Fig. 8 Validation of metabolite assignments by synthesis of 3HP-Leu, 3HP-Phe and N-propionyl-Leu authentic standards.
a, EIC for m/z 202.1085 (negative ion mode), corresponding to C9H16NO4-, from exo-metabolome extracts of DL238 fed OP50 or DL238 fed OP50 supplemented with 64 nM vitamin B12, as indicated. To extracts of DL238 fed OP50 supplemented with vitamin B12, synthetic 3HP-Leu was added to achieve final concentrations of 25 nM and 75 nM. b, MS/MS spectra (negative ion mode) of natural and synthetic 3HP-Leu with major fragmentation reactions and fragment ions. c, EIC for m/z 236.0928, corresponding to C12H14NO4-, from exo-metabolome extracts of N2, N2 HPHD-1L268P, and synthetic 3HP-Phe. d, MS/MS spectra (negative ion mode) of natural and synthetic 3HP-Phe and major fragmentation reactions. e, EIC for m/z 186.1134, corresponding to C9H16NO3-, from exo-metabolome extracts of N2, N2 HPHD-1L268P, or synthetic N-propionyl-Leu. f, MS/MS spectra (negative ion mode) of natural and synthetic N-propionyl-Leu and major fragmentation reactions.
Extended Data Fig. 9 Abundance of 3HP-AAs in hphd-1 edited strains.
Quantification of 3HP-AA conjugates in exo- and endo-metabolome extracts of CRISPR–Cas9 HPHD-1-edited strains, parental strains, and HB101 bacteria only, as indicated. Data represent four biologically independent experiments and bars indicate mean ± s.d. p-values calculated by unpaired, two-sided t-test with Welch correction in which edited strains were compared to the corresponding parental strains. ns, not significant. Source data are provided as a Source Data file.
Extended Data Fig. 10 Abundance of N-propionyl-AAs in hphd-1 edited strains.
Quantification of N-propionyl-AA conjugates in exo- and endo-metabolome extracts of CRISPR–Cas9 HPHD-1-edited strains, parental strains, and HB101 bacteria only, as indicated. Data represent four biologically independent experiments and bars indicate mean ± s.d. p-values calculated by unpaired, two-sided t-test with Welch correction in which edited strains were compared to the corresponding parental strains. ns, not significant. N-propionyl-Tyr could not be reliably quantified in the endo-metabolome due to interference from a co-eluting metabolite. Source data are provided as a Source Data file.
Extended Data Fig. 11 Abundance of 3HP and 3HP-AAs in wild strains.
a, Quantification of 3HP and b, 3HP-AAs in exo- and endo-metabolome extracts of N2, DL238, additional wild strains and HB101 bacteria only, as indicated. Exact n for each strain is presented in Supplementary Table 12. Bars indicate mean ± s.d. p-values calculated by unpaired, two-sided t-test with Welch correction in which wild strains were compared to N2. ns, not significant. Source data are provided as a Source Data file.
Extended Data Fig. 12 Abundance of N-propionyl-AAs in wild strains.
Quantification of N-propionyl-AAs in exo- and endo-metabolome extracts of N2, DL238, additional wild strains and HB101 bacteria only, as indicated. Exact n for each strain is presented in Supplementary Table 12. Bars indicate mean ± s.d. p-values calculated by unpaired, two-sided t-test with Welch correction in which wild strains were compared to N2. ns, not significant. Source data are provided as a Source Data file.
Supplementary information
Supplementary Figures
This file includes Supplementary Figures containing reaction schemes for the chemical synthesis section and NMR spectra of synthetic compounds.
Supplementary Table 1
List of annotated metabolites detected by LC–MS related to iCEL1314 or the Small Molecule Identifier database (SMID-DB, www.smid-db.org) in endo-metabolome, including m/z, retention time, fold change and P-value (unpaired, two-sided t-test) for each wild strain compared against the N2 reference strain.
Supplementary Table 2–8
Lists of features detected by LC–MS, including m/z, retention time, fold change, and P-value (unpaired, two-sided t-test) for each wild strain compared against the N2 reference strain. Each table is a separate tab listed in order: negative ion C18 exo-metabolome, positive ion C18 exo-metabolome, negative ion C18 endo-metabolome, positive ion C18 endo-metabolome, negative ion post-column ion pairing C18 endo-metabolome, negative ion HILIC endo-metabolome, positive ion HILIC endo-metabolome.
Supplementary Table 9
Manually curated strain-specific metabolites characterized by HPLC–MS, including m/z, retention time, ionization mode, proposed molecular ion, strain of interest, and tentative compound class assignment, where applicable (see Fig. 1c). Features were selected from comparative analysis of one strain against the average of the other three strains; the criteria were fivefold enriched or depleted with P-value < 0.01 (unpaired, two-sided t-test).
Supplementary Table 10
Complete list of metabolites identified by GC–MS, including m/z, retention time, fold change and P-value (unpaired, two-sided t-test) for each wild strain compared against the N2 reference strain for both the exo- and the endo-metabolome extracts.
Supplementary Table 11
All single-nucleotide variants (SNVs) in the propionate shunt and canonical propionate metabolism genes. This table includes the gene name and chromosome, nucleotide position, reference sequence, alternate sequence, the consequence of the variant, and the strains from this study that harbour a given variant. A complete and searchable list of all SNVs in all currently sequenced wild strains is available at CeNDR (www.elegansvariation.org).
Supplementary Table 12
Exact number of replicates analysed (n) for wild strains in Figure 4 and in Extended Data Figures 11 and 12.
Supplementary Table 13
Complete list of proteins and accession numbers used to generate the sequence logos in Fig. 3a. See Methods for more details.
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Fox, B.W., Ponomarova, O., Lee, YU. et al. C. elegans as a model for inter-individual variation in metabolism. Nature 607, 571–577 (2022). https://doi.org/10.1038/s41586-022-04951-3
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DOI: https://doi.org/10.1038/s41586-022-04951-3
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