{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T16:37:39Z","timestamp":1793205459729,"version":"4.5.0"},"posted":{"date-parts":[[2026,3,5]]},"group-title":"Microbiology","reference-count":74,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,3,5]],"date-time":"2026-03-05T00:00:00Z","timestamp":1772668800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"NIH Common Fund","award":["1DP2DK139569"],"award-info":[{"award-number":["1DP2DK139569"]}],"id":[{"id":"https:\/\/ror.org\/001d55x84","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,10,24]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Individuals consuming an identical diet often exhibit vast differences in their physiological response to the same nutrients. Studies of identical twins and genetically identical laboratory animals have both shown that much of this variability cannot be explained by differences in genetics. Differences in gut microbes and local microflora have emerged as a leading potential source of this variability, but mechanistic investigations of three-way host-microbe-diet interactions are difficult in most animals. Here, we find that dietary sugar availability suppresses the longevity, dauer formation and gene expression changes of\n                  <jats:italic>daf-2<\/jats:italic>\n                  (insulin-like receptor) mutants fed\n                  <jats:italic>Escherichia coli<\/jats:italic>\n                  OP50, but not\n                  <jats:italic>daf-2<\/jats:italic>\n                  mutants fed many other bacteria. To determine how sugar availability and bacteria intersect to affect\n                  <jats:italic>C. elegans<\/jats:italic>\n                  insulin signaling we conducted transposon mutagenesis screens and found that the effects of sugar availability on\n                  <jats:italic>C. elegans<\/jats:italic>\n                  insulin signaling depend on bacterial pyruvate dehydrogenase activity. We further found that reducing bacterial pyruvate dehydrogenase activity results in increased pyruvate and lactate accumulation and induced host expression of the acid sphingomyelinase\n                  <jats:italic>asm-3<\/jats:italic>\n                  . Lastly, we find that\n                  <jats:italic>asm-3<\/jats:italic>\n                  is required for the loss of pyruvate dehydrogenase activity to alter the phenotype of\n                  <jats:italic>daf-2<\/jats:italic>\n                  mutants. Collectively, our findings establish a novel link between bacterial pyruvate metabolism and host insulin signaling that is mediated by altering the expression of a host acid sphingomyelinase.\n                <\/jats:p>","DOI":"10.64898\/2026.03.04.709558","type":"posted-content","created":{"date-parts":[[2026,3,6]],"date-time":"2026-03-06T05:15:38Z","timestamp":1772774138000},"source":"Crossref","is-referenced-by-count":0,"title":["Bacterial metabolites alter the consequences of reduced insulin signaling in\n                  <i>C. elegans<\/i>\n                  via increasing the expression of the acid sphingomyelinase\n                  <i>asm-3<\/i>"],"prefix":"10.64898","author":[{"given":"Marco E.","family":"Mechan-Llontop","sequence":"first","affiliation":[{"name":"Van Andel Research Institute, Department of Metabolism and Nutritional Programing, Grand Rapids, MI, 49503, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelsie M.","family":"Nauta","sequence":"additional","affiliation":[{"name":"Van Andel Research Institute, Department of Metabolism and Nutritional Programing, Grand Rapids, MI, 49503, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Darrick R.","family":"Gates","sequence":"additional","affiliation":[{"name":"Van Andel Research Institute, Department of Metabolism and Nutritional Programing, Grand Rapids, MI, 49503, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao","family":"Wang","sequence":"additional","affiliation":[{"name":"Van Andel Research Institute, Department of Metabolism and Nutritional Programing, Grand Rapids, MI, 49503, USA"},{"name":"The Van Andel Research Institute Graduate School, Grand Rapids, MI, 49503, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason","family":"Cooper","sequence":"additional","affiliation":[{"name":"Van Andel Research Institute, Department of Metabolism and Nutritional Programing, Grand Rapids, MI, 49503, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas O.","family":"Burton","sequence":"additional","affiliation":[{"name":"Van Andel Research Institute, Department of Metabolism and Nutritional Programing, Grand Rapids, MI, 49503, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026102809150968000_2026.03.04.709558v2.1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2023.02.003"},{"key":"2026102809150968000_2026.03.04.709558v2.2","unstructured":"Human postprandial responses to food and potential for precision nutrition | Nature Medicine. https:\/\/www.nature.com\/articles\/s41591-020-0934-0."},{"key":"2026102809150968000_2026.03.04.709558v2.3","doi-asserted-by":"publisher","DOI":"10.1007\/s13238-020-00814-7"},{"key":"2026102809150968000_2026.03.04.709558v2.4","doi-asserted-by":"publisher","DOI":"10.1038\/nature07540"},{"key":"2026102809150968000_2026.03.04.709558v2.5","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2019.07.004"},{"key":"2026102809150968000_2026.03.04.709558v2.6","doi-asserted-by":"publisher","DOI":"10.1038\/nm.4358"},{"key":"2026102809150968000_2026.03.04.709558v2.7","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-19753-9"},{"key":"2026102809150968000_2026.03.04.709558v2.8","doi-asserted-by":"publisher","DOI":"10.1038\/srep32002"},{"key":"2026102809150968000_2026.03.04.709558v2.9","doi-asserted-by":"crossref","first-page":"e0146509","DOI":"10.1371\/journal.pone.0146509","article-title":"The Gut Microbiome Is Altered in a Letrozole-Induced Mouse Model of Polycystic Ovary Syndrome","volume":"11","year":"2016","journal-title":"PLOS ONE"},{"key":"2026102809150968000_2026.03.04.709558v2.10","unstructured":"Association between Polycystic Ovary Syndrome and Gut Microbiota | PLOS One. https:\/\/journals.plos.org\/plosone\/article?id=10.1371\/journal.pone.0153196."},{"key":"2026102809150968000_2026.03.04.709558v2.11","unstructured":"Frontiers | Dysbiosis of Gut Microbiota Associated with Clinical Parameters in Polycystic Ovary Syndrome. https:\/\/www.frontiersin.org\/journals\/microbiology\/articles\/10.3389\/fmicb.2017.00324\/full."},{"key":"2026102809150968000_2026.03.04.709558v2.12","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-023-06466-x"},{"key":"2026102809150968000_2026.03.04.709558v2.13","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2020.05.013"},{"key":"2026102809150968000_2026.03.04.709558v2.14","doi-asserted-by":"crossref","first-page":"1881","DOI":"10.3390\/microorganisms9091881","article-title":"Cholesterol-to-Coprostanol Conversion by the Gut Microbiota: What We Know, Suspect, and Ignore","volume":"9","year":"2021","journal-title":"Microorganisms"},{"key":"2026102809150968000_2026.03.04.709558v2.15","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-019-0509-0"},{"key":"2026102809150968000_2026.03.04.709558v2.16","doi-asserted-by":"publisher","DOI":"10.2337\/db10-0308"},{"key":"2026102809150968000_2026.03.04.709558v2.17","doi-asserted-by":"crossref","unstructured":"Zhang, Y.-L. , Li, Z.-J. , Gou, H.-Z. , Song, X.-J. & Zhang, L . The gut microbiota\u2013bile acid axis: A potential therapeutic target for liver fibrosis. Front. Cell. Infect. Microbiol. 12, (2022).","DOI":"10.3389\/fcimb.2022.945368"},{"key":"2026102809150968000_2026.03.04.709558v2.18","doi-asserted-by":"crossref","unstructured":"Larraufie, P. et al. SCFAs strongly stimulate PYY production in human enteroendocrine cells. Sci. Rep. 8, 74 (2018).","DOI":"10.1038\/s41598-017-18259-0"},{"key":"2026102809150968000_2026.03.04.709558v2.19","doi-asserted-by":"publisher","DOI":"10.1038\/ijo.2014.153"},{"key":"2026102809150968000_2026.03.04.709558v2.20","doi-asserted-by":"publisher","DOI":"10.2337\/db11-1019"},{"key":"2026102809150968000_2026.03.04.709558v2.21","doi-asserted-by":"publisher","DOI":"10.2337\/db16-0924"},{"key":"2026102809150968000_2026.03.04.709558v2.22","doi-asserted-by":"publisher","DOI":"10.2337\/db08-1637"},{"key":"2026102809150968000_2026.03.04.709558v2.23","doi-asserted-by":"publisher","DOI":"10.1534\/genetics.115.174631"},{"key":"2026102809150968000_2026.03.04.709558v2.24","doi-asserted-by":"publisher","DOI":"10.1534\/genetics.115.177998"},{"key":"2026102809150968000_2026.03.04.709558v2.25","unstructured":"daf-2, an Insulin Receptor-Like Gene That Regulates Longevity and Diapause in Caenorhabditis elegans | Science. https:\/\/www.science.org\/doi\/full\/10.1126\/science.277.5328.942."},{"key":"2026102809150968000_2026.03.04.709558v2.26","doi-asserted-by":"crossref","unstructured":"Penkov, S. et al. A metabolic switch regulates the transition between growth and diapause in C. elegans. BMC Biol. 18, 31 (2020).","DOI":"10.1186\/s12915-020-0760-3"},{"key":"2026102809150968000_2026.03.04.709558v2.27","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2009.10.003"},{"key":"2026102809150968000_2026.03.04.709558v2.28","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1005982"},{"key":"2026102809150968000_2026.03.04.709558v2.29","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1080\/19390211.2016.1212959","article-title":"Lower Doses of Fructose Extend Lifespan in Caenorhabditis elegans","volume":"14","year":"2017","journal-title":"J. Diet. Suppl"},{"key":"2026102809150968000_2026.03.04.709558v2.30","first-page":"679.16","article-title":"Fructose Extends Lifespan and Reduces Intestinal Fat Deposition in Caenorhabditis elegans","volume":"30","year":"2016","journal-title":"FASEB J"},{"key":"2026102809150968000_2026.03.04.709558v2.31","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-021-85046-3"},{"key":"2026102809150968000_2026.03.04.709558v2.32","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2014.01.047"},{"key":"2026102809150968000_2026.03.04.709558v2.33","doi-asserted-by":"crossref","first-page":"3025","DOI":"10.1534\/g3.120.401309","article-title":"CeMbio - The Caenorhabditis elegans Microbiome Resource","volume":"10","year":"2020","journal-title":"G3 GenesGenomesGenetics"},{"key":"2026102809150968000_2026.03.04.709558v2.34","unstructured":"Construction of Escherichia coli K-12 in-frame, single-gene knockout mutants: the Keio collection | Molecular Systems Biology. https:\/\/www.embopress.org\/doi\/full\/10.1038\/msb4100050."},{"key":"2026102809150968000_2026.03.04.709558v2.35","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1912628116"},{"key":"2026102809150968000_2026.03.04.709558v2.36","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.05.036"},{"key":"2026102809150968000_2026.03.04.709558v2.37","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-025-08635-6"},{"key":"2026102809150968000_2026.03.04.709558v2.38","doi-asserted-by":"crossref","unstructured":"Tauffenberger, A. , Fiumelli, H. , Almustafa, S. & Magistretti, P. J . Lactate and pyruvate promote oxidative stress resistance through hormetic ROS signaling. Cell Death Dis. 10, 653 (2019).","DOI":"10.1038\/s41419-019-1877-6"},{"key":"2026102809150968000_2026.03.04.709558v2.39","doi-asserted-by":"publisher","DOI":"10.1111\/j.1474-9726.2010.00640.x"},{"key":"2026102809150968000_2026.03.04.709558v2.40","doi-asserted-by":"publisher","DOI":"10.1038\/88850"},{"key":"2026102809150968000_2026.03.04.709558v2.41","unstructured":"WormEnrichr. https:\/\/maayanlab.cloud\/WormEnrichr\/account.html."},{"key":"2026102809150968000_2026.03.04.709558v2.42","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0045890"},{"key":"2026102809150968000_2026.03.04.709558v2.43","doi-asserted-by":"publisher","DOI":"10.64898\/2026.09.14.751545"},{"key":"2026102809150968000_2026.03.04.709558v2.44","doi-asserted-by":"publisher","DOI":"10.1096\/fj.08-108043"},{"key":"2026102809150968000_2026.03.04.709558v2.45","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M101207200"},{"key":"2026102809150968000_2026.03.04.709558v2.46","doi-asserted-by":"crossref","unstructured":"Pilon, M . Revisiting the membrane-centric view of diabetes. Lipids Health Dis. 15, 167 (2016).","DOI":"10.1186\/s12944-016-0342-0"},{"key":"2026102809150968000_2026.03.04.709558v2.47","doi-asserted-by":"crossref","unstructured":"Han, H.-F. et al. Dietary bacteria control C. elegans fat content through pathways converging at phosphatidylcholine. eLife 13, (2024).","DOI":"10.7554\/eLife.96473"},{"key":"2026102809150968000_2026.03.04.709558v2.48","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-019-03319-7"},{"key":"2026102809150968000_2026.03.04.709558v2.49","doi-asserted-by":"publisher","DOI":"10.1016\/j.copbio.2017.01.008"},{"key":"2026102809150968000_2026.03.04.709558v2.50","doi-asserted-by":"crossref","unstructured":"Feng, M. , Gao, B. , Garcia, L. R. & Sun, Q . Microbiota-derived metabolites in regulating the development and physiology of Caenorhabditis elegans. Front. Microbiol. 14, (2023).","DOI":"10.3389\/fmicb.2023.1035582"},{"key":"2026102809150968000_2026.03.04.709558v2.51","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.03.046"},{"key":"2026102809150968000_2026.03.04.709558v2.52","doi-asserted-by":"crossref","first-page":"1584","DOI":"10.1038\/s42255-024-01098-5","article-title":"Host\u2013microbe interactions rewire metabolism in a C. elegans model of leucine breakdown deficiency","volume":"6","year":"2024","journal-title":"Nat. Metab"},{"key":"2026102809150968000_2026.03.04.709558v2.53","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2019.07.010"},{"key":"2026102809150968000_2026.03.04.709558v2.54","unstructured":"A RAPID METHOD OF TOTAL LIPID EXTRACTION AND PURIFICATION. https:\/\/cdnsciencepub.com\/doi\/abs\/10.1139\/o59-099."},{"key":"2026102809150968000_2026.03.04.709558v2.55","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-50128-z"},{"key":"2026102809150968000_2026.03.04.709558v2.56","doi-asserted-by":"crossref","first-page":"11638","DOI":"10.1038\/s41467-025-66499-w","article-title":"A noncanonical polyamine from bacteria antagonizes host mitochondrial function","volume":"16","year":"2025","journal-title":"Nat. Commun"},{"key":"2026102809150968000_2026.03.04.709558v2.57","doi-asserted-by":"publisher","DOI":"10.2307\/2346786"},{"key":"2026102809150968000_2026.03.04.709558v2.58","unstructured":"Chambers, J. M. & Hastie, T. J. Linear Models. in Statistical Models in S eds (Wadsworth & Brooks\/Cole., 1992)."},{"key":"2026102809150968000_2026.03.04.709558v2.59","unstructured":"Chambers, J. M. & Hastie, T. J . Statistical Models in S. in (Wadsworth & Brooks\/Cole., 1992)."},{"key":"2026102809150968000_2026.03.04.709558v2.60","unstructured":"pairwise.t.test function - RDocumentation. https:\/\/www.rdocumentation.org\/packages\/stats\/versions\/3.6.2\/topics\/pairwise.t.test."},{"key":"2026102809150968000_2026.03.04.709558v2.61","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-61779-839-9_16"},{"key":"2026102809150968000_2026.03.04.709558v2.62","doi-asserted-by":"crossref","first-page":"10","DOI":"10.14806\/ej.17.1.200","article-title":"Cutadapt removes adapter sequences from high-throughput sequencing reads","volume":"17","year":"2011","journal-title":"EMBnet.journal"},{"key":"2026102809150968000_2026.03.04.709558v2.63","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bts635"},{"key":"2026102809150968000_2026.03.04.709558v2.64","unstructured":"R: The R Project for Statistical Computing. https:\/\/www.r-project.org\/."},{"key":"2026102809150968000_2026.03.04.709558v2.65","unstructured":"Bioconductor - Home. https:\/\/bioconductor.org\/."},{"key":"2026102809150968000_2026.03.04.709558v2.66","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-014-0550-8"},{"key":"2026102809150968000_2026.03.04.709558v2.67","unstructured":"Bash - GNU Project - Free Software Foundation. https:\/\/www.gnu.org\/software\/bash\/."},{"key":"2026102809150968000_2026.03.04.709558v2.68","doi-asserted-by":"crossref","unstructured":"Wickham, H. ggplot2: Elegant Graphics for Data Analysis. (2016).","DOI":"10.1007\/978-3-319-24277-4_9"},{"key":"2026102809150968000_2026.03.04.709558v2.69","unstructured":"Yan L (2025). ggvenn: Draw Venn Diagram by \u2018ggplot2\u2019. R package version 0.1.19, https:\/\/github.com\/yanlinlin82\/ggvenn."},{"key":"2026102809150968000_2026.03.04.709558v2.70","unstructured":"pheatmap function - RDocumentation. https:\/\/www.rdocumentation.org\/packages\/pheatmap\/versions\/1.0.13\/topics\/pheatmap."},{"key":"2026102809150968000_2026.03.04.709558v2.71","unstructured":"org.Ce.eg.db. Bioconductor http:\/\/bioconductor.org\/packages\/org.Ce.eg.db\/."},{"key":"2026102809150968000_2026.03.04.709558v2.72","unstructured":"One-step inactivation of chromosomal genes in Escherichia coli K-12 using PCR products | PNAS. https:\/\/www.pnas.org\/doi\/10.1073\/pnas.120163297."},{"key":"2026102809150968000_2026.03.04.709558v2.73","doi-asserted-by":"publisher","DOI":"10.1128\/JB.00619-08"},{"key":"2026102809150968000_2026.03.04.709558v2.74","doi-asserted-by":"crossref","unstructured":"Hibbs, M. et al. SPELL Version 2.0.3 Exploring the functional landscape of gene expression: directed search of large microarray compendia. Bioinformatics 23, (2007).","DOI":"10.1093\/bioinformatics\/btm403"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.03.04.709558","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T16:15:33Z","timestamp":1793204133000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.64898\/2026.03.04.709558"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,5]]},"references-count":74,"URL":"https:\/\/doi.org\/10.64898\/2026.03.04.709558","relation":{},"subject":[],"published":{"date-parts":[[2026,3,5]]},"subtype":"preprint"}}