{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T21:56:07Z","timestamp":1791928567610,"version":"4.3.4"},"reference-count":38,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,5,26]],"date-time":"2025-05-26T00:00:00Z","timestamp":1748217600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Infect. Microbiol."],"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>This study aims to conduct a comprehensive analysis of the differences in gut microbiota and metabolomics in preterm infants stratified by gestational age.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Fresh fecal samples were collected from neonates within the first 3 days after birth. The gut microbiota composition and the changes in specific taxa abundance were analyzed using 16S rRNA sequencing. Metabolomic profiling was performed using liquid chromatography-tandem mass spectrometry (LC-MS\/MS). Participants were categorized into four groups based on gestational age at birth: PreA group (34\u201336 weeks), PreB group (32\u201333 weeks), PreC group (28\u201331 weeks), and control group (37\u201342 weeks). Metabolic pathways were identified through metabolomics analysis, referencing the Kyoto Encyclopedia of Genes and Genomes (KEGG) database.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Notably, Principal Coordinates Analysis (PCoA) showed clear separation among samples from all groups, with significant differences noted in the PreC group when compared with the other three. We found a strong association between <jats:italic>Escherichia-Shigella<\/jats:italic> and <jats:italic>Ureaplasma<\/jats:italic> genera with infants born before 32 weeks of gestation, suggesting a higher risk of opportunistic infections for preterm infants under this gestational threshold. As gestational age increases, <jats:italic>Megamonas<\/jats:italic> and <jats:italic>Prevotella<\/jats:italic> gradually emerged, while <jats:italic>Escherichia-Shigella<\/jats:italic> and <jats:italic>Ureaplasma<\/jats:italic> progressively diminished. KEGG enrichment analysis indicated that Pyrimidine metabolism was a differentially regulated pathway between the PreA group and the control group. Interestingly, the only major differential metabolic pathway between the PreB group and the control group was Arachidonic acid metabolism. The bubble diagram revealed significant enrichment of differential metabolites in Pyrimidine and beta-Alanine metabolism pathways when comparing the PreC group with the control group.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Significant differences were observed in the fecal microbiome and metabolome between preterm and full-term infants, particularly in those born before 32 weeks of gestation. These findings suggested that the gut microbial system in preterm infants undergone progressive maturation, approaching a \u201chealthy\u201d state characteristic of full-term infants as gestational age increases.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fcimb.2025.1530653","type":"journal-article","created":{"date-parts":[[2025,5,26]],"date-time":"2025-05-26T05:16:53Z","timestamp":1748236613000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Fecal 16S rRNA sequencing and metabolomics reveal abnormal metabolism activity in preterm infants with different gestational ages"],"prefix":"10.3389","volume":"15","author":[{"given":"Ling","family":"Liu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liang","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jincheng","family":"Dai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiangsheng","family":"Cai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benqing","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,5,26]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2014.00427","article-title":"The intestinal microbiome in early life: health and disease","volume":"5","author":"Arrieta","year":"2014","journal-title":"Front. Immunol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1038\/nmeth.2276","article-title":"Quality-filtering vastly improves diversity estimates from Illumina amplicon sequencing","volume":"10","author":"Bokulich","year":"2013","journal-title":"Nat. Methods"},{"key":"B3","doi-asserted-by":"publisher","first-page":"335","DOI":"10.1038\/nmeth.f.303","article-title":"QIIME allows analysis of high-throughput community sequencing data","volume":"7","author":"Caporaso","year":"2010","journal-title":"Nat. Methods"},{"key":"B4","doi-asserted-by":"publisher","first-page":"922","DOI":"10.1038\/s41564-024-01628-7","article-title":"Prevotella copri and microbiota members mediate the beneficial effects of a therapeutic food for malnutrition","volume":"9","author":"Chang","year":"2024","journal-title":"Nat. Microbiol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"3881","DOI":"10.3390\/jcm10173881","article-title":"Gut microbiota composition and its metabolites in different stages of chronic kidney disease","volume":"10","author":"Chen","year":"2021","journal-title":"J. Clin. Med."},{"key":"B6","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1038\/s41390-018-0022-z","article-title":"The premature infant gut microbiome during the first 6 weeks of life differs based on gestational maturity at birth","volume":"84","author":"Chernikova","year":"2018","journal-title":"Pediatr. Res."},{"key":"B7","doi-asserted-by":"publisher","first-page":"749","DOI":"10.3390\/nu14040749","article-title":"Arachidonic acid as mechanotransducer of renin cell baroreceptor","volume":"14","author":"Das","year":"2022","journal-title":"Nutrients"},{"key":"B8","doi-asserted-by":"publisher","first-page":"996","DOI":"10.1038\/nmeth.2604","article-title":"UPARSE: highly accurate OTU sequences from microbial amplicon reads","volume":"10","author":"Edgar","year":"2013","journal-title":"Nat. Methods"},{"key":"B9","doi-asserted-by":"publisher","first-page":"136","DOI":"10.1186\/s40168-022-01327-7","article-title":"Capturing the antibiotic resistome of preterm infants reveals new benefits of probiotic supplementation","volume":"10","author":"Guitor","year":"2022","journal-title":"Microbiome."},{"key":"B10","doi-asserted-by":"publisher","first-page":"251","DOI":"10.1002\/biof.1336","article-title":"Arachidonic acid and lipoxin A4 attenuate alloxan-induced cytotoxicity to RIN5F cells in vitro and type 1 diabetes mellitus in vivo","volume":"43","author":"Gundala","year":"2017","journal-title":"Biofactors"},{"key":"B11","doi-asserted-by":"publisher","first-page":"494","DOI":"10.1101\/gr.112730.110","article-title":"Chimeric 16S rRNA sequence formation and detection in Sanger and 454-pyrosequenced PCR amplicons","volume":"21","author":"Haas","year":"2011","journal-title":"Genome Res."},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1186\/s40168-016-0213-y","article-title":"Evolution of gut microbiota composition from birth to 24 weeks in the INFANTMET Cohort","volume":"5","author":"Hill","year":"2017","journal-title":"Microbiome."},{"key":"B13","doi-asserted-by":"publisher","first-page":"1804","DOI":"10.1038\/s41390-021-01663-8","article-title":"Spontaneous preterm delivery is reflected in both early neonatal and maternal gut microbiota","volume":"91","author":"Hiltunen","year":"2022","journal-title":"Pediatr. Res."},{"key":"B14","doi-asserted-by":"publisher","first-page":"179","DOI":"10.1177\/0310057X20903732","article-title":"Gut microbiota in surgical and critically ill patients","volume":"48","author":"Ho","year":"2020","journal-title":"Anaesth Intensive Care"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1038\/s41390-024-03676-5","article-title":"Synergism between TLR4 and B. infantis in the development of the premature intestine","author":"Huang","year":"2025","journal-title":"Pediatr. Res"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1080\/19490976.2021.1951113","article-title":"The effect of early probiotic exposure on the preterm infant gut microbiome development","volume":"13","author":"Hui","year":"2021","journal-title":"Gut Microbes."},{"key":"B17","doi-asserted-by":"publisher","first-page":"2453","DOI":"10.1038\/s41598-018-20827-x","article-title":"Intestinal microbiota development and gestational age in preterm neonates","volume":"8","author":"Korpela","year":"2018","journal-title":"Sci. Rep."},{"key":"B18","doi-asserted-by":"publisher","first-page":"780","DOI":"10.1002\/kjm2.12878","article-title":"The impact of gut microbiota on morbidities in preterm infants","volume":"40","author":"Lai","year":"2024","journal-title":"Kaohsiung J. Med. Sci."},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2022.945851","article-title":"Changes in intestinal microflora and its metabolites underlie the cognitive impairment in preterm rats","volume":"12","author":"Lu","year":"2022","journal-title":"Front. Cell Infect. Microbiol."},{"key":"B20","doi-asserted-by":"publisher","first-page":"586","DOI":"10.1038\/s41586-021-03539-7","article-title":"DHODH-mediated ferroptosis defence is a targetable vulnerability in cancer","volume":"593","author":"Mao","year":"2021","journal-title":"Nature."},{"key":"B21","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1016\/j.tim.2012.12.001","article-title":"Development of intestinal microbiota in infants and its impact on health","volume":"21","author":"Matamoros","year":"2013","journal-title":"Trends Microbiol."},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2020.00439","article-title":"Evolution of the gut microbiome in early childhood: A cross-sectional study of chinese children","volume":"11","author":"Niu","year":"2020","journal-title":"Front. Microbiol."},{"key":"B23","doi-asserted-by":"publisher","first-page":"1329","DOI":"10.1542\/peds.2008-1113","article-title":"Extremely Low Gestational Age Newborn Study I. Perinatal correlates of Ureaplasma urealyticum in placenta parenchyma of singleton pregnancies that end before 28 weeks of gestation","volume":"123","author":"Olomu","year":"2009","journal-title":"Pediatrics."},{"key":"B24","doi-asserted-by":"publisher","first-page":"1296","DOI":"10.1016\/j.clnu.2020.08.013","article-title":"Effect of donor human milk on host-gut microbiota and metabolic interactions in preterm infants","volume":"40","author":"Pineiro-Ramos","year":"2021","journal-title":"Clin. Nutr."},{"key":"B25","doi-asserted-by":"publisher","first-page":"382","DOI":"10.1038\/s41398-021-01504-6","article-title":"Gut microbiota signature in treatment-naive attention-deficit\/hyperactivity disorder","volume":"11","author":"Richarte","year":"2021","journal-title":"Transl. Psychiatry"},{"key":"B26","doi-asserted-by":"publisher","first-page":"e2584","DOI":"10.7717\/peerj.2584","article-title":"VSEARCH: a\u00a0versatile open source tool for metagenomics","volume":"4","author":"Rognes","year":"2016","journal-title":"PeerJ."},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.1002533","article-title":"Revised estimates for the number of human and bacteria cells in the body","volume":"14","author":"Sender","year":"2016","journal-title":"PLoS Biol."},{"key":"B28","doi-asserted-by":"publisher","first-page":"496","DOI":"10.1016\/j.tibtech.2015.06.011","article-title":"Proteobacteria: microbial signature of dysbiosis in gut microbiota","volume":"33","author":"Shin","year":"2015","journal-title":"Trends Biotechnol."},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2022.919317","article-title":"Very preterm children gut microbiota comparison at the neonatal period of 1 month and 3.5 Years of Life","volume":"13","author":"Toubon","year":"2022","journal-title":"Front. Microbiol"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2020.00891","article-title":"Comparing gut microbiome in mothers\u2019 Own breast milk- and formula-fed moderate-late preterm infants","volume":"11","author":"Wang","year":"2020","journal-title":"Front. Microbiol."},{"key":"B31","doi-asserted-by":"publisher","first-page":"2","DOI":"10.2174\/1566524021666210302144720","article-title":"Leukaemia infection diagnosis and intestinal flora disorder","volume":"22","author":"Wang","year":"2021","journal-title":"Curr. Mol. Med"},{"key":"B32","doi-asserted-by":"publisher","first-page":"183","DOI":"10.1186\/s12859-017-1579-y","article-title":"metaX: a flexible and comprehensive software for processing metabolomics data","volume":"18","author":"Wen","year":"2017","journal-title":"BMC Bioinf."},{"key":"B33","doi-asserted-by":"publisher","first-page":"142","DOI":"10.1038\/s41390-021-01738-6","article-title":"The bacterial gut microbiome of probiotic-treated very-preterm infants: changes from admission to discharge","volume":"92","author":"Westaway","year":"2022","journal-title":"Pediatr. Res."},{"key":"B34","doi-asserted-by":"publisher","first-page":"1652","DOI":"10.21037\/atm-20-7514","article-title":"Arachidonic acid inhibits the production of angiotensin-converting enzyme in human primary adipocytes via a NF-kappaB-dependent pathway","volume":"8","author":"Xu","year":"2020","journal-title":"Ann. Transl. Med."},{"key":"B35","doi-asserted-by":"publisher","first-page":"1353","DOI":"10.1038\/s41598-020-80278-1","article-title":"Neonatal intensive care unit (NICU) exposures exert a sustained influence on the progression of gut microbiota and metabolome in the first year of life","volume":"11","author":"Yap","year":"2021","journal-title":"Sci. Rep."},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2022.804887","article-title":"The change of cytokines and gut microbiome in preterm infants for bronchopulmonary dysplasia","volume":"13","author":"Zhang","year":"2022","journal-title":"Front. Microbiol."},{"key":"B37","doi-asserted-by":"publisher","first-page":"5545","DOI":"10.18632\/aging.205663","article-title":"A pyrimidine metabolism-related signature for prognostic and immunotherapeutic response prediction in hepatocellular carcinoma by integrating analyses","volume":"16","author":"Zhang","year":"2024","journal-title":"Aging (Albany NY)."},{"key":"B38","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1007\/s13258-020-01029-0","article-title":"Metagenomics analysis of the gut microbiome in healthy and bacterial pneumonia forest musk deer","volume":"43","author":"Zhao","year":"2021","journal-title":"Genes Genomics"}],"container-title":["Frontiers in Cellular and Infection Microbiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcimb.2025.1530653\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,5,26]],"date-time":"2025-05-26T05:16:55Z","timestamp":1748236615000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcimb.2025.1530653\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,26]]},"references-count":38,"alternative-id":["10.3389\/fcimb.2025.1530653"],"URL":"https:\/\/doi.org\/10.3389\/fcimb.2025.1530653","relation":{},"ISSN":["2235-2988"],"issn-type":[{"value":"2235-2988","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,5,26]]},"article-number":"1530653"}}