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Here, we employed metabolomics and metagenomics to examine systemic biological adaptations associated with dietary sugar restriction and (subsequent) hepatic fat reductions in youth with NAFLD. Data\/samples were from a randomized controlled trial in adolescent boys (11\u201316 years, mean \u00b1 SD: 13.0 \u00b1 1.9 years) with biopsy-proven NAFLD who were either provided a low free-sugar diet (LFSD) (n = 20) or consumed their usual diet (n = 20) for 8 weeks. Plasma metabolomics was performed on samples from all 40 participants by coupling hydrophilic interaction liquid chromatography (HILIC) and C18 chromatography with mass spectrometry. In a sub-sample (n = 8 LFSD group and n = 10 usual diet group), 16S ribosomal RNA (rRNA) sequencing was performed on stool to examine changes in microbial composition\/diversity. The diet treatment was associated with differential expression of 419 HILIC and 205 C18 metabolite features (p &lt; 0.05), which were enriched in amino acid pathways, including methionine\/cysteine and serine\/glycine\/alanine metabolism (p &lt; 0.05), and lipid pathways, including omega-3 and linoleate metabolism (p &lt; 0.05). Quantified metabolites that were differentially changed in the LFSD group, compared to usual diet group, and representative of these enriched metabolic pathways included increased serine (p = 0.001), glycine (p = 0.004), 2-aminobutyric acid (p = 0.012), and 3-hydroxybutyric acid (p = 0.005), and decreased linolenic acid (p = 0.006). Microbiome changes included an increase in richness at the phylum level and changes in a few genera within Firmicutes. In conclusion, the LFSD treatment, compared to usual diet, was associated with metabolome and microbiome changes that may reflect biological mechanisms linking dietary sugar restriction to a therapeutic decrease in hepatic fat. Studies are needed to validate our findings and test the utility of these \u201comics\u201d changes as response biomarkers.<\/jats:p>","DOI":"10.3390\/metabo13030401","type":"journal-article","created":{"date-parts":[[2023,3,9]],"date-time":"2023-03-09T02:01:47Z","timestamp":1678327307000},"page":"401","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Metabolome \u00d7 Microbiome Changes Associated with a Diet-Induced Reduction in Hepatic Fat among Adolescent Boys"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8402-0118","authenticated-orcid":false,"given":"Catherine C.","family":"Cohen","sequence":"first","affiliation":[{"name":"Department of Pediatrics, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helaina","family":"Huneault","sequence":"additional","affiliation":[{"name":"Nutrition & Health Sciences Doctoral Program, Laney Graduate School, Emory University, Atlanta, GA 30322, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolyn J.","family":"Accardi","sequence":"additional","affiliation":[{"name":"Department of Medicine, School of Medicine, Emory University, Atlanta, GA 30322, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dean P.","family":"Jones","sequence":"additional","affiliation":[{"name":"Department of Medicine, School of Medicine, Emory University, Atlanta, GA 30322, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ken","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Medicine, School of Medicine, Emory University, Atlanta, GA 30322, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2274-4284","authenticated-orcid":false,"given":"Kristal M.","family":"Maner-Smith","sequence":"additional","affiliation":[{"name":"Emory Integrated Lipidomics Core, School of Medicine, Emory University, Atlanta, GA 30322, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming","family":"Song","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Louisville School of Medicine, Louisville, KY 40202, USA"},{"name":"Hepatobiology and Toxicology Center, University of Louisville School of Medicine, Louisville, KY 40202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean A.","family":"Welsh","sequence":"additional","affiliation":[{"name":"Nutrition & Health Sciences Doctoral Program, Laney Graduate School, Emory University, Atlanta, GA 30322, USA"},{"name":"Department of Pediatrics, School of Medicine, Emory University, Atlanta, GA 30322, USA"},{"name":"Children\u2019s Healthcare of Atlanta, Atlanta, GA 30322, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia A.","family":"Ugalde-Nicalo","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Rady Children\u2019s Hospital San Diego, San Diego, CA 92123, USA"},{"name":"Department of Pediatrics, School of Medicine, University of California, San Diego, CA 92093, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey B.","family":"Schwimmer","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Rady Children\u2019s Hospital San Diego, San Diego, CA 92123, USA"},{"name":"Department of Pediatrics, School of Medicine, University of California, San Diego, CA 92093, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miriam B.","family":"Vos","sequence":"additional","affiliation":[{"name":"Nutrition & Health Sciences Doctoral Program, Laney Graduate School, Emory University, Atlanta, GA 30322, USA"},{"name":"Department of Pediatrics, School of Medicine, Emory University, Atlanta, GA 30322, USA"},{"name":"Children\u2019s Healthcare of Atlanta, Atlanta, GA 30322, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,3,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1388","DOI":"10.1542\/peds.2006-1212","article-title":"Prevalence of fatty liver in children and adolescents","volume":"118","author":"Schwimmer","year":"2006","journal-title":"Pediatrics"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Anderson, E.L., Howe, L.D., Jones, H.E., Higgins, J.P., Lawlor, D.A., and Fraser, A. 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