{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T22:25:15Z","timestamp":1781821515069,"version":"3.54.5"},"reference-count":48,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2023,5,25]],"date-time":"2023-05-25T00:00:00Z","timestamp":1684972800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Italian Minister of Health","award":["748"],"award-info":[{"award-number":["748"]}]},{"name":"Italian Minister of Health","award":["1159"],"award-info":[{"award-number":["1159"]}]},{"name":"Apulia Region-D.G.R.","award":["748"],"award-info":[{"award-number":["748"]}]},{"name":"Apulia Region-D.G.R.","award":["1159"],"award-info":[{"award-number":["1159"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Together with its comorbidities, nonalcoholic fatty liver disease (NAFLD) is likely to rise further with the obesity epidemic. However, the literature\u2019s evidence shows how its progression can be reduced by the administration of calorie-restrictive dietary interventions and physical activity regimens. The liver function and the gut microbiota have been demonstrated to be closely related. With the aim of ascertaining the impact of a treatment based on the combination of diet and physical activity (versus physical activity alone), we recruited 46 NAFLD patients who were divided into two groups. As a result, we traced the connection between volatile organic compounds (VOCs) from fecal metabolomics and a set of statistically filtered clinical variables. Additionally, we identified the relative abundances of gut microbiota taxa obtained from 16S rRNA gene sequencing. Statistically significant correlations emerged between VOCs and clinical parameters, as well as between VOCs and gut microbiota taxa. In comparison with a physical activity regimen alone, we disclose how ethyl valerate and pentanoic acid butyl ester, methyl valerate, and 5-hepten-2-one, 6-methyl changed because of the positive synergistic effect exerted by the combination of the Mediterranean diet and physical activity regimens. Moreover, 5-hepten-2-one, 6-methyl positively correlated with Sanguinobacteroides, as well as the two genera Oscillospiraceae-UCG002 and Ruminococcaceae\u00a0UCG010 genera.<\/jats:p>","DOI":"10.3390\/nu15112457","type":"journal-article","created":{"date-parts":[[2023,5,25]],"date-time":"2023-05-25T02:00:55Z","timestamp":1684980055000},"page":"2457","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Synergistic Effect of Diet and Physical Activity on a NAFLD Cohort: Metabolomics Profile and Clinical Variable Evaluation"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0176-7046","authenticated-orcid":false,"given":"Francesco Maria","family":"Calabrese","sequence":"first","affiliation":[{"name":"Department of Soil, Plant and Food Science, University of Bari Aldo Moro, 70126 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3805-7681","authenticated-orcid":false,"given":"Giuseppe","family":"Celano","sequence":"additional","affiliation":[{"name":"Department of Soil, Plant and Food Science, University of Bari Aldo Moro, 70126 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8650-348X","authenticated-orcid":false,"given":"Caterina","family":"Bonfiglio","sequence":"additional","affiliation":[{"name":"National Institute of Gastroenterology S. De Bellis, IRCCS Research Hospital, Via Turi 27, 70013 Castellana Grotte, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5044-4625","authenticated-orcid":false,"given":"Angelo","family":"Campanella","sequence":"additional","affiliation":[{"name":"National Institute of Gastroenterology S. De Bellis, IRCCS Research Hospital, Via Turi 27, 70013 Castellana Grotte, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3697-0127","authenticated-orcid":false,"given":"Isabella","family":"Franco","sequence":"additional","affiliation":[{"name":"National Institute of Gastroenterology S. De Bellis, IRCCS Research Hospital, Via Turi 27, 70013 Castellana Grotte, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-9282-0509","authenticated-orcid":false,"given":"Alessandro","family":"Annunziato","sequence":"additional","affiliation":[{"name":"Department of Soil, Plant and Food Science, University of Bari Aldo Moro, 70126 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5140-8060","authenticated-orcid":false,"given":"Gianluigi","family":"Giannelli","sequence":"additional","affiliation":[{"name":"National Institute of Gastroenterology S. De Bellis, IRCCS Research Hospital, Via Turi 27, 70013 Castellana Grotte, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4232-8760","authenticated-orcid":false,"given":"Alberto Ruben","family":"Osella","sequence":"additional","affiliation":[{"name":"National Institute of Gastroenterology S. De Bellis, IRCCS Research Hospital, Via Turi 27, 70013 Castellana Grotte, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2010-884X","authenticated-orcid":false,"given":"Maria","family":"De Angelis","sequence":"additional","affiliation":[{"name":"Department of Soil, Plant and Food Science, University of Bari Aldo Moro, 70126 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,5,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"310","DOI":"10.3748\/wjg.v28.i3.310","article-title":"Non-Alcoholic Fatty Liver Disease and Hepatocellular Carcinoma: Clinical Challenges of an Intriguing Link","volume":"28","author":"Chrysavgis","year":"2022","journal-title":"World J. Gastroenterol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1002\/hep.29367","article-title":"The Diagnosis and Management of Nonalcoholic Fatty Liver Disease: Practice Guidance from the American Association for the Study of Liver Diseases","volume":"67","author":"Chalasani","year":"2018","journal-title":"Hepatology"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1867","DOI":"10.1136\/gutjnl-2021-325724","article-title":"Non-Alcoholic Fatty Liver Disease and Incident Major Adverse Cardiovascular Events: Results from a Nationwide Histology Cohort","volume":"71","author":"Simon","year":"2022","journal-title":"Gut"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1121","DOI":"10.1002\/hep.32427","article-title":"Metabolic Subtypes of Patients with NAFLD Exhibit Distinctive Cardiovascular Risk Profiles","volume":"76","author":"Bruzzone","year":"2022","journal-title":"Hepatology"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"576","DOI":"10.1097\/MCO.0b013e32836410a4","article-title":"The Gut-Liver Axis","volume":"16","author":"Visschers","year":"2013","journal-title":"Curr. Opin. Clin. Nutr. Metab. Care"},{"key":"ref_6","first-page":"174","article-title":"The Gut Microbiome and Ferroptosis in MAFLD","volume":"11","author":"Ji","year":"2023","journal-title":"J. Clin. Transl. Hepatol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"994404","DOI":"10.3389\/fncel.2022.994404","article-title":"The Gut-Microbiota-Brain Changes across the Liver Disease Spectrum","volume":"16","author":"Higarza","year":"2022","journal-title":"Front. Cell. Neurosci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"10358","DOI":"10.1038\/s41598-018-28563-y","article-title":"Fatty Liver Is Associated with Blood Pathways of Inflammatory Response, Immune System Activation and Prothrombotic State in Young Finns Study","volume":"8","author":"Taipale","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1038\/nature10809","article-title":"Inflammasome-Mediated Dysbiosis Regulates Progression of NAFLD and Obesity","volume":"482","author":"Elinav","year":"2012","journal-title":"Nature"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1038\/nrgastro.2015.200","article-title":"Immunology in the Liver--From Homeostasis to Disease","volume":"13","author":"Heymann","year":"2016","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"652","DOI":"10.1007\/s12072-020-10081-7","article-title":"The Role of Neutrophils in Innate Immunity-Driven Nonalcoholic Steatohepatitis: Lessons Learned and Future Promise","volume":"14","author":"Wu","year":"2020","journal-title":"Hepatol. Int."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"103768","DOI":"10.1016\/j.ebiom.2021.103768","article-title":"Peripheral Immune Cells in NAFLD Patients: A Spyhole to Disease Progression","volume":"75","author":"Lin","year":"2022","journal-title":"EBioMedicine"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2133","DOI":"10.1152\/physrev.00063.2017","article-title":"Mechanisms of Insulin Action and Insulin Resistance","volume":"98","author":"Petersen","year":"2018","journal-title":"Physiol. Rev."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"614","DOI":"10.1016\/S2468-1253(18)30124-9","article-title":"Non-Invasive Diagnosis of Liver Fibrosis in Patients with Alcohol-Related Liver Disease by Transient Elastography: An Individual Patient Data Meta-Analysis","volume":"3","author":"Thiele","year":"2018","journal-title":"Lancet Gastroenterol. Hepatol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"998","DOI":"10.1111\/hepr.13826","article-title":"Serum Levels of Immunoglobulin M-Free Inhibitors of Macrophage\/CD5L as a Predictive and Early Diagnostic Marker for Nonalcoholic Steatohepatitis-Associated Hepatocellular Carcinoma","volume":"52","author":"Okanoue","year":"2022","journal-title":"Hepatol. Res."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Hrncir, T., Hrncirova, L., Kverka, M., Hromadka, R., Machova, V., Trckova, E., Kostovcikova, K., Kralickova, P., Krejsek, J., and Tlaskalova-Hogenova, H. (2021). Gut Microbiota and NAFLD: Pathogenetic Mechanisms, Microbiota Signatures, and Therapeutic Interventions. Microorganisms, 9.","DOI":"10.3390\/microorganisms9050957"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"S244","DOI":"10.3350\/cmh.2022.0364","article-title":"Eating, Diet, and Nutrition for the Treatment of NAFLD","volume":"29","author":"Semmler","year":"2022","journal-title":"Clin. Mol. Hepatol."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Calabrese, F.M., Disciglio, V., Franco, I., Sorino, P., Bonfiglio, C., Bianco, A., Campanella, A., Lippolis, T., Pesole, P.L., and Polignano, M. (2022). A Low Glycemic Index Mediterranean Diet Combined with Aerobic Physical Activity Rearranges the Gut Microbiota Signature in NAFLD Patients. Nutrients, 14.","DOI":"10.3390\/nu14091773"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Tutino, V., De Nunzio, V., Caruso, M.G., Bonfiglio, C., Franco, I., Mirizzi, A., De Leonardis, G., Cozzolongo, R., Giannuzzi, V., and Giannelli, G. (2018). Aerobic Physical Activity and a Low Glycemic Diet Reduce the AA\/EPA Ratio in Red Blood Cell Membranes of Patients with NAFLD. Nutrients, 10.","DOI":"10.3390\/nu10091299"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1295","DOI":"10.1007\/s00125-018-4582-6","article-title":"Fibre Supplementation for the Prevention of Type 2 Diabetes and Improvement of Glucose Metabolism: The Randomised Controlled Optimal Fibre Trial (OptiFiT)","volume":"61","author":"Honsek","year":"2018","journal-title":"Diabetologia"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Franco, I., Bianco, A., Mirizzi, A., Campanella, A., Bonfiglio, C., Sorino, P., Notarnicola, M., Tutino, V., Cozzolongo, R., and Giannuzzi, V. (2020). Physical Activity and Low Glycemic Index Mediterranean Diet: Main and Modification Effects on NAFLD Score. Results from a Randomized Clinical Trial. Nutrients, 13.","DOI":"10.3390\/nu13010066"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1007\/BF02291575","article-title":"An Index of Factorial Simplicity","volume":"39","author":"Kaiser","year":"1974","journal-title":"Psychometrika"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1596","DOI":"10.1038\/s42255-021-00501-9","article-title":"Non-Alcoholic Fatty Liver Disease: The Interplay between Metabolism, Microbes and Immunity","volume":"3","author":"Tilg","year":"2021","journal-title":"Nat. Metab."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"19355","DOI":"10.18632\/oncotarget.8466","article-title":"Distinctly Altered Gut Microbiota in the Progression of Liver Disease","volume":"7","author":"Xie","year":"2016","journal-title":"Oncotarget"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"e010342","DOI":"10.1136\/bmjopen-2015-010342","article-title":"Association between White Blood Cell Count and Non-Alcoholic Fatty Liver Disease in Urban Han Chinese: A Prospective Cohort Study","volume":"6","author":"Wang","year":"2016","journal-title":"BMJ Open"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"100117","DOI":"10.1016\/j.jhepr.2020.100117","article-title":"Imaging and Immunometabolic Phenotyping Uncover Changes in the Hepatic Immune Response in the Early Phases of NAFLD","volume":"2","author":"Diniz","year":"2020","journal-title":"JHEP Rep."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"444","DOI":"10.1164\/rccm.201811-2210OC","article-title":"Exhaled Volatile Organic Compounds Are Able to Discriminate between Neutrophilic and Eosinophilic Asthma","volume":"200","author":"Schleich","year":"2019","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"6862439","DOI":"10.1155\/2017\/6862439","article-title":"Hepatic Immune Microenvironment in Alcoholic and Nonalcoholic Liver Disease","volume":"2017","author":"Byun","year":"2017","journal-title":"Biomed. Res. Int."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"101833","DOI":"10.1016\/j.clinre.2021.101833","article-title":"Trans-Anethole Attenuates Diet-Induced Nonalcoholic Steatohepatitis through Suppressing TGF-\u03b2-Mediated Fibrosis","volume":"46","author":"Zhang","year":"2022","journal-title":"Clin. Res. Hepatol. Gastroenterol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1021\/np960012r","article-title":"Caparratriene, an Active Sesquiterpene Hydrocarbon from Ocotea Caparrapi","volume":"59","author":"Palomino","year":"1996","journal-title":"J. Nat. Prod."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"108027","DOI":"10.1016\/j.diabres.2020.108027","article-title":"Fasting C-Peptide Is a Significant Indicator of Nonalcoholic Fatty Liver Disease in Obese Children","volume":"160","author":"Han","year":"2020","journal-title":"Diabetes Res. Clin. Pract."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1016\/j.cccn.2005.03.038","article-title":"Fatty Acid Methyl Esters Are Detectable in the Plasma and Their Presence Correlates with Liver Dysfunction","volume":"359","author":"Aleryani","year":"2005","journal-title":"Clin. Chim. Acta"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"341","DOI":"10.3109\/00365521.2014.983160","article-title":"Characterization of Lean Patients with Nonalcoholic Fatty Liver Disease: Potential Role of High Hemoglobin Levels","volume":"50","author":"Akyuz","year":"2015","journal-title":"Scand. J. Gastroenterol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"577","DOI":"10.5604\/01.3001.0012.0920","article-title":"Association Between Serum Hemoglobin Levels and Non Alcoholic Fatty Liver Disease in a Mexican Population","volume":"17","author":"Uribe","year":"2018","journal-title":"Ann. Hepatol."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Gerber, Y., VanWagner, L.B., Yaffe, K., Terry, J.G., Rana, J.S., Reis, J.P., and Sidney, S. (2021). Non-Alcoholic Fatty Liver Disease and Cognitive Function in Middle-Aged Adults: The CARDIA Study. BMC Gastroenterol., 21.","DOI":"10.1186\/s12876-021-01681-0"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"905","DOI":"10.1016\/j.jhep.2018.06.023","article-title":"Urea Cycle Dysregulation in Non-Alcoholic Fatty Liver Disease","volume":"69","author":"Marrone","year":"2018","journal-title":"J. Hepatol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"717","DOI":"10.1093\/gerona\/glt152","article-title":"Branched Chain Amino Acids Are Associated with Muscle Mass in Functionally Limited Older Adults","volume":"69","author":"Lustgarten","year":"2014","journal-title":"J. Gerontol. A Biol. Sci. Med. Sci."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1159\/000090499","article-title":"Relationship between Insulin Resistance and Lipid Peroxidation and Antioxidant Vitamins in Hypercholesterolemic Patients","volume":"50","author":"Shin","year":"2006","journal-title":"Ann. Nutr. Metab."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1054","DOI":"10.1016\/j.cmet.2017.04.001","article-title":"Gut Microbiome-Based Metagenomic Signature for Non-Invasive Detection of Advanced Fibrosis in Human Nonalcoholic Fatty Liver Disease","volume":"25","author":"Loomba","year":"2017","journal-title":"Cell. Metab."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1014","DOI":"10.1136\/gutjnl-2017-315084","article-title":"Gut Microbiome Analysis as a Tool towards Targeted Non-Invasive Biomarkers for Early Hepatocellular Carcinoma","volume":"68","author":"Ren","year":"2019","journal-title":"Gut"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"934113","DOI":"10.3389\/fnut.2022.934113","article-title":"Gut Microbiota-Mitochondrial Inter-Talk in Non-Alcoholic Fatty Liver Disease","volume":"9","author":"Zhang","year":"2022","journal-title":"Front. Nutr."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1016\/j.tetlet.2004.11.120","article-title":"Self-Aldol Condensation of Unmodified Aldehyde in Supercritical Carbon Dioxide Catalyzed by Amine Grafted on Silica","volume":"46","author":"Hagiwara","year":"2005","journal-title":"Tetrahedron Lett."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Hasegawa, T., Iino, C., Endo, T., Mikami, K., Kimura, M., Sawada, N., Nakaji, S., and Fukuda, S. (2020). Changed Amino Acids in NAFLD and Liver Fibrosis: A Large Cross-Sectional Study without Influence of Insulin Resistance. Nutrients, 12.","DOI":"10.20944\/preprints202005.0127.v1"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"432","DOI":"10.1016\/j.jfda.2017.01.008","article-title":"Effects of Lemongrass Oil and Citral on Hepatic Drug-Metabolizing Enzymes, Oxidative Stress, and Acetaminophen Toxicity in Rats","volume":"26","author":"Li","year":"2018","journal-title":"J. Food Drug. Anal."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2062","DOI":"10.1021\/acs.jafc.5b06159","article-title":"Ginger Essential Oil Ameliorates Hepatic Injury and Lipid Accumulation in High Fat Diet-Induced Nonalcoholic Fatty Liver Disease","volume":"64","author":"Lai","year":"2016","journal-title":"J. Agric. Food Chem."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"e2104373","DOI":"10.1002\/advs.202104373","article-title":"Multiomics Analysis Reveals the Impact of Microbiota on Host Metabolism in Hepatic Steatosis","volume":"9","author":"Zeybel","year":"2022","journal-title":"Adv. Sci."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1007\/s11418-019-01363-y","article-title":"Bioconversion of Essential Oil Components of Perilla Frutescens by Saccharomyces Cerevisiae","volume":"74","author":"Kimura","year":"2020","journal-title":"J. Nat. Med."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"15587","DOI":"10.3390\/molecules181215587","article-title":"Antimicrobial and Antioxidant Activities and Effect of 1-Hexadecene Addition on Palmarumycin C2 and C3 Yields in Liquid Culture of Endophytic Fungus Berkleasmium Sp. Dzf12","volume":"18","author":"Mou","year":"2013","journal-title":"Molecules"}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/15\/11\/2457\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:41:35Z","timestamp":1760125295000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/15\/11\/2457"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,5,25]]},"references-count":48,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2023,6]]}},"alternative-id":["nu15112457"],"URL":"https:\/\/doi.org\/10.3390\/nu15112457","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,5,25]]}}}