{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T13:36:32Z","timestamp":1790775392735,"version":"4.1.0"},"reference-count":44,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2018,8,16]],"date-time":"2018-08-16T00:00:00Z","timestamp":1534377600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100011738","name":"Lee Kong Chian School of Medicine, Nanyang Technological University","doi-asserted-by":"publisher","award":["Start-Up Grant"],"award-info":[{"award-number":["Start-Up Grant"]}],"id":[{"id":"10.13039\/501100011738","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Interdisciplinary Graduate School, NITHM, Nanyang Technological University, Singapore.","award":["Bench Fees & Scholarship"],"award-info":[{"award-number":["Bench Fees & Scholarship"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Antibiotics lead to increased susceptibility to colonization by pathogenic organisms, with different effects on the host-microbiota relationship. Here, we show that metronidazole treatment of specific pathogen-free (SPF) mice results in a significant increase of the bacterial phylum Proteobacteria in fecal pellets. Furthermore, metronidazole in SPF mice decreases hind limb muscle weight and results in smaller fibers in the tibialis anterior muscle. In the gastrocnemius muscle, metronidazole causes upregulation of Hdac4, myogenin, MuRF1, and atrogin1, which are implicated in skeletal muscle neurogenic atrophy. Metronidazole in SPF mice also upregulates skeletal muscle FoxO3, described as involved in apoptosis and muscle regeneration. Of note, alteration of the gut microbiota results in increased expression of the muscle core clock and effector genes Cry2, Ror-\u03b2, and E4BP4. PPAR\u03b3 and one of its important target genes, adiponectin, are also upregulated by metronidazole. Metronidazole in germ-free (GF) mice increases the expression of other core clock genes, such as Bmal1 and Per2, as well as the metabolic regulators FoxO1 and Pdk4, suggesting a microbiota-independent pharmacologic effect. In conclusion, metronidazole in SPF mice results in skeletal muscle atrophy and changes the expression of genes involved in the muscle peripheral circadian rhythm machinery and metabolic regulation.<\/jats:p>","DOI":"10.3390\/ijms19082418","type":"journal-article","created":{"date-parts":[[2018,8,16]],"date-time":"2018-08-16T11:39:08Z","timestamp":1534419548000},"page":"2418","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":65,"title":["Metronidazole Causes Skeletal Muscle Atrophy and Modulates Muscle Chronometabolism"],"prefix":"10.3390","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1240-2771","authenticated-orcid":false,"given":"Ravikumar","family":"Manickam","sequence":"first","affiliation":[{"name":"Lee Kong Chian School of Medicine, Nanyang Technological University, 11 Mandalay Road, Singapore 308232, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0782-4099","authenticated-orcid":false,"given":"Hui Yun Penny","family":"Oh","sequence":"additional","affiliation":[{"name":"Lee Kong Chian School of Medicine, Nanyang Technological University, 11 Mandalay Road, Singapore 308232, Singapore"},{"name":"Interdisciplinary Graduate School, NTU Institute for Health Technologies, Nanyang Technological University, 50 Nanyang Avenue, Singapore 639798, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chek Kun","family":"Tan","sequence":"additional","affiliation":[{"name":"Lee Kong Chian School of Medicine, Nanyang Technological University, 11 Mandalay Road, Singapore 308232, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eeswari","family":"Paramalingam","sequence":"additional","affiliation":[{"name":"Lee Kong Chian School of Medicine, Nanyang Technological University, 11 Mandalay Road, Singapore 308232, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5966-9089","authenticated-orcid":false,"given":"Walter","family":"Wahli","sequence":"additional","affiliation":[{"name":"Lee Kong Chian School of Medicine, Nanyang Technological University, 11 Mandalay Road, Singapore 308232, Singapore"},{"name":"Center for Integrative Genomics, University of Lausanne, Le G\u00e9nopode, CH-1015 Lausanne, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2018,8,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1093\/toxsci\/kfw150","article-title":"From the cover: Exposure to oral antibiotics induces gut microbiota dysbiosis associated with lipid metabolism dysfunction and low-grade inflammation in mice","volume":"154","author":"Jin","year":"2016","journal-title":"Toxicol. 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