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However, there have been no investigations regarding the comparative effects that the microbiome may have on RmTBI in adolescents and adults. Therefore, we examined the influence of microbiome depletion prior to RmTBI on microbial composition and metabolome, in adolescent and adult Sprague Dawley rats. Rats were randomly assigned to standard or antibiotic drinking water for 14 days, and to subsequent sham or RmTBIs. The gut microbiome composition and metabolome were analysed at baseline, 1 day after the first mTBI, and at euthanasia (11 days following the third mTBI). At euthanasia, intestinal samples were also collected to quantify tight junction protein (<jats:italic>TJP1<\/jats:italic> and <jats:italic>occludin<\/jats:italic>) expression. Adolescents were significantly more susceptible to microbiome depletion via antibiotic administration which increased pro-inflammatory composition and metabolites. Furthermore, RmTBI induced a transient increase in \u2018beneficial bacteria\u2019 (<jats:italic>Lachnospiraceae<\/jats:italic> and <jats:italic>Faecalibaculum<\/jats:italic>) in only adolescents that may indicate compensatory action in response to the injury. Finally, microbiome depletion prior to RmTBI generated a microbiome composition and metabolome that exemplified a potentially chronic pathogenic and inflammatory state as demonstrated by increased <jats:italic>Clostridium innocuum<\/jats:italic> and <jats:italic>Erysipelatoclostridium<\/jats:italic> and reductions in <jats:italic>Bacteroides and Clostridium Sensu Stricto<\/jats:italic>. Results highlight that adolescents are more vulnerable to RmTBI compared to adults and dysbiosis prior to injury may exacerbate secondary inflammatory cascades.<\/jats:p>","DOI":"10.1371\/journal.pone.0278259","type":"journal-article","created":{"date-parts":[[2022,11,30]],"date-time":"2022-11-30T18:35:30Z","timestamp":1669833330000},"page":"e0278259","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":22,"title":["Age matters: Microbiome depletion prior to repeat mild traumatic brain injury differentially alters microbial composition and function in adolescent and adult rats"],"prefix":"10.1371","volume":"17","author":[{"given":"Marissa","family":"Sgro","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"Iacono","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Glenn R.","family":"Yamakawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zoe N.","family":"Kodila","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin J.","family":"Marsland","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5291-5083","authenticated-orcid":true,"given":"Richelle","family":"Mychasiuk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2022,11,30]]},"reference":[{"issue":"12","key":"pone.0278259.ref001","doi-asserted-by":"crossref","first-page":"987","DOI":"10.1016\/S1474-4422(17)30371-X","article-title":"Traumatic brain injury: integrated approaches to improve prevention, clinical care, and research","volume":"16","author":"AIR Maas","year":"2017","journal-title":"Lancet Neurol"},{"issue":"1","key":"pone.0278259.ref002","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1080\/02699052.2017.1380228","article-title":"Repeated mild traumatic brain injury produces neuroinflammation, anxiety-like behaviour and impaired spatial memory in mice","volume":"32","author":"JI Broussard","year":"2018","journal-title":"Brain Inj"},{"issue":"8","key":"pone.0278259.ref003","doi-asserted-by":"crossref","first-page":"1353","DOI":"10.1089\/neu.2008.0858","article-title":"Traumatic brain injury and intestinal dysfunction: uncovering the neuro-enteric axis","volume":"26","author":"V Bansal","year":"2009","journal-title":"J Neurotrauma"},{"issue":"9","key":"pone.0278259.ref004","doi-asserted-by":"crossref","first-page":"1543","DOI":"10.1093\/jn\/nxz105","article-title":"Lactobacillus acidophilus Exerts Neuroprotective Effects in Mice with Traumatic Brain Injury","volume":"149","author":"Y Ma","year":"2019","journal-title":"The Journal of Nutrition"},{"issue":"12","key":"pone.0278259.ref005","doi-asserted-by":"crossref","first-page":"2776","DOI":"10.3748\/wjg.v9.i12.2776","article-title":"Alterations of intestinal mucosa structure and barrier function following traumatic brain injury in rats","volume":"9","author":"CH Hang","year":"2003","journal-title":"World J Gastroenterol"},{"issue":"3","key":"pone.0278259.ref006","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1542\/peds.2010-2005","article-title":"American Academy of Pediatrics. 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