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Chondroitin sulfate (CS) is a naturally occurring glycosaminoglycan (GAG) in human breast milk (HM) and has been shown to reduce inflammation. We hypothesized that supplementation with CS in an experimental NEC model would alter microbial diversity, favorably alter the cytokine profile, and (like other sulfur compounds) improve outcomes in experimental NEC via the eNOS pathway. NEC was induced in 5\u2010day\u2010old pups. Six groups were studied (<jats:italic>n<\/jats:italic>\u2009=\u20099\u201315\/group): (1) WT breastfed and (2) Formula fed controls, (3) WT NEC, (4) WT NEC\u2009+\u2009CS, (5) eNOS KO (knockout) NEC, and (6) eNOS KO NEC\u2009+\u2009CS. Pups were monitored for clinical sickness score and weights. On postnatal day 9, the pups were killed. Stool was collected from rectum and microbiome analysis was done with 16\u2009s rRNA sequencing. Intestinal segments were examined histologically using a well\u2010established injury scoring system and segments were homogenized and analyzed for cytokine profile. Data were analyzed using GraphPad Prism with <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05 considered significant. CS supplementation in formula improved experimental NEC outcomes when compared to NEC alone. CS supplementation resulted in similar improvement in NEC in both the WT and eNOS KO mice. CS supplementation did not result in microbial changes when compared to NEC alone. Our data suggest that although CS supplementation improved outcomes in NEC, this protection is not conferred via the eNOS pathway or alteration of microbial diversity. CS therapy in NEC does improve the intestinal cytokine profile and further experiments will explore the mechanistic role of CS in altering immune pathways in this disease.<\/jats:p>","DOI":"10.14814\/phy2.15819","type":"journal-article","created":{"date-parts":[[2023,9,12]],"date-time":"2023-09-12T03:10:10Z","timestamp":1694488210000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Chondroitin sulfate supplementation improves clinical outcomes in a murine model of necrotizing enterocolitis"],"prefix":"10.14814","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3576-8584","authenticated-orcid":false,"given":"Krishna","family":"Manohar","sequence":"first","affiliation":[{"name":"Department of Surgery Indiana University School of Medicine (IUSM)  Indianapolis Indiana USA"},{"name":"Riley Hospital for Children at Indiana University Health  Indianapolis Indiana 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