{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T07:44:27Z","timestamp":1793259867923,"version":"4.5.0"},"reference-count":30,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2025,10,30]],"date-time":"2025-10-30T00:00:00Z","timestamp":1761782400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Health and Medical Research Council, Australia (NHMRC) Investigator Grant","award":["2020\/GNT1194358"],"award-info":[{"award-number":["2020\/GNT1194358"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Gastrointestinal symptoms often persist in children with Hirschsprung\u2019s disease (HD) even after \u201ccorrective\u201d pull-through surgery. Alteration of the gut microbiota (\u201cdysbiosis\u201d) has emerged as a potential contributing factor. Animal studies show gut ecosystem changes that are both intrinsic to HD and caused by bowel resection itself, but human studies comparing the intestinal microbiota of children with HD and healthy children are limited. We collected food frequency dietary surveys, clinical and symptom data, and stool samples from 15 post-operative children with HD and 15 healthy controls (HCs). We performed 16S rRNA gene sequencing from the stool samples and quantified faecal calprotectin as a measure of gastrointestinal inflammation. Despite no global changes in the microbiota between HD and HC cohorts and no differences between individuals with and without a history of HD-associated enterocolitis (HAEC), we identified evidence of altered microbiota development and inflammatory trajectories in HD. In HCs, alpha diversity increased with age (r = 0.83, p &lt; 0.001), while calprotectin levels declined (Spearman\u2019s \u03c1 = \u22120.53, p = 0.04). These age-related patterns were absent in HD. Across the combined cohort, lower alpha diversity was associated with higher faecal calprotectin (Spearman\u2019s \u03c1 = \u22120.47, p = 0.01). In HD, Fusobacteria abundance showed a strong positive correlation with calprotectin (Spearman\u2019s \u03c1 = 0.76, adjusted p = 0.02). Pediatric Quality of Life (PedsQL) and gastrointestinal disease-specific symptom scores were lower in HD compared to HC but were not directly linked to microbial diversity or inflammation. Overall, we observed a divergence from healthy peers in the typical developmental trajectory of gut microbial communities and inflammation in children with HD that may involve Fusobacteria. Children with HD reported reduced health-related quality of life compared with HC, consistent with ongoing gastrointestinal symptoms. No microbiota differences were associated with HAEC history, though this may reflect limited sample size.<\/jats:p>","DOI":"10.3390\/ijms262110570","type":"journal-article","created":{"date-parts":[[2025,10,31]],"date-time":"2025-10-31T01:23:59Z","timestamp":1761873839000},"page":"10570","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Altered Development of Gut Microbiota and Gastrointestinal Inflammation in Children with Post-Operative Hirschsprung\u2019s Disease"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0216-6912","authenticated-orcid":false,"given":"Caitlin E.","family":"Murphy","sequence":"first","affiliation":[{"name":"School of Clinical Medicine, Discipline of Paediatrics and Child Health, UNSW Medicine and Health, University of New South Wales, Randwick 2052, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5543-9438","authenticated-orcid":false,"given":"Michael J.","family":"Coffey","sequence":"additional","affiliation":[{"name":"School of Clinical Medicine, Discipline of Paediatrics and Child Health, UNSW Medicine and Health, University of New South Wales, Randwick 2052, Australia"},{"name":"Department of Gastroenterology, Sydney Children\u2019s Hospital, Randwick 2031, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Quinlan","family":"Chen","sequence":"additional","affiliation":[{"name":"School of Clinical Medicine, Discipline of Paediatrics and Child Health, UNSW Medicine and Health, University of New South Wales, Randwick 2052, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan","family":"Adams","sequence":"additional","affiliation":[{"name":"School of Clinical Medicine, Discipline of Paediatrics and Child Health, UNSW Medicine and Health, University of New South Wales, Randwick 2052, Australia"},{"name":"Department of Paediatric Surgery, Sydney Children\u2019s Hospital, Randwick 2031, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chee Y.","family":"Ooi","sequence":"additional","affiliation":[{"name":"School of Clinical Medicine, Discipline of Paediatrics and Child Health, UNSW Medicine and Health, University of New South Wales, Randwick 2052, Australia"},{"name":"Department of Gastroenterology, Sydney Children\u2019s Hospital, Randwick 2031, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9353-8787","authenticated-orcid":false,"given":"Josie","family":"van Dorst","sequence":"additional","affiliation":[{"name":"School of Clinical Medicine, Discipline of Paediatrics and Child Health, UNSW Medicine and Health, University of New South Wales, Randwick 2052, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Salyer, S.W. (2007). Chapter 13\u2014Pediatric Emergencies: A. Emergencies and Resuscitations. Essential Emergency Medicine, W.B. Saunders.","DOI":"10.1016\/B978-141602971-7.10013-3"},{"key":"ref_2","unstructured":"Caballero, B., Finglas, P.M., and Toldr\u00e1, F. (2016). Colon: Diseases and Disorders. Encyclopedia of Food and Health, Academic Press."},{"key":"ref_3","unstructured":"Merrow, A.C., and Hariharan, S. (2018). Hirschsprung Disease. Imaging in Pediatrics, Elsevier."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2273","DOI":"10.1111\/j.1440-1746.2006.04750.x","article-title":"Long-term continence after surgery for Hirschsprung\u2019s disease","volume":"22","author":"Trajanovska","year":"2007","journal-title":"J. Gastroenterol. Hepatol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"622","DOI":"10.1097\/SLA.0000000000001695","article-title":"Bowel Function and Quality of Life After Transanal Endorectal Pull-through for Hirschsprung Disease: Controlled Outcomes up to Adulthood","volume":"265","author":"Neuvonen","year":"2017","journal-title":"Ann. Surg."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1055\/s-2008-1038325","article-title":"Quality of life of patients with Hirschsprung\u2019s disease at 5\u201320 years post pull-through operations","volume":"18","author":"Niramis","year":"2008","journal-title":"Eur. J. Pediatr. Surg."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Dai, Y., Deng, Y., Lin, Y., Ouyang, R., and Li, L. (2020). Long-term outcomes and quality of life of patients with Hirschsprung disease: A systematic review and meta-analysis. BMC Gastroenterol., 20.","DOI":"10.1186\/s12876-020-01208-z"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1002\/bjs.11059","article-title":"Long\u2013term functional outcomes and quality of life in patients with Hirschsprung\u2019s disease","volume":"106","author":"Meinds","year":"2019","journal-title":"Br. J. Surg."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Chantakhow, S., Khorana, J., Tepmalai, K., Boonchooduang, N., Chattipakorn, N., and Chattipakorn, S.C. (2021). Alterations of Gut Bacteria in Hirschsprung Disease and Hirschsprung-Associated Enterocolitis. Microorganisms, 9.","DOI":"10.3390\/microorganisms9112241"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"594","DOI":"10.1097\/MPG.0000000000001999","article-title":"Intestinal Microbiota in Hirschsprung Disease","volume":"67","author":"Neuvonen","year":"2018","journal-title":"J. Pediatr. Gastroenterol. Nutr."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1007\/s12519-009-0038-x","article-title":"Detection of intestinal bifidobacteria and lactobacilli in patients with Hirschsprung\u2019s disease associated enterocolitis","volume":"5","author":"Shen","year":"2009","journal-title":"World J. Pediatr."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1016\/j.jpedsurg.2020.06.018","article-title":"A piglet model of iatrogenic rectosigmoid hypoganglionosis reveals the impact of the enteric nervous system on gut barrier function and microbiota postnatal development","volume":"56","author":"Arnaud","year":"2021","journal-title":"J. Pediatr. Surg."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Tour\u00e9, A.M., Landry, M., Souchkova, O., Kembel, S.W., and Pilon, N. (2019). Gut microbiota-mediated Gene-Environment interaction in the TashT mouse model of Hirschsprung disease. Sci. Rep., 9.","DOI":"10.1038\/s41598-018-36967-z"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"874","DOI":"10.1111\/j.1365-2982.2012.01937.x","article-title":"Intestinal aganglionosis is associated with early and sustained disruption of the colonic microbiome","volume":"24","author":"Ward","year":"2012","journal-title":"Neurogastroenterol. Motil."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Hegde, S., Lin, Y.-M., Golovko, G., Khanipov, K., Cong, Y., Savidge, T., Fofanov, Y., and Shi, X.-Z. (2018). Microbiota dysbiosis and its pathophysiological significance in bowel obstruction. Sci. Rep., 8.","DOI":"10.1038\/s41598-018-31033-0"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Li, Y., Poroyko, V., Yan, Z., Pan, L., Feng, Y., Zhao, P., Xie, Z., and Hong, L. (2016). Characterization of Intestinal Microbiomes of Hirschsprung\u2019s Disease Patients with or without Enterocolitis Using Illumina-MiSeq High-Throughput Sequencing. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0162079"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1016\/j.bbrc.2014.01.104","article-title":"Characterization of the intestinal microbiome of Hirschsprung\u2019s disease with and without enterocolitis","volume":"445","author":"Yan","year":"2014","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/j.jcf.2017.07.011","article-title":"Age-related levels of fecal M2-pyruvate kinase in children with cystic fibrosis and healthy children 0 to 10 years old","volume":"17","author":"Garg","year":"2018","journal-title":"J. Cyst. Fibros."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1093\/ibd\/izac194","article-title":"Searching for a Consensus Among Inflammatory Bowel Disease Studies: A Systematic Meta-Analysis","volume":"29","author":"Morgan","year":"2023","journal-title":"Inflamm. Bowel Dis."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1186\/s12935-021-01886-z","article-title":"The dysbiosis signature of Fusobacterium nucleatum in colorectal cancer-cause or consequences? A systematic review","volume":"21","author":"Ranjbar","year":"2021","journal-title":"Cancer Cell Int."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Santoru, M.L., Piras, C., Murgia, A., Palmas, V., Camboni, T., Liggi, S., Ibba, I., Lai, M.A., Orr\u00f9, S., and Blois, S. (2017). Cross sectional evaluation of the gut-microbiome metabolome axis in an Italian cohort of IBD patients. Sci. Rep., 7, Erratum in Sci. Rep. 2018, 8, 4993. https:\/\/doi.org\/10.1038\/s41598-018-23330-5.","DOI":"10.1038\/s41598-017-10034-5"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Forbes, J.D., Chen, C.-y., Knox, N.C., Marrie, R.-A., El-Gabalawy, H., de Kievit, T., Alfa, M., Bernstein, C.N., and Van Domselaar, G. (2018). A comparative study of the gut microbiota in immune-mediated inflammatory diseases\u2014Does a common dysbiosis exist?. Microbiome, 6.","DOI":"10.1186\/s40168-018-0603-4"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"797","DOI":"10.1016\/j.clnu.2017.03.025","article-title":"A randomized trial to determine the impact of a digestion resistant starch composition on the gut microbiome in older and mid-age adults","volume":"37","author":"Alfa","year":"2018","journal-title":"Clin. Nutr."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1362","DOI":"10.3748\/wjg.v28.i13.1362","article-title":"Generic and disease-specific health-related quality of life in patients with Hirschsprung disease: A systematic review and meta-analysis","volume":"28","author":"Huizer","year":"2022","journal-title":"World J. Gastroenterol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"e033916","DOI":"10.1136\/bmjopen-2019-033916","article-title":"Evaluating the Alimentary and Respiratory Tracts in Health and disease (EARTH) research programme: A protocol for prospective, longitudinal, controlled, observational studies in children with chronic disease at an Australian tertiary paediatric hospital","volume":"10","author":"Coffey","year":"2020","journal-title":"BMJ Open"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2156254","DOI":"10.1080\/19490976.2022.2156254","article-title":"Diet and the gut-lung axis in cystic fibrosis\u2014Direct & indirect links. Gut Microbes","volume":"10","author":"McKay","year":"2023","journal-title":"Gut Microbes"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1456","DOI":"10.1053\/j.gastro.2016.02.015","article-title":"Childhood Functional Gastrointestinal Disorders: Child\/Adolescent","volume":"150","author":"Hyams","year":"2016","journal-title":"Gastroenterology"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1097\/MPG.0000000000000414","article-title":"PedsQL gastrointestinal symptoms module: Feasibility, reliability, and validity","volume":"59","author":"Varni","year":"2014","journal-title":"J. Pediatr. Gastroenterol. Nutr."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1186\/1479-5868-6-62","article-title":"Reproducibility and comparative validity of a food frequency questionnaire for Australian children and adolescents","volume":"6","author":"Watson","year":"2009","journal-title":"Int. J. Behav. Nutr. Phys. Act."},{"key":"ref_30","first-page":"507","article-title":"Frequency Distribution of the Values of the Correlation Coefficient in Samples from an Indefinitely Large Population","volume":"10","author":"Fisher","year":"1915","journal-title":"Biometrika"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/21\/10570\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,31]],"date-time":"2025-10-31T01:30:35Z","timestamp":1761874235000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/21\/10570"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,30]]},"references-count":30,"journal-issue":{"issue":"21","published-online":{"date-parts":[[2025,11]]}},"alternative-id":["ijms262110570"],"URL":"https:\/\/doi.org\/10.3390\/ijms262110570","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,30]]}}}