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Children with Hirschsprung disease exhibited alterations in host–microbial co-metabolism after pull-through operation

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Abstract

Purpose

This study aims to compare the fecal metabolome in post pull-through HD with and without HAEC patients and healthy young children using nuclear magnetic resonance (NMR) spectroscopy.

Methods

Fresh fecal samples were collected from children under 5 years of age in both post-pull-through HD patients and healthy Thai children. A total of 20 fecal samples were then analyzed using NMR spectroscopy.

Results

Thirty-four metabolites identified among HD and healthy children younger than 5 years were compared. HD samples demonstrated a significant decrease in acetoin, phenylacetylglutamine, and N-acetylornithine (corrected p value = 0.01, 0.04, and 0.004, respectively). Succinate and xylose significantly decreased in HD with HAEC group compared to HD without HAEC group (corrected p value = 0.04 and 0.02, respectively). Moreover, glutamine and glutamate metabolism, and alanine, aspartate, and glutamate metabolism were the significant pathways involved, with pathway impact 0.42 and 0.50, respectively (corrected p value = 0.02 and 0.04, respectively).

Conclusion

Differences in class, quantity, and metabolism of protein and other metabolites in young children with HD after pull-through operation were identified. Most of the associated metabolic pathways were correlated with the amino acids metabolism, which is required to maintain intestinal integrity and function.

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Data availability

Data can be accessed at Open Science Framework (https://osf.io/bvs96/).

References

  1. Nicholson JK, Lindon JC (2008) Metabonomics. Nature 455:1054–1056

    Article  CAS  PubMed  Google Scholar 

  2. Nicholson JK, Holmes E, Kinross J, Burcelin R, Gibson G, Jia W, Pettersson S (2012) Host-gut microbiota metabolic interactions. Science 336:1262–1267. https://doi.org/10.1126/science.1223813

    Article  CAS  PubMed  Google Scholar 

  3. Chang PV, Hao L, Offermanns S, Medzhitov R (2014) The microbial metabolite butyrate regulates intestinal macrophage function via histone deacetylase inhibition. Proc Natl Acad Sci 111:2247–2252. https://doi.org/10.1073/pnas.1322269111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Demehri FR, Frykman PK, Cheng Z, Ruan C, Wester T, Nordenskjöld A, Kawaguchi A et al (2016) Altered fecal short chain fatty acid composition in children with a history of Hirschsprung-associated enterocolitis. J Pediatr Surg 51:81–86. https://doi.org/10.1016/j.jpedsurg.2015.10.012

    Article  PubMed  Google Scholar 

  5. Phetcharaburanin J, Lees H, Marchesi JR, Nicholson JK, Holmes E, Seyfried F, Li JV (2016) Systemic characterization of an obese phenotype in the zucker rat model defining metabolic axes of energy metabolism and host-microbial interactions. J Proteome Res 15:1897–1906. https://doi.org/10.1021/acs.jproteome.6b00090

    Article  CAS  PubMed  Google Scholar 

  6. Sengupta A, Ghosh S, Basant A, Malusare S, Johri P, Pathak S, Sharma S, Sonawat HM (2011) Global host metabolic response to Plasmodium vivax infection: a 1H NMR based urinary metabonomic study. Malar J 10:1–13. https://doi.org/10.1186/1475-2875-10-384

    Article  Google Scholar 

  7. Thompson GN, Walter JH, Bresson JL, Ford GC, Lyonnet SL, Chalmers RA, Saudubray JM et al (1990) Sources of propionate in inborn errors of propionate metabolism. Metabolism 39:1133–1137. https://doi.org/10.1016/0026-0495(90)90084-P

    Article  CAS  PubMed  Google Scholar 

  8. Wang Y, Christopher BA, Wilson KA, Muoio D, McGarrah RW, Brunengraber H, Zhang GF (2018) Propionate-induced changes in cardiac metabolism, notably CoA trapping, are not altered by l-carnitine. Am J Physiol Endocrinol Metab 315:E622–E633

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Chen L, Zhou L, Chan ECY, Neo J, Beuerman RW (2011) Characterization of the human tear metabolome by LC–MS/MS. J Proteome Res 10:4876–4882. https://doi.org/10.1021/pr2004874

    Article  CAS  PubMed  Google Scholar 

  10. Larsson JMH, Karlsson H, Sjövall H, Hansson GC (2009) A complex, but uniform O-glycosylation of the human MUC2 mucin from colonic biopsies analyzed by nano LC/MSn. Glycobiology 19:756–766. https://doi.org/10.1093/glycob/cwp048

    Article  CAS  PubMed  Google Scholar 

  11. Ten-Doménech I, Ramos-Garcia V, Piñeiro-Ramos JD, Gormaz M, Parra-Llorca A, Vento M, Kuligowski J, Quintás G (2020) Current practice in untargeted human milk metabolomics. Metabolites 10:43. https://doi.org/10.3390/metabo10020043

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Pini Prato A, Gentilino V, Giunta C, Avanzini S, Parodi S, Mattioli G, Martucciello G, Jasonni V (2008) Hirschsprung’s disease: 13 Years’ experience in 112 patients from a single institution. Pediatr Surg Int 24:175–182. https://doi.org/10.1007/s00383-007-2089-1

    Article  PubMed  Google Scholar 

  13. Pastor AC, Osman F, Teitelbaum DH, Caty MG, Langer JC (2009) Development of a standardized definition for Hirschsprung’s-associated enterocolitis: a Delphi analysis. J Pediatr Surg 44:251–256. https://doi.org/10.1016/j.jpedsurg.2008.10.052

    Article  PubMed  Google Scholar 

  14. EssamElhalaby BA, Coran AG, Blane CE, Hirschl RB, Teitelbaum Ann Arbor DH (1995) Enterocolitis associated with Hirschsprung’s disease: a clinical-radiological characterization based on 168 patients. J Pediatr Surg 30:76–83

    Article  Google Scholar 

  15. Menezes M, Puri P (2006) Long-term outcome of patients with enterocolitis complicating Hirschsprung’s disease. Pediatr Surg Int 22:316–318. https://doi.org/10.1007/s00383-006-1639-2

    Article  PubMed  Google Scholar 

  16. Minford JL, Ram A, Turnock RR, Lamont GL, Kenny SE, Rintala RJ, Lloyd DA, Baillie CT (2004) Comparison of functional outcomes of Duhamel and transanal endorectal coloanal anastomosis for Hirschsprung’s disease. J Pediatr Surg 39:161–165. https://doi.org/10.1016/j.jpedsurg.2003.10.004

    Article  CAS  PubMed  Google Scholar 

  17. Suita S, Taguchi T, Ieiri S, Nakatsuji T (2005) Hirschsprung’s disease in Japan: analysis of 3852 patients based on a nationwide survey in 30 years. J Pediatr Surg 40:197–202. https://doi.org/10.1016/j.jpedsurg.2004.09.052

    Article  PubMed  Google Scholar 

  18. Marty TL, Seo T, Sullivan JJ, Matlak ME, Black RE, Johnson DG (1995) Rectal irrigations for the prevention of postoperative enterocolitis in Hirschsprung’s disease. J Pediatr Surg 30:652–654. https://doi.org/10.1016/0022-3468(95)90681-9

    Article  CAS  PubMed  Google Scholar 

  19. Neuvonen MI, Korpela K, Kyrklund K, Salonen A, de Vos W, Rintala RJ et al (2018) Intestinal microbiota in Hirschsprung disease. J Pediatr Gastroenterol Nutr 67:594–600. https://doi.org/10.1097/MPG.0000000000001999

    Article  PubMed  Google Scholar 

  20. Prato PA, Cavalieri D, Bartow-McKenney C, Hudspeth K, Mosconi M, Rossi V, Avanzini S et al (2019) A metagenomics study on Hirschsprung’s disease associated enterocolitis: biodiversity and gut microbial homeostasis depend on resection length and patient’s clinical history. Front Pediatr 1:326. https://doi.org/10.3389/fped.2019.00326

    Article  Google Scholar 

  21. Aworanti O, Hung J, McDowell D, Martin I, Quinn F (2013) Are routine dilatations necessary post pull-through surgery for Hirschsprung disease? Eur J Pediatr Surg 23:383–388. https://doi.org/10.1055/s-0033-1333635

    Article  PubMed  Google Scholar 

  22. Roorda D, Abeln ZA, Oosterlaan J, Van Heurn LW, Derikx JM (2019) Botulinum toxin injections after surgery for Hirschsprung disease: systematic review and meta-analysis. World J Gastroenterol 25:3268–3280. https://doi.org/10.3748/wjg.v25.i25.3268

    Article  PubMed  PubMed Central  Google Scholar 

  23. AladdeinMattar BF, Coran AG, Teitelbaum Ann Arbor DH (2003) MUC-2 mucin production in Hirschsprung’s disease: possible association with enterocolitis development. J Pediatr Surg. https://doi.org/10.1053/jpsu.2003.50071

    Article  Google Scholar 

  24. Aslam A, Spicer RD, Corfield AP (1997) Children with Hirschsprung’s disease have an abnormal colonic mucus defensive barrier independent of the bowel innervation status. J Pediatr Surg 32:1206–1210

    Article  CAS  PubMed  Google Scholar 

  25. Cheng Z, Zhao L, Dhall D, Ruegger PM, Borneman J, Frykman PK, Zani A et al (2018) Bacterial microbiome dynamics in post pull-through Hirschsprung-associated enterocolitis (HAEC): an experimental study employing the endothelin receptor B-null mouse model. Front Surg. https://doi.org/10.3389/fsurg.2018.00030

    Article  PubMed  PubMed Central  Google Scholar 

  26. Nakamura H, O’Donnell AM, Marayati NF, Tomuschat C, Coyle D, Puri P (2019) Altered expression of inflammasomes in Hirschsprung’s disease. Pediatr Surg Int 35:15–20. https://doi.org/10.1007/s00383-018-4371-9

    Article  PubMed  Google Scholar 

  27. Shen DH, Shi CR, Chen JJ, Yu SY, Wu Y, Yan WB (2009) Detection of intestinal bifidobacteria and lactobacilli in patients with Hirschsprung’s disease associated enterocolitis. World J Pediatr. https://doi.org/10.1007/s12519-009-0038-x

    Article  PubMed  Google Scholar 

  28. Plekhova V, De Paepe E, Van Renterghem K, Van Winckel M, Hemeryck LY, Vanhaecke L (2021) Disparities in the gut metabolome of post-operative Hirschsprung’s disease patients. Sci Rep 11:1–10. https://doi.org/10.1038/s41598-021-95589-0

    Article  CAS  Google Scholar 

  29. Tang W, Su Y, Yuan C, Zhang Y, Zhou L, Peng L, Wang P et al (2020) Prospective study reveals a microbiome signature that predicts the occurrence of post-operative enterocolitis in Hirschsprung disease (HSCR) patients. Gut Microbes 00:1–13. https://doi.org/10.1080/19490976.2020.1711685

    Article  Google Scholar 

  30. Gratton J, Phetcharaburanin J, Mullish BH, Williams HRT, Thursz M, Nicholson JK et al (2016) Optimized sample handling strategy for metabolic profiling of human feces. Anal Chem 88:4661–4668. https://doi.org/10.1021/acs.analchem.5b04159

    Article  CAS  PubMed  Google Scholar 

  31. Wishart DS, Feunang YD, Marcu A, Guo AC, Liang K, Vázquez-Fresno R, Sajed T et al (2018) HMDB 4.0: the human metabolome database for 2018. Nucleic Acids Res 46:D608–D617. https://doi.org/10.1093/nar/gkx1089

    Article  CAS  PubMed  Google Scholar 

  32. Wishart DS, Jewison T, Guo AC, Wilson M, Knox C, Liu Y, Djoumbou Y et al (2012) HMDB 3.0—the human metabolome database in 2013. Nucleic Acids Res 41:D801–D807. https://doi.org/10.1093/nar/gks1065

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Wishart DS, Knox C, Guo AC, Eisner R, Young N, Gautam B, Hau DD et al (2009) HMDB: a knowledgebase for the human metabolome. Nucleic Acids Res 37:D603–D610. https://doi.org/10.1093/nar/gkn810

    Article  CAS  PubMed  Google Scholar 

  34. Wishart DS, Tzur D, Knox C, Eisner R, Guo AC, Young N, Cheng D et al (2007) HMDB: the human metabolome database. Nucleic Acids Res 35:D521–D526. https://doi.org/10.1093/nar/gkl923

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Maukonen J (2012) Characterization of the human predominant fecal microbiota: with special focus on the clostridial clusters IV and XIVa. Dissertation, the aalto university school of chemical technology Finland

  36. Shimshoni E, Ghini V, Solomonov I, Luchinat C, IritSagi PT (2020) Integrated metabolomics and proteomics of symptomatic and early pre-symptomatic states of colitis. BioRxiv. https://doi.org/10.1101/2020.03.22.002196

    Article  Google Scholar 

  37. Garner CE, Smith S, de Lacy CB, White P, Spencer R, Probert CSJ, Ratcliffe NM (2007) Volatile organic compounds from feces and their potential for diagnosis of gastrointestinal disease. FASEB J 21:1675–1688. https://doi.org/10.1096/fj.06-6927com

    Article  CAS  PubMed  Google Scholar 

  38. Walker V, Mills GA, Hall MA, Lowes JA (1989) Carbohydrate fermentation by gut microflora in preterm neonates. Arch Dis Child 64:1367–1373. https://doi.org/10.1136/adc.64.10_spec_no.1367

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Austin KM (2012) The pathogenesis of Hirschsprung’s disease-associated enterocolitis. Semin Pediatr Surg 21:319–327. https://doi.org/10.1053/j.sempedsurg.2012.07.006

    Article  PubMed  Google Scholar 

  40. Moldave K, Meister A (1957) Synthesis of phenykacetylglutamine by human tissue. J Biol Chem 229:463–476

    Article  CAS  PubMed  Google Scholar 

  41. Nemet I, Saha PP, Gupta N, Zhu W, Romano KA, Skye SM, Cajka T et al (2020) A cardiovascular disease-linked gut microbial metabolite acts via adrenergic receptors. Cell 180:862-877.e22. https://doi.org/10.1016/j.cell.2020.02.016

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Yu F, Feng X, Li X, Luo Y, Wei M, Zhao T, Xia J (2021) Gut-derived metabolite phenylacetylglutamine and white matter hyperintensities in patients with acute ischemic stroke. Front Aging Neurosci. https://doi.org/10.3389/fnagi.2021.675158

    Article  PubMed  PubMed Central  Google Scholar 

  43. Goedert JJ, Sampson JN, Moore SC, Xiao Q, Xiong X, Hayes RB, Ahn J et al (2014) Fecal metabolomics: assay performance and association with colorectal cancer. Carcinogenesis 35:2089–2096. https://doi.org/10.1093/carcin/bgu131

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Ohkohchi N, Himukai M, Igarashi Y, Kasai M (1986) Mechanism of D-xylose transport in human small intestine. J Pediatr Gastroenterol Nutr 5:372–378. https://doi.org/10.1097/00005176-198605000-00006

    Article  CAS  PubMed  Google Scholar 

  45. Ehrenpreis ED, Salvino M, Craig RM (2001) Improving the serum D-xylose test for the identification of patients with small intestinal malabsorption. J Clin Gastroenterol 33:36–40. https://doi.org/10.1097/00004836-200107000-00009

    Article  CAS  PubMed  Google Scholar 

  46. Lerch MM, Braun J, Harder M, Hofstaädter F, Schumpelick V, Matern S, Biochem D (1989) Postoperative adaptation of the small intestine after total colectomy and J-pouch-anal anastomosis. Dis Colon Rectum 32:600–608. https://doi.org/10.1007/BF02554181

    Article  CAS  PubMed  Google Scholar 

  47. Macias-Ceja DC, Ortiz-Masiá D, Salvador P, Gisbert-Ferrándiz L, Hernández C, Hausmann M, Rogler G, Esplugues JV et al (2018) Succinate receptor mediates intestinal inflammation and fibrosis. Mucosal Immunol 121(12):178–187. https://doi.org/10.1038/s41385-018-0087-3

    Article  CAS  Google Scholar 

  48. Ooi M, Nishiumi S, Yoshie T, Shiomi Y, Kohashi M, Fukunaga K, Nakamura S et al (2011) GC/MS-based profiling of amino acids and TCA cycle-related molecules in ulcerative colitis. Inflamm Res 60:831–840. https://doi.org/10.1007/S00011-011-0340-7/FIGURES/2

    Article  CAS  PubMed  Google Scholar 

  49. Banerjee A, Herring CA, Chen B, Kim H, Simmons AJ, Southard-Smith AN, Allaman MM et al (2020) Succinate produced by intestinal microbes promotes specification of tuft cells to suppress ileal inflammation. Gastroenterology 159:2101-2115.e5. https://doi.org/10.1053/j.gastro.2020.08.029

    Article  CAS  PubMed  Google Scholar 

  50. Tedelind S, Westberg F, Kjerrulf M, Vidal A (2007) Anti-inflammatory properties of the short-chain fatty acids acetate and propionate: a study with relevance to inflammatory bowel disease. World J Gastroenterol 28:2826–2832

    Article  Google Scholar 

  51. Segain JP, Raingeard de la Blétière D, Bourreille A, Leray V, Gervois N, Rosales C et al (2000) Butyrate inhibits inflammatory responses through NFkappaB inhibition: implications for Crohn’s disease. Gut 47:397–403

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Wu G (2010) Functional amino acids in growth, reproduction, and health. Adv Nutr 1:31–37. https://doi.org/10.3945/an.110.1008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Wu G, Wu Z, Dai Z, Yang Y, Wang W, Liu C, Wang B et al (2013) Dietary requirements of “nutritionally non-essential amino acids” by animals and humans. Amino Acids 44:1107–1113. https://doi.org/10.1007/s00726-012-1444-2

    Article  CAS  PubMed  Google Scholar 

  54. Yan Z, Poroyko V, Gu S, Zhang Z, Pan L, Wang J et al (2014) Characterization of the intestinal microbiome of Hirschsprung’s disease with and without enterocolitis. Biochem Biophys Res Commun 445:269–274. https://doi.org/10.1016/j.bbrc.2014.01.104

    Article  CAS  PubMed  Google Scholar 

  55. Chong PP, Chieng D-S, Lee Yean Low AH, Shamsudin MN, HFS and KPN, (2006) Recurrent candidaemia in a neonate with Hirschsprung’s disease: fluconazole resistance and genetic relatedness of eight Candida tropicalis isolates. J Med Microbiol 55:423–428. https://doi.org/10.1099/jmm.0.46045-0

    Article  CAS  PubMed  Google Scholar 

  56. Mellon AF, Deshpande SA, Mathers JC, Bartlett K (2000) Effect of oral antibiotics on intestinal production of propionic acid. Arch Dis Child 82:169–172. https://doi.org/10.1136/adc.82.2.169

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Mullish BH, McDonald JAK, Thursz MR, Marchesi JR (2018) Antibiotic-associated disruption of microbiota composition and function in cirrhosis is restored by fecal transplant. Hepatology 68:1205. https://doi.org/10.1002/hep.30037

    Article  CAS  PubMed  Google Scholar 

  58. Lee E, Shin A, Jeong K-W, Jin B, Jnawali HN, Shin S et al (2014) Role of phenylalanine and valine10 residues in the antimicrobial activity and cytotoxicity of piscidin-1. PLoS ONE 9:e114453. https://doi.org/10.1371/journal.pone.0114453

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Jiang M, Gong Q-Y, Lai S-S, Cheng Z-X, Chen Z-G, Zheng J et al (2019) Phenylalanine enhances innate immune response to clear ceftazidime-resistant Vibrio alginolyticus in Danio rerio. Fish Shellfish Immunol 84:912–919. https://doi.org/10.1016/j.fsi.2018.10.071

    Article  CAS  PubMed  Google Scholar 

  60. Allison C, Macfarlane GT (1989) Influence of pH, nutrient availability, and growth rate on amine production by Bacteroides fragilis and Clostridium perfringens. Appl Environ Microbiol 55:2894–2898. https://doi.org/10.1128/aem.55.11.2894-2898.1989

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported by grants from Faculty of Medicine, Khon Kaen University (Grant No. IN63253) to Kanokrat Thaiwatcharamas and Thailand Science Research and Innovation (TSRI) to Watcharin Loilome.

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Faculty of Medicine, Khon Kaen University, IN63253, Thailand Science Research and Innovation.

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K.T., W.L., J.P., P.T., and P.K. made substantial contributions to the conception and design of the work. K.T. and J.P. made substantial contributions to the acquisition of data, analysis, and interpretation of data. J.P. and P.H. made substantial contributions to the analysis of data and the creation of new software used in the work. K.T., J.P., S.C., and W.L. drafted the work or revised it critically for important intellectual content. K.T. wrote the main manuscript text. J.P. and P.H. prepared figures 1-6. All authors reviewed the manuscript.

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Correspondence to Jutarop Phetcharaburanin.

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Thaiwatcharamas, K., Loilome, W., Ho, P.N. et al. Children with Hirschsprung disease exhibited alterations in host–microbial co-metabolism after pull-through operation. Pediatr Surg Int 40, 87 (2024). https://doi.org/10.1007/s00383-024-05667-3

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