Dietary modulation of gut microbes extends survival in Hirschsprung disease mouse model

Diet may influence the severity of inflammatory complications in Hirschsprung disease (HSCR), according to preclinical findings published September 23, 2026, in Gastroenterology.¹ In a mouse model of HSCR, animals on one standard diet lived roughly 3 times longer than when the same model was fed an alternative standard diet, and investigators linked that gap to diet-driven changes in butyrate, colonic epithelial oxygen, and Enterobacteriaceae overgrowth.²

The work targets Hirschsprung-associated enterocolitis (HAEC), the most serious and common complication of HSCR and the leading cause of death in these patients.³ During HAEC episodes, children may "have bacteria move from inside the bowel into their bloodstream," raising the risk of fatal sepsis, said senior author Robert Heuckeroth, MD, PhD, a pediatric gastroenterologist in the Division of Gastroenterology, Hepatology and Nutrition at Children's Hospital of Philadelphia (CHOP) and research director of CHOP's Lustgarten Center for GI Motility.² He noted that the complication has long been recognized yet remains poorly understood.²

Burden of Hirschsprung disease and HAEC in children

HSCR occurs in approximately 1 in 5000 births³ and results from enteric neurons failing to form properly in the intestinal wall and being entirely absent at the distal bowel, causing functional obstruction.² Surgery is required, but some children continue to experience constipation and abdominal distension afterward.² A 2023 meta-analysis estimated preoperative and postoperative HAEC incidence at about 23% each, with recurrent HAEC in about 8%.³ A separate systematic review found that postoperative HAEC risk was comparable to preoperative risk regardless of surgical method or segment length.⁴

HAEC is now attributed to a combination of epithelial barrier dysfunction, abnormal mucus production, and altered gut microbes rather than obstruction alone, yet why some children develop it and others never do remains unknown.²

How diet altered butyrate, colonic oxygen, and Enterobacteriaceae in the HSCR model

The study began when collaborators at CHOP and Université du Québec à Montréal noticed that the same HSCR model survived much longer at one institution than the other.² Investigators reasoned that environmental differences might explain this, just as some children with HSCR are very ill shortly after birth while others appear well for months or years.²

Led by Naomi E. B. Tjaden, MD, PhD, and Megan Liou, PhD, the team found that mice on the diet associated with shorter survival showed microscopic and cellular colonic changes and lower fecal butyrate than mice on the protective diet.² Butyrate, a short-chain fatty acid produced as commensal microbes digest fiber, resistant starch, and certain amino acids, fuels and protects colonic epithelial cells and regulates gene expression.²

Mice on the detrimental diet also had abnormal colonic epithelial mitochondria and abnormally high epithelial oxygen, which may deplete beneficial microbes and allow oxygen-tolerant Enterobacteriaceae to overgrow.² Animals with high fecal Enterobacteriaceae rapidly developed colitis, and eliminating these bacteria prolonged survival.²

Parallels between Hirschsprung disease and inflammatory bowel disease

Heuckeroth said the findings suggest unexpected mechanistic similarities between inflammatory bowel disease (IBD) and HSCR, noting that diet already has a substantial role in managing conditions such as IBD.² The group hopes the work will lead to diet-based therapy for affected children.²

Limitations of the preclinical Hirschsprung disease data

All findings come from mice. The press release does not specify the composition of the 2 diets, how Enterobacteriaceae were eliminated, or how the results might apply to infant feeding with breast milk or formula. No clinical trial has tested dietary modification to prevent HAEC in children. Until human data are available, the results are best viewed as hypothesis-generating rather than grounds for changing nutritional management in patients with HSCR.

References

1. Tjaden NEB, Liou M, et al. Dietary modulation of intestinal microbes prolongs survival in a Hirschsprung disease mouse model. Gastroenterology. Published online September 23, 2026. doi:10.1053/j.gastro.2026.09.007

2. Children's Hospital of Philadelphia researchers find dietary interventions may prevent inflammatory symptoms associated with Hirschsprung disease. News release. Children's Hospital of Philadelphia. September 23, 2026. Accessed September 24, 2026. https://www.eurekalert.org/news-releases/1144954

3. Zhang X, Sun D, Xu Q, et al. Risk factors for Hirschsprung disease-associated enterocolitis: a systematic review and meta-analysis. Int J Surg. 2023. doi:10.1097/JS9.0000000000000473

4. Hagens J, Reinshagen K, Tomuschat C. Prevalence of Hirschsprung-associated enterocolitis in patients with Hirschsprung disease. Pediatr Surg Int. Published online September 30, 2021. doi:10.1007/s00383-021-05020-y