Dietary changes can prevent Hirschsprung disease symptoms

A multi-institutional study led by researchers at Children's Hospital of Philadelphia (CHOP) discovered for the first time that dietary interventions might prevent inflammatory symptoms associated with Hirschsprung disease, a bowel motility disorder. The findings were published today bDietary changesy the journal Gastroenterology.

Hirschsprung disease is a potentially life-threatening birth defect in which neurons of the enteric nervous system – the "brain" of the gut –do not form properly in the wall of the intestine and are completely missing at the end of the bowel. Children with Hirschsprung disease typically have severe constipation and difficulty passing stool and gas due to a functional obstruction caused by poor motility in the region lacking enteric neurons. Surgical intervention is required to treat the disease, but some children continue to have complications such as constipation and abdominal distension after surgery.

One dangerous complication of Hirschsprung disease is called Hirschsprung disease associated enterocolitis (HAEC). This complication was once thought to be due to the obstructive bowel process of the disease, but now thought to be caused by a combination of epithelial barrier dysfunction, abnormal bowel mucus production and altered gut microbes. However, even with an improved understanding of what underlies HAEC, it is still not known why some children with Hirschsprung get HAEC and others never do.

During HAEC episodes children may have bacteria move from inside the bowel into their bloodstream, putting them at risk for sepsis, which can be fatal. We have known about this for a long time, and yet it's still not very well understood."

Robert Heuckeroth, MD, PhD, senior study author, pediatric gastroenterologist in the Division of Gastroenterology, Hepatology and Nutrition at CHOP and Research Director and Norman and Irma Braman Endowed Chair of CHOP's Lustgarten Center for GI Motility

During an international collaboration with labs at Université du Québec à Montréal, researchers noticed that a preclinical model of Hirschsprung disease lived much longer at one institution than at another. The researchers decided to investigate this phenomenon because some children with Hirschsprung disease are very ill shortly after birth, but others appear well for months or years. The researchers reasoned that differences in the environment might explain the survival differences in the mouse model, and that similar mechanisms might underlie differences in symptom severity in children with Hirschsprung disease. After some investigation, they discovered that their HSCR animal model on a standard diet lived about three-times longer than when the same model was fed an alternative standard diet. This prompted the researchers to study how diet may influence symptoms and survival, a topic barely considered in the Hirschsprung disease literature.

Naomi E.B. Tjaden, MD, PhD, a pediatric gastroenterologist with the Division of Gastroenterology, Hepatology and Nutrition at CHOP and Megan Liou, PhD, a microbiologist in the Heuckeroth research group, led the study and found that the standard diet associated with shorter survival ("detrimental diet") induced microscopic and cellular changes in the colons of the animal models. The detrimental diet-fed models had lower levels of fecal butyrate – produced by beneficial gut microbes as they digest dietary fiber, resistant starch, and specific amino acids – compared with models fed a protective diet. Butyrate is a short-chain fatty acid that protects epithelial cells that line the colon, serving as an energy source and regulating gene expression.

The study team also discovered that detrimental diet-fed models had abnormal colon epithelial mitochondria – the "batteries" of cells – and abnormally elevated oxygen in colon epithelium. The high oxygen levels may eliminate some beneficial gut microbes and instead allow gut bacteria that tolerate high oxygen levels like Enterobacteriaceae to overgrow. The investigators discovered that the Hirschsprung models with high levels of Enterobacteriaceae in the stool rapidly develop colon inflammation. Eliminating Enterobacteriaceae prolonged Hirschsprung model survival.

"Our findings suggest unexpected similarities between mechanisms underlying inflammatory bowel disease (IBD) and Hirschsprung's disease," Heuckeroth said. "We know that diet can have a profound effect in the management of many diseases including IBD. Now there is an opportunity to explore diet connections to Hirschsprung disease, which we hope will lead to new diet-based therapy for affected children."