Newly Identified Enteric Nervous System Precursors in the Mesentery Make One Skip, But Not For Joy!

In 1888 Harald Hirschsprung described 2 children who had marked abdominal distention and severe chronic constipation, unresponsive to therapy. Unfortunately, these children became emaciated, developed diarrhea, and died by 1 year of age, probably from what is now called Hirschsprung disease–associated enterocolitis. At autopsy, their colon was markedly dilated, thick, and ulcerated. In 1949 Orvar Swenson, Harold Rheinlander, and Israel Diamond demonstrated that people with Hirschsprung disease lack enteric neurons in the distal colon and that the region without neurons was narrow and did not have propagated contractions. Since 1954 there have been sporadic reports of skip segment Hirschsprung disease. Skip segment Hirschsprung disease refers to bowel regions with enteric nervous system ganglia that are surrounded by otherwise aganglionic intestine (ie, bowel where enteric nervous system is absent).

The primary treatment for Hirschsprung disease is removal of distal bowel that lacks enteric nervous system. To distinguish aganglionic bowel from enteric nervous system–containing bowel, surgeons take small biopsies in many sites starting in distal colon. When a region with enteric ganglia is discovered, the usual assumption is that more proximal bowel also contains enteric nervous system. Because there is a low enteric nervous system density “transition zone” between aganglionic bowel and “normal” enteric nervous system–containing bowel, it is recommended that surgeons resect aganglionic bowel starting at least 5 cm proximal to the most distal enteric nervous system–containing biopsy. Although surgery is life-saving, obstructive symptoms and enterocolitis (explosive diarrhea and bowel inflammation) are common after surgery, a problem often attributed to incomplete removal of the transition zone. In some cases, however, repeat biopsy demonstrates a region where the enteric nervous system is completely absent, leading to redo surgery to resect more aganglionic bowel. The reasons for retained aganglionic bowel in some children after surgery are not well understood, but 1 possibility is skip segment Hirschsprung disease.

A recent article in Cellular and Molecular Gastroenterology and Hepatology by Yu et al provides remarkable new insight into skip segment Hirschsprung disease by examining human colon resected from children with Hirschsprung disease and using mouse models. Table 1 summarizes the prior literature, which includes only 34 human skip segment Hirschsprung disease case reports. The authors then used the “Swiss-roll” technique to examine colon removed from 183 children with Hirschsprung disease and discovered 2 additional skip segment Hirschsprung disease cases (1.09% incidence). I do not know of any similar large series examining human Hirschsprung resection specimens to look for skip segment Hirschsprung disease. A separate large cohort would be valuable to confirm the 1% incidence of skip segment Hirschsprung disease and to more definitively characterize skip segment Hirschsprung disease pathology. For example, because tissue is sectioned it is not easy to tell if there are only a few ganglia or if there are much larger regions of enteric nervous system–containing bowel within the skip segment.

The mouse model studies by Yu et al include several novel observations. First, using Wnt1 to drive expression of TdTomato in neural crest lineages, they identified a small population of TdTomato+ cells within the mesentery that we (and others) ignored for the past 2 decades while working with this same mouse line. They provide compelling evidence that these “mesenteric neural crest cells” are a subset of vagal neural crest that enter the bowel after migrating through the mesentery and then contribute to the enteric nervous system. This adds to an increasingly complex literature suggesting enteric nervous system precursors include vagal, sacral, and sympathoenteric neural crest–derived cells, Schwann cell precursors, and perhaps even bowel epithelial cells. Yu et al further suggest that in some cases, these mesenteric neural crest could generate substantial regions of interconnected enteric nervous system ganglia that are well separated from other enteric nervous system cells, leading to skip segment Hirschsprung disease. To support this hypothesis they present remarkably beautiful images of enteric nervous system from Wnt1; R26; Ednrb-/- mice. Eighty percent (45/56) of these mice had bowel aganglionosis that includes the entire colon and extends into the distal small bowel. Fifty-five percent (31/56) of the Wnt1; R26; Ednrb-/- mice had a skip segment Hirschsprung disease region suggesting that EDNRB mutations might commonly underlie skip segment Hirschsprung disease, a potentially testable hypothesis. One additional very interesting observation is that in contrast to Wnt1; R26; Ednrb-/- mice, animals of the Ednrb-/- genotype, had aganglionosis restricted to the distal colon 88% (30/34) of the time. This demonstrates for the first time (to my knowledge) that Wnt1Cre and R26tdTom lineages can substantially alter enteric nervous system developmental biology. This should prompt a re-evaluation of prior literature (including our own studies) to determine if conclusions drawn from Wnt1; R26 mice commonly used in enteric nervous system studies might need to be reinterpreted.

I am delighted to see that there is still a lot to learn about Hirschsprung disease and enteric nervous system biology. The spectacular images provided by Yu et al made their work even more enjoyable.