Tjaden, N. E. B.; Liou, M. J.; Sax, S.; Lassoued, N.; Lou, M.; Schneider, S.; Beigel, K.; Eisenberg, J. D.; Loeffler, E.; Anderson, S. E.; Yan, G.; Litichevskiy, L.; Dohnalova, L.; Zhu, Y.; Jin, D. M. J. C.; Raab, J.; Furth, E. E.; Thompson, Z.; Rubenstein, R. C.; Pilon, N.; Thaiss, C. A.; Heuckeroth, R.

Hirschsprung disease (HSCR) is a birth defect where enteric nervous system (ENS) is absent from distal bowel. Bowel lacking ENS fails to relax, causing partial obstruction. Affected children often have \"Hirschsprung disease associated enterocolitis\" (HAEC), which predisposes to sepsis. We discovered survival of Piebald lethal (sl/sl) mice, a well-established HSCR model with HAEC, is markedly altered by two distinct standard chow diets. A \"Protective\" diet increased fecal butyrate/isobutyrate and enhanced production of gut epithelial antimicrobial peptides in proximal colon. In contrast, \"Detrimental\" diet-fed sl/sl had abnormal appearing distal colon epithelium mitochondria, reduced epithelial mRNA involved in oxidative phosphorylation, and elevated epithelial oxygen that fostered growth of inflammation-associated Enterobacteriaceae. Accordingly, selective depletion of Enterobacteriaceae with sodium tungstate prolonged sl/sl survival. Our results provide the first strong evidence that diet modifies survival in a HSCR mouse model, without altering length of distal colon lacking ENS.