Dietary manipulation of intestinal microbes prolongs survival in a mouse model of Hirschsprung disease

  1. Naomi E. Butler Tjaden
  2. Megan J. Liou
  3. Sophie E. Sax
  4. Nejia Lassoued
  5. Meng Lou
  6. Sabine Schneider
  7. Katherine Beigel
  8. Joshua D. Eisenberg
  9. Emma Loeffler
  10. Sierra E. Anderson
  11. Guang Yan
  12. Lev Litichevskiy
  13. Lenka Dohnalová
  14. Yixuan Zhu
  15. Daniela Min Jing Che Jin
  16. Jessica Raab
  17. Emma E. Furth
  18. Zachary Thompson
  19. Ronald C. Rubenstein
  20. Nicolas Pilon
  21. Christoph A. Thaiss
  22. Robert O. Heuckeroth
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Abstract

Enterocolitis is a common and potentially deadly manifestation of Hirschsprung disease (HSCR) but disease mechanisms remain poorly defined. Unexpectedly, we discovered that diet can dramatically affect the lifespan of a HSCR mouse model (Piebald lethal,sl/sl) where affected animals die from HAEC complications. In thesl/slmodel, diet alters gut microbes and metabolites, leading to changes in colon epithelial gene expression and epithelial oxygen levels known to influence colitis severity. Our findings demonstrate unrecognized similarity between HAEC and other types of colitis and suggest dietary manipulation could be a valuable therapeutic strategy for people with HSCR.

Abstract

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 ofPiebald 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-fedsl/slhad abnormal appearing distal colon epithelium mitochondria, reduced epithelial mRNA involved in oxidative phosphorylation, and elevated epithelial oxygen that fostered growth of inflammation-associatedEnterobacteriaceae. Accordingly, selective depletion ofEnterobacteriaceaewith sodium tungstate prolongedsl/slsurvival. Our results provide the first strong evidence that diet modifies survival in a HSCR mouse model, without altering length of distal colon lacking ENS.

Highlights

  • Two different standard mouse diets alter survival in thePiebald lethal(sl/sl) mouse model of Hirschsprung disease, without impacting extent of distal colon aganglionosis (the region lacking ENS).

  • Piebald lethalmice fed the “Detrimental” diet had many changes in colon epithelial transcriptome including decreased mRNA for antimicrobial peptides and genes involved in oxidative phosphorylation. Detrimental diet fedsl/slalso had aberrant-appearing mitochondria in distal colon epithelium, with elevated epithelial oxygen that drives lethalEnterobacteriaceaeovergrowth via aerobic respiration.

  • Elimination ofEnterobacteriaceaewith antibiotics or sodium tungstate improves survival ofPiebald lethalfed the “Detrimental diet”.

Graphical abstract

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