Analyzing new ways to treat Hirschsprung disease

Nejia Lassoued¹,Rodolphe Soret^1,2, Alexis Yero Diaz¹, Mohammad-Ali Jenabian^1,2, Sabine Schneider³, Robert Heuckeroth³ & Nicolas Pilon^1,2

¹Département des Sciences Biologiques, Université du Québec à Montréal (UQAM), Montréal, Québec, Canada;² Centre d’excellence en recherche sur les maladies orphelines—Fondation Courtois (CERMO-FC), Université du Québec à Montréal, Montréal, Québec, Canada;³ Department of Pediatrics, the University of Pennsylvania Perelman School of Medicine and The Children’s Hospital of Philadelphia Research Institute, Philadelphia, Pennsylvania

Hirschsprung disease is characterized by the absence of enteric neural ganglia in the colon, resulting in intestinal blockage and death by sepsis. The only strategy currently available for treating this severe disease is surgical removal of the affected area, but the risk of enterocolitis and death by sepsis remains high.

To circumvent the need for surgery, the Pilon lab has developed a regenerative approach by which local administration of the neurotrophic factor GDNF triggers the formation of neural ganglia in the otherwise aganglionic zone of different mouse models and human patient tissues. About 35% of the neoformed ganglia are derived from Schwann cells located on extrinsic nerves. Using a variety of genetic tools for cell lineage tracing, ongoing work now aims to identify the other cell types that generate the remaining 65% of GDNF-induced ganglia.We are also studying the effect of GDNF on the colon immune system by flow cytometry. Preliminary results suggest that abnormal proportions of immune cells observed in the colon of sick mice become normalized back to WT immune cell proportions upon GDNF treatment.

Concurrently, studies in collaboration with the Heuckeroth lab in Philadelphia indicate that there are pro-survival non-genetic factors that directly restore colon function, bypassing the need for GDNF-induced ganglia.Wediscovered that thegut microbiotaof mice housed in Philadelphia is notably enriched in Lachnospiraceae, a bacteria family that produce butyrate known to protect and repair the colon. This microbiota change appears to be triggered by the different food used in each institution. UQAM food decreases lifespan of Philadelphia mice while Philadelphia food increases lifespan of UQAM mice.