GDNF enemas improve epithelial and immune defects in both aganglionic and ganglionic colon of Hirschsprung mice

Hirschsprung disease, a severe birth defect, occurs when the enteric nervous system (ENS) ganglia in the distal bowel are missing. This absence leads to increased epithelial permeability and an overactive immune system. These issues can cause gut microbes to enter the colon wall and bloodstream, leading to enterocolitis and sepsis.

Current treatment involves surgically removing the aganglionic segment, but this does not cure the disease and can leave patients with recurring gastrointestinal complications, including a high risk of enterocolitis. Researchers are exploring a regenerative medicine strategy that involves stimulating tissue-resident ENS progenitors through rectal administration of the neurotrophic factor GDNF.

This study reveals that GDNF therapy not only regenerates the ENS but also has broader gastrointestinal benefits. These benefits extend beyond the aganglionic distal colon to the ENS-containing proximal colon. GDNF treatment lowers bacterial translocation in both the local area and peripheral organs, leading to the restoration of crucial epithelial junction proteins.

Additionally, multiparameter flow cytometry analysis shows that GDNF treatment has a wide-ranging anti-inflammatory effect, primarily impacting innate immunity over adaptive immunity. These findings suggest that GDNF treatment can restore proper epithelial and immune cell balance, offering potential therapeutic options not just for Hirschsprung disease but also for other intestinal disorders with related pathologies.