Gastrointestinal dysfunction contributes to weight loss in Huntington's disease mice

Weight loss is the most important non-neurological complication of Huntington's disease (HD). It correlates with disease progression and affects the quality of life of HD patients, suggesting that it could be a valuable target for therapeutic intervention. The mechanism underlying weight loss in HD is unknown. Mutant huntingtin, the protein that causes the disease, is not only expressed in the brain, but also along the gastrointestinal (GI) tract. Here we demonstrate that the GI tract of HD mice is affected. At the anatomical level we observed loss of enteric neuropeptides, as well as decreased mucosal thickness and villus length. Exploring the functions of the GI system we found impaired gut motility, diarrhea, and malabsorption of food. The degree of malabsorption was inversely associated with body weight, suggesting that GI dysfunction plays an important role in weight loss in HD mice. In summary, these observations suggest that the GI tract is affected in HD mice and that GI dysfunction contributes to nutritional deficiencies and weight loss.

Research highlights► The enteric nervous system is affected in R6/2 mice. ► Mucosal thickness and villus length are decreased in the gut of R6/2 mice. ► R6/2 mice suffer from malabsorption of nutrients across the gastrointestinal tract. ► Malabsorption of nutrients contributes to weight loss in R6/2 mice.