Characterization of Gastric Mucosa Biopsies Reveals Alterations in Huntington's Disease

Abstract

Weight loss is an important complication of Huntington’s disease (HD), however the mechanism for weight loss in HD is not entirely understood. Mutant huntingtin is expressed in the gastrointestinal (GI) tract and, in HD mice, mutant huntingtin inclusions are found within the enteric nervous system along the GI tract. A reduction of neuropeptides, decreased mucosal thickness and villus length, as well as gut motility impairment, have also been shown in HD mice. We therefore set out to study gastric mucosa of patients with HD, looking for abnormalities of mucosal cells using immunohistochemistry. In order to investigate possible histological differences related to gastric acid production, we evaluated the cell density of acid producing parietal cells, as well as gastrin producing cells (the endocrine cell controlling parietal cell function). In addition, we looked at chief cells and somatostatin-containing cells. In gastric mucosa from HD subjects, compared to control subject biopsies, a reduced expression of gastrin (a marker of G cells) was found. This is in line with previous HD mouse studies showing reduction of GI tract neuropeptides.

Gastrointestinal Hemorrhage and Diffuse Bowel Dilation in Huntington Disease

“… 6 , 14 Furthermore, there may be a histologic etiology; evaluation of the gastric mucosa of HD-like mice identified abnormalities in the densities of chief cells and G cells, suggesting a predisposition of HD patients toward upper gastrointestinal inflammation. 15 Gastrointestinal manifestations of HD are heterogenous and can reduce the quality of life of individuals with HD. In this report, we report a unique case of an individual with progressive HD with preexisting dysphagia who presented with gastrointestinal inflammation and found to have significant small and large bowel dilation.…”

Systemic Symptoms in Huntington's Disease: A Comprehensive Review

“…These symptoms could, at least in theory, be linked to mutated HTT (mHTT) expression in peripheral organs. 52,53 Indeed, mHTT has been detected in many peripheral organs in animal models, including the heart, liver, pancreas and kidneys. 54 However, more recent studies could not identify mutated Htt in the diseased heart of mice HD models with symptomatic cardiomyopathy.…”

“…These symptoms could, at least in theory, be linked to mutated HTT (mHTT) expression in peripheral organs 52,53 . Indeed, mHTT has been detected in many peripheral organs in animal models, including the heart, liver, pancreas and kidneys 54 .…”

“…Esophagitis (32.4%) and gastritis (33.8%) were described in one retrospective cohort study of 68 HD patients who underwent esophagogastroduodenoscopies, 93 with only 29.4% of the patients reporting gastrointestinal pain or acid reflux. This abnormality was attributed to an increase in the cell density of pepsinogen‐producing chief cells of the fundus of HD patients, 52 or loss of enteric neurons resulting in delayed gastric emptying. Routine upper GI endoscopy, however, is not recommended in patients with HD 91 …”

Does the Gut Microbial Metabolome Really Matter? The Connection between GUT Metabolome and Neurological Disorders

“…The results of performed human randomized clinical trials positively correlate with the data obtained in mouse models in which gut microbiota dysbiosis was observed. A Huntington’s mouse model revealed endocrine hormonal abnormalities, improper intestinal morphology (decreased mucosal thickness, and villus length), and damaged neuropeptide production [ 165 , 166 , 167 ].…”