Diagnostic Potential of Alternations of Bile Acid Profiles in the Plasma of Patients with Huntington's Disease

Abstract

Huntington's disease (HD) is characterized by progressive involuntary chorea movements and cognitive decline. Recent research indicates that metabolic disturbance may play a role in its pathogenesis. Bile acids, produced during cholesterol metabolism in the liver, have been linked to neurodegenerative conditions. This study investigated variations in plasma bile acid profiles among individuals with HD. Plasma levels of 16 primary and secondary bile acids and their conjugates were analyzed in 20 healthy controls and 33 HD patients, including 24 with symptoms (symHD) and 9 carriers in the presymptomatic stage (preHD). HD patients exhibited significantly higher levels of glycochenodeoxycholic acid (GCDCA) and glycoursodeoxycholic acid (GUDCA) compared to healthy controls. Conversely, isolithocholic acid levels were notably lower in the HD group. Neurotoxic bile acids (glycocholic acid (GCA) + glycodeoxycholic acid (GDCA) + GCDCA) were elevated in symHD patients, while levels of neuroprotective bile acids (ursodeoxycholic acid (UDCA) + GUDCA + tauroursodeoxycholic acid (TUDCA)) were higher in preHD carriers, indicating a compensatory response to early neuronal damage. These results underscore the importance of changes in plasma bile acid profiles in HD and their potential involvement in disease mechanisms. The identified bile acids (GCDCA, GUDCA, and isolithocholic acid) could potentially serve as markers to distinguish between HD stages and healthy individuals. Nonetheless, further research is warranted to fully understand the clinical implications of these findings and their potential as diagnostic or therapeutic tools for HD.

Keywords: Huntington’s disease; bile acid; glycochenodeoxycholic acid; glycoursodeoxycholic acid; isolithocholic acid.

Figure 1

(A) Hierarchical clustering heatmap displaying candidate bile acids. The dendrogram on the left side represents the clustering of these bile acids. The colors on top of the heatmap correspond to the following different groups: healthy controls (HC), patients with presymptomatic Huntington’s disease (preHD), and symptomatic Huntington’s disease (symHD). The colors in the heatmap indicate normalized intensities, scaled to a mean of zero and unit variance for each feature. (B) Group averages of candidate bile acids, with merged data from HD and preHD. Abbreviations: HCA, hyocholic acid; CDCA, chenodeoxycholic acid; CA, cholic acid; GUDCA, glycoursodeoxycholic acid; TUDCA, tauroursodeoxycholic acid; UDCA, ursodeoxycholic acid; GHCA, glycohyocholic acid; GCA, glycocholic acid; GCDCA, glycochenodeoxycholic acid; GDCA, glycodeoxycholic acid; DCA, deoxycholic acid.

Figure 2

Receiver operating characteristic (ROC) curves and box plots comparing plasma levels of (A) glycochenodeoxycholic acid (GCDCA), (B) glycoursodeoxycholic acid (GUDCA), and (C) isolithocholic acid between patients with Huntington’s disease (HD), symptomatic Huntington’s disease (symHD), presymptomatic Huntington’s disease (preHD), and healthy controls (HC). The shaded area under the ROC curve (AUC) represents the performance in distinguishing HD from HC. The red dots and lines indicate the optimal cut-off points that maximize the sensitivity and specificity of the metabolites for discriminating HD from HC. In the box plots, the black dots represent the metabolite level of each sample, the black center line represents the median, while the red, green, or blue boxes indicate the 25th to 75th percentiles. The black whiskers mark the 5th and 95th percentiles, and the mean values are represented by yellow diamonds. * p < 0.05, ** p < 0.01, *** p < 0.001, statistically significant between two groups (Mann–Whitney U test with Benjamini–Hochberg test). (D) ROC analysis of the three bile acids using a support vector machine. One hundred cross-validations were conducted, and the results were averaged to generate the plot. Abbreviations: GCDCA, glycochenodeoxycholic acid; GUDCA, glycoursodeoxycholic acid.

Figure 3

Schematic representation of the alterations of bile acids involved in the synthesis pathway in HD. Primary bile acids are converted to secondary bile acids by the gut microbiome. 24(S)-hydroxycholesterol from the brain mainly involves the alternative pathway. GCDCA and GUDCA levels are elevated and iso-LCA decreased in Huntington’s disease patients (HD) (presymptomatic HD (preHD) + symptomatic HD (symHD), and the total of neurotoxic bile acids (GCA + GDCA + GCDCA) is higher in symHD compared to healthy controls (HC). Conversely, the sum of neuroprotective BAs (UDCA + GUDCA + TUDCA) is increased in preHD carriers compared to HC. Also, it is noted that decreased CYP46A1 and 24(S)-hydroxycholesterol levels in HD have been shown in previously published papers. Abbreviations: CA, cholic acid; CDCA, chenodeoxycholic acid; TCA, taurocholic acid; GCA, glycocholic acid; TCDCA, taurochenodeoxycholic acid; GCDCA, glycochenodeoxycholic acid; DCA, deoxycholic acid; LCA, lithocholic acid; UDCA, ursodeoxycholic acid; TDCA, taurodeoxycholic acid; GDCA, glycodeoxycholic acid; TUDCA, tauroursodeoxycholic acid; GUDCA, glycoursodeoxycholic acid; Iso-LCA, Isolithocholic acid.