# Beyond bile acids synthesis: metabolomics profiling highlights extensive metabolic dysregulation and treatment response in CTX

## TL;DR

This study uses metabolomics to show that CTX causes widespread metabolic changes beyond bile acid disruption, and some of these changes can be partially reversed with treatment.

## Contribution

The study reveals new metabolic pathways affected by CTX and demonstrates the early response to CDCA therapy using comprehensive metabolomic profiling.

## Key findings

- Untreated CTX shows depletion of bile acid intermediates and elevated sterol precursors.
- CDCA therapy partially restores bile acid intermediates and phosphatidylethanolamines toward normal levels.
- Metabolomic profiling identifies disruptions in fatty acid metabolism, NAD+ synthesis, and sphingolipids in CTX.

## Abstract

Cerebrotendinous xanthomatosis (CTX) is an inherited metabolic disorder caused by variants in CYP27A1 leading to loss of sterol-27-hydroxylase activity. Sterol-27-hydroxylase generates two classes of bioactive signaling molecules: bile acids and oxysterols. The broader metabolic consequences resulting from perturbations in bile acid and oxysterol signaling and their reversibility with FDA-approved treatment chenodeoxycholic acid (CDCA), are not fully described.

To establish a comprehensive map of metabolic consequences of CTX, we performed large-scale, untargeted plasma metabolomics in a single subject with CTX, both before and after 6 months of CDCA therapy, and compared results with a reference cohort of over 1100 individuals. Data were analyzed for significant metabolite changes and pathway alterations.

Untreated CTX exhibited marked depletion of bile acid intermediates and elevations in sterol precursors, consistent with the known enzymatic block in this pathway. Metabolomics highlighted additional pathways affected by bile acid and oxysterol signaling such as fatty acid metabolism, NAD+ de novo synthesis, phosphatidylethanolamines, sphingolipids and ferroptosis. Following six months of CDCA therapy, sterol precursors normalized, bile acid intermediates partially recovered, and phosphatidylethanolamines were restored toward reference ranges, while steroid and phosphatidylcholine metabolites remained largely unchanged.

This study exposes the comprehensive nature of metabolic disturbance in CTX beyond the bile acids pathway, revealing perturbations in bile acids, steroids, fatty acids, phospholipids and NAD+ synthesis and highlights the dynamic early response to CDCA therapy. The metabolomic profile of untreated CTX can be leveraged for diagnostic screening. These findings report new candidate biomarkers for diagnosis and monitoring and underscore the potential of metabolomics to uncover broader metabolic consequences in rare disease.