Integrated Metabolomic and Transcriptomic Analyses Reveal Alterations in the Serotonergic Synapse Pathway and a...

Area of Science:

• Gastroenterology
• Neuroscience
• Metabolomics
• Transcriptomics

Background:

• Ulcerative colitis (UC) diagnosis traditionally relies on invasive procedures.
• Understanding the complex interplay between systemic metabolism and neuroendocrine signaling in UC pathogenesis is crucial.
• Existing diagnostic methods have limitations, necessitating novel approaches.

Purpose of the Study:

• To integrate serum metabolomics and mucosal transcriptomics for a deeper understanding of UC pathogenesis.
• To identify key molecular players and pathways involved in the gut-brain axis dysfunction in UC.
• To develop and validate a novel, non-invasive diagnostic biomarker signature for UC.

Main Methods:

• Multi-omics profiling of serum metabolites and mucosal differentially expressed genes (DEGs).
• Prioritization of neurotransmitter receptor-related genes (NRRGs) using machine learning algorithms (LASSO, Random Forest, SVM-RFE).
• Development and validation of a three-gene diagnostic nomogram using independent cohorts, ROC curve analysis, and DCA.

Main Results:

• Identification of 334 dysregulated metabolites and 3093 DEGs, converging on the serotonergic synapse pathway.
• Discovery of specific molecular alterations, including tryptophan depletion, SLC6A4 downregulation, and altered serotonin signaling.
• A robust three-gene signature (HTR3C, RPS6KA6, NETO2) achieved an AUC > 0.96 for UC diagnosis in training and validation cohorts.

Conclusions:

• The study delineates a neuroimmune mechanism in UC involving serotonergic synapse dysregulation.
• A novel three-gene nomogram shows strong potential as a preliminary diagnostic biomarker signature for UC.
• Further validation in prospective cohorts is needed to establish clinical utility compared to existing markers.