# Exploring the CDCA-Scd1 Axis: Molecular Mechanisms Linking the Colitis Microbiome to Neurological Deficits

## TL;DR

Chronic colitis in mice leads to brain dysfunction, and this study identifies a link through the CDCA-Scd1 pathway, which can be improved with CDCA supplementation.

## Contribution

This study identifies the CDCA-Scd1 axis as a novel molecular mechanism linking colitis microbiome to neurological deficits.

## Key findings

- Chronic colitis in mice caused anxiety, depression, and memory impairment.
- Colitis microbiome reduced brain CDCA and Scd1 levels, along with MUFA concentrations.
- CDCA supplementation reversed colitis and improved brain function by boosting Scd1 and MUFAs.

## Abstract

Inflammatory bowel disease is a risk factor for brain dysfunction; however, the underlying mechanisms remain largely unknown. In this study, we aimed to explore the potential molecular mechanisms through which intestinal inflammation affects brain function and to verify these mechanisms. Mice were treated with multiple cycles of 1% w/v dextran sulfate sodium (DSS) in drinking water to establish a chronic colitis model. Behavioral tests were conducted using the open field test (OFT), tail suspension test (TST), forced swimming test (FST), and Morris water maze test (MWM). Brain metabolomics, transcriptomics, and proteomics analyses were performed, and key target proteins were verified using qPCR and immunofluorescence. Four cycles of DSS administration induced colitis, anxiety, depression, and spatial memory impairment. The integrated multi-omics characterization of colitis revealed decreased brain chenodeoxycholic acid (CDCA) levels as well as reduced stearoyl-CoA desaturase (Scd1) gene and protein expression. Transplantation of the colitis microbiome resulted in anxiety, depression, impaired spatial memory, reduced CDCA content, decreased Scd1 gene and protein expression, and lower concentrations of monounsaturated fatty acids (MUFAs), palmitoleate (C16:1), and oleate (C18:1) in the brain. In addition, CDCA supplementation improved DSS-induced colitis, alleviated depression and spatial memory impairment, and increased Scd1 gene and protein expression as well as MUFA levels in the brain. The gut microbiome induced by colitis contributes to neurological dysfunction, possibly through the CDCA–Scd1 signaling axis. CDCA supplementation alleviates colitis and depressive behavior, likely by increasing Scd1 expression in the brain.