# Taurocholic Acid Is Associated With Disturbed Functional Connectivity in the Hippocampus of Patients With Depression

## TL;DR

This study finds that taurocholic acid, linked to gut microbiome changes, may contribute to depression by affecting brain function in the hippocampus.

## Contribution

The study identifies taurocholic acid as a key bile acid metabolite associated with depression and its effects on brain connectivity and behavior.

## Key findings

- Elevated taurocholic acid levels in MDD patients are reversed by antidepressant treatment.
- Taurocholic acid impairs hippocampal neurogenesis and induces depression-like behavior in mice.
- Serum TCA levels correlate with altered hippocampal functional connectivity in MDD patients.

## Abstract

Major Depressive Disorder (MDD) is characterized by abnormal metabolic profiles along the microbiome‐gut‐brain axis. Bile acids (BAs), a class of steroid compounds regulated by the host and microbes, are increasingly shown to become dysregulated in models of depression. However, the identity of key regulatory BA metabolite in patients with MDD and associated mechanism remain to be clarified. Here, a prospective observational study in patients with depression (n = 235) and control subjects (n = 232) for identifying functional BA metabolites regulating depressive behavior and brain functional connectivity is performed. Using comparative metabolomics assay, an increased level of taurocholic acid (TCA) in the serum of patients with MDD is observed, which is reversed by anti‐depressant treatments. Transferring fecal microbiome from patients with MDD induced TCA accumulation to the hippocampus of recipient mice exhibiting depression‐like behavior. TCA supplementation suppressed hippocampal neurogenesis, triggered microglial activation, and elicited depression‐like behavior in mice, which are alleviated by a sphingosine‐1‐phosphate receptor 2 (S1PR2) antagonist. In patients with MDD, functional neuroimaging and spearman correlation analysis revealed that circulating TCA is strongly correlated with functional connectivity in the subregions of hippocampus. The results highlight the potential of harnessing TCA as a prognostic marker and therapeutic target for depression.

This study identifies elevated taurocholic acid (TCA) in Major Depressive Disorder patients. Gut microbiome‐associated TCA impairs hippocampal neurogenesis, triggers microglia activation, and elicits depression‐like behavior in mice via the S1PR2. In patients, functional neuroimaging reveals that serum TCA levels correlate with altered functional connectivity within hippocampal subregions. These findings position TCA as a potential prognostic biomarker and therapeutic target for depression.