# TUDCA Ameliorates Cognitive Impairment in APP/PS1 Mice by Modulating the Microbiota–Gut–Brain Axis

## TL;DR

TUDCA improves cognitive function in Alzheimer's disease mice by affecting gut health and brain inflammation.

## Contribution

This study reveals that TUDCA improves cognition in AD mice via microbiota-gut-brain axis modulation and independent mechanisms.

## Key findings

- TUDCA reduced amyloid-beta accumulation and inflammation in the brain and peripheral tissues.
- TUDCA improved gut barrier function and altered gut microbiota composition.
- Fecal microbiota transplantation showed TUDCA-modulated microbiota improved memory in AD mice.

## Abstract

Tauroursodeoxycholic acid (TUDCA), a bile acid conjugate, has been suggested to improve cognition in models of Alzheimer’s disease (AD), although its underlying mechanisms remain unclear. This study aimed to evaluate the effects of TUDCA and its potential pathways in APP/PS1 mice. Behavioral tests, assessments of amyloid-β (Aβ) deposition, neuroinflammation, peripheral inflammatory responses, intestinal barrier integrity, and gut microbiota composition were performed, along with pseudo-sterile mouse experiments and fecal microbiota transplantation (FMT). The expression of genes related to the TLR4/NF-κB/NLRP3 pathway was also examined. TUDCA significantly ameliorated cognitive impairments, reduced Aβ accumulation, and suppressed inflammatory responses in both the central nervous system and peripheral tissues. It improved intestinal barrier function and reshaped gut microbial composition by reducing pro-inflammatory taxa. FMT demonstrated that TUDCA-modulated microbiota contributed to improved learning and memory in AD mice, whereas antibiotic-induced pseudo-sterility indicated that TUDCA also exerted cognitive benefits independent of gut flora. Moreover, TUDCA inhibited the activation of the TLR4/NF-κB/NLRP3 pathway. In conclusion, TUDCA alleviates AD-related cognitive deficits partly through modulation of the microbiota–gut–brain axis while also acting via microbiota-independent mechanisms, supporting its potential as a promising therapeutic strategy for AD.