# Huang-Lian-Jie-Du decoction alleviates cognitive impairment in periodontitis rats through restoring microbiota-gut-brain axis and inhibiting neuroinflammation via TLR4/NF-κB pathway

## TL;DR

This study shows that Huang-Lian-Jie-Du decoction improves cognitive issues in periodontitis rats by balancing gut bacteria and reducing brain inflammation.

## Contribution

The study reveals a novel mechanism by which HLJDD alleviates periodontitis-induced cognitive impairment via the microbiota-gut-brain axis and TLR4/NF-κB pathway.

## Key findings

- HLJDD reduces alveolar bone loss and improves cognitive function in periodontitis rats.
- The decoction restores gut microbiota balance and enhances intestinal and blood-brain barrier integrity.
- HLJDD suppresses neuroinflammation by inhibiting the TLR4/NF-κB signaling pathway.

## Abstract

Huang-Lian-Jie-Du decoction (HLJDD), a typical formulation for heat clearance and detoxification, shows therapeutic potential for oral diseases and cognitive impairment. Nevertheless, the mechanism by which HLJDD influences periodontitis-induced cognitive impairment via the microbiota-gut-brain axis remains unknown.

We investigated HLJDD’s neuroprotective effects in periodontitis rats, focusing on its modulation of the microbiota-gut-brain axis and underlying molecular mechanisms.

Chemical profiling of HLJDD was performed via UHPLC-Q-Exactive Orbitrap HRMS. Periodontitis was induced in SD rats using ligatures and Porphyromonas gingivalis for 2 weeks, followed by 8-week treatments with HLJDD (0.75/1.5/3 g/kg/day), doxycycline (10 mg/kg/day), or vehicle. Alveolar bone loss was assessed via micro-CT, while cognitive function was assessed via the Morris water maze (MWM). Hippocampal and colon pathology was analyzed via H&E, Nissl staining, and immunohistochemistry. The composition of gut microbiota was analyzed by 16S rDNA sequencing. The tight junction proteins in hippocampus and colon were examined by RT- qPCR and immunofluorescence (IF). Inflammatory cytokine levels in intestinal and hippocampus tissue and serum were quantified by ELISA. Network pharmacology predicted potential mechanisms, and Western blotting assessed TLR4/NF-κB pathway proteins.

HLJDD contained 94 bioactive compounds and significantly attenuated alveolar bone loss, improved cognitive function, and reduced neuronal damage and Aβ deposition. It restored gut microbiota homeostasis, enhanced intestinal and blood–brain barrier integrity, and suppressed neuroinflammation by modulating pro- and anti-inflammatory cytokines. Mechanistically, HLJDD inhibited TLR4/NF-κB signaling, suggesting its therapeutic potential in periodontitis-related cognitive impairment.

HLJDD ameliorates cognitive impairment in periodontitis by modulating the microbiota-gut-brain axis, reducing neuroinflammation, and inhibiting TLR4/NF-κB activation. These findings support its potential as a novel therapeutic strategy for periodontitis-associated cognitive impairment.

The online version contains supplementary material available at 10.1186/s13020-025-01235-6.