Parabacteroides goldsteinii mitigates parkinsonism in LRRK2 mutant mice by reducing neuroinflammation through Gut-Brain axis.
Journal
Journal of advanced research
ISSN
2090-1224
Date Issued
2025-12-23
Author(s)
Li, Hsun
Hsu, Chia-Lang
Lin, Tzu-Lung
Chuang, Hsiao-Li
Lin, Han-I
Ho, En-Peng
Chen, Yi-Hsuan
Liu, Chia-Wei
Chuang, Ya-Ting
Lung, Yun-Yi
Lien, Chia-Jung
Chen, Huan-Yun
Lu, Chia-Chen
Lai, Hsin-Chih
Abstract
Introduction Alterations in the gut microbiota accompanied by intestinal inflammation are early features of Parkinson’s disease (PD). Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene represent a common genetic risk factor for PD and inflammatory bowel disease. Parabacteroides goldsteinii has been reported to alleviate intestinal and systemic inflammation. However, whether modulation of the gut microenvironment at early disease stage can attenuate PD progression remains unclear. Objective To investigate the impact of P. goldsteinii colonization prior to the onset of motor dysfunction on PD progression. Methods We established a germ-free PD mouse model carrying the LRRK2 G2019S mutation and administered P. goldsteinii orally at the pre-symptomatic stage to evaluate its effects on motor performance and PD-related neuropathology. Spatial and bulk RNA transcriptomic analyses of brain tissue, together with cytokine profiling, were conducted to assess central changes. To investigate gut immunomodulatory mechanisms, we performed intestinal bulk and single-cell RNA sequencing, spectral flow cytometry as well as cellular bioenergetic analyses. Results Germ-free conditions partially alleviated PD-like phenotypes in LRRK2 G2019S mice. Colonization with P. goldsteinii at 5-months of age, prior to motor symptom onset, further improved locomotor performance, reduced neuronal α-synuclein aggregations, and mitigated microglial activation and dopaminergic neurodegeneration. Neuroprotection was mediated through enhanced noncanonical neuronal IL-12 receptor–dependent neurotrophic support without activating the canonical STAT4 phosphorylation pathway, along with suppression of microglial activation and downregulation of LRRK2 kinase activity. At the intestinal level, P. goldsteinii suppressed TLR4-driven inflammation, expanded anti-inflammatory intraepithelial CD4+CD8αα+ T cells, promoted dendritic cell and macrophage differentiation, upregulated epithelial tight-junction genes, and improved mitochondrial bioenergetics in intestinal cells. Conclusion P. goldsteinii colonization attenuates the progression of LRRK2 -associated parkinsonism by restoring intestinal homeostasis and reducing neuroinflammation. These findings underscore the therapeutic potential of modulating the gut–immune–brain axis during the prodromal stage of PD. © 2025 The Author(s).
Subjects
Gut microbiota
Gut-brain axis
Leucine rich repeat kinase 2
Parabacteroides goldsteinii
Parkinson’s disease
SDGs
Publisher
Elsevier B.V.
Description
In Press
Type
journal article