Dysbiosis of gut microbiota inhibits NMNAT2 to promote neurobehavioral deficits and oxidative stress response in the 6-OHDA-lesioned rat model of Parkinson’s disease Original paper

What was studied?

This study by Yu et al. directly investigated the mechanistic link between gut microbiota dysbiosis and neurobehavioral deficits in Parkinson’s disease (PD) using a combination of human multi-omics data and in vivo rat models. The researchers analyzed shotgun metagenomic sequencing data from PD patients and healthy controls to characterize differences in gut microbiota diversity, abundance, and function. Bioinformatics analyses identified microbial pathways and genes of interest, particularly those relating to the NAD+ anabolic pathway and the gene NMNAT2. Subsequently, the team used a 6-hydroxydopamine (6-OHDA) rat model of PD to experimentally test whether fecal microbiota transplantation (FMT) and genetic modulation of NMNAT2 could influence neurobehavioral outcomes and oxidative stress. The study aimed to clarify the pathophysiological mechanism by which gut microbiota composition impacts PD progression, focusing on the regulatory role of NMNAT2 in the brain.

Who was studied?

The study included two main populations. First, for the metagenomic and transcriptomic analyses, the researchers accessed publicly available datasets containing fecal samples from 31 male, early-stage, drug-naive PD patients and 28 age-matched healthy individuals. For validation and mechanistic experiments, adult male Wistar rats were used. These rats were assigned to various groups: sham-operated controls, 6-OHDA-lesioned (PD model), and treatment groups receiving FMT, NMNAT2 overexpression, or NMNAT2 knockdown in combination with FMT. Group sizes for animal experiments were n=8 per group. The combined use of human data and a well-established animal model allowed the researchers to bridge human microbiome associations with mechanistic interrogation in vivo.

Most important findings

A key focus of this study was the identification of distinct microbiome signatures in PD. PD patients exhibited significant reductions in alpha diversity and distinct beta diversity compared to controls. Taxonomically, PD patients had an increased abundance of Akkermansia muciniphila, Alistipes shahii, and Verrucomicrobia, while healthy individuals had higher levels of Prevotella copri, Coprococcus, and Lachnospiraceae. Functionally, the gut microbiota from PD patients was enriched in NAD+ anabolic pathway genes, notably with higher abundance of Alistipes shahii (linked to the NAD+ pathway) and reduced Coprococcus (more abundant in controls).

Transcriptomic analysis of brain tissues revealed that NMNAT2, a key NAD+ pathway gene, was significantly downregulated in PD patients’ substantia nigra, prefrontal cortex, and putamen. In the 6-OHDA rat model, NMNAT2 expression was also diminished, correlating with neurobehavioral deficits (motor impairments) and heightened oxidative stress (increased MDA, reduced GSH, SOD, and GSH-Px). Strikingly, FMT from healthy rats restored NMNAT2 expression, improved behavioral outcomes, and reduced oxidative stress. Overexpression of NMNAT2 recapitulated these protective effects, while NMNAT2 knockdown negated the benefits of FMT, underscoring NMNAT2’s central role in mediating the gut–brain axis in PD.

Key implications

The study’s findings have substantial implications for both clinical and translational research in PD. First, they establish that gut microbiota dysbiosis in PD is mechanistically linked to disease progression via suppression of NMNAT2 and consequent disturbances in NAD+ metabolism and oxidative homeostasis. Second, FMT emerges as a promising therapeutic strategy—not just for symptom relief but also for modifying disease biology by targeting microbial regulation of neuroprotective pathways. Critically, the identification of microbial taxa (e.g., Akkermansia, Alistipes, Coprococcus) and their association with NAD+ anabolic activity highlights potential microbiome-derived biomarkers or targets for intervention. These results support the integration of gut microbiome signatures, particularly those affecting NAD+ metabolism, into PD biomarker databases and suggest that restoring NMNAT2 activity (via FMT or other approaches) may offer neuroprotective benefits in PD.

Citation

Yu J, Meng J, Qin Z, Yu Y, Liang Y, Wang Y, Min D. Dysbiosis of gut microbiota inhibits NMNAT2 to promote neurobehavioral deficits and oxidative stress response in the 6‑OHDA‑lesioned rat model of Parkinson’s disease. J Neuroinflammation. 2023;20:117. doi:10.1186/s12974-023-02782-1