Gut commensals play important roles in maintaining the homeostasis of human health. Previous studies indicated that the abundance of P. goldsteinii in animal hosts was increased by the administration of prebiotics such as polysaccharides purified from iconic oriental medicinal fungi. Subsequently, P. goldsteinii was found to exert beneficial effects on the amelioration of multiple chronic inflammation-associated diseases. Even so, during the process of the development of P. goldsteinii as a next-generation probiotic (NGP), care has to be taken when it is used as a functional food ingredient. In this study, we isolated a novel P. goldsteinii strain, RV-01, from the feces of a healthy adult and carried out comprehensive analyses of its genomic and phenotypic characteristics. Bioinformatic analysis of P. goldsteinii RV-01 revealed the absence of potential virulence genes, as well as the presence of genes and traits potentially beneficial to human health, such as the production of short-chain fatty acids, anti-inflammatory lipopolysaccharides, and zwitterionic capsular polysaccharides, as well as immune regulatory proteins. To circumvent any potential side effects, the P. goldsteinii RV-01 was autoclaved before proceeding to the nonclinical safety assessment. The autoclaved P. goldsteinii RV-01 retained its anti-inflammatory effect in human colon epithelial cells. In addition to the three genotoxicity assays, 28-day subacute and 90-day subchronic animal toxicity studies (the highest dose tested was equivalent to 8.109 × 10¹⁰P. goldsteinii RV-01 cells/kg body weight/day) were also implemented. The results of all studies were negative for toxicity. These results support the conclusion that autoclaved P. goldsteinii RV-01 is safe for use as a food ingredient.

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. To investigate the impact of P. goldsteinii colonization prior to the onset of motor dysfunction on PD progression. 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. 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. 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.