Phase 2 Controlled Trial Tests Potential of Probiotics in Parkinson-Related Depression, Mood Disorders

An ongoing phase 2, double-blind, placebo-controlled, feasibility trial, dubbed ProD, is testing the efficacy and safety of a multi-strain probiotic to treat depression and mood disorder symptoms in patients with Parkinson disease (PD). The hope is that this study, which is actively recruiting and collecting data, will provide further understanding of the connection between gut-brain axis and PD, potentially setting up a larger, phase 3 trial examining a probiotic in this patient population.¹

The 12-week pilot study looks to enroll 60 individuals aged 40-80 with mild to moderate PD who also have mild to moderate depression. Patients in the study will receive placebo or the probiotic, a multi-strain formulation of 9 common probiotics, including mostly anaerobic, lactic acid-fermenting species implicated in SCFA synthesis.

The design of the study, presented in a poster at the 2025 International Congress of Parkinson’s Disease and Movement Disorders (MDS), held October 5-9, in Honolulu, Hawaii, calls for on-site visits at weeks 0 and 12, with phone check-ins at weeks 4 and 8. During this 12-week study, the primary outcome will be change in depressive symptoms, while other secondary outcomes comprise PD motor and non-motor symptoms, cognition, anxiety, apathy, stool frequency, and more.

Led by Silke Appel-Cresswell, MD, a movement disorder neurologist and associate professor at the Djavad Mowafaghian Center for Brain Health, UBC, the trial also includes several other inflammatory markers of study, such as blood serum cytokine and metabolite analysis. Study authors will also take a look at sex hormones, cortisol, various neurotransmitters, and more, while focusing on an intent-to-treat population. In the trial, microbial signatures are analyzed using fecal shotgun metagenomic sequencing, with classification and diversity assessed via QIIME2, microbial reads classified through Kraken2, and functional profiling performed using Super-Focus.

The idea behind testing probiotics in PD is through targeting the gut-brain axis, a bidirectional communication network that links the gastrointestinal tract, immune syste, and central nervous system. Many patients with PD exhibit gut dysbiosis– reduced microbial diversity, loss of short-chain fatty acid (SCFA)–producing bacteria, and overgrowth of proinflammatory species. Probiotics may help repopulate beneficial bacteria, restoring metabolic and microbial equilibrium.

There have been a number of published research articles on probiotics for PD, including studies that tracked depressive symptoms or broader mood outcomes. To date, the strongest PD-specific mood signal came from a 2023 meta-analysis, which reported improved motor symptoms, gastrointestinal dysfunction, anxiety, and depression with probiotics.

The meta-analysis, published in Food Function, comprised 9 randomized trials of 663 patients with PD. Overall, treatment with probiotics led to significantly improved motor symptoms (UPDRS-III scores: standardized mean difference [SMD], -0.28, 95% CI, -0.49 to -0.07, I² = 7%), constipation and constipation-related quality of life (Bristol scores: SMD, 0.54 [95% CI, 0.35 to 0.73] I² = 0%; bowel movement scores: SMD, 0.83 [95% CI, 0.59 to 1.07] I² = 43%; CSBMs: SMD, 0.56 [95% CI, 0.30 to 0.82] I² = 0%; PAC-QCL scores: SMD, -0.84 [95% CI, -1.08 to -0.60] I² = 0%).²

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Additional data from the meta-analyses revealed significant enhancements in anxiety and depression parameters, assessed through Hamilton Anxiety Rating Scale (HAMD; SMD, -0.35; 95% CI, -0.60 to -0.10, I² = 0%) and HADM-17 scores (SMD, -0.33; 95% CI, -0.59 to -0.08, I² = 0%). Notably, the use of probiotics led to reduced use of laxatives (SMD, -0.27; 95% CI, -0.53 to -0.01, I² = 15%) and increased GSH levels in the serum of patients with PD (SMD, 0.52; 95% CI, 0.14 to 0.90, I² = 0%).

Another 2023 published study looked at Lacticaseibacillus paracasei strain Shirota (LcS) supplementation on clinical responses, gut microbiota and fecal metabolites in patients with PD (n = 128). In the study, patients were randomly assigned to either probiotics (LcS-fermented milk, containing 1 × 10¹⁰ living LcS cells) or placebo for 12 weeks.

All told, supplementation with LcS significantly improved constipation-related and other non-motor symptoms in patients with PD. While overall gut microbiota composition and fecal metabolites remained largely unchanged, LcS intake increased the abundance of the Lacticaseibacillus genus relative to baseline and placebo. Additionally, fecal L-tyrosine levels decreased while plasma L-tyrosine concentrations rose in the probiotic group, suggesting enhanced amino acid absorption. Overall, these findings indicated that LcS supplementation, despite minimal microbiome-wide alterations, may exert beneficial physiological effects relevant to non-motor symptom management in PD.³

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REFERENCES
1. Lemkow A, Kuan A, Lam J, et al. Probiotic Treatment for Depression and Associated Mood Disorders in Parkinson’s Disease – A Randomized, Placebo-Controlled Trial (Short Title: ProD). Presented at: 2025 MDS Congress; October 5-10; Hawaii. Abstract S700
2. Chu C, Yu L, Li Y, et al. Meta-analysis of randomized controlled trials of the effects of probiotics in Parkinson's disease. Food Function. 2023;14(8):3406-3422. doi:10.1039/d2fo03825k.
3. Yang X, He X, Xu S, et al. Effect of Lacticaseibacillus paracasei strain Shirota supplementation on clinical responses and gut microbiome in Parkinson's disease†. Food Function. 2023;14:6828-6839. doi:10.1039/D3FO00728F