Alterations in gut microbiome may reflect early biological changes associated with Parkinson’s disease (PD), potentially appearing years before the onset of motor symptoms.

In a large international analysis, over 25% of gut microbial species differed in abundance between individuals with PD and healthy control individuals, with 176 microbial species showing differences overall.

Many of these same microbial changes were also present in individuals who carry the high-risk GBA1 gene variant but have not yet developed symptoms.

The GBA1 gene is one of the strongest known genetic risk factors for PD, increasing risk up to 30-fold, and carriers, many of whom remain asymptomatic, offer a window into early disease biology.

“In recent years there has been a growing recognition of the links between Parkinson’s disease — a brain disorder — and gut health,” lead investigator Anthony Schapira, MD, professor at UCL Queen Square Institute of Neurology in London, England, said in a news release.

“Here we have strengthened that evidence and shown that microbes in the gut can reveal signs of Parkinson’s and may be an early warning signal of Parkinson’s risk years before symptom onset.”

The study was published online on April 20 in Nature Medicine.

A Growing Body of Evidence

Growing evidence has linked PD to changes in the gut microbiome, with prior studies showing distinct microbial patterns in patients and suggesting a connection between gut health and brain function.

In the cross-sectional, multicenter study, researchers sought to determine whether gut microbiome differences extend beyond diagnosed PD and into genetically at-risk but clinically unaffected individuals, and whether these microbial signatures align with early clinical features.

Participants were recruited from the UK and Italy, with external validation cohorts from the US, Korea, and Türkiye. The primary cohort included 464 participants: 271 individuals with PD, 43 nonmanifesting carriers of the GBA1 variant, and 150 healthy control participants.

There were 638 participants with PD and 319 healthy control participants in the additional cohorts.

Healthy controls were the partners of patients. This helped minimize potential confounders including variability in diet and lifestyle. On average, participants were in their early 60s and those with PD were more likely to be male compared to controls.

Participants provided stool samples collected at home using standardized kits that stabilized microbial DNA prior to sequencing. Shotgun metagenomic sequencing was used to profile gut microbial composition at species-level resolution. Additional analyses assessed functional microbial pathways and metabolic potential.

Clinical evaluations included both motor and nonmotor assessments, such as olfaction, cognition, sleep behavior, mood, and autonomic function. Patients with PD had a mean disease duration of 6.4 years, and most patients were receiving dopaminergic therapy.

Genetic testing confirmed GBA1 status and screened additional PD-related mutations, including variants in LRRK2 and other PD-associated genes.

Dietary habits were assessed using validated food frequency questionnaires, and dietary quality scores were calculated based on intake of fruit, vegetables, fish, sugar, and fat.

Gut Changes Mirror Symptom Burden

The researchers identified 176 microbial species that differed significantly between individuals with PD and controls. Some bacterial species were increased in PD, whereas others were decreased compared with healthy individuals.

Species more abundant in PD included Streptococcus and Bifidobacterium, whereas beneficial butyrate-producing bacteria such as Roseburia and Faecalibacterium were reduced.

Of the 176 species identified, 142 also differed between healthy controls and asymptomatic GBA1 carriers, suggesting that many microbiome alterations are present even before clinical disease develops in individuals at genetic risk.

In GBA1 carriers, the gut microbiome showed an intermediate pattern between healthy individuals and those with PD. This pattern was also associated with early nonmotor symptoms, suggesting that microbiome changes may reflect early disease-related changes.

The microbiome profile is linked to clinical features associated with PD, co-lead author Stanislav Dusko Ehrlich, PhD, honorary professor at the at UCL Queen Square Institute of Neurology, told Medscape Medical News. “In individuals who are not clinically diseased, it is associated mostly with nonmotor symptoms, as expected for the body-first PD.”

Greater microbiome alterations were associated with worse motor and nonmotor features, including depression, autonomic dysfunction, constipation, and cognitive changes, as well as longer disease duration.

“Microbiome alterations indicate that disease is progressing before the motor symptoms appear,” Ehrlich said.

Diet Quality and Disease Risk

Diet quality was associated with microbiome patterns, with poorer diet scores and lower fruit and vegetable intake observed in individuals with more PD-like microbiome changes.

Ehrlich noted that this association could suggest the risk may be mitigated by appropriate diet.

“This opens avenues for prevention of PD, by identifying individuals at risk and offering the nutritional advice to diminish the risk. It also opens avenues for slowing disease progression, by appropriate nutritional interventions,” he said.

Acknowledging the study’s limitations, including its cross-sectional design and inability to establish causation, Ehrlich said the findings nonetheless provide further insight into the relationship between the gut microbiome composition and the risk for PD.

“Just knowing that microbiome alterations are strongly linked to progression of the disease in patients and progression towards the disease in healthy, could encourage neurologists to advise microbiome analysis and conversation with nutritionists to their patients,” he said.

New Insight into PD Pathogenesis

Multiple studies consistently show differences in the gut microbiome between people with PD and those without it, Rachel Dolhun, MD, DipABLM, principal medical advisor at the Michael J. Fox Foundation (MJFF)for Parkinson’s Research, New York City, told Medscape Medical News. However, it remains unclear whether these changes play a causal role, contribute to disease development, or occur because of the disease itself.

The microbiome varies widely between individuals, said Dolhun, who was not involved in the study.

She noted that the microbiome is shaped by multiple factors, including diet, environment, underlying health conditions, and medications, and emphasized that this variability represents a key limitation of the current analysis.

Despite these challenges, Dolhun said, the findings reflect an important shift in the field toward understanding PD at its earliest biological stages.

She said microbiome profiling is not yet ready for clinical use but is a promising area that could play a significant role in the future.

Future longitudinal studies will be critical to determine whether microbiome signatures can reliably predict disease onset and how they evolve over time, Dolhun noted.

“The more that we understand about this connection, the more we will be able to personalize our medicine, our diagnoses, and our treatments,” she said.

The study was supported by the Medical Research Council and the by Aligning Science Across Parkinson’s through The MJFF for Parkinson’s Research. Disclosure information for study authors is available in the original study publication. Dolhun is the principal medical advisor at the MJFF.