Relationships of gut microbiota, short-chain fatty acids, inflammation, and the gut barrier in Parkinson’s disease Original paper

What was studied?

This original research article investigated the interrelationships among gut microbiota composition, short-chain fatty acid (SCFA) production, inflammation, and gut barrier integrity in Parkinson’s disease (PD). The aim was to clarify how these microbiome-related factors interact and contribute to PD pathophysiology and symptomatology. The study compared stool and plasma biomarkers—including SCFA levels, inflammatory mediators, and gut permeability markers—between PD patients and matched healthy controls. Associations between these biomarkers, the composition and diversity of gut microbiota, and clinical features of PD (including both motor and non-motor symptoms) were systematically analyzed. The research also assessed how these relationships varied by sex and between PD and control groups, providing a detailed view of microbiome-host interactions in PD.

Who was studied?

The cohort comprised 55 patients diagnosed with PD and 56 healthy control subjects, originally recruited for a gut microbiota pilot study and followed up with comprehensive sampling and clinical data collection. Participants were generally matched for age, sex, and body mass index, with most PD patients in early to mid-stage disease (Hoehn and Yahr scale 2–3). Extensive clinical data included questionnaires on diet, non-motor symptoms, PD severity, gastrointestinal problems, and constipation. Stool samples were self-collected at home and refrigerated until delivery to the clinic, and venous blood samples were collected for plasma biomarker analysis. After excluding participants with incomplete data, the final analysis included 111 subjects.

Most important findings

The study revealed several key microbiome-related findings. PD patients exhibited significantly higher stool calprotectin (an inflammatory marker) and lower levels of SCFAs—specifically butyric and propionic acid—compared to controls, with some differences being sex-dependent. Notably, reductions in butyric acid were more pronounced in male PD patients, while female patients had higher stool calprotectin and lower plasma CXCL8 (IL-8).

Importantly, inflammatory markers in plasma and stool were highly correlated within each compartment, but there was no correlation between the same markers measured in plasma versus stool. This suggests that systemic and gut immune responses are distinct in PD. Furthermore, levels of stool SCFAs and inflammatory or gut permeability markers (e.g., zonulin, NGAL) were not directly related, indicating complex host-microbiome interactions that differ from simple linear associations.

Age at PD onset was positively correlated with stool SCFA levels, especially butyric acid, and negatively correlated with stool CXCL8 and IL-1β, suggesting that reduced SCFAs and increased gut inflammation may contribute to earlier disease onset. Microbiota diversity (alpha and beta diversity) was intricately linked to both PD symptom severity and to levels of stool SCFAs, inflammatory, and permeability markers. For instance, in PD patients, higher microbial diversity was associated with more severe motor symptoms, whereas in controls, higher diversity was inversely related to SCFA levels and certain inflammatory markers.

At the taxonomic level, abundance of classic SCFA-producing genera (Butyricicoccus, Roseburia, Clostridium sensu stricto) positively correlated with SCFA levels, while Akkermansia, Escherichia/Shigella, and Bifidobacterium (in PD patients) showed negative associations. Notably, the Prevotella enterotype was less common in PD and associated with higher butyric acid and lower NGAL and zonulin, suggesting a potential protective role.

Key implications

This study provides strong evidence for a disrupted gut environment in PD characterized by reduced SCFA production, increased intestinal inflammation, and altered microbial composition and diversity. The lack of correlation between stool and plasma inflammatory markers underscores the importance of compartment-specific evaluation in PD biomarker research. The associations between lower SCFA levels, gut inflammation, and earlier PD onset suggest that microbiome-mediated mechanisms may influence disease progression and present modifiable targets. Additionally, the distinct microbial associations found in PD versus controls (such as the negative relationship between Bifidobacterium and butyric acid in PD) highlight potential shifts in functional roles of key taxa in disease states. These findings argue for further longitudinal studies and multi-omics approaches to better understand the causal pathways and support the development of microbiome-based interventions or biomarkers for PD.

Citation

Aho VTE, Houser MC, Pereira PAB, Chang J, Rudi K, Paulin L, Hertzberg V, Auvinen P, Tansey MG, Scheperjans F. Relationships of gut microbiota, short-chain fatty acids, inflammation, and the gut barrier in Parkinson’s disease. Molecular Neurodegeneration. 2021;16:6. doi:10.1186/s13024-021-00427-6