Intestinal Biomarkers and PD non-motor Phenotype Links: A Review

Clinical Overview

This case–control study of 95 adults with established Parkinson’s disease (PD) evaluated how gut inflammation, microbiota composition, and genetic predisposition to inflammatory bowel disease (IBD) relate to PD manifestations. Fecal calprotectin, six short-chain fatty acids (SCFAs), 16S rRNA-based microbiota diversity, and polygenic risk scores (PRS) for IBD subtypes and PD were quantified from stool and blood. Nearly half of participants reported constipation. Constipation was associated with higher non-motor scores (UPDRSI, UPDRSII, NMSQ_total; adjusted p≤0.03), elevated fecal calprotectin, longer disease duration, lower microbial alpha-diversity, and lower fecal SCFAs. Cluster analysis identified an intestinally “pro-inflammatory/low-diversity” PD subtype with more severe non-motor symptoms and higher IBD-related PRS.

What was reviewed and who was studied

The paper reports a cross-sectional analysis of 95 neurologist-confirmed PD patients (mean age 69 years, 37.9% female) from a German tertiary center (disease duration median 82 months). Stool was used to measure fecal calprotectin and SCFAs (acetic, propionic, butyric, isobutyric, valeric, isovaleric acids) and to profile gut microbiota via 16S rRNA sequencing; blood-derived genotypes generated PRS for IBD (CD, UC, IBD overall) and PD. Disease activity, constipation (NMSQ-5, CSS), and non-motor burden (UPDRS I–III, NMSQ_total, MMSE) were linked to these intestinal and genetic markers using multivariable regression and k-means clustering.

Major findings

Finding	Detail
Constipation and non-motor PD burden	Constipation (48.4% prevalence) was associated with higher UPDRSI (median 2 vs 1, p=0.008), UPDRSII (13 vs 10, p=0.005), and NMSQ_total (12 vs 9, p=3×10⁻⁴); associations with UPDRSI, UPDRSII, and NMSQ_total remained after adjustment (adj.p≤0.03).
Constipation severity and symptoms	Higher CSS scores correlated linearly with UPDRSI and NMSQ_total (adj.p=0.002 and 0.02), but not UPDRSIII, indicating selective linkage with non-motor rather than motor manifestations.
Fecal calprotectin and disease duration	Median fecal calprotectin was 56 μg/g stool. Calprotectin was higher in constipated patients (p=0.02), increased across constipation quartiles, and remained associated with longer PD duration after adjustment (adj.p=0.02).
SCFAs, microbiota diversity, and PD course	Higher SCFAs correlated with later PD onset, shorter disease duration, lower levodopa equivalent daily dose (LEDD), and higher Chao1/Shannon diversity; longer disease duration predicted lower SCFAs and lower alpha-diversity after adjustment.
Genetic risk and non-motor disability	Higher PRS-IBD and PRS-UC were independently associated with worse UPDRSII (adj.p=0.02 for both); PRS-PD and PRS-CD related to lower microbiota alpha-diversity but not to UPDRSII.
Intestinal inflammatory clusters	K-means clustering on PRS-CD, calprotectin, and Chao1 identified a cluster with higher PRS-CD/PRS-IBD, lower diversity, lower SCFAs, and more severe non-motor symptoms (UPDRSII, CSS, NMSQ_total), without age or onset differences. Microbiota in this cluster was enriched for Actinobacteria/Bifidobacteriaceae/Lactobacillaceae and depleted for Bacteroidetes/Prevotellaceae.

Implications for Microbial Metallomics

The study links gut inflammatory and microbial metabolic states (SCFA production and diversity) to PD non-motor phenotypes, defining intestinally inflamed PD subtypes that could, in future work, be interrogated for parallel shifts in microbial metal handling.

Concept	Implication
Elevated fecal calprotectin with constipation and longer PD duration	Demonstrates a chronic intestinal inflammatory milieu in a PD subgroup; metallomic studies could layer gut metal speciation onto this inflammatory axis to test whether intestinal metal handling co-segregates with PD phenotype.
Reduced microbial alpha-diversity in more symptomatic patients and high PRS-IBD	Suggests genetically primed, low-diversity ecosystems in PD may be more prone to inflammatory dysbiosis; integrating metallo-omics could identify whether loss of particular taxa coincides with loss of key metal-transforming functions.
Lower fecal SCFAs in the high-burden cluster	SCFA depletion marks a metabolically impaired microbiome in more symptomatic PD; future designs could assess whether SCFA-poor states coincide with altered microbial metal redox chemistry relevant to epithelial barrier and immune activation.
PRS-IBD/PRS-UC association with daily activity impairment	Genetic risk for gut inflammation stratifies PD non-motor severity, providing a host-genetic scaffold on which to map combined microbiome and metallomic signatures of gut–brain axis vulnerability.
Distinct microbiota taxa in the more inflamed cluster	Enrichment of Actinobacteria/Bifidobacteriaceae/Lactobacillaceae and depletion of Bacteroidetes/Prevotellaceae in high-risk patients defines clear compositional states where targeted metal–microbe interaction studies could be anchored.
Absence of direct metal measurements	The lack of metal or metalloid data highlights a critical gap; this biomarker framework is directly extensible to concurrent profiling of fecal and mucosal metal species alongside calprotectin, SCFAs, and diversity.

Limitations

The study is cross-sectional, limiting causal inference about whether intestinal inflammation and dysbiosis precede or follow PD worsening. Participants were required to consent and complete study tasks, under-representing patients with severe cognitive impairment and likely attenuating associations with cognition. All subjects were of European ancestry, and detailed data on diet, water intake, physical activity, and anti–TNF-α therapy were not collected, constraining adjustment for key constipation and inflammation determinants.

Future perspectives

Logical next steps include longitudinal follow-up of PD cohorts with repeated fecal calprotectin, SCFAs, and microbiota profiling to determine whether intestinal biomarkers predict incident PD or the trajectory of non-motor decline. Integration of additional fecal markers of permeability and inflammation already highlighted by the authors, alongside expanded clinical phenotyping (including cognitively impaired patients), would refine intestinally defined PD subtypes. Within this same framework, adding fecal and mucosal metal/metalloid speciation and redox profiling could test whether specific intestinal metallomic states track with the high-IBD-PRS, low-diversity, low-SCFA cluster identified here.

Key takeaways for Researchers and Clinicians

In adults with long-standing PD from a German tertiary center, constipation and higher non-motor symptom burden co-occur with elevated fecal calprotectin, reduced microbiota alpha-diversity, and lower fecal SCFAs, independent of age and disease duration. Genetic susceptibility to IBD, particularly via higher PRS-IBD and PRS-UC, aligns with worse UPDRSII scores, while cluster analysis isolates a PD subtype characterized by pro-inflammatory intestinal profiles, low diversity, low SCFAs, and enrichment of taxa previously associated with PD.

Methodologically, the combination of fecal biomarkers (calprotectin, SCFAs), 16S-based diversity metrics, and genome-wide PRS offers a tractable framework for gut-focused PD subtyping that could readily incorporate metallomic measurements. Clinically, these data support considering intestinal inflammation and dysmotility as targets for stratified interventions—such as microbiota-modulating or anti-inflammatory approaches—in PD patients with prominent non-motor symptoms. A concise translational hook is that “intestinal biomarker panels may help flag PD patients whose gut–brain axis, and potentially gut metallome, is most relevant to disease expression.”

Citation

Chai Z, Ouyang Y, Debebe A, et al. Intestinal biomarkers, microbiota composition, and genetic predisposition to inflammatory bowel disease as predictors of Parkinson’s disease manifestation. Journal of Parkinson’s Disease. 2025;15(4):766–779. doi:10.1177/1877718X251328567