Campaign run · Parkinson's disease
parkinson-gut-brain-axis-r3
Despite a decade of "gut-brain-axis in PD" review literature, no published study has formally tested whether the PD-gut-dysbiosis signature (Wallen 2022) is paralleled in DMNX-resident neuron transcriptomic dysregulation in PD (Fullard 2024 DMNX slab), and whether plasma DDC / immunometabolic proteomic markers (Bayati, Hällqvist) sit on the mechanistic path.
Status
- How far it got
- Stopped before planning
Stopped before writing any hypotheses: a dry-run test, a launch superseded by an immediate relaunch, a usage limit or a process failure.
- Why it stopped
This run stopped before the planning stage for an operational reason, not a scientific one. Runs in this group are dry-run tests, launches superseded by an immediate relaunch, runs that hit a usage limit, or one process failure. The released data do not say which of these applies to an individual run. No run in the campaign stopped before planning because data were unavailable.
- Recorded status
Stopped without a final status. The run stopped without recording a final status.
- Census class
Early stop. Census class is a label from an earlier, process-level census of the campaign. It does not map one-to-one onto the stages above. How the classes compare.
Research question
The sentence under the run id is quoted from this brief.
Full research brief given to the run
Wallen, Z.D., Demirkan, A., Twa, G., ..., Payami, H. (Nat Commun 13:6958, 2022; DOI 10.1038/s41467-022-34667-x; SRA PRJNA834801; Zenodo 7246185) reported that >30% of bacterial species, genes, and metabolic pathways are altered in PD vs. controls in a shotgun-metagenomic cohort of 490 PD + 234 controls, describing a "disease-permissive" PD microbiome (elevated opportunistic pathogens, reduced SCFA producers, dysregulated neuroactive signaling).
The Fullard / N M et al. multi-region snRNA-seq atlas (Sci Data 11:1274, 2024; CELLxGENE collection d5d0df8f-4eee-49d8-a221- a288f50a1590; 100 donors, 5 regions, 2.1M nuclei) includes the dorsal motor nucleus of the vagus (DMNX) — the Braak stage 1 region that receives vagal afferents from the gut and is among the earliest CNS sites of Lewy pathology.
Despite a decade of "gut-brain-axis in PD" review literature, no published study has formally tested whether the PD-gut-dysbiosis signature (Wallen 2022) is paralleled in DMNX-resident neuron transcriptomic dysregulation in PD (Fullard 2024 DMNX slab), and whether plasma DDC / immunometabolic proteomic markers (Bayati, Hällqvist) sit on the mechanistic path.
Because the Wallen and Fullard cohorts have no individual-donor overlap, this proposal does not test individual-level mediation but tests signature-level alignment via canonical correlation, pathway enrichment, and triple-omics meta-analysis. This is the informative design under public-data constraints.
Hypotheses (pre-registered):
H1 (primary — bacterial-pathway-to-DMNX-gene-pathway enrichment alignment): The Wallen 2022 PD-vs-ctrl differential MetaCyc pathway list (q < 0.05 from ANCOM-BC, top 100 by effect size) and the Fullard DMNX-derived PD-vs-ctrl Reactome/KEGG enrichment list (computed on per-donor pseudobulk, top 100) share significantly more pathway-membership genes / shared KEGG modules than expected by chance, with hypergeometric p < 0.01. Concretely: of the top 100 Wallen pathways, ≥ 15 map via KEGG-Reactome bridging to KEGG modules that also appear in the top 100 Fullard DMNX enriched modules, where chance expectation is ≈ 6 under a hypergeometric null.
H2 (secondary — vagal-target gene module alignment): A pre-defined "vagal-afferent target" gene module (vagal-sensory neuron markers + their transcriptional targets: TRPV1, ASIC3, P2RX2, CHRNA3, CHAT, PHOX2B, MNX1; their KEGG pathway "Cholinergic synapse" hsa04725 + "Vagal innervation" downstream targets) is differentially expressed in DMNX between PD and ctrl with FDR < 0.05, AND its expression direction is anti-correlated with the Wallen 2022 SCFA- producer abundance signature: PD = decreased SCFA producers + decreased vagal-target signal (Spearman ρ < -0.3 on random-pair permutation null over pseudo-cohort matched means).
H3 (secondary — neuroinflammatory cross-modality): DMNX microglia in the Fullard atlas show PD-vs-ctrl up-regulation of the LPS-response and pattern-recognition-receptor (TLR4, TLR2, CD14, NLRP3) module, AND the magnitude of this upregulation correlates positively with the Wallen 2022 LPS-producer abundance signature when both are normalised to z-scores within their respective cohorts.
H4 (secondary — protein-MR triangulation): Of the proteins nominated as causal for PD by the Storm 2025 Mendelian-randomisation analysis (UKB Olink × Nalls 2019 GWAS — public sumstats only, no individual-level UKB access required for the MR direction we test), the subset with bacterial-pathway-membership in Wallen 2022's PD- enriched pathways constitutes a "triangulated" panel; we test whether this panel size > expected by chance under permutation null over the full Storm-nominated protein set.
H5 (secondary — alternative axes): We pre-register and test 3 alternate gene modules (catecholamine biosynthesis, ferroptosis pathway, cuproptosis pathway) as negative controls — these should NOT show signature alignment with gut-microbiome signatures via the same H1 methodology. If they DO, the H1 signal is suspect.
A null finding on H1 would be informative — it would mean that signature-level gut-brain harmonisation is undetectable from bulk-pathway alignment alone, motivating per-individual multi-omic data acquisition (PPMI Project 196 + microbiome).
The research question comes from the topic's current research brief. All attempts at a topic share it; earlier attempts may have started from an earlier wording.