parkinson-gut-brain-axis-r4

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.