Introduction
Maintenance laxative is associated with stemming of temporal increase in rigidity in Parkinson’s disease (PD), indicative of underlying gut microbiome perturbation.1 Longer colonic transit has been linked to faecal short-chain-fatty acids (SCFAs) deficit outside PD, but not (possibly due to laxatives) within.2 We question whether a deficit in microbial SCFA producers might drive rigidity. Furthermore, is tremor, a dissimilar PD facet (phenotypic cluster analysis), unrelated to SCFA producers? Indeed, is the pathogenesis of different PD phenomena masked by using PD status as outcome. We contrast our findings with those for PD and Inflammatory Bowel Disease (IBD)3 status.
Aims & Methods
We analyse bacteriome predictor hierarchy for rigidity and tremor displacement, objectively quantified across diagnostic divide,1 using PacBio full length 16S rRNA gene sequencing in 75 participants with diagnosed PD, 112 without, with yearly repetition of stool samples (306). At each taxonomic rank, mixed effects linear regression models were used after logarithmic transformation of outcome. Measurement conditions and demographic factors were included as predictors, with subject as a random intercept. Initially, single variable analyses were performed for each taxon, considering linear, and first and second order fractional polynomials. Candidates were selected for consideration in multivariable models using p-values, selecting predictors and simplifying their relationship to outcome where indicated. Finally, excluded taxa were added into the model and any found important included.
Results
Predictor hierarchy approach revealed clear patterns along taxonomic branches from phylum to order for these two PD facets.
There was a protective association for phylum Desulfobactererota for rigidity, with an escalation to 21% decrease above 50th centile of abundance range, and a non-monotonic association for tremor with 49% decrease above 75th centile, but proceeded by a 28% increase upto 50th centile. Similar associations were traced to order level,
Phylum Bacillota also had a protective association for rigidity with 36% decrease across abundance range. Its class Clostrida showed a 47% decrease, and orders Peptostreptococcales–Tissierellales and Lachnospirales 29 and 51%, respectively. For tremor, an unconvincing association was seen with Bacillota, but Clostridia had a protective association with a 15% decrease. Its only order associated was Monoglobales with 39% decrease in tremor at abundance upto 50th centile, plateauing after in a non-monotonic relationship.
In contrast, in systematic review, the above taxa were not reported as associated with PD (33 papers) or IBD (23) status. However, within the Bacillota lineage, family Lachnospiraceae and genus Peptostreptococcus had, respectively, a protective association with IBD and a risk with Crohn’s disease.3
Conclusion
The non‑parallel progression of PD facets fits with different drivers and mediators. Bacillota predictors of rigidity are typical of their class Clostridia: abundant, well‑characterized obligate anaerobes, known to produce SCFAs and other fermentation products. In contrast, tremor predictor, Monoglobales, does not share the defining anaerobic feature, and currently its metabolite profile is unknown.
Regression framework used ensures that disease facets are outcome variables and confounded associations identified. Permutation multivariate analysis of variance, typically used in published literature, cannot account for confounding and is incompatible with causal frameworks.
References
- Augustin A, Guennec AL, Umamahesan C, et al.Faecal metabolite deficit, gut inflammation and diet in Parkinson's disease: Integrative analysis indicates inflammatory response syndrome. Clin Transl Med. 2023;13(1):e1152. doi: 10.1002/ctm2.1152.
- Augustin AD, Charlett A, Weller C, et al. Quantifying rigidity of Parkinson's disease in relation to laxative treatment: a service evaluation. Br J Clin Pharmacol. 2016;82(2):441-50. doi: 10.1111/bcp.12967.
- Khan I, Ullah N, Zha L, et al. Alteration of Gut Microbiota in Inflammatory Bowel Disease (IBD): Cause or Consequence? IBD Treatment Targeting the Gut Microbiome. Pathogens. 2019;8(3):126. doi: 10.3390/pathogens8030126.