Peripheral aetiopathogenic drivers and mediators of Parkinson's disease and co-morbidities: role of gastrointestinal microbiota

Abstract

We seek an aetiopathogenic model for the spectrum of Parkinson's disease (PD), functional bowel disease, depression and cognitive impairment. The adopted concept is that systemic immuno-inflammatory processes mediate neuro-inflammation. The model would be based on phenotype, exposome (including gastrointestinal microbiome), milieu (immuno-inflammatory and metabolome), human genetics and their interactions. It would enable a patient's position, to be understood in terms of drivers, perpetuators and mediators, and a future position, with and without intervention, predicted. Even the cardinal facets of PD may have different drivers: halting one may allow escape down subordinate pathways. Peptic ulceration is prodromal to PD. In our randomised placebo-controlled trial, hypokinesia improved over the year following biopsy-proven Helicobacter pylori eradication and rigidity worsened. This was independent of any (stable, long t½) antiparkinsonian medication. There are pointers to an autoimmune process: for example, surveillance-confirmed hypokinesia effect was indication specific. During surveillance, successive antimicrobial courses, other than for Helicobacter, were associated with cumulative increase in rigidity. Exhibiting laxatives appeared to stem the overall temporal increase, despite antiparkinsonian medication, in rigidity. Thus, intestinal dysbiosis may be a major source of bystander neuronal damage. There are biological gradients of objective measures of PD facets on circulating inflammatory markers and leucocyte subset counts. Moreover, lactulose hydrogen breath test positivity for small-intestinal bacterial overgrowth (present in two thirds of PD patients) is associated with the same subsets: higher natural killer and total CD4+ counts and lower neutrophils. With greater aetiopathogenic understanding, relatively low cost and on-the-shelf medication could have a major impact. A new generation of animal models, based on the gut microbiome, is envisaged.

Keywords: Aetiology; Autoimmunity; Bystander damage; Helicobacter; Intestinal dysbiosis; Parkinson’s and overlap diseases; Pathogenesis.

Fig. 1

Cumulative worsening of objectively measured rigidity with successive antimicrobial interventions in PD

Fig. 2

Schematic representation of the effect of H. pylori eradication on stride length and flexor rigidity in PD. Estimated mean time trends following successful blinded-active (black), open-active (grey) and placebo (dashed). Rejection of null hypothesis was based on double-blind protocol analysis of time trends in the primary outcome, stride length, reinforced by intention-to-treat analysis on its final measurement in blinded phase (p = 0.005), despite inclusion of the two proven eradication failures following blinded-active

Fig. 3

a Electron micrographs illustrating a cloud of irregular lysosomes in a duodenal enterocyte in a PD patient with SIBO, at low magnification (right) and higher (left). b Electron micrographs illustrating protein arrays encapsulated in a double membrane, at low magnification (left: multiple bodies) and higher (right: body amongst (normal) mitochondria), where arrays are seen longitudinally and in transverse section