Non- Helicobacter pylori Helicobacters, a Treatable Provocateur of Parkinson's Disease: Hypothesis, Evidence and Species Specificity

Epidemiological and eradication trial evidence indicates that Helicobacter pylori, a major causative factor in peptic ulcer and gastric cancer, is a driver of the hypokinesia of Parkinson's disease (PD). Psychological (cognitive impairment, depression and anxiety) and gastrointestinal (peptic ulceration and constipation) PD features can precede the symptomatic onset of motor features by decades. We hypothesise that the non-H. pylori Helicobacters (NHPH), which have farm, companion and wild animals as their main hosts, can have a role in PD aetiopathogenesis. In those occupationally at risk of NHPH infection, we address whether there is increased mortality with PD, or depression or suicide. Our systematic review gave evidence that occupational exposure to animals/their products is associated with excess mortality with PD. Indeed, whilst livestock farming increased the risk, crop farming decreased it. Moreover, excess mortality from non-Hodgkin lymphoma in livestock farmers is compatible with NHPH being causal. Our scoping review showed that farmers, veterinarians and abattoir workers have an increased risk of depression and suicide; whether their depression is associated with being down the pathway to PD and/or the presence of Helicobacter infection needs investigation. Regarding Helicobacter species specificity, the link between the presence of NHPH in gastric biopsy and PD was described using a ureA polymerase chain reaction (PCR) assay, targeting the most-commonly named NHPH, H. suis. We describe its redesign and optimisation as a probe-based PCR, confirming the exclusion of H. pylori but not H. suis specificity (additionally identifying 6 species of a 22-NHPH-species panel). The exploration of the zoonotic hypothesis requires a non-invasive pan-Helicobacter PCR screen, allowing the detection and molecular grouping of Helicobacter species.