A link between gut and brain axis is widely implicated in the causation of Parkinson’s disease. We take a joined-up approach to considering the gut as a target for therapeutic intervention to modify the disease process. We use continuous objective measurements of facets of Parkinson’s disease, in all participants, irrespective of having crossed the threshold for clinical diagnosis. Thus, the work is relevant to not just those with Parkinson’s disease status, but those down the pathway to the diagnosis. The run-in to can often be traced back for decades before clinical diagnosis. It can affect mental health (e.g. depression and anxiety) and physical well-being (e.g. constipation, falls and fractures). 

 

New findings1 were:- Deficits in stool short chain fatty acids and a cluster of bacterial products, including tryptophan, were linked to a sluggish large intestine. In the case of the tryptophan cluster, deficits were also linked to slowness and poverty of movement and tremor but not to muscle stiffness. Deficits in the stool of bacterial products with anti-inflammatory and anti-fungal properties were linked to a faster pulse. A marker of acute inflammatory cell migration to the gut, the stool calprotectin concentration, was forty four percent greater in Parkinson’s disease. Indeed, the value exceeded a cut-point for inflammatory bowel disease (e.g. ulcerative colitis and Crohn’s disease), in sixteen percent. A higher concentration of calprotectin in stool was associated with a higher dietary intake of maltose and sucrose. The emerging picture is of a whole-body inflammatory response consequent on intestinal inflammation. The clinical picture was described by deficits in products of the community of intestinal microbes essential to gut health. Limitations are that the statistical modelling did not encompass any direct inflammatory effect of the microbes dwelling in the gut lumen, or of microbes and their immunogenic components that had crossed over the gut wall barrier. These aspects are being addressed. The impact is that targeting Parkinson’s disease as a forme fruste of whole-body inflammatory response, consequent on intestinal inflammation and deficits in microbial products is indicated.  

​

We are also interested in a causal role for Helicobacter (a bacterial genus involved in stomach ulcers and cancer) in neuropsychiatric diseases started with Parkinson’s disease (PD). A systematic review1 addressed the inter-relationship of Helicobacter and PD, and the benefits of eradicating Helicobacter in PD. We found that the assumption that any benefit of Helicobacter eradication results from improved absorption of medication (especially levodopa) was unjustified. The inter-relationship between Helicobacter and PD was well-established. The virulence of Helicobacter pylori, the species for which humans are the primary host, influenced the risk, severity and progression of PD. Indeed, the birth cohort effect, the expected increasing risk based on birth year of having antibodies against the virulence marker was absent in PD, suggesting a causal link. Successful Helicobacter pylori eradication in PD was disease modifying (even in treatment-naïve patients), but not preventive. Poverty of movement regressed following eradication and overall motor severity lessened. Helicobacter pylori eradication may influence gastrointestinal community of microbes adversely, unlocking the next stage in the natural history, the development of rigidity. Failed eradication worsens hypokinesia, as does the presence/persistence of Helicobacter pylori at molecular level only. We conclude that Helicobacter pylori is one driver of PD.

 

Passage of a disease from animals to humans (zoonosis) might explain the excess mortality from PD and lymphoma in livestock, but not arable, farmers.2 Indeed, Helicobacter is causally associated with gastric lymphoma. We evaluated the pathological significance of NHPH, detected in DNA extracted from gastric-biopsy, using a polymerase chain reaction (PCR) assay, validated by genetic sequencing. We found that the relative-frequency, non-Helicobacter pylori Helicobacters (NHPH) to Helicobacter pylori, was ten-times greater in 60 patients with PD than in 256 controls. We explored, in these 60 patients, associations of presence/absence NHPH with all-cause mortality. NHPH had been detected in 19 of these on one or more occasion, only two having co-existent Helicobacter pylori. Hazard-of-death was twelve times greater with NHPH positivity than with negativity (Figure). Helicobacter pylori presence did not influence the hazard.  Regarding the potential zoonotic reservoir in the UK, the frequency of Helicobacter-like-organisms was determined in freshly-slaughtered pigs, nature being ascertained by sequencing. Organisms immunostaining for Helicobacter, with the corkscrew appearance typical of NHPH, were seen in 47 percent of 111 pig-stomachs. We conclude that NHPH is associated with all-cause mortality in PD and has a potential zoonotic reservoir.

​

​