Gastrointestinal dysfunction in Parkinson’s disease

: gut microbiota, inflammation and endophenotypes

1. To review the available literature on GID, gastrointestinal barriers to levodopa transport and absorption, gut dysbiosis, gut-brain axis, and use of probiotics in PD;

2. To investigate whether constipation – considered within the range of NMS as a clinical manifestation of GID and an established risk factor for PD development - is also a biomarker of disease progression;

3. To investigate whether intake of a four-strain probiotic (SymproveTM) in patients with PD and constipation leads to:

- Improvements of motor parameters;

- improvement of NMS other than constipation;

- improvements of quality of life;

by potentially inducing changes in the gut microbiota composition, reducing levels of intestinal and systemic inflammation and/or improving levodopa pharmacokinetics.

1. A narrative review on GID, gastrointestinal barriers to levodopa transport and absorption (incorporated publication), gut dysbiosis, gut-brain axis, and a systematic review on preclinical and clinical evidence on the use of probiotics in PD (incorporated publication);

2. A longitudinal analysis with a focus on data on constipation (as a marker of GID) and cognitive impairment (as a marker of disease progression) collected from 196 de novo patients with PD followed in the world largest non-motor-focused longitudinal cohort study, the National Institute for Health Research portfolio-adopted Non-motor International Longitudinal Study (NILS) led by Professor K. Ray Chaudhuri and coordinated by Ms A. Rizos from King's College Hospital and King's College London, United Kingdom. For external validity, the NILS results were further investigated in an additional and independent cohort of 423 de novo patients with PD patients from the Parkinson’s Progression Markers Initiative (PPMI) database (incorporated publication);

3. A three-month, randomised, double-blind, placebo-controlled, multicentre study evaluating the effect of SymproveTM versus placebo on gut microbiota composition, motor as well as NMS, markers of systemic inflammation, and levodopa pharmacokinetics in patients with PD and constipation (the SymPD study). This is one of the first studies of this nature with a wide range of motor and non-motor outcomes assessed.

1. A published narrative review indicated that GID is a common and troublesome aspect of PD with possible implications on levodopa pharmacokinetics and the development of motor and non-motor fluctuations. Recent clinical and preclinical evidence has also supported the role of the gut microbiota and gut-brain axis in the pathogenesis of PD; this has set the basis for the use of gut microbiota-modulating interventions, such as probiotics, in PD. A published systematic review suggested that despite the encouraging preclinical data, translational research has resulted in level I evidence for the use of probiotics to treat constipation only in PD without clinical evidence for their beneficial effect on other symptoms of PD.

2. Early presence of constipation is associated with faster development of cognitive impairment in two multicentre and independent cohorts of patients with de novo PD, suggesting a shared pathophysiological background. Constipation is a candidate biomarker for disease progression in PD.

3. Results from the SymPD study showed that 12-week intake of the four-strain probiotic SymproveTM was effective to beneficially enrich the gut microbiome and reduce ‘time-to-ON’ as well as total NMS burden (driven by improvements of constipation and fatigue) in patients with PD and constipation.