Fight Aging!

The results of the clinical trial in Parkinson's disease patients outlined in today's open access paper are interesting on a number of levels. Analysis of the gut microbiome in patients with Parkinson's disease and Alzheimer's disease has shown that many patients have a characteristically different balance of microbial populations. Some of the specific microbes involved are thought to be harmful. This suggests a contributing role for age-related dysbiosis of the gut microbiome in neurodegenerative conditions. This may be due to an increase in chronic inflammation, or due to other mechanisms that involve specific microbial species and their activities. It was certainly reasonable to test rejuvenation of the gut microbiome via fecal microbiota transplant from a younger individual as a treatment for Parkinson's disease.

Unfortunately, the intervention did not work in this case; it did not improve Parkinson's symptoms. The researchers offer some thought on why this be due to the specific protocol used. More discovery and optimization may be needed in order to produce a useful change in the gut microbiome. Equally, it could be the case that in Parkinson's disease specifically, a poor gut microbiome causes early harm but becomes irrelevant in later stages of the condition. This would occur via seeding of misfolded, pathological α-synuclein that replicates and spreads from the gut to the brain via the nervous system. By the time symptoms show up, misfolded α-synuclein is entrenched in the brain and the gut microbiome no longer matters. In this scenario, fixing the gut microbiome is closing the barn door after the horse has already left.

Fecal Microbiota Transplantation for Treatment of Parkinson Disease

Gut dysfunction is a prevalent, frequently premotor symptom in Parkinson disease (PD) and associated with faster progression. Gut microbiota (GMB) impacts PD pathology and symptoms, and GMB composition is linked to motor and nonmotor symptoms as well as disease progression. Interventions targeting GMB, such as fecal microbiota transplantation (FMT), have shown promising symptomatic and potentially neuroprotective effects in PD animal models. The underlying mechanisms are incompletely understood, but could involve changes in metabolism and immune activation. While several randomized clinical trials have suggested efficacy of probiotics for constipation in PD, with respect to FMT, only small and mostly uncontrolled studies are published suggesting safety and improvement of motor and nonmotor symptoms irrespective of the method of application. This study aimed to assess safety and symptomatic efficacy of FMT in PD.

In the FMT group in this randomized clinical trial, neither clinically meaningful improvement of PD symptoms vs placebo nor major safety concerns were observed. Donor FMT achieved a sustained GMB change close to what is observed between individuals. In the placebo group, dissimilarity remained somewhat higher than observed longitudinally in healthy individuals, indicating a persistent moderate alteration of GMB composition in the placebo group. However, the GMB alterations did not translate into observable clinical or biomarker improvements. This apparent futility or, for some readouts even worsening, is in contrast to previously published reports. Several studies showed improved motor function, increased striatal dopamine and serotonin, and reduced dopaminergic neuron loss, neuroinflammation, and gut inflammation in PD rodent models after FMT. Mostly uncontrolled or small clinical studies suggested safety of FMT in PD irrespective of the method of application and the potential for improvement of motor and nonmotor symptoms.

This negative trial may give important insights to design future improved and hopefully successful trials of this intervention. There is no consensus on many practical aspects of FMT, such as selection of donors and recipients, preparation of the fecal material (e.g., aerobic or anaerobic conditions, concentration of cryoprotectant, and transferred amount), pretreatment with antibiotics, and method of application (eg, upper vs lower gastrointestinal tract and single vs multiple dosing). Also, for clinical trials, there is no consensus about the best comparator (e.g., inert placebo vs autotransplant). Encouraging results from the probiotics field suggest that impact on motor and nonmotor PD symptoms through GMB manipulation is possible, however.