Fecal Transplant a New Approach for Parkinson's Disease?

Fecal microbiota transplantation (FMT) for Parkinson's disease (PD) is safe but does not offer clinically meaningful improvement in symptoms, results of a new, randomized placebo-controlled trial show.

However, investigators discovered some interesting insights from the study, which they believe may help in designing future "improved, and hopefully successful, trials" with the intervention.

"Further studies — for example, through modified fecal microbiota transplantation approaches or bowel cleansing — are warranted," they concluded. 

The study was published online in JAMA Neurology on July 29. 

Gut Dysfunction an Early Symptom

Investigators led by Filip Scheperjans, MD, Helsinki University Hospital, Finland, explained that gut dysfunction is a prevalent, early symptom in PD and is associated with more rapid disease progression. 

Interventions targeting gut microbiota, such as FMT, have shown promising symptomatic, and potentially neuroprotective, effects in animal models of PD. 

Although several randomized clinical trials suggest efficacy of probiotics for PD-related constipation, only limited clinical information on FMT is available.

In the current trial, 48 patients with PD aged 35-75 years with mild to moderate symptoms and dysbiosis of fecal microbiota were randomized in a 2:1 ratio to receive FMT or placebo infused into the cecum via colonoscopy. 

All patients had whole-bowel lavage starting the day before the colonoscopy. Fecal microbiota transplantation was administered as a single-dose and without antibiotic pretreatment. 

Active treatment was a freeze-stored preparation of 30 g of feces from one of two donors who were healthy individuals without dysbiosis. The preparation was mixed with 150 mL of sterile physiologic saline and 20 mL of 85% glycerol for cryoprotection to improve viability of microbes. Placebo was the carrier solution alone, consisting of 180 mL of sterile physiologic saline and 20 mL of 85% glycerol.

The primary endpoint, a change in PD symptoms as assessed on the Unified Parkinson's Disease Rating Scale (UPDRS) at 6 months, did not differ between the two study groups.

Gastrointestinal adverse events were more frequent in the FMT group, occurring in 16 patients (53%) vs one patient (7%) in the placebo group. But no major safety concerns were observed.

Secondary outcomes and post hoc analyses showed a greater increase in dopaminergic medication, which may indicate faster disease progression, but also improvement in certain motor and nonmotor outcomes in the placebo group. 

Microbiota changes were more pronounced after FMT, but dysbiosis status was reversed more frequently in the placebo group. 

The researchers noted that the apparent futility in this trial is in contrast to several previous small clinical studies of fecal transplant that have suggested the potential for improvement of PD symptoms. 

In addition, encouraging results from the probiotics field suggest that an impact on motor and nonmotor PD symptoms through gut microbiota manipulation is possible. 

The researchers raised the possibility that the placebo procedure was not an inert comparator, given the relatively strong and sustained gut microbiota alteration and dysbiosis conversion observed in the placebo group, and suggested that the colonic cleansing procedure may also have had some beneficial effect. 

"It seems possible that, after cleansing of a dysbiotic gut microbiota, recolonization leads to a more physiologic gut microbiota composition with symptom improvement in the placebo group. This warrants further exploration of modified fecal microbiota transplantation approaches and bowel cleansing in Parkinson's disease," they conclude. 

Distinct Gut Microbiome 

In an accompanying editorial, Timothy R. Sampson, PhD, Emory University School of Medicine, Atlanta, pointed out that dozens of independent studies have now demonstrated a distinct gut microbiome composition associated with PD, and experimental data suggest that this has the capacity to incite inflammatory responses; degrade intestinal mucosa; and dysregulate a number of neuroactive and amyloidogenic molecules, which could contribute to the disease. 

He noted that three other small placebo-controlled studies of fecal transplantation in PD showed slightly more robust responses in the active treatment group, including improvements in UPDRS scores and gastrointestinal symptoms.

However, these studies tested different FMT procedures, including lyophilized oral capsules given at different dosing frequencies and either nasojejunal or colonic transfusion following a standard bowel preparation.

In addition, there is no consensus on pretransplant procedures, such as antibiotics or bowel clearance, and the choice of donor microbiome is probably essential, because there may be certain microbes required to shift the entire community, Sampson wrote. 

Understanding how microbial contributions directly relate to PD would identify individuals more likely to respond to peripheral interventions, and further exploration is needed to shed light on particular microbes that warrant targeting for either enrichment or depletion, he added. 

"Despite a lack of primary end point efficacy in this latest study, in-depth comparison across these studies may reveal opportunities to refine fecal microbiota transplantation approaches. Together, these studies will continue to refine the hypothesis of a microbial contribution to Parkinson's disease and reveal new therapeutic avenues," Sampson concluded.

'Planting Grass in a Yard Full of Weeds'

Commenting for Medscape Medical News, James Beck, PhD, chief scientific officer of the Parkinson's Foundation, New York, said that whether FMT are helpful remains to be determined. 

"The key question that needs to be solved is how to best perform these transplants. One issue is that you cannot plant grass when the yard is full of weeds. However, if you take too hard an approach killing the weeds — that is, with powerful antibiotics — you jeopardize the new grass, or in this case, the bacteria in the transplant. Solving that issue will be important as we consider whether this is effective or not."

Beck added that there is still much to be learned from research into the gut microbiota. "I am hopeful with additional effort we will have answers soon."