Constipation is a common complaint in patients with Parkinson’s disease (PD).
Fecal microbiome transplantation (FMT) and pre- and probiotics are potential options for treating constipation and restoring the microbiome of patients with Parkinson’s disease (PD), but scientists warn that clinical data are scarce, and more research is needed before supporting their use.
They present their findings in a review article in the Journal of Parkinson’s Disease.
The study found three key components in the rapid processing of emotions to quickly recognize a potential friend or foe – an ability essential to survival.
In this review, investigators evaluate the current state of knowledge about the potential for using FMT and pre- and probiotics to restore the normal microbial balance of the gut in PD patients and highlight the questions that still need to be answered.
FMT consists of transferring liquid filtrate feces from a healthy screened individual to a patient via nasogastric or nasoduodenal tube, enema, or colonoscope.
“FMT is an interesting option for restoring the changes in the microbiome of PD patients,” explained lead investigator Teus van Laar, MD, PhD, Director of the Parkinson Expertise Center Groningen, Department of Neurology, University Medical Center Groningen, University of Groningen, The Netherlands.
“It is an attractive technique because the administration is relatively simple and in general it has only a mild pattern of adverse effects. However, no rigorous clinical trials have been performed yet, which leaves multiple questions open about the presumed optimal content of FMT, the route of administration, the volume of FMT and the long-term effects.”
Administration of Lactobacillus and Bifidobacterium over a period of 4-12 weeks has repeatedly proven to be effective in treating constipation in PD. However, no solid clinical data are available about the possible effects of these probiotic treatments on motor symptoms or progression of PD.
Following promising results of prebiotics in animal studies, the first clinical trial on the use of FMT in PD patients is now underway at the University of Ghent (Belgium) and is scheduled to be completed by the end of 2019. With target recruitment of 40 PD patients and follow-up intervals of three months for up to one year, the trial will assess the development of PD symptoms.
Investigators noted that the trial’s inclusion criteria did not include or exclude constipation, which may complicate the interpretation of results.
The investigators recommend that FMT treatments in patients with PD should wait until better clinical data become available in order to select the right target populations and have good estimates of anticipated clinical effects. They highlight several knowledge gaps that need to be addressed first:
- FMT has not yet proven to be effective on motor symptoms or progression of PD
- Which route of administration of FMT is optimal
- Optimal donor content and frequency of FMT in PD
- Probiotics in PD have so far only been shown to have an effect on constipation
- Prebiotics have only been shown to have an effect in animal models and have not yet been tested in clinical trials
- Possible adverse effects and possible contra-indications of FMT are still unknown
In this review, investigators evaluate the current state of knowledge about the potential for using FMT and pre- and probiotics to restore the normal microbial balance of the gut in PD patients and highlight the questions that still need to be answered.
“FMT is a black box with too many unanswered questions at the moment, also with respect to safety concerns,” concluded Prof. van Laar.
“FMT or the use of pro- and prebiotics might become standard treatments in selected subgroups of PD patients in the future, but there are no good data yet in the public domain to support their use in PD patients.
We hope this review will activate colleagues to start proper research on this topic as soon as possible, rather than to begin therapy without conclusive clinical data.”
PD is a slowly progressive disorder that affects movement, muscle control and balance. It is the second most common age-related neurodegenerative disorder affecting about 3% of the population by the age of 65 and up to 5% of individuals over 85 years of age. Although the jury is still out, research has shown that it may actually begin in the enteric nervous system, the part of the autonomic nervous system that controls the gastrointestinal organs.
Parkinson’s disease (PD) is a debilitating neuromotor disorder affecting the nigrostriatal pathway in the midbrain. In the United States, PD is the second most common neurodegenerative disease.
It has an incidence of 14 per 100 000 people in the total population, however, the incidence increases to 160 per 100 000 in individuals 65 years and older.1 The lifetime risk of the disease is estimated to be 4.4% for men and 3.7% for women in the United States at birth.2
An estimated 1 million people are affected by this progressive disorder of the central nervous system (CNS). Globally, it is estimated that over 3 million patients may suffer from PD.3,4
PD is characterized by an array of motor symptoms ranging from tremors, rigidity, bradykinesia (often akinesia), and postural abnormalities (characterized by a shuffling gait).
Very common neuropsychiatric symptoms include depression, anxiety, apathy, cognitive decline, dementia, and psychosis. In addition, many non-neurological and non-motor symptoms of the gastrointestinal (GI) tract such as constipation, bloating, urinary incontinence, anosmia, and blunted affect are also observed.5–7
Histopathologically, the disease is associated with an accumulation of Lewy bodies, which are intra-cytoplasmic eosinophilic deposits composed of a misfolded protein, α-synuclein, in the basal ganglia neurons, especially in the caudate nucleus and the putamen.5
Based on available evidence, it has been postulated that depletion of the dopaminergic neurons in the substantia nigra in the midbrain results in a defect in the thalamic signaling to the cerebral cortex.5 This presumably results in the characteristic signs and symptoms of PD. The multiple factors associated with the pathogenesis and progression of PD are summarized in Table 1.
Table 1
Factors Associated With Pathogenesis and Progression of Parkinson’s Disease
| Phenomenon | Description | Degree of Association | Reference |
|---|---|---|---|
| Loss of dopaminergic activity | Silencing of neuronal dopamine generation in the substantia nigra | High: proximate cause, potentially reversible | Siderowf and Stern,8 2003 |
| Inclusion of Lewy bodies | Aggregation of α-synuclein | High: appears in the gut in the prodromal phase | |
| Sex differences | Greater prevalence among men | High: brain sex dimorphism | Gillies et al,9 2014 |
| Gut dysbiosis | Prodromal symptoms of PD | High: strong association with the microbiome | Minato et al,10 2017 |
| Aging | Advancing age | High-Moderate | |
| Environmental factors | Exposure to neurotoxins in the gut lead to loss of dopaminergic activity | Moderate | Yadav et al,11 2013 |
| Parkin ligase | Loss linked to mutations in the PRKN gene | Moderate: familial form of PD | Kitada et al,12 1998 |
| Glucagon-like peptide synthetic homolog: exenatide | Insulinotropic gut hormone; may have a protective function in the gut-brain axis | Moderate: ameliorates PD symptoms | Kim et al,13 2017 |
| SRY gene in the male Y chromosome | Regulates expression of tyrosine hydroxylase, rate-determining step to dopamine | Indeterminate | Dewing et al,14 2006 |
| Ultrasound thalamotomy | Effective in medication-refractory tremor-dominant PD | Indeterminate: may disrupt Lewy bodies | Bond et al,15 2017 |
PD, Parkinson’s disease; PRKN, parkin RBR E3 ubiquitin protein ligase; SRY, sex determining region Y.
The currently available treatment modalities for PD fall under medical, surgical or supplementary therapies.
The cornerstone of medical therapies for the treatment of PD include the combination of levodopa-carbidopa, which increases dopamine levels for neural transmission in the diseased areas of the brain.16
Additional pharmacological options include synthetic dopamine receptor agonists (eg, ropinirole and pramipexole) which stimulate dopamine receptor and catechol-O-methyl transferase inhibitors, and reduce dopamine and levodopa degradation outside the brain to increase its availability at the site of action at the midbrain.16
Similarly, monoamine oxidase inhibitors (eg, selegiline and rasagiline) prolong the duration of action of dopamine and its analogues, and leads to an improvement in the symptoms of PD.16
The current surgical options available for the treatment of PD are limited and rarely used. However, surgery is considered for patients who have fluctuating responses to levodopa treatment, intractable tremor, or dyskinesia.
Deep brain stimulation is a novel surgical method that involves an implant of electrodes in certain areas of the brain such as the sub-thalamic nuclei, and a pulse generator similar to an artificial pacemaker located just below the clavicle.17 Once in place, the pacemaker generates impulses to stimulate the implanted electrodes that in turn block the subthalamic signals, which improves motor symptoms of PD.17
The role of diet and nutritional supplements in the management of PD has also been studied. Mischley et al18 conducted a cross-sectional analysis study conducted in 1053 patients, which concluded that foods associated with a reduction in the progression of PD include fresh (uncanned or non-frozen) vegetables, fruits, nuts, seeds, herbs, non-fried fish, olive oil, coconut oil, and spices (P < 0.05). Supplements enacting a similar reduction in PD progression included CoQ10 and fish oil (P < 0.05).
Foods associated with the worsening of PD (P < 0.05) included canned fruits and vegetables, diet and non-diet soda, fried foods, beef, ice cream, yogurt, and cheese. Similarly, iron supplementation was associated with a faster progression of PD (P < 0.05).18 Polyphenols and flavonoids have been studied in a wide range of in vitro and in vivo models of neurological diseases. These nutrients, found in plants and microbes, have showcased a neuroprotective role in PD.19 Another prospective study in Sweden was conducted by Yang et al20 in 2 population-based cohorts (38 937 women and 45 837 men) to understand dietary antioxidants and the risk of PD. During a 14.9 year follow-up, 1329 PD cases were identified. The intake of vitamin E and beta-carotene was associated with a lower risk of PD in the identified patients.20
Modulators of Gut Dysbiosis, and the Potential Role of Probiotics and Fecal Microbiota Transplantation in Intestinal and Neurological Diseases
Probiotics
Probiotics are live microorganisms, delivered in the form of drug, food, supplements, and formula. A typical probiotic is comprised primarily of bacteria that occur naturally in the human gut. When administered in adequate strength and frequency, they may provide health benefits to the host.98
Most probiotics available commercially contain Lactobacillus, Bifidobacterium, or Saccharomyces spp.99,100 Fujiya et al101 reviewed 20 randomized controlled trials in 1004 subjects who had active IBD (ulcerative colitis [UC] and Crohn’s disease), exploring the role of probiotics as a therapeutic modality.
Treatment with probiotics demonstrated comparable results in clinical response, remission rate, and maintenance of remission of UC equivalent to mesalazine, but no statistical significance in these parameters was found in patients with Crohn’s disease.101
More recently, the potential benefits of probiotics have also been studied in irritable bowel syndrome (IBS) in 53 randomized control trials reviewed by Ford et al102 in a total of 5545 patients.
Although, patients with IBS who were treated with probiotics had a beneficial effect on global IBS symptoms, however there was no definitive evidence about their efficacy.102
Additionally in this review, 5 trials of similar design on the use of rifaximin in non-constipated IBS patients were evaluated, which suggested higher efficacy of rifaximin than placebo.102
Barichella et al103 studied the effect of probiotics and prebiotic fiber in constipation associated with PD. In this study, 120 patients were randomly assigned (2:1) to either fermented milk containing prebiotic fiber and probiotics (n = 80) or placebo (n = 40), once a day for 4 weeks period.103 The higher increase in number of complete bowel movements in group on probiotics was observed as compared to placebo (P = 0.002).103 The probiotic was composed of Streptococcus salivarius, subsp. thermophilus, Enterococcus faecium, Lactobacillus rhamnosus GG, Lactobacillus acidophilus, Lactobacillus plantarum, Lactobacillus paracasei, Lactobacillus delbrueckii, subsp. bulgaricus, and Bifidobacterium (fermented milk).103
Similarly, a randomized, double-blind placebo-controlled trial was conducted by Tamtaji et al,104 to evaluate clinical and metabolic response to probiotic administration in people with PD. In this study, subjects were randomly assigned (n = 30 each group) to receive 8 × 109 CFU/day probiotic or placebo, for a period of 12 weeks.104 Compared with placebo, group taking probiotics had a significant reduction (P = 0.010) in MDS-UPDRS (quantitative measure of clinical symptoms in PD) indicating favorable response to probiotic therapy in patients in PD.104 The probotic administered in this study was composed of Lactobacillus acidophilus, Bifidobacterium bifidum, Lactobacillus reuteri, and Lactobacillus fermentum in encaplsulated form.104
Messaoudi et al105 studied the psychological effects of members of the Bifidobacterium and Lactobacillus genera when administered as probiotics, the outcome suggesting a reduction in negative mood in healthy individuals.
Probiotics considered to confer mental health benefits through interaction with other commensal gut microbiota are known as psychobiotics. They exert anxiolytic and antidepressant effects altering emotional, cognitive, systemic and neural indices.106
This novel concept of psychobiotics has been studied in male mice, wherein probiotic administration resulted in a decrease in proinflammatory cytokines and increase in anti-inflammatory cytokines, ultimately demonstrating cognitive and emotional improvement.107,108 As previously discussed, low counts of B. fragilis and Bifidobacterium have been associated with worsening of PD.10
Fecal Microbiota Transplant
FMT is the process of delivering fecal material from healthy donors to prospective patients in order to reestablish a stable microbiota in the gut.109,110
The procedure of FMT has been well described previously.111–116 FMT has been shown to be safe and efficacious in the management of recurrent Clostridium difficile infection (RCDI).
This has encouraged investigations related to the effects of FMT in other diseases caused or exacerbated by gut dysbiosis. FMT has also been proposed as a treatment modality for IBD.
Jacob et al117 studied the efficacy and use of FMT as a novel treatment in patients with UC. In this study, a fecal preparation with high microbial diversity was prepared using stool from 2 donors, and the clinical endpoint was response, remission and mucosal healing at week four.117
Seven out of 20 patients who received FMT showed a clinical response, with 3 subjects in remission and 2 demonstrating mucosal healing.117 Mucosal healing was assessed by mucosal CD4+ T cell analysis, which showed reduction in type 1 helper T cells and regulatory T cells post-FMT.117
Similarly, Costello et al118 reported results from a randomized, double-blinded clinical trial in 73 adults with mild to moderately active UC. Patients were randomized to receive either donor FMT (dFMT; n = 38) or autologous FMT (prepared from their own stool; n = 35).118 The dFMT sample was a combination of stool from 3 to 4 extensively screened healthy donors and was prepared anaerobically.118
The treatment was well tolerated and at the end of 8 weeks, 32% (12 out of 38 patients) who had received dFMT achieved a primary outcome of steroid-free remission as compared with 9% (3 out of 35 patients) who had received autologous FMT.118
Secondary outcome in the form of clinical response was achieved in 55% (21 out of 38 patients) of the dFMT treatment group compared with 23% (8 out of 35 patients) of the autologous FMT group.118
At the end of 1 year, 42% (5 out of 12 patients) who had achieved remission at 8 weeks maintained remission.118 There have been 3 additional randomized clinical trials of FMT in UC, which showed similar promising outcomes.119–121
The beneficial effects of this therapy have also been explored in IBS. In a double-blinded, randomized, placebo-controlled, parallel-group, single center trial, FMT (n = 55) was compared with placebo (n = 28) for symptom relief in 83 patients with IBS.122 The patients with IBS who received FMT showed considerable improvement in their clinical presentation as compared to the placebo group, though results were not statistically significant.122
Additionally, in a randomized, double-blind placebo-controlled study by Halkjær et al,123 FMT failed to provide symptom relief as compared to placebo in patient with IBS. However, the gut microbiota composition changes were observed in FMT group.123
The limitation in the study design was inclusion of all IBS subtypes, duration of treatment and quantity of fecal microbiota transplanted to the patient.123 Larger studies with better stratification of patients of IBS and standardization of FMT are required to examine the role of FMT in IBS.
More recently, there has been a growing interest of the benefits of FMT in GI as well as non-GI diseases.
The evidence for treatment of neurological disorders with FMT is limited. However, more recently, case series of patients of multiple aclerosis (MS),124 myoclonus-dystonia,125 autism,126,127 depression,128,129 and chronic fatigue syndrome130 successfully treated with FMT have opened new horizons for more promising trials in defining FMT as a potential treatment for such conditions (Table 2).
Frémont et al131 published a study of successful cure rate of 70% patient in a study of 60 cases of chronic fatigue syndrome, also known as myalgic encephalomyelitis, having received FMT. Furthermore, human and animal models have been developed to show a role of gut dysbiosis in the etiopathogenesis of MS.
A case report of 3 patients with MS demonstrated marked remission of both diarrheal and neurological symptoms after receiving FMT.124
Table 2
Summary of Neuropsychiatric Disorders Associated With Gut Microbiota Dysbiosis
| Neuropsychiatric disorder | Reference | Study type |
|---|---|---|
| Parkinson’s disease | Borody et al,92 2009 | Case report |
| Multiple sclerosis | Borody et al,124 2011 | Case reporta |
| Myoclonus-dystonia | Borody et al,125 2011 | Case reporta |
| Autism | Finegold et al,132 2002 | Observational study |
| Song et al,133 2004 | Observational study | |
| Chronic fatigue syndrome | Borody et al,130 2012 | Cohort studya |
| Frémont et al,131 2013 | Observational study |
aFecal microbiota transplantation used in these studies.
In light of these findings, it is possible that FMT could play a role in the modulation of PD and its progression. In addition, conclusions drawn from the analysis of microbiota present in healthy FMT donor samples could be valuable in identifying microbes that may confer beneficial physical and mental effects on the host. Use of these microbes in the form of probiotics may also be a novel treatment modality for PD.
Role of Fecal Microbiota Transplant in Parkinson’s Disease
To date, the role of FMT has not been examined in PD patients. The close relationship amongst factors such as gut dysbiosis, increased intestinal permeability and associated neurological dysfunction suggest that the gut microbiota modification may provide a potential therapeutic option in these group of patients.134
This suggestion is based on recently published studies which suggest significant alterations in gut microbiota in recipients of FMT. These administrations of FMT in RCDI patients restores the gut microbiome to a profile resembling that of a healthy individual.13
5 We have postulated long term administration of FMT may provide a novel therapeutic modality to patients with PD. The rationale for the efficacy of FMT in human diseases stems from recent reports showing that gut microbial dysbiosis resulting in inflammation and disruption of the tight junctions (known as “leaky gut”) leading to the absorption of bacterial toxins and cascade of biochemical, microbial and immunological changes which results in range of both GI and non-GI diseases and disorders.34
Based on the growing evidence pointing to a role of gut dysbiosis in the pathogenesis of PD, it seems prudent that additional prospective well controlled clinical trials are conducted for the evaluation of FMT as a treatment for debilitating neurological diseases.
Ongoing Research
A clinical trial is in progress to evaluate FMT as a therapeutic modality in the management of PD.136
In this trial (US Clinical Trial No. NCT03026231), DuPont136 are planning to characterize the intestinal microbiome in PD.
Further aims are to evaluate the safety of lyophilized PRIM-DJ2727 given orally, and to identify fecal microbiome changes following weekly administration of this biological preparation in subjects with PD.136
Microbial diversity in fecal samples will be indicated by the Shannon Diversity Index, and richness in fecal samples will be indicated by the number of taxonomies per participant and the most abundant phylum in each fecal sample.136
Clinically, the study evaluates neurologic function as indicated by the score on MDS-UPDRS and quality of life as indicated by a score on the self-survey Parkinson’s Disease Questionnaire 39, and memory as assessed by a score on the Montreal cognitive assessment.136 Although the safety, efficacy, and required quantity of lyophilized FMT capsules have been studied in mouse model in the setting of RCDI with an excellent cure rate,137 the amount and number of repeated administrations of lyophilized capsules required in humans and for PD need to be further explored in a prospective clinical trial.
There is a growing need for well controlled randomized double-blind clinical trials to establish the role of FMT and probiotics in the treatment of not only PD but other chronic degenerative neurological disorders as well.
Summary
- PD is a neurodegenerative α-synucleopathy affecting nigrostriatal pathway in the midbrain, characterized by an array of motor, neuropsychiatric and GI symptoms.
- Recent studies have suggested a link between PD and inflammation in GI tract. Inflammatory changes have been observed in these group of patients of PD in ENS, vagus nerve branches along with changes in the microbiome of the gut.
- Mechanisms which have been demonstrated to play a potential role in pathogenesis of PD include; evidence of inflammation in the CNS and the ENS, along with leaky gut, gut dysbiosis, molecular mimicry, and inflammaging.
- Several studies have linked changes in gut microbiome with associated symptoms of PD as well as UPDRS.
- Probiotics and FMT are being explored as a therapeutic modality in various GI and non-GI disorders with gut dysbiosis.
- Since current pharmacotherapy options are limited in PD patients, we have postulated that long term administration of tailored probiotics and/or FMT may provide a novel noninvasive therapeutic modality to PD patients. However, long term well controlled double blinded clinical trials will be needed to access the clinical efficacy of these therapeutic modalities in PD patients.
Conclusions
Several lines of evidence point to developing links between the GI microbiome and the CNS in humans. The wide range of evidence extends from (1) an anecdotal case report, wherein a patient with symptoms of PD noted marked improvement on antibiotics presumably due to modulation of his bacterial microbiome;92 (2) detection of abnormalities in the GI microbiome (gut dysbiosis) in patients with PD;89,92,93 and (3) the discovery of inflammatory changes in the intestinal mucosa, ENS, vagus nerve, and the brain of patients with PD. Furthermore, the mouse model studies have substantiated the growing web of links between the pathological changes in the brain of patients with PD and their GI tract and its resident microbiota. These remarkable observations have inspired several studies intended to evaluate the modulatory role of genetically-tailored and scientifically customized probiotics in patients with PD. Additionally, a well-controlled clinical trial of lyophilized FMT capsules is currently in progress in patients with PD.136 These studies along with future developments in this field will shed some more light on the emerging complex and intricate relationship between the gut microbiome and the CNS including the human brain and associated disorders.
Source:
IOS Press
Media Contacts:
Diana Murray – IOS Press
Image Source:
The image is in the public domain.
Original Research: Open access
“Faecal Transplantation, Pro- and Prebiotics in Parkinson’s Disease; Hope or Hype?”. Teus van Laar et al.
Human Brain Mapping doi:10.3233/JPD-191802.
