The role of the microbiome in health and human disease has emerged at the forefront of medicine in the 21st century. Over the last 2 decades evidence has emerged to suggest that inflammation-derived oxidative damage and cytokine induced toxicity may play a significant role in the neuronal damage associated with Parkinson’s disease (PD). Presence of pro-inflammatory cytokines and T cell infiltration has been observed in the brain parenchyma of patients with PD. Furthermore, evidence for inflammatory changes has been reported in the enteric nervous system, the vagus nerve branches and glial cells. The presence of α-synuclein deposits in the post-mortem brain biopsy in patients with PD has further substantiated the role of inflammation in PD. It has been suggested that the α-synuclein misfolding might begin in the gut and spread “prion like” via the vagus nerve into lower brainstem and ultimately to the midbrain; this is known as the Braak hypothesis. It is noteworthy that the presence of gastrointestinal symptoms (constipation, dysphagia, and hypersalivation), altered gut microbiota and leaky gut have been observed in PD patients several years prior to the clinical onset of the disease. These clinical observations have been supported by in vitro studies in mice as well, demonstrating the role of genetic (α-synuclein overexpression) and environmental (gut dysbiosis) factors in the pathogenesis of PD. The restoration of the gut microbiome in patients with PD may alter the clinical progression of PD and this alteration can be accomplished by carefully designed studies using customized probiotics and fecal microbiota transplantation.
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.
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 (
Although an array of medical and surgical interventions are available for the treatment of PD, a comprehensive management strategy to prevent the progression of the disease is far from a reality. Most patients on long-term dopamine replacement therapy develop a resurgence of symptoms such as disabling dyskinesia, occasional psychosis, and/or characteristic disease-related symptoms such as tremors and rigidity.21,22 Many patients also develop dopamineresistant-motor and non-motor symptoms after years of treatment, and become poor candidates for further medial therapy. Finally, none of these modalities have been known to alter the natural history of the disease after the onset of symptoms.22 Therefore, new therapeutic modalities are needed in the future, not only to prevent disease progression but also to find a cure for PD. In this review, we have focused on the potential role of modulation of gut microbiota in an attempt to attenuate associated inflammation in the gut, enteric nervous system (ENS), and CNS. Recent observations linking inflammation in the CNS, ENS, and GI tract to gut dysbiosis have raised the possibility of new treatment modalities in PD. These include cultured or genetically engineered “tailor-made” probiotics and long-term administration of fecal microbiota transplant (FMT) to restore normal gut microbiota to slow the progression of PD.
PD is a slowly progressing disorder, but this progression is highly variable from patient to patient. Life expectancy is marginally reduced.23 Death is usually the result of complications from impaired movement such as a fall with fracture leading to immobility, aspiration from severe dysphagia, and bowel obstruction from poor gut motility. Prognosis is generally based on favorable indicators, which include prominent tremors without significant rigidity, absence of gait disorder or bradykinesia, normal cognition, and positive attitude. Negative indicators include postural instability and bradykinesia without tremor, recurrent episodes of falling, apathy, cognitive decline, depression and/or anxiety, dysphagia, and orthostatic hypotension. In the last decade, there has been an increase of research demonstrating the benefit of exercise on managing the motor symptoms of PD. There is a need for early identification of these indicators to provide therapy that can modulate the disease process favorably. Probiotics and FMT may play a role in reducing the progression of the disease and improve psychomotor and neurological symptoms.
A possible role of glial cell dysregulation and its association with inflammation has also been demonstrated in the CNS of patients with PD.24 Devos et al25 evaluated 19 PD patients and 14 age-matched controls to look for inflammatory and glial cell markers in their intestinal biopsies. They found evidence of increased inflammatory cytokines such as IL-6 and IL-1β and enhanced expression of glial cell markers (ie, glial fibrillary acidic protein [GFAP] and SRY-Box 10 [Sox-10]) using real time polymerase chain reaction. These findings have pointed towards the involvement of the gut-brain axis in the pathogenesis of PD.25 These investigators however, did not find a correlation between the levels of pro-inflammatory cytokines or glial cell markers with disease severity, GI symptoms or cumulative lifetime dose of L-dopa.25 Several factors such as the presence of glial cell markers in the myenteric and Auerbach’s plexus in the intestinal mucosa, and increased glial cell dysfunction and oxidative stress in the Substantia Nigra pars compacta of patients of PD provide possible links between the development of inflammation in the nervous system and PD.24
Increased levels of pro-inflammatory cytokines such as IL-6 and TNF-α have been observed in the cerebrospinal fluid of patients with PD.26–28 There has been growing evidence to show that oxidative stress and cytokine-dependent toxicity could play a role in the pathogenesis of neuronal damage in the substantia nigra.29,30 Brochard et al29 have reported increased infiltration of reactive lymphocytes in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treated mice, which has further strengthened this claim.
A study conducted by Sampson et al31 provides in vivo evidence to support a similar hypothesis of colonic inflammation in the pathogenesis of PD. The study involved germ-free mice and wild type mice. Each category was further subdivided to either specific pathogen free or α-synuclein overexpressing (ASO) mice. A series of tests of gross motor and fine motor function indicated a significantly higher risk of motor impairment and development of disease symptoms in the specific pathogen free and the ASO varieties.31 Moreover, it was shown that transplanting fecal microbiota from PD patients demonstrating gut dysbiosis to mice leads to a significantly higher chance of developing disease symptoms as compared to transplanting fecal microbiota from healthy donors.31 The risk was significantly higher in ASO varieties as compared to the wild type varieties. The study thus concluded that both genetic (ASO overexpression) and environmental (gut dysbiosis) factors play a role in the pathogenesis of PD.31
These emerging pieces of evidence suggest that inflammation may have a substantial role in the development and progression of PD. Furthermore, gut dysbiosis may precede glial cell dysfunction several years before the onset of the disease.25
The ENS is the intrinsic nervous system of the GI tract that works autonomously. It is comprised of thousands of small ganglia throughout the GI tract. Each ganglion consists of neurons and glial cells but lacks a connective tissue element. The enteric glial cells have been studied extensively for a possible role in pathogenesis of the disease. Studies have shown that enteric glial cells are similar to glial cells present in the CNS of humans both structurally and functionally.22,23 As discussed before, these enteric glial cells are immunoreactive to canonical astrocyte markers (GFAP and S100-β).32,33 Recent studies suggest that enteric glial cell dysfunction in PD patients may be playing an important role modulating increased gut permeability. Forsyth et al34 conducted a very important study to evaluate changes in the intestinal permeability in PD patients as compared to healthy subjects. In this study, they obtained mucosal biopsies from intestines (sigmoid colon) and used immunochemistry tools to assess bacterial translocation, to detect nitrotyrosine (oxidative stress), and α-synuclein.34 In addition, they also evaluated serum markers of endotoxin exposure including lipopolysaccharide binding protein (LBP).34 The outcome of the study highlighted a significant increase in intestinal permeability in PD patients, which correlated with increased intestinal mucosa staining for
There are 2 major sets of ganglia found in the ENS: the myenteric ganglia and the submucosal ganglia. The parasympathetic and sympathetic nervous systems send input to the ENS and receive input from afferent nerve fibers via the vagus nerve and spinal afferent pathways. Due to these 2-way pathways, the ENS interacts with sympathetic prevertebral ganglia and the CNS.37
The increasing interest in the role of non-neurological factors in the pathogenesis of PD stems from the fact that only 10% of PD cases have a strong genetic predisposition.38 To date there is growing evidence of the role of environmental and intrinsic host factors in its pathophysiology.31 The “gut microbiota” refers to the totality of the microbial species residing in our gut, including bacteria, fungi, archaea, and viruses. The current data suggest that there are over 100 trillion species of microbes harbored by the gut environment.39 Over a period of time the gut microbiome signature of each individual becomes unique due to environmental and host factors.40 The gut-brain axis is believed to be a bidirectional signaling pathway between the gut and the brain.41–44 The intestinal barrier consists of multiple layers that include the gut flora and external mucus layer, epithelial layer, and lamina propria. In addition to its role in absorbing nutrients, the epithelial layer serves as a physical barrier against invading pathogens due to tight junctions between epithelial cells. The normal gut microbiome is non-pathogenic in nature, and its members coexist with the enterocytes, providing additional support in intestinal barrier function. Changes in the gut microbiome can potentially play a role in many neurological diseases and it has been reported that GI symptoms (constipation, dysphagia, hypersalivation and swallowing disorders) along with gut dysbiosis and leaky gut precede the onset of symptoms in autism, anxiety, depression and PD by 5–10 years.44–46
Intestinal barrier impairment leads to a spread of bacteria across the tight junctions into the mesenteric lymphoid tissue.47 This introduces new bacterial products to the lymphoid tissue, thereby activating mucosal immune cells to release inflammatory cytokines and vagal nervous system activation.47 These cascades of events may lead to the release of neuroactive peptides that modulate the CNS and ENS.48,49 Many patients suffer from GI symptoms such as constipation and bloating long before the onset of the hallmark motor symptoms of PD.50 Several researchers hypothesize that gut inflammation and deposition of aberrant α-synuclein fibrils in the ENS initiate the process that leads to a retrograde spread via the vagal and the glossopharyngeal nerve trunks to the neuronal tissue in the CNS (Figure).51,52 This is supported by the fact that α-synuclein deposits have been found early on, in the ENS of individuals with PD.53 However, a recent study by Lee et al,54 in patients with PD (n = 35) compared deposition of α-synuclein in intestinal mucosal ENS as compared to controls (n = 52) to assess GI dysfunction. In this study, the proportion of self-reported constipation and functional constipation was significantly higher in PD patients than in controls (
Louveau et al56 discovered a network of lymphatic vessels lining dural sinuses carrying both fluid and immune cells from cerebrospinal fluid. This observation opens the door to the possibility that cytokines from the GI tract may interact more with the CNS than previously understood. Any microbial dysbiosis that potentially triggers an inflammatory cascade in the CNS can potentially cause dysfunction of the immune system, leading to the development of neurodegenerative diseases like PD.
There has been increased interest in the recognition of the role of Toll-like receptors (TLRs) in the pathogenesis of PD. TLRs recognize conserved motifs found in microorganisms and initiate a cascade of immunological responses. TLRs are class of mammalian receptors that play a role in innate immunity and inflammation.57 Any overstimulation of the innate immune system due to stimuli like gut dysbiosis, along with “leaky gut” may provoke local and systemic inflammation, leading to enteric neuroglial activation and triggering of α-synuclein pathology. There are 13 identified TLRs in mammals, and ten have been noted in humans. TLRs are found in a variety of human tissues including immune system related cell types such as B cells, mast cells, NK cells, T-reg cells, macrophages, monocytes, dendritic cells, neutrophils, and basophils, along with non-immune cells such as epithelial cells and endothelial cells.58,59 They are also present on neurons and glial cells in both the PNS and CNS in humans.60 TLRs are involved in the activation of several downstream pathways of inflammation, including the nuclear factor-kappa B (NF-kB) pathway, mitogen-activated protein kinases (MAPK) pathway, and/or the interferon-regulatory factor (IRF) signaling pathway.61,62 α-synuclein is a small protein of the synuclein family of proteins.63 It is encoded by the SCNA gene, present on the long arm of chromosome 4 in humans64 and it is highly expressed in neural tissues, especially the CNS in humans, and primarily at presynaptic terminals.65 α-synuclein is considered to act as a “brake” in dopaminergic neurotransmission in humans.66 It shows dynamic changes in its conformation with relation to its environment and is considered to behave as a “natively unfolded” protein. α-synuclein is highly soluble and intrinsically disordered under normal conditions.67 Aggregation of α-synuclein is known to cause synucleinopathies, which are types of neurodegenerative disorders, including PD.68 Fellner et al69 showed in murine model studies that TLR4 interacts with α-synuclein, initiating microglial responses, which are associated with PD. In a transgenic mouse model study, the TLR4 ablation was found to be associated with impairment of the microglial phagocytic response to α-synuclein.69 This abnormality led to an accumulation of α-synuclein and more dopaminergic degeneration in the substantia nigra, suggesting a critical role of TLR4 in the clearance of α-synuclein.70
Molecular mimicry is a mechanism where foreign antigen(s) share nucleotide sequence or structural similarities with self-antigen(s). It has been widely studied in pathogenesis of viral diseases such as measles, herpes simplex virus, hepatitis B virus and in pathogenesis of autoimmune diseases. Neurodegenerative disorders like PD are characterized by deposition of α-synuclein in basal ganglia and putamen in CNS. It has been proposed by Friedland, that misfolding of these neuronal proteins found in PD, maybe triggered by molecular mimicry induced template cross-seeding similar to transmission of prion diseases in CNS.71 Cross-seeding is a phenomenon in which an endogenous or an exogenous protein may induce beta sheet misfolding of a host protein with a different primary structure.72 Spreading of these misfolded proteins seems to occur along neuronal connections through axonal membranes similar to prion disease like cell to cell spread with neuronal connectivity.72 The basis of molecular mimicry in PD may originate from the fact that the gut bacteria are known to produce extracellular amyloid, which can lead to activation of innate immune system. These events can potentially lead to priming of neuroinflammation and disease pathogenesis in CNS in PD patients via pathway of molecular mimcry.73–75
Ageing is associated with increased low grade chronic inflammation, called “inflammaging.” It is characterized by the presence of latent infections with viruses such as cytomegalovirus along with increased circulating levels of inflammatory markers like TNF-α, IL-6, and C-reactive protein.76 It appears with advancing age, microbiota composition in the gut changes as compared to young controls.77 And, these alterations in gut microbiota may be associated with higher levels of inflammatory mediators such as IL-6 and IL-8.78 Therefore it follows, altered gut microbiota in elderly may play a role in pathogenesis of PD via inflammaging.
It seems quite likely that gut dysbiosis associated with dietary changes may lead to the activation of various inflammatory cascades in the ENS, CNS, and vagus nerve, resulting in an accumulation of α-synuclein with subsequent dopaminergic degeneration in the substantia nigra.
Bacterial density varies markedly in the different parts of the human GI tract. The proximal GI tract is generally populated by Streptococcaceae and Lactobacillaceae (101–103), while the distal small bowel is home to Lactobacillaceae, Erysipelotrichaceae and Enterobacteriaceae (104–107). The colon is populated by bacterial families including Bacteriodaceae, Ruminococcaceae, Prevotellaceae, and Clostridiaceae (1011–1012).79–84 The stomach contains commensal species from the families Lactobacillaceae and Streptococcaceae in the epithelial layer.79–84 In the small intestine, Lactobacillaceae and segmented filamentous bacteria are the most abundant.79–84 The outer mucous layer of the colon has an abundance of
Gut dysbiosis is the alteration in structural and/or functional configuration of the gut microbiota causing disruption of gut homeostasis.85 This homeostasis can be disturbed by several factors such as dietary alterations, antibiotic exposure, infections, disease states, and aging. Scher et al84 studied the gut microbiota in patients of psoriatic arthritis and psoriasis of the skin. There was relative decrease in
Recently, an unusual case of early PD was treated with colchicine and antibiotics, which not only improved constipation, but reduced symptoms associated with PD as well. This isolated, anecdotal case observation suggests a possible link between gut dysbiosis and PD.92 Finally, a recent study conducted by Hill-Burns et al93 showed a significant disruption of the gut microbiome in PD. The study evaluated 197 cases of PD with matched 130 controls, and findings included significant alterations in the relative abundance of Bifidobacteriaceae, Christensenellaceae, Tissierellaceae, Lachnospiraceae, Lactobacillaceae, Pasteurellaceae, and Verrucomicrobiaceae.93
Further insight into the mechanism of involvement of the gut-brain axis has been provided by Bienenstock et al,94 who described a link between the deficiency of SCFA such as butyrate and propionate and the deficiency in neurotransmitters such as gamma-aminobutyric acid. In addition they suggested a link between altered host immune response and altered microglial signaling affecting CNS and peripheral nervous system functioning.94 More recently, Unger et al95 conducted an age- and sex-matched controlled trial in 34 subjects and 34 controls, demonstrating that the levels of SCFA and the gut microbiome differed significantly between patients with PD and control groups, leading to increased gut dysmotility, decreased neurotransmitter synthesis and ENS dysfunction in the diseased group. In a mouse model, SCFA were also shown to affect the expression of gut T-regulatory cells that lead to increased levels of cytokines like IL-10 and TGF-β, which play a crucial role in the neuro-immune inflammatory pathway.96 Larraufie et al97 showed that butyrate increases the TLR-dependent responses and their expression in a cellular model of human enteroendocrine L-cells. These findings provide strong evidence supporting the role of gut dysbiosis in patients with PD.
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
Messaoudi et al105 studied the psychological effects of members of the
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
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
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.
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.135 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.
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.
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.
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.
The authors would like to thank Dr Howard Weiss MD, Director of Parkinson’s Disease and Movement Disorder programs at the LifeBridge Health Brain and Spine Institute and Associate Professor of Neurology at the Johns Hopkins University School of Medicine, and Dr Tara Dutta MD, Assistant Professor of Neurology at the University of Maryland School of Medicine for their critical review and input for this manuscript. The authors would also like to thank the Harry and Jeanette Weinberg Foundation, the James and Carolyn Frenkil Foundation, the Eric Cowan Fund, and Friedman & Friedman, LLP for their generous support.