Diseases and Disorders

The Gut in Parkinson’s Disease Pathogenesis

Richard Zhu


Abstract

Parkinson’s disease (PD) is a prevalent neurodegenerative disease affecting millions globally [1]. Patients with the condition experience neuronal death in the central nervous system and can have both motor and non-motor symptoms. The gut microbiome and intestinal conditions have been shown to be linked to PD through the gut-brain axis. Changes in the gut could result in characteristic aspects of PD pathology, including alpha-synuclein and inflammation [2][3]. The interconnectedness of the two organ systems has resulted in two competing hypotheses for the disease progression [4]. Regardless, this burgeoning field of research will not only greatly improve understanding of a major nervous system condition, but will also lead to better treatments.
 

Parkinson’s Disease

Parkinson’s disease (PD) is a movement disorder that is the second most prevalent neurodegenerative condition globally [5]. The pathophysiology of this disease is characterized by a loss of dopaminergic neurons in the substantia nigra pars compacta , a structure that is involved in facilitating movement [6][7]. Other pathological hallmarks of PD include neuroinflammation and aggregations of alpha-synuclein (α-Syn) termed Lewy bodies and Lewy neurites present within neurons, which can disrupt cell function [8][9][10]. These pathological changes lead to the symptoms of PD. Classic motor symptoms include bradykinesia, tremors in a relaxed physical position (resting tremor), and rigidity [11]. Changes in an individual’s gait, ability to speak, balance, facial expressions, and handwriting can also be present [10][12]. There are often non-motor consequences of PD as well, such as dementia, depression, constipation, loss of smell (anosmia), and REM sleep behavior disorder [13][14].

 

Human Gut Microbiome & Gut-Brain Axis

The gut-brain axis (GBA) is a predominantly neural communication system that includes the central nervous system (CNS), enteric nervous system (ENS), and hypothalamic-pituitary-adrenal (HPA) axis [15]. The vagus nerve, in particular, forms a physical link between the CNS and ENS, allowing the bidirectional transmission of information [16]. The GBA thus provides a pathway for the gut microbiome to influence the nervous and endocrine systems. For example, lack of microbes within the gut is associated with decreased levels of brain-derived neurotrophic factor (BDNF) and increased amounts of adrenocorticotropic hormone, a key component of the HPA stress response [15][17][18]. BDNF, in particular, has been linked to various nervous system diseases, such as PD, multiple sclerosis, and Alzheimer’s disease [19][20]. Given such changes in chemical communication signals, it is reasonable that the GBA is implicated in multiple diseases such as anxiety, major depressive disorder, and autism spectrum disorder (ASD) [21][22]. 

Increased intestinal permeability to substances within the GI tract, immune dysfunction, and dysbiosis (imbalances in number and species of gut bacteria) have been specifically associated with ASD patients [23]. There is evidence for shifts in the two dominant gut microbe phyla: Bacteroidetes bacteria are increased, while Firmicutes are present at decreased levels compared to controls [23]. On a genus level, however, Clostridium bacteria (which are part of the Firmicutes phylum) have been shown to increase in patients with ASD and are linked to the gastrointestinal aspects of the disease [23].

 

The Gut’s Influence on PD

The GBA is thought to play a significant role in PD pathogenesis as well due to a variety of factors. In a retrospective study of PD patients (n=93), it was found that prodromal symptoms—which are symptoms that appear earlier than classical diagnostic symptoms—were present up to twenty-two years before the initial diagnosis [24]. Among these, constipation was present, on average, 16.8 years before the PD diagnosis [24]. This, in association with the greater than 50% prevalence of constipation in PD patients, helps to demonstrate the influence of gut dysfunction on PD [25]. 

In PD, like in ASD, intestinal permeability is increased compared to control groups. Such permeability is also correlated with the presence of α-Syn, a major pathological hallmark of PD, in the intestinal mucosa, which could point to a link between the gut and PD pathogenesis [2]. A recent study also demonstrated that α-Syn in the intestines of rats can be transported through the vagus nerve (which innervates many abdominal structures) and into the brain stem [26]. The prominent effects of the GBA on PD can be demonstrated by eliminating this connection and observing ensuing changes in the disease. Svensson et al. (2015) analyzed the risk of PD within patients who had superselective vagotomies (where only selected branches of the vagus nerve are severed), truncal vagotomies (where the entire nerve is severed), and no vagotomies. They found that the risk of PD was lower for patients who underwent truncal vagotomy and had their GBA disrupted [27].

Additionally, bacteria are thought to be involved in the increased permeability and development of the disease. E. coli, specifically, has been correlated with the increased gut permeability in those with PD, while a general increase in small intestinal bacterial overgrowths (SIBOs) is linked to PD. The overall gut microbial control of intestinal permeability through tight junction regulation is also well established [28]. 

Nonetheless, α-Syn and constipation are not the only PD signs linked to gut dysfunction. There is evidence to suggest that the neuroinflammation present in PD patients could also result from intestinal microbiota and inflammation. Studies have shown that inflammatory cytokines are increased in the guts of PD patients and that lipopolysaccharide (LPS), a bacterial endotoxin, in the blood of PD patients is linked to gut permeability [3]. How do these microbial and inflammatory alterations affect neuroinflammation? Studies in rodents have demonstrated that LPS can lead to increases in various cytokines within brain structures [29][30]. Gut inflammation in inflammatory bowel disease (IBD) also influences cognitive problems such as depression, and a similar situation of intestinal inflammation leading to systemic and neural inflammation could be present in PD [31]. Furthermore, the inflammation pathways in IBD are directly applicable to PD patients due to an association between these two diseases, with one study demonstrating that those with IBD have a 28% greater chance of developing PD [33]. Finally, peripheral inflammation has also been shown to increase neuroinflammatory responses in patients with rheumatoid arthritis, further hinting at the influence of inflammation outside the brain on conditions within the nervous system [34].

Evidence has thus demonstrated the influential role of the GBA in PD, with changes within the gut and its neural connections influencing the development of the neurodegenerative condition.

 

Controversy Over Hypotheses

In accordance with the previous discussion on the GBA’s influence on PD, a “gut-first” hypothesis has been proposed where the gut is initially dysfunctional [4]. As described previously, inflammation and α-Syn aggregates then travel via the vagus nerve and other pathways to the brain, where they can influence the development of PD pathology. This hypothesis is further supported by research in REM sleep behavior disorder (RBD), a prodromal and non-motor symptom associated with the gut-first hypothesis of PD development [4]. Patients with RBD are at high risk for neurodegenerative diseases, as over 80% will eventually develop PD or a related condition [35]. Borghammer et al. (2019) thus proposed that peripheral nervous system (PNS) damage should precede damage in the CNS since the inflammation and α-Syn aggregates are first generated in the periphery. This assertion was supported by their data, which showed that patients with RBD experienced increased damage to sympathetic and parasympathetic neurons (both aspects of the PNS) but decreased damage to the putamen (in the CNS) compared to PD patients [4]. Since the presence of RBD is thought to precede the onset of PD motor symptoms, these results provide evidence for the gut-first hypothesis.

However, other scientists contest the gut-first hypothesis, hypothesizing that the PD pathology first develops in the brain and subsequently spreads to other areas of the body, including the gut. This form of PD development is associated with PD patients without RBD, where there is an initial loss of putaminal dopaminergic neurons and a later increase in parasympathetic damage in the periphery [36].

As described, the precise developmental trajectory of PD is still a controversial topic, with evidence for both brain-first and gut-first hypotheses. Indeed, some scientists have proposed that the two can coexist, predicting that there are multiple subtypes of PD with different directional paths for the propagation of inflammation and α-Syn aggregates [36].

 

Concluding Remarks

The influence of the gut and intestinal microbiota on PD development is being increasingly investigated. The gut is implicated in a host of PD-related factors, ranging from vagotomies and prodromal symptoms to neuroinflammation and α-Syn. Not only does this increase understanding of the pathogenesis and risk factors for a prevalent and serious disease, but it also contributes to the development of treatments for PD. Probiotics have been shown to ameliorate the condition in animal models, and there is evidence for the benefits of fecal microbiota transplantation in PD patients [37][38]. The burgeoning view of a gut-influenced PD model could thus improve the lives of millions with the disease.


References


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Richard Zhu

Richard Zhu


Richard Zhu is a rising junior at the Peddie School in Hightstown, NJ. He is fascinated by all fields of biology, but is especially interested in neuroscience. He can often be found dissecting wildflowers or poring over neurosurgery videos. He was a National Bronze Medalist in the 2020 USA Biology Olympiad and is currently conducting bioinformatics research on horizontal gene transfer. When not immersed in science, he loves to swim and write poetry. His works (many of which are centered around neuroscience metaphors) have been recognized nationally in the Scholastic Art & Writing Awards and published in Polyphony Lit, the Bitter Fruit Review, and others.