User:Pripriva/Neurodegenerative Diseases and the Gut-Brain Axis

= Gut-Brain Axis (GBA) and Parkinson's Disease (PD) = Parkinson's Disease (PD), the second most common neurodegenerative disease after Alzheimer's Disease, affects 1% of people over 60 years of age. In the past three decades, the number of PD cases has doubled globally from 2.5 million in 1990 to 6.1 million in 2016. As of 2022, there are ~10 million PD cases globally. In the United States, the estimated prevalence of PD by 2030 is estimated will be ~1.24 million. These numbers are expected to increase as life expectancy and the age of the general population increase. PD is a multisystem and multifactorial disease, where many factors, such as the environment, gut, lifestyle and genetics, play a crucial role in the onset and progression of the disease.

PD Pathology
The neuropathological hallmarks of PD include the loss of dopaminergic neurons in the substantia nigra pars compacta region of the brain (shown in Figure 1) and the presence of aggregated alpha-synuclein. Under physiological conditions, alpha-synuclein, a protein encoded by the SNCA gene, is found at the synapses of neurons where it regulates synaptic signaling and plasticity, such as inhibiting neurotransmitters release. It is most abundantly found in the brain and to a smaller extent in other tissues, such as the gut and heart. Under pathological conditions in PD, alpha-synuclein undergoes a conformational change, resulting in a misfolded insoluble protein that aggregates into beta-sheets and forms protein inclusions called Lewy Bodies. Aggregated alpha-synuclein loses its ability to bind at the membrane, disrupting cellular processes and synaptic formation. It is hypothesized to propagate in a prion-like manner, spreading within and between other cells, eventually leading to neurodegeneration or cell death and promoting the progression of PD (Figure 1). These pathological changes are also been found peripherally (outside of the central nervous system), occurring even in earlier stages of PD. However, the mechanisms involved in these changes are not well understood. 

The brain spread SPREAD pattern OF ALPHA SYN IN THE BRAIN maybe move this to the gut alpha syn pathology section

PD Symptomology
The clinical presentation of PD include both motor and non-motor symptoms summarized in Figure 2. The cardinal motor symptoms of PD are as rigidity, abnormal gait, resting tremor, stiffness, bradykinesia, and dystonia. Non-motor symptoms include autonomic dysfunction, olfaction dysfunction, cognitive impairment, urinogenital complications, hyposmia, depression, asymmetric vague shoulder pain, gastrointestinal (GI) dysfunction, and REM sleep behavior disorder (acting out dreams during REM). In early stages of PD, non-motor symptoms occur prior to the onset of motor symptoms, contributing to a delay in PD diagnosis and even misdiagnosis in up to 15% of cases. And by the time motor symptoms appear and treatment is initiated, there is greater than 50% dopaminergic neuronal cell loss in the substantia nigra. Therefore, non-motor symptoms are valuable biomarkers of early stages of PD and provide a potential avenue for early disease diagnosis and early intervention. <--disease modifying strategies

Gastrointestinal dysfunction in PD
GI symptoms can occur up to 20 years prior to the onset of clinical motor symptoms. The potential involvement of the gut in PD was first suggested over 200 years ago by James Parkinson, when he states, “a disordered state of the stomach and bowels may induce a morbid action in a part of the medulla spinalis”. However, the crosstalk between the gut and the brain was not fully understood and was not extensively explored in PD until more recently in the last two decades. There is increasing evidence that demonstrates the role of gastrointestinal (GI) dysfunction in the initiation of neurodegeneration as well as the pathogenesis of PD.

Increasing evidence from studies done in PD patients and animal models further demonstrate a significant role of gastrointestinal (GI) dysfunction has in the initiation and pathogenesis of PD. 

Anatomy
The GI tract is divided into two main sections - upper and lower. As illustrated in Figure 3 (from the top down), the upper GI tract consists of the mouth, esophagus, stomach and small intestine (duodenum, jejunum, and ileum). The lower GI tract is made up of the large intestine (colon, cecum, rectum) and the anus. On the tissue level, the GI tract is made up of four layers - mucosa, submucosa, muscularis and serosa (Figure__). Within these layers, the myenteric plexus and the submucosal plexus are part of the Enteric Nervous System (ENS), which is distributed throughout the GI tract.

GBA refers to the bidirectional interaction between the enteric nervous system (the gut) and the central nervous system (the brain and spinal cord) that occurs via the vagal nerve of the parasympathetic nervous system as shown in Figure ___.

neuro-immune-endocrine mediators. (CITE 2015: The gut-brain axis: interactions between enteric microbiota, central and enteric nervous systems).The GBA involves many systems such as the immune system (figure 4)

Function
Major functions of the GI tract include motility, secretion, digestion, absorption, excretion and protection. The main responsibility of the upper GI tract (stomach and small intestine) is digestion and absorption. In the lower GI tract, the large intestine primarily focuses on preparing for elimination by removing fluids (desiccation) and compacting the waste, while the sigmoid colon and rectum provide storage before excretion.

The muscularis layer of the GI tract contracts to mix and move ingested contents along. The mucosa layer serves as a barrier and gatekeeper to the external environment. The movement across and the integrity of this barrier are controlled by epithelial cells containing tight junctions and adherens junctions. The mucosa layer, being at the lumen innermost part of the GI tract, also communicates with the gut microbiota, monitoring its composition via secretary IgA and immune sensing antimicrobial peptides. As such, it serves as a immunological barrier, containing the immune cells (macrophages, B-cells and T-cells) found within the lamina propia.

Secretions and blood flow are regulated by the submucosal plexus, while muscle contractions are controlled by the myenteric plexus. The ENS communicates with the central nervous system (CNS) via the vagus nerve of the parasympathetic nervous system (PNS). The vagus nerve is ~90% afferent, mainly communicating information away from the ENS to the CNS. The CNS in response regulates GI motility via vagal reflexes. Nonetheless, this motility is maintained even if the connection between the ENS and CNS is severed.

As ingested content moves throughout the GI tract, there are also accessory organs, such as the pancreas, liver, salivary glands and gallbladder (shown in Figure 3), that contribute to the digestion process. Food digestion begins in the mouth through mastication or chewing, breaking the content into smaller pieces. The bolus of food is then propelled from the pharynx to the stomach by the esophagus via esophageal peristalsis (waves of coordinated muscle contractions that move ingested content along the GI tract). Enzymes and gastric acid in the stomach further digest the bolus of food, which gets termed chyme. Chyme continues to move into the small intestine, where nutrients are absorbed from the digestion of fats, proteins and carbohydrates. Once it reaches the large intestine, it is called feces and becomes further prepared for elimination followed by storage in the colon and expulsion from the rectum.

include the timing and expand on the symptoms more
more symptoms -->


 * upper GI symptoms:
 * what is upper? dysphasia is a swallowing impairment that results in inadequate mastication (chewing), body mass index below than 20, weight loss and malnutrition. Drooling is also common as a result of the difficulties with swallowing and not with saliva secretion, which is actually decreased in PD.
 * oropharyngeal dysphagia: Swallowing involves three phases - oral, pharyngeal, esophageal, of which the first two are affected in oropharyngeal dysphagia, resulting in choking/ aspiration. This motor symptom affects 35% of patients and worsens with the disease progression, but does improve with medication.
 * gastroparesis: This results in the paralysis of the stomach that contributes to 50% of patients feeling bloated and full while 15% experience vomiting and nausea.
 * Diagnostic tool: Solid meal scintigraphy as well as a breath test are used to measure gastric emptying time (GET), which is prolonged in PD patients. Other methods include MRI based imaging and electromagnetic capsule system.
 * small intestinal bacterial overgrowth (SIBO): results in diarrhea, abdominal discomfort, bloating and can lead to absorption issues of PD medications.


 * lower GI symptoms: constipation is characterized by straining during defecation or having less than 3 bowel movements per week, which occurs in 40-50% of PD patients. --> I HAVE REALLY NICE IMAGES FOR THIS BUT i NEED TO CONFIRM THAT THE REVIEW (JOURNAL OF CLINICAL MEDICINE) IS CREATIVE COMMONS

Other symptoms include:

- Hypersalivation from decreased swallowing frequency

- increased risk of ulcer disease

-Inflammatory bowel disease and irritable bowel syndrome

''' Maybe have a table that summarizes the main and "other" symptoms? '''

--> I MAY COMBINE THIS WITH THE TREATMENT table below AND JUST MAKE A HUGE TABLE - THOUGHTS?

---This is a good idea if you can also fill in the treatment for the other symptoms like IBD and Ulcer.

GI Pathology
Alpha-synuclein is .... and found in the brain, but is also found in the gut.... as well as the GI ENS.

pathology can also be found in the gut of PD patients. There are many in vivo studies that have shown alpha-synuclein pathology in biopsies of intestinal tissue from PD patients. Pathology is also seen in the motor nucleus of vagus (DMV) in the medulla oblongata of the brain and associated vagal nerve - areas that connect to the GI. Specifically in the GI tract (Figure 3), pathology has a rostral-caudal gradient pattern where there is no pathology in the upper esophagus, but the most affected regions are the lower esophagus (contributing to the swallowing symptoms) and the stomach with sparse pathology in the colon.

Paper that talks about alpha syn studies in the gut in PD patients.

include microbiota transfer of alpha-syn

Braak's hypothesis
spread of alpha-syn in the gut to the brain

Alpha-synuclein transmission from Gut to Brain There is a lower risk in PD with truncal vagotomy, DEFINE LATER. Animal models via injections alpha-synuclein fibrils into the gut further supported the hypothesis of retrograde spreading of pathology. These studies further support Braak's hypothesis, a dual-hit hypothesis, which proposes that alpha-synuclein aggregation occurs peripherally, such as in the gut, prior to spreading to the brain. Figure 5 shows the alpha-synuclein prion like transmission from the gut, through the vagus nerve to where it connects at the base of the brain. Figure 6 shows the spread from the base of the brain throughout the brain.

Animal studies maybe include under Braak's
Many animal studies have reported the bi-directional movement of alpha-synuclein between the CNS and ENS. alpha-synuclein can be detected in the visceral motor nerve terminals and the preganglionic vagus nerve after the overexpression of alpha-synuclein in the midbrain of rats. Conversely, injections of preformed fibrils (pathological alpha-synuclein) into the colon of mice induced pathological changes in endogenous alpha-synuclein in the brainstem.

fecal transplants --> and

Altered Microbiota in PD
Gut barrier dysfunction

intestinal barrier and Inflammation

Markers of intestinal inflammation in PD

=== what it is found in --> The microbiome is composed of viruses, fungi, bacteria, === The microbiota is located throughout the GI tract.

group the bacteria

good or bad? for PD

major neuro inflam regulators they do

sex differences in microbiota (reoprodution)

TABLE HERE

The Impact of the Microbiota Dysfunction on the treatment of PD
Levadopa

- Since levodopa remains in the stomach longer due to the decreased gastric emptying, it gets converted into dopamine preventing it from being able to get into the brain via not being able to cross the BBB. Camicinal improves gastric emptying and hence better levodopa absorption into the brain.

- overgrowth of bacteria in the small intestine can metabolize levodopa into dopamine, preventing it from reaching the brain.

- There is mixed evidence if and how Helicobacter pylori reduces levodopa PK (absorption).

Genetics
Genome-wide association studies (GWAS) has linked several autosomal dominant (SNCA, LRRK2, GBA) and recessive (DJ-1, PINK1, PARK7, Parkin) mutations to the development of PD. However, there is variable penetrance in even the most common genetic risk factor of PD, LRRK, where <30% of carriers develop PD. This further suggests the involvement of other factors, such as the environment, in the increased vulnerability of developing the disease and in clinical presentation of symptoms of genetic forms of PD.


 * LRRK2: LRRK2 is expressed by innate and adaptive immune cells as well as by enteric neurons in the small intestine. After exposure to certain enteric pathogens, LRRK2 modulates the intestinal inflammatory response via the secretion of anti-microbial components. This is also seen in patients with Crohn's Disease, where greater levels of LRRK2 are found in the colon. In in vitro studies, LRRK2 mutation (G2019S) results in changes in intestinal gene expression in epithelial cells associated with GI impairment.
 * SNCA: many pathogens have been associated with with SNCA genes
 * PINK1 and PRKN: play role in clearance of damaged mitochondria and associated with PD mitochondria dysfunction. one study showed that knocking out PINK1 in mice results in an inflammatory response and PD like motor symptoms.

Aging
Aging, a major risk factor of PD, results in alterations to the gut microbiota's biodiversity, where it increases from infancy to adult and then begins to decline with age. There are many factors that contribute to this decline, such as the immune system, changes in lifestyle, the environment, medications, other diseases, and organ dysfunction. The decrease in biodiversity with age is associated with a decrease in intestinal epithelial barrier integrity, resulting in the leakage of neurotransmitters, LPS, SCFA and bacterial antigens as well as the breakdown of the neuro-immune system.

Inflammation
Neuroinflammation

It is hypothesized that intestinal and periphery inflammation further worsen the neuroinflammatory response on the disease progression. Some PD patients have intestinal inflammation as well as a breakdown of the intestinal epithelial barrier integrity,

Peripheral immune cells are found in the brains of patients with PD and

Helicobacter pylori infection and small intestinal bacterial overgrowth

INFECTION

markers of intestinal inflammation and barrier dysfunction

more info -->

Environmental Toxins
Geography, housing, Pathogens, neurotoxins and viruses

bacteria Antigens

There is an increased risk of PD with exposures to herbicides and pesticides on farms as well as bacteria found in drinking well water. Exposure to herbicides and pesticides in animal models result in movement disorder and the loss of dopaminergic neurons. In other animal studies, exposure to pesticide rotenone resulted in alpha synuclein being released from enteric neurons into the extracellular matrix. In vitro studies also showed that secreted alpha-synuclein can be undergo transneuronal retrograde movement, where it can be taken up by other neurons or non-neuronal cell types. Moreover, the gut of PD patients exposed to herbicides and pesticides showed an increase in xenobiotics degradation pathway.

Diet
There are many epidemiological studies that demonstrate the significant impact of diet on the onset and exacerbation of PD through its influence on the composition of the gut microbiota.

Mediterranean diet = reduced risk of PD

caffeine/ coffee drinkers

Other: smokers and coffee drinkers = lower risk of PD
smokers

sleep quality

Targeting the Microbiota-GBA in PD
- Fecal microbiota transplantation

- Postbiotics, small-molecule drugs and biologics

prebiotic info -->

Extra: (may be deleted later)
Blood brain barrier role? This was first suggested over 200 years ago by James Parkinson “a disordered state of the stomach and bowels may induce a morbid action in a part of the medulla spinalis”. Nonetheless, the important role of the GI in PD pathogenesis has only been more extensively explored in the last two decades.

are hard to recognize, especially when motor symptoms, such as tremor, are absent.

Non-motor symptoms begin in the earlier stages of PD (prodromal stage) prior to motor symptoms, contributing to a delay in PD diagnosis and even misdiagnosis in up to 15% of cases.

Such features can be potential early PD biomarkers used for early detection and early diagnosis of PD.

mitochondrial dysfunction as well as increased neuroinflammation, oxidative stress, and apoptosis