The Role of Microbiota Gut-Brain Axis and Its Effect on Neurodegenerative Diseases

Introduction

Gut microbiota is described as the community of microorganisms residing in the human and animal digestive system. Various microorganisms such as bacteria, viruses, parasites, fungi, and more than 100 million bacteria, with over 3 million genes live in the gastrointestinal tract (Zhu et al., 2015). These microorganisms have developed a mutual symbiotic relationship with the human body, and over the years, research has found how these microbes can influence the human physiological systems throughout life by modulating gut motility, homeostasis, intestinal barrier and absorption of nutrients (Carabotti et al., 2015). Furthermore, microbes in the gut are also involved in bi-directional communication throughout the endocrine, nervous, and immune system, making up the gut-brain axis. The connection between the brain and gut is very intricate and it includes the enteric nervous system, the Vagus nerve, and the immune system. The gut bacteria consist of six major phyla; Bacteroidetes and Firmicutes being the dominant, followed by Proteobacteria, Actinomycetes, Verrucomicrobia, and Fusobacteria (Zhu et al., 2015). Age and diet have a significant impact on the microflora in the gut. In addition, the changes in the gut flora often result in changes in the gut barrier function resulting in increased secretion of toxic substances leading to diseases. The central nervous system (CNS) is intricately connected to the gastrointestinal tract and plays a role to regulate homeostasis and maintain healthy gut function. Dysbiosis can result in pathogenesis and can further progress nervous system related diseases such as Alzheimer’s disease, Parkinson’s, and Multiple Sclerosis (Fung et al., 2017). Recent research has provided a new direction to study various CNS diseases by studying the complex relationship between the gut and the brain. Further review will look at how the gut microbe interaction with human body affects the pathology of several neurodegenerative diseases.

Method

           Most experimental designs rely on mouse models to investigate the relationship between the microbiome in the gut and its effect on the overall body. The connection between disease pathogenesis and the intestinal microbiota comes from studies utilizing germ-free mouse models (Carding et al., 2015). The severity and the incidence of certain diseases are reduced under germ-free conditions, which is consistent with other studies done (Quigley 2017). The microbiota acts as a “trigger” for disease progression; however, to this date, scientists find it difficult to identify “pathogenic” strains of bacteria responsible for the diseases (Carding et al., 2015). To study intestinal bacteria closely, a fecal sample collection is often used, DNA is extracted, and bacteria are then identified (Cekanaviciute et al., 2017). There are three main techniques used to detect gut microbiota. First, being from the bacteria culture. Second, using molecular biology techniques which does not require a bacterial culture. Third, the most efficient technique, by using a high–throughput sequencing technology which looks at the specific DNA sequences. Stool sample culture is usually the most time-consuming, but the latter two are used to isolate bacterial DNA very efficiently and effectively (Zhu et al., 2017).

Literature review

Classification and function of different types of bacteria

The human intestinal microbiome includes about 100 trillion bacterial cells, some good and some bad, which account for more than 1000 different species making it highly diverse genetically and physiologically (Carding et al., 2015). The majority of the microorganisms belong to two types of phyla; Firmicutes, which account for 51% of the population and Bacteroidetes, which account for 48% of the intestinal population (Westfall et al., 2017).

The remaining constitutes the phyla; Proteobacteria, Actinobacteria, Fusobacteria, Spirochaetes, Verrucomicrobia, and Lentisphaerae (Westfall et al., 2017).

The gut microbiota functions to ferment indigestible carbohydrates into the three most abundant short-chain fatty acids (SCFA); acetate, propionate, and butyrate (Zhu et al., 2017). Acetate is produced as a byproduct by anaerobic bacteria in the gut; propionate is produced by Bacteroidetes and butyrate produced by Firmicutes (Zhu et al., 2018). These molecules are important to the human body as they can regulate immune function. For example, butyrate has anti-inflammatory properties, making it an important energy source for colonocytes (Zhu et al., 2018).  This molecule can generate intestinal regulatory T cells, which circulate throughout the body to maintain the blood-brain barrier (BBB), modulate the Central Nervous System (CNS) microglia activity, and maintain intestinal wall integrity (Westfall et al., 2017). The gastrointestinal microbiome is also able to help develop the gut-associated lymphoid tissue (GALT), with the thin mucosal surface, which acts as a permeable barrier to protect the body from invasion in the gut (Zhu et al., 2018). In the GALT, T regulatory cells and T killer cells can mature and suppress an autoimmune response from outside the gut (Chu et., al 2018). Therefore, it is very important for the human body to have a greater population of healthy bacteria, as the composition of various gut bacteria is required to maintain many physiological functions such as regulating host metabolism, homeostasis, neurological development, immune regulation, vitamin synthesis, and digestion. This intricate relationship between host and gut microbiota is vital in determining the health of each individual.

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Changes in the composition of intestinal microbiota depend on two main factors; Age and Diet. Studies have shown how different diets can cause significant changes in the human body. By examining fecal samples, researchers have found phyla Bacteroidetes, genera of Bacteroides were mainly associated in people who ate a diet rich in protein and animal fats, while genera Prevotella was associated with high carbohydrate diets (Zhu et al., 2017). Individuals with obesity are known to have an imbalance of gut bacteria, causing a predisposition to certain diseases (Westfall et al., 2017). There is a predominance of Firmicutes and a low proportion of Bacteroidetes in these individuals. This low proportion of bacteria might be involved in facilitating the growth of other phyla, which all compete for energy, resulting in dysbiosis (Westfall et al., 2017).

Aside from diet, age is another factor responsible for shifting the balance between various species of bacteria. As the function of each organ declines, it is usually accompanied by the development of inflammation. This can affect the composition of gut bacteria resulting in leakage of the gut and overall systemic inflammation. According to (Westfall et., al 2017) the proportions of Firmicutes and Bacteroidetes change with the increase in pathogenic strains such as Proteobacteria spp. And a decrease in beneficial strains such as Bifidobacteria spp. Due to changes in the composition of certain bacteria in the intestine, this can alleviate or prevent symptoms of neurodegenerative diseases.

Gut-Brain Axis and Routes of Communication

The gut-brain axis is a bi-directional signaling pathway between the gastrointestinal tract (GI) and central nervous system (CNS). This signaling pathway is involved in many functions such as the regulation of homeostasis, immune system, as well as the endocrine system. This pathway is regulated through the CNS, the enteric nervous system (ENS), and the Vagus nerve (Zhu et al., 2017). The main routes of communication include the ENS and CNS. The regulation of enteric nerves consists of four levels. The first level is involved solely in local regulation of enteric nerves. The ENS has divided into two nerve plexuses; myenteric and submucosal plexuses. Motor and sensory neurons connecting to the ENS are also involved in information integration and processing. The second level gets information from the CNS and ENS transmitted to the prevertebral ganglia (Zhu et al., 2017). The third level is the CNS; which transmits information to the ENS and also acts on the gastrointestinal effector cells through the actions of ANS (Zhu et al., 2017). It can also regulate information to the ENS by the neuroendocrine system, which can regulate smooth muscle, glands, and blood vessels (Zhu et al., 2017). Lastly, the fourth level consists of executive brain regions where information from the cortex and subcortical parts travel down towards specific areas of the brain stem nuclei from the basal ganglia (Zhu et al., 2017).

The Vagus nerve, which is the tenth cranial nerve, also interfaces with the parasympathetic system and can control many organs such as the heart, lungs, and the digestive tract. Gut bacteria can affect brain functions through the Vagus nerve (Fung et al., 2017). Studies have shown that after a vagotomy procedure in mice, gut bacteria are not able to influence behavioral changes seen in wildtype mice (Zhu et al., 2017). All of these levels of the neural network are the functional and structural basis that make up the microbiota-gut-brain axis.

Besides the nervous system, the gut and the brain can communicate through the immune system by cytokines and also by endocrine messages carried out by gut hormones (Zhu et al., 2017). The hypothalamic pituitary adrenal axis (HPA) is part of the neuroendocrine regulation. It is the central stress response system. The HPA can act on the adrenal glands, releasing various glucocorticoids, mineralocorticoids or catecholamines. All of these can alter the gut composition, which can affect immune responses (Zhu et al., 2017).

Lastly, gut bacteria can affect immunogenic factors by regulating the production of cytokines and interleukins (Zhu et al., 2017). They also regulate the function of lymphocytes and can affect antigen-presenting cells. Through these routes of communication, the GI tract can communicate with the brain, especially the CNS. Gut microbiota can influence neurological functions through these routes to affect human health (Zhu et al., 2017).

Gut Bacteria and Neurodegenerative diseases

Studies have shown that changes in gut microorganisms can lead to cognitive changes. This is often observed with individuals suffering from neurodegenerative disorders such as Alzheimer’s, Parkinson’s, and Multiple Sclerosis. Furthermore, cells in the gastrointestinal tract and microorganisms can regulate changes in chemical factors such as cytokines and interleukins (Fung et al., 2017). Gut bacteria are also able to produce harmful byproducts that damage the intestinal barrier, causing the release of toxic substances and proteins which enter the circulatory system (Zhu et al., 2017). With the advancement in sequencing and metagenomics, the study of

gut bacteria and its metabolism have demonstrated that microbial composition is significantly different from a patient who has Parkinson’s and Alzheimer’s diseases (Fung et al., 2017).

Various types of infections have been linked to neurodegenerative diseases.

According to (Quigley et al., 2017), patients suffering from Parkinson’s have a higher prevalence of small intestinal bacterial overgrowth with Helicobacter pylori being in greater number. Studies have also been linked with PD patients having a lower composition of anti-inflammatory genera such as Blautia, Faecalibacterium, Roseburia with a greater composition of pro-inflammatory bacteria such as Proteobacteria, Enterococcaceae, and Enterobacteriaceae (Quigley et al., 2017).  There is dysbiosis of gut bacteria observed in patients with Alzheimer’s, with suppression of anti-inflammatory bacteria such as Eubacterium rectale and an increase of pro-inflammatory bacteria, Escherichia and Shigella (Vogt et al., 2017). The adult microbiome is not very stable, and it’s affected by many factors which can lead to the progression of neurodegenerative disease. The bacteria can synthesize metabolites, which maintain a stable environment around them (Fung et al., 2017). Dysbiosis results in an imbalance of this stable microbiome; as a result, certain bacterium releases exogenous and endogenous toxic substances leading to inflammation due to immune response (Chu et al., 2018). The immune response is needed to regulate blood-brain barrier permeability, activate microglia, limit astrocyte pathogenicity, and express myelin genes(Quigley 2017). Patients suffering from autoimmune disease such as Multiple Sclerosis have been observed and data collected through experimentation on animal models shows gut dysbiosis in these subjects compared to controls. Release of various pro-inflammatory factors, cytokines, and interleukins have shown to contribute to MS pathology (Jangi et al., 2016).

Alzheimer’s Disease

   AD is associated with dementia and as a progressive neurodegenerative disease it worsens over time. Some symptoms of this disease involve difficulty in remembering recent events, the problem with speech, disorientation, mood swings, and behavioral issues. The cause for this disease is still unknown, but it is hypothesized that AD is caused by plaque buildup in the brain consisting of misfolded beta-amyloid fibrils, oligomers, and hyperphosphorylated tau proteins (Zhan et al., 2016). The amyloid plaques are composed of AB cleaved from APP. This transmembrane protein is important in physiological processes such as neuronal development, signaling, and transport (Vogt et al., 2017). It has been hypothesized that exposure to bacterial amyloid proteins in the gut can trigger changes and enhance the immune response to endogenous neural amyloid in the brain (Quigley 2017).

Studies have shown that plaque buildup is seen in various brain regions such as the cerebral cortex, locus coeruleus, and hippocampus (Vogt et al., 2017). Oxidative damage and inflammation are two conditions which aggravate neurodegenerative diseases. Recent studies have linked pathogenic microbes residing in the gut in the development and progression of AD pathology. One study compared the composition of the gut microbiome in participants with and without AD. Fecal samples were collected, and bacterial 16S rRNA gene sequencing of the DNA was performed to identify microorganisms (Zhan et al., 2016). Researchers found participants with AD had decreased microbial richness and diversity when compared to controls. They found a significantly different taxonomic composition of bacteria between the two groups; these functional alterations play an important role in immune activation and systemic inflammation through the gut-brain axis (Vogt et al., 2017).

Gut bacteria composition in Alzheimer’s

A recent study looked at gram-negative bacterial molecules and their association with AD neuropathology (Zhan et al.,2016). Lipopolysaccharides are made up of lipds and polysaccheries and are large molecules composed of O antigen These antigens are found in the outer membrance of gram negative bacterium. Previous studies reported gram-negative bacteria such as Escherichia coli could form amyloid plaques by reaching the brain through the systemic circulation (Zhan et al., 2016).In an experiment researchers took brain samples from gray and white matter  and looked at LPS biomarkers and E Coli DNA. E Coli and LPS levels were greater in AD brain compared to control brains. LPS was colocalized with stained amyloid plaques and vessels in the brain (Zhan et al., 2016). Previous studies demonstrated the late onset of AD could be associated with infection from Spirochetes, P gingivalis, Chlamydophila pneumonia, and Helicobacter pylori. This study was different than the previous because LPS colocalized with the amyloid plaque and with perivascular amyloid in AD brain.This data suggests that LPS could be associated with AD pathology (Vogt et al., 2017).

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To distinguish which bacteria are more prevalent in individuals with AD, researchers looked at fecal samples, and by sequencing, DNA found phylum Firmicutes were decreased in the AD group. Notably, the composition of Firmicutes was also reduced in individuals with type 2 diabetes and obesity. Diabetes and insulin resistance are associated with an increase in the risk of developing AD; insulin resistance is known to decrease cerebral glucose metabolism and increase amyloid deposition, which can increase the risk of AD. Fecal samples of participants with AD also showed an increase in phylum Bacteroidetes; an abundant group of gram-negative bacteria in the gut. A major component of these bacteria; LPScan trigger systemic inflammation. In addition, AD participants also exhibited decreased composition of Actinobacteria, members of the Bifidobacterium genus, are an integral part of the gut microbiome. They are associated with anti-inflammatory properties, decreased intestinal permeability, and are shown to decrease levels of LPS (Vogt et al., 2017).

As a result of dysbiosis, there is a disruption of the intestinal barrier, which leads to increased permeability of bacteria. This localization of bacteria often leads to immune response leading to inflammation. Constant excessive inflammation causes migration of polymorphonuclear cells from the circulation to the gut, proinflammatory cytokines and reactive oxygen species leading to neuronal cell death which can impair the function of phagocytosis leading to accumulation of amyloid proteins (Quigley 2017). As AD progresses, these neurodegenerative changes are often coupled with outside factors such as diet, drugs, and age-associated with reduced microbial diversity. Further studies should consider other confounding factors to study host-microbe interactions in the prevention of AD.

Parkinson’s Disease

PD is considered one of the most prevalent neurodegenerative disease affecting the central nervous system, mainly the motor system. PD is caused by loss of dopaminergic neurons in the substantia nigra located in the midbrain. This loss of neuronal cells in PD is usually linked to alpha-synuclein accumulation in the brain leading to a degeneration of dopaminergic neurons, which affects signaling in other regions of the brain (Fasano et al., 2013). Patients suffering from PD undergo symptoms associated with motor features such as tremor, bradykinesia, rigidity, and posture stability. As PD progresses, patients show non-motor symptoms related to gastrointestinal, sensory dysfunction, and depression. One major non-motor symptom seen in 80% of PD patients is constipation, and this has been linked to gut-brain communication through the enteric nervous system (Felice et al., 2016). In recent years, studies have shown the dysbiosis of gut bacteria linking to PD progression. Dysbiosis impacts gut permeability, which leads to bacterial and endotoxin translocation resulting in alpha-synuclein accumulation.

Patient’s who are suffering from PD, their bodies often undergo a significant amount of mitchondrial dysfunction, a higher amount of ROS resulting in oxidative stress, and lastly inflammation; as these are considered to be the main signs in patients suffering from PD. The aggregation of alpha-synuclein inside neurons can affect mitochondria activity leading to oxidative stress in the neuron. Low level of oxidative stress is critical to maintaining signaling pathways and gene transcription. Persistent altered levels of oxidative species lead to inflammation not only in the brain but also in the gastrointestinal mucous. Therefore, it is important to understand the relationship of the bidirectional communication between gut microbiota and the nervous system in the development of PD (Houser & Tansey 2017).

There is growing evidence of abnormal alpha-synuclein aggregation outside the brain in the enteric nervous system neurons of myenteric submucosal plexus of the gastrointestinal tract (Felice et al., 2016). Researchers looked at the concentration of this aggregation and followed the innervation pattern of the vague nerve. Animal studies have demonstrated, mice that underwent hemi vagotomy had less dopaminergic cell death and less alpha-synuclein in the nucleus of the Vagus nerve (Mulak & Bonaz 2015). It has been hypothesized that alpha-synuclein may travel from the intestine to the brain via the Vagus nerve, but further studies are required to understand the exact mechanisms. Furthermore, it has been known that gut microbes may act as a possible trigger for the buildup of intestinal alpha-synuclein. Bacteria produce proteins, whose shape can cause other protein to misfold and aggregate such as prions. These misfolded proteins can propagate from one cell to other, causing progression of the disease (Mulak & Bonaz 2015).

Gut bacteria composition in Parkinson’s disease

The composition of microbes in patients with PD compared to healthy individuals is highly variable. According to a study done by Keshavarizan et al., the composition of the fecal microbiome of 38 PD patients and 34 healthy controls showed an increase in anti-inflammatory butyrate-producing bacteria from genera Blautia and Roseburia in feces of controls than in PD patients. Furthermore, proinflammatory Proteobacteria were significantly abundant in mucous of PD patients than in controls. Looking at metagenomics, a large number of metabolism genes were not expressed in PD patients, whereas genes involved in LPS synthesis and bacterial secretion systems were significantly higher. This study provides evidence of dysbiosis, which triggered inflammation and resulted in progression of PD pathology (Keshavarizan et al., 2015).

There has been a concept of molecular mimicry that has been proposed in recent years. These pathways of molecular mimicry induced by bacterial proteins involve TLR2, NFkB, and others. It has been documented that inflammation in certain brain regions seen in PD is associated with upregulation of TLR2 signaling (Mulak & Bonza 2015). Studies show patients with PD have reduced number of Prevotellaceae; this results in a reduction of mucin synthesis and an increased intestinal permeability leading to systemic exposure of various pathogens and endotoxins responsible for alpha-synuclein aggregation, protein misfolding and mimicry (Mulak & Bonza 2015). The role of Helicobacter pylori has been studied extensively in patients with PD as gastric ulcers are associated with this bacterium. Studies have shown that Helicobacter pylori infection increases the risk of PD by triggering autoimmunity resulting in neuronal damage. Conversely, eradication of infection has been shown to slow down symptoms of PD. Currently, L-dopa is used in conjunction with medication to eradicate the bacterial infection and has been shown to increase the bioavailability of certain PD medications and reduce motor symptoms (Mulak & Bonza 2015).

Multiple Sclerosis

Multiple Sclerosis is a progressive neurological demyelinating disease in which the myelin sheath covering neurons in the white matter of the brain and spinal cord are damaged. Myelin sheath is lipid rich tissues that insulate nerve cell axons for faster transmission of electrical impulses. They are formed in the central nervous system by oligodendrocytes and in the peripheral nervous system by Schwann cells (Cekanaviciute et al., 2017). Patients suffering from MS have damaged nerve cells, which disrupts their ability to communicate. Signs and symptoms of MS differ in each individual depending on the lesions in the nervous system. Some common symptoms include loss of sensitivity, tingling, numbness, muscle weakness, blurred vision, visual problems, depression, and mood disorders (Cekanaviciute et al., 2017). There are four types of MS, and these are important in determining the severity and appropriate treatments. About 85% suffer from relapsing remitting MS having the first sign of symptoms in the early 20s (Chen et al., 2016). Most move to secondary progressive MS after ten to twenty years and shows signs of stiff, tight leg muscles, bowel, and bladder problems and have a harder time with depression and problem solving. The third type is the primary progressive MS which accounts for about 10 to 15% of patients and lastly progressive relapsing MS, where patients experience distinct attacks of symptoms, and these attacks get worse over time (Chen et al., 2016).

MS is an immune mediated disease; it involves both genetic and environmental factors. The exact cause of MS is still unknown to this day, but recent evidence points to a combination of factors which include immunologic factors and infection factors mainly starting from the gastrointestinal tract (Chen et al., 2016). Patients suffering from MS have an abnormal immune system with damage to CNS. There are many different pathways and cells involved in the abnormal immune response. The two main types of immune cells involved are T cells and B cells; T cells mature in the thymus and activate in the lymph system enter the CNS, release cytokines and chemicals that cause inflammation and damage (Chen et al., 2016).

Furthermore, T cells also help to activate B cells; these produce antibodies and activate other proteins which progress pathology of MS. Several studies have documented evidence how bacteria can regulate T cell mediated adaptive immune response and contribute to MS pathology. The recent study hypothesized that intestinal bacteria are important in impacting pathology of MS (Cekanaviciute et al., 2017). Microbiomes of 71 healthy and 71 MS patients were analyzed, and they found Akkermansia muciniphila and Acinetobacter calcoaceticus were found in abundance, previous studies have shown these induce pro inflammatory response in blood mononuclear cells, Conversely, there was a reduction in Parabacteroides distasonis and these have been documented to be stimulators of anti-inflammatory IL-10, CD4, CD25 and T reg cells (Cekanaviciute et al., 2017). Aside from immune system, environmental factors and genetics factors also play a role in the pathology of MS. Gut dysbiosis is caused due to many factors such as smoking, stress, alcohol addiction, western diet, and reduced vitamin D intake (Shahi et al., 2018).

Studies have been conducted on germ free mice to look at the different composition of bacteria and immunological responses. Monocolonization of germ free mice with specific bacteria has been a vital tool to study immune response. It has been documented that monocolonization can trigger CD25, FoxP3, and T reg cell differentiation, which alters MS phenotype. For example, colonization of P.distasonis is associated with T reg differentia in germ free mice to promote an anti-inflammatory response in immune cells of MS patients (Cekanaviciute et al., 2017). This study model also has its setback because it cannot completely represent bacterial functions within the microbiome. Also using mouse host, the microbes would have different functions in mice than in human cells (Cekanaviciute et al., 2017).

Gut bacteria composition in Multiple Sclerosis

Many studies have looked at gut composition in patients with MS. One study looked at fecal samples of 31 MS patients and used sequencing to look at the composition of various microbes. They found rich species diversity with Firmicutes accounting for 58.6%, Bacteroidetes with 40.4%, Proteobacteria with 0.7% and Actinobacteria with 0.1%. The overall species richness compared to healthy controls was not significantly different. However, this was the case only in patients who did not have active diseases and was in remission. Patients with active MS reported less diverse species richness compared to healthy controls (Chen et al., 2016). Researchers observed a lower abundance of Bacteroidetes, which is in agreement with previous studies that showed a significant decrease in Clostridium and Bacteroidetes (Jangi et al., 2016). Recent studies have shown an increase in Methanobrevibacter and Akkermansia and a decrease in Butyricimonas in MS patients. These bacteria have an immunoregulatory effect on mucin synthesis and changing it into short chain fatty acids. The Butyricimonas play a vital role in producing butyrate, which has anti inflammatory properties by inducing T reg cells in the gastrointestinal tract. Overall, patients with MS have gut dysbiosis, thus regulating microbiota could be a treatment option in the future for patients suffering from MS (Shahi et al., 2018).

Based on these observations, gut microbiota may be considered a factor in determining the severity and progression of MS. However, most studies done have a small sample size, in future large scale studies would be needed to look at the time and overall progression of MS and constantly monitoring the gut microbiome (Chen et al., 2016).

Conclusion

Gut flora is an ecological system which has a symbiotic relationship with humans as a host. The human body relies on the gut bacteria to ferment indigestible dietary fiber into SCFA. Others can synthesize crucial vitamins which aid in nutrition. Gut microbes are also important in protecting the host from pathogens and maintain a healthy immune system and intestinal integrity.  There are many factors, such as environment, genetics, age, and diet, which can influence the composition of the gastrointestinal tract. These changes can expose the human body to various diseases. Emerging evidence has shown how gut dysbiosis is linked to neurodegenerative diseases such as Alzheimer’s, Parkinson’s’, and Multiple sclerosis. One of the major factors affecting the human brain in these disorders is triggering inflammation due to protein misfolding and aggregation. Gut dysbiosis results in leakage of the intestinal barrier which exposes the human body to pathogens. These pathogens can reach the CNS and trigger immune responses resulting in the progression of neurodegenerative diseases. Future studies are looking at how drug therapy can balance gut dysbiosis to alleviate symptoms of these diseases.

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