La consommation d'un régime riche en graisses provoque diverses maladies métaboliques, notamment le syndrome métabolique et le diabète de type 2 en développant une résistance à l'insuline et même en diminuant la production d'insuline.

Par exemple un bon moyen d'induire un syndrome de Parkinson chez les rats est de leur donner un régime alimentaire très riche en graisse. On a parfois qualifié la maladie d'Alzheimer comme étant diabète de type 3.

Un mystère est celui de la SLA (maladie de Charcot) où on a souvent une résistance à l'insuline, mais très rarement un diabète en comorbidité. Il semble aussi que l'existence protéines mal repliées dans le cytoplasme des malades soit liée à un stress du réticulum endoplasmique, un organe des cellules dont la fonction est justement de replier les protéines nouvellement produites par les ribosomes, avant leur expédition vers leur destination dans l'appareil de Golgi.

Une exposition à long terme aux acides gras saturés (acides gras saturés) dans les cellules β pancréatiques provoque une désensibilisation et une altération de la sécrétion d'insuline.

Par exemple, la consommation pendant trois mois de régime alimentaire très riche en graisse contenant de la graisse de porc et de l'huile de tournesol (80 % de graisse) réduit chez la souris la teneur en insuline des îlots pancréatiques (50 %), l'ARNm de la proinsuline (35 %), la biosynthèse et la sécrétion de l'insuline en réponse au glucose (50 %) , et l'oxydation du glucose.

Selon des recherches antérieures, WFS1 (syndrome de Wolfram 1) est impliqué dans la synthèse et la libération d'insuline, ainsi que dans la préservation de la masse des cellules β pancréatiques. Ce gène Wfs1 a été identifié pour la première fois par Wolfram et Wagener (1983) chez des patients atteints du syndrome de Wolfram (c.-à-dire un diabète sucré et une atrophie du nerf optique).

Le gène WFS1 exprime une glycoprotéine dans le réticulum endoplasmique (réticulum endoplasmique) des cellules β pancréatiques, du cœur, du placenta, des poumons et du cerveau.

Les acides gras saturés comme le palmitate induisent un stress réticulum endoplasmique. Des études ont montré qu'il existe une relation mutuelle entre le stress oxydatif et le stress réticulum endoplasmique. On l'acide trouve dans l'huile de palme, mais aussi dans toutes les graisses et huiles animales (beurre, fromage, lait et viande) ou végétales.

Pendant le stress du réticulum endoplasmique, l'expression de WFS1 augmente pour inhiber la signalisation de ce stress et ainsi empêcher l'apoptose (l'un des processus aboutissant à la mort de la cellule).

Etant donné le rôle de la protéine WFS1 dans le maintien de l'homéostasie du réticulum endoplasmique, on s'attend à ce que l'expression de cette protéine soit augmentée dans le réticulum endoplasmique des cellules β, et sa translocation vers le cytoplasme est réduite et conduit à une diminution du GSIS des îlots pancréatiques et teneur en insuline.

Bien que de nombreuses études aient étudié les effets de chaque régime alimentaire très riche en graisse et l'implication de WFS1 dans la synthèse et la sécrétion d'insuline, aucune étude n'a examiné l'interaction de régime alimentaire très riche en graisse et WFS1 en relation avec la synthèse et la sécrétion d'insuline et donc l'homéostasie du glucose.

Après le sevrage, les rats ont été divisés en six groupes et nourris avec un régime alimentaire normal et régime alimentaire très riche en graisse (30%) pendant 20 semaines, puis de l'acide 4-phényl butyrique (4-PBA, un inhibiteur du stress réticulum endoplasmique) a été administré. On notera qu'il s'agit d'une des deux composantes de l'AMX0035.

Après avoir effectué un test de tolérance au glucose, les animaux ont été disséqués et leurs pancréas ont été prélevés pour extraire l'réticulum endoplasmique, l'isolement des îlots et l'évaluation du GSIS. De plus, les biomarqueurs du stress du réticulum endoplasmique pancréatique.

Ce régime alimentaire très riche en graisse a diminué les niveaux de protéine pancréatique WFS1 et de GSH, et augmenté l'activité de la catalase pancréatique. En conséquence, il a augmenté les niveaux de protéines BIP, CHOP et WFS1 dans le RE extrait du pancréas. De plus, le régime alimentaire très riche en graisse a provoqué une intolérance au glucose et a diminué la teneur en GSIS et en insuline des îlots.

Cependant, l'administration de 4-PBA a restauré les niveaux antérieurs. Il semble donc bien que la consommation de régime alimentaire très riche en graisse en induisant un stress réticulum endoplasmique pancréatique ait altéré les niveaux d'expression de WFS1, réduit la teneur en GSIS et en insuline des îlots et finalement altéré l'homéostasie du glucose.

L'administration de 4-PBA ne me semble pas être une solution au problème du stress du réticulum endoplasmique, par contre c'est certainement un moyen de pallier à une conséquence dramatique de ce stress: La mort cellulaire, ce qui dans le cas de la SLA intervient très certainement sur les cellules qui consomment le plus d'énergie comme les muscles squelettiques et les neurones moteurs.

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Consuming a high fat diet causes various metabolic diseases including metabolic syndrome and type 2 diabetes by developing insulin resistance and even decreasing insulin production.

For example a good way to induce Parkinson's syndrome in rats is to feed them a very high fat diet. Alzheimer's disease has sometimes been referred to as type 3 diabetes.

A mystery is that of ALS (Charcot's disease) where we often have insulin resistance, but very rarely comorbid diabetes. It also seems that the existence of misfolded proteins in the cytoplasm of patients is linked to stress in the endoplasmic reticulum, a cell organ whose function is precisely to fold the proteins newly produced by the ribosomes, before they are sent to their destination in the Golgi apparatus.

Long-term exposure to saturated fatty acids (SAFAs) in pancreatic β cells causes desensitization and impaired insulin secretion.

For example, consumption for three months of a very high fat diet containing pork fat and sunflower oil (80% fat) reduced the insulin content of pancreatic islets in mice (50%), proinsulin mRNA (35%), insulin biosynthesis and secretion in response to glucose (50%), and glucose oxidation.

According to previous research, WFS1 (Wolfram syndrome 1) is involved in insulin synthesis and release, as well as mass preservation of pancreatic β cells. This Wfs1 gene was first identified by Wolfram and Wagener (1983) in patients with Wolfram syndrome (i.e. diabetes mellitus and optic nerve atrophy).

The WFS1 gene expresses a glycoprotein in the endoplasmic reticulum (endoplasmic reticulum) of pancreatic β cells, heart, placenta, lungs and brain.

Saturated fatty acids like palmitate induce endoplasmic reticulum stress. Studies have shown that there is a mutual relationship between oxidative stress and endoplasmic reticulum stress. It is found in palm oil, but also in all animal (butter, cheese, milk and meat) or vegetable fats and oils.

During endoplasmic reticulum stress, WFS1 expression increases to inhibit stress signaling and thus prevent apoptosis (one of the processes leading to cell death).

Given the role of the WFS1 protein in maintaining endoplasmic reticulum homeostasis, it is expected that the expression of this protein is increased in the endoplasmic reticulum of β-cells, and its translocation to the cytoplasm is reduced. and leads to a decrease in pancreatic islet GSIS and insulin content.

Although many studies have investigated the effects of each very high fat diet and the involvement of WFS1 in insulin synthesis and secretion, no study has examined the interaction of very high fat diet and WFS1 in relation to insulin synthesis and secretion and therefore glucose homeostasis.

After weaning, the rats were divided into six groups and fed a normal diet and a very high fat (30%) diet for 20 weeks, followed by 4-phenyl butyric acid (4-PBA, an inhibitor endoplasmic reticulum stress) was administered. Note that this is one of the two components of the AMX0035.

After performing a glucose tolerance test, the animals were dissected and their pancreases removed for endoplasmic reticulum extraction, islet isolation, and GSIS evaluation. Additionally, pancreatic endoplasmic reticulum stress biomarkers.

This very high-fat diet decreased pancreatic protein WFS1 and GSH levels, and increased pancreatic catalase activity. As a result, it increased the levels of BIP, CHOP and WFS1 proteins in the ER extracted from the pancreas. In addition, the very high-fat diet caused glucose intolerance and decreased GSIS and insulin content of islets.

However, administration of 4-PBA restored previous levels. It therefore appears that consumption of very high fat diet by inducing pancreatic endoplasmic reticulum stress altered WFS1 expression levels, reduced GSIS and islet insulin content and ultimately impaired glucose homeostasis.

The administration of 4-PBA does not seem to me to be a solution to the problem of the stress of the endoplasmic reticulum, on the other hand it is certainly a means of mitigating a dramatic consequence of this stress: Cell death, which

Yet, administration of 4-PBA does not seem to me to be a solution to the problem of the stress of the endoplasmic reticulum, on the other hand it is certainly a means of mitigating a dramatic consequence of this stress: Cell death, which in the case of ALS most certainly affects the cells that consume the most energy, such as skeletal muscles and motor neurons.

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There is growing evidence that patients with type 2 diabetes mellitus have an increased risk of developing Parkinson's disease and share similar dysregulated pathways. There is growing evidence that patients with type 2 diabetes mellitus have an increased risk of developing Parkinson’s disease and share similar dysregulated pathways, which suggests the presence of common underlying pathological mechanisms.

Type 2 diabetes develops from insulin resistance, leading to a variety of detrimental effects on metabolism and inflammation. Similar dysregulation of glucose and energy metabolism are early events in the pathogenesis of sporadic Parkinson's disease and to some degree in Alzheimer's disease as well as amyotrophic lateral sclerosis (Lou Gehrig disease). Trials of intranasal insulin administered to patients with mild cognitive dysfunction and early Alzheimer's disease led to improvements in verbal memory and cognition.

For example it is possible to induce a Parkinson disease like in rats, by feeding them with a high fat diet. Scientists in a new publication, aimed to determine whether the risk of Parkinson disease increases as diabetes progresses among patients with type 2 Diabetes mellitus.

Using a nationally representative database from the Korean National Health Insurance System, 2,362,072 individuals with type 2 Diabetes mellitus who underwent regular health checkups during 2009-2012 were followed up until the end of 2018.

There is still no universal agreement on the optimal data needed to create a reliable diabetes severity measure, despite the presence of some diabetes-specific severity indices.

The diabetes severity score parameters included the number of oral hypoglycemic agents, diabetes duration, insulin use, or presence of chronic kidney disease, diabetic retinopathy, or cardiovascular disease.

Each of these characteristics was scored as one unit of diabetes severity and their sum was defined as a diabetes severity score from 0-6.

The scientists identified 17,046 incident Parkinson disease cases during the follow-up. Each component of the diabetes severity score showed a similar intensity for the risk of Parkinson disease.

Diabetes severity, as measured by diabetic complication status, treatment complexity, and duration of diabetes, was strongly associated with an increased risk for Parkinson’s disease. All characteristics indicative of diabetes severity had an additive association with the risk of Parkinson’s disease in patients with type 2 DM. The coexistence of conditions such as retinopathy, nephropathy, CVD, the complexity of diabetes treatments, or the long duration of diabetes was more strongly associated with Parkinson’s disease risk than the presence of a single condition alone. People with a diabetes severity score of 4 or higher had a more than doubled risk of Parkinson’s disease compared with those with a score of 0, and those with a score of 6 had a 2.78-fold increased risk of Parkinson’s disease. These associations became stronger for younger diabetic patients.

Compared with subjects with no parameters, HR values of Parkinson disease were 1.09 in subjects with one diabetes severity score parameter, 1.28 in subjects with two parameters, 1.55 in subjects with three parameters, 1.96 in subjects with four parameters, 2.08 in subjects with five parameters, and 2.78 in subjects with six parameters.

Diabetes severity was associated with an increased risk of developing Parkinson disease. Severe diabetes may be a risk factor for the development of Parkinson disease. Yet this was an observational study, so the association found between the stratification parameters and endpoints may not be causal.

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Parkinson's disease is the second most prevalent neurodegenerative disease of the central nervous system, with an estimated 5,000,000 cases worldwide. Parkinson disease pathology is characterized by the accumulation of misfolded α-synuclein, which is thought to play a critical role in the pathogenesis of the disease.

Animal models of Parkinson disease suggest that activation of Abelson tyrosine kinase plays an essential role in the initiation and progression of α-synuclein pathology and initiates processes leading to degeneration of dopaminergic and nondopaminergic neurons.

Four drugs, nilotinib, dasatinib, bosutinib and ponatinib are src tyrosine kinase inhibitor used for the treatment of chronic myelogenous leukemia. Given the potential role of c-Abl in Parkinson disease, a c-Abl inhibitor library was developed to identify orally bioavailable c-Abl inhibitors capable of crossing the blood-brain barrier based on predefined characteristics, leading to the discovery of IkT-148009.

IkT-148009, a brain-penetrant c-Abl inhibitor with a favorable toxicology profile, was analyzed for therapeutic potential in animal models of slowly progressive, α-synuclein-dependent Parkinson disease.

In mouse models of both inherited and sporadic Parkinson disease, IkT-148009 suppressed c-Abl activation to baseline and substantially protected dopaminergic neurons from degeneration when administered therapeutically by once daily oral gavage beginning 4 weeks after disease initiation.

Recovery of motor function in Parkinson disease mice occurred within 8 weeks of initiating treatment concomitantly with a reduction in α-synuclein pathology in the mouse brain. These findings suggest that IkT-148009 may have potential as a disease-modifying therapy in Parkinson disease.

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We know that in ALS it is important to maintain the BMI at 27, which is incredibly difficult practically for patients but also psychologically for caregivers who do not understand that becoming mildly obese can be beneficial. This is especially true if the patient previously had a very healthy weight profile.

Several publications hint at similar benefits of weight gain in Parkinson's disease. Early weight loss is a typical symptom in Parkinson's disease patients and this may be accompanied by cognitive decline.

This observational study used data from the Parkinson’s Progression Markers Initiative cohort. The patients underwent annual non-motor assessments covering neuropsychiatric, sleep-related, and autonomic symptoms for up to 8 years of follow-up. Cognitive function was measured using the Montreal Cognitive Assessment (MoCA) and detailed neuropsychological testing. Linear mixed-effects models were applied to investigate the association of early weight change with longitudinal evolution of cognitive and other non-motor symptoms.

358 individuals with Parkinson's disease who had just received a diagnosis but had not yet begun taking medication for the condition were the subject of the study. They were 61 years old on average. 174 individuals free of Parkinson's disease were compared to them. While observational studies generally produce results similar to those conducted as randomized controlled trials, an observational study draws inferences from a sample to a population where the independent variable is not under the control of the researcher so it is possible there are some hidden bias in such studies.

A change in body weight of more than 3% during the study's first year was deemed to be either weight gain or loss. 98 individuals lost weight, 59 individuals gained weight, and 201 individuals maintained their weight.

Prior to the study's start and then once a year for up to eight years, participants took a test of their thinking abilities. They also looked for other non-motor symptoms, like anxiety, depression, and difficulty falling asleep, that Parkinson's patients might experience.

When compared to Parkinson's patients who maintained their weight, those who lost weight saw a decline in their scores annually. Fluency skills, showed the greatest decline in thinking abilities.

Conversely, Parkinson's patients who gained weight saw a slower decline in their processing speed test scores than those who kept their weight.

Weight change did not correlate with any other nonmotor symptoms.

There was no connection between weight change and results on the thinking skills test among individuals without Parkinson's disease.

According to Jun, "These results highlight the potential significance of weight management in the early stages of Parkinson's disease." If taking measures to prevent weight loss can slow cognitive deterioration in people with Parkinson's disease, more research is required to confirm this. ".

This observational study only demonstrates an association; it does not establish a causal relationship between weight changes and changes in thinking abilities. Yet diet change in order to gain weigth in a healthy manner is something that patients and carers can easily do at home.

Association of Early Weight Change With Cognitive Decline in Patients With Parkinson Disease

Body Mass Index, Abdominal Adiposity, and Incidence of Parkinson Disease in French Women From the E3N Cohort Study

Initial BMI and Weight Loss over Time Predict Mortality in Parkinson Disease

Trihexyphenidyl (marketed as Artane and others) is an antispasmodic drug used to treat stiffness, tremors, spasms, and poor muscle control. It is an agent of the antimuscarinic class and is often used in management of Parkinson's disease. It was approved by the FDA for the treatment of Parkinson's in the US in 2003.

Artane has been shown to have several sides effects, some similar to Parkinson's symptoms, in particular people who are older or who have psychiatric conditions may become confused or develop delirium.

Despite growing concerns about Trihexyphenidyl causing cognitive decline in tremor-dominant Parkinson disease patients, the underlying neural correlates remain unclear. Therefore, the authors investigated the effects of this drug on prefrontal executive function and spontaneous neural activity in patients with tremor-dominant Parkinson disease by utilizing functional near-infrared spectroscopy.

The authors recruited 30 patients with tremor-dominant Parkinson disease, including 15 patients receiving the treatment and 15 patients not receiving Trihexyphenidyl.

The researchers performed comprehensive neuropsychological and clinical assessments to evaluate each patient's cognitive function, mental status, and clinical symptoms.

They measured brain activation elicited from the verbal fluency task and changes in amplitude of low-frequency fluctuations at rest to investigate executive function and spontaneous neural activity, respectively. In addition, the authors examined the relationship between altered activation during task and resting state and neuropsychological and clinical data.

Compared with tremor-dominant Parkinson disease patients not taking Trihexyphenidyl, tremor-dominant Parkinson disease patients taking the treatment showed no differences on neuropsychological tests.

However, there was insufficient activity of the dorsolateral prefrontal cortex, ventrolateral prefrontal cortex, and the orbitofrontal cortex related to the frontoparietal network at rest.

Furthermore, functional near-infrared spectroscopy results were positively correlated with scores of multiple cognitive domain functions.

These findings suggest that Trihexyphenidyl treatment may lead to prefrontal dysfunction in tremor-dominant Parkinson disease patients, attenuating brain activation in executive function and cognition-related spontaneous neural activity.

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Patients have long said that diets can relieve symptoms of diseases such as Alzheimer's and Parkinson's. Many ALS patients take supplements in varying amounts and types. These claims have long been derided by scientists, yet scientists are now starting to change their minds.

The authors of a new scientific article therefore investigated whether a high fiber diet influences microglial function in mouse models of Parkinson's disease that overexpress α-synuclein. These mice are called ASO (α-synuclein overexpressing) mice.

Parkinson's disease is a disease characterized by α-synuclein pathology and/or dopamine deficiency resulting from degeneration of the substantia nigra (a region of the midbrain).

Although Parkinson's disease is primarily classified as a brain disorder, 70-80% of patients experience gastrointestinal symptoms, primarily constipation, but also abdominal pain and increased intestinal permeability which usually manifest in prodromal stages (Forsyth et al. 2011; Yang et al 2019).

Braak postulated nearly 20 years ago that α-synuclein aggregation can begin in the gastrointestinal tract or olfactory bulb, and eventually reach the brainstem, substantia nigra, and neocortex via the vagus nerve ( Braak et al. 2003). A growing body of evidence supports the potential for gut-to-brain spread of α-synuclein pathology in rodents (S. Kim et al. 2019; B. Liu et al. 2017; Svensson et al. 2015).

The vagus nerve, a long winding nerve, is a major two-way information signaling pathway between the gut and the brain. Vagotomy is the surgical section of the pneumogastric nerve, or vagus nerve, at the level of the abdomen. Vagotomy has been used for decades and most patients who have had such surgery and are still alive are now elderly. A Swedish registry study investigated the risk of Parkinson's disease in patients who underwent vagotomy and hypothesized that truncal vagotomy is associated with a protective effect.

The scientists found that the risk of Parkinson's disease was indeed reduced in patients who underwent a complete truncal vagotomy, whereas there was no risk reduction in those who underwent a selective vagotomy. The risk of Parkinson's disease is also reduced after truncal vagotomy compared to the general population. These epidemiological findings are important and support the hypothesis that Parkinson's disease begins in the gut and not initially in the brain. This provides further evidence for the involvement of the vagus nerve in disease development.

Many important chemical compounds (nowadays we say "molecular" to make it sound important) are produced in the intestine and end up in the brain via the bloodstream. Many of them are made or have their production regulated by gut microbes.

These include short chain fatty acids tryptophan, leptin and ghrelin. Short chain fatty acids include butyrate, propionate and acetate. Butyrate is a known inhibitor of histone deacetylases (HDACs) and in doing so acts as an epigenetic regulator. Cytokines, key immune-regulating molecules produced in the gut, can travel through the bloodstream and influence brain function, particularly in regions of the brain where the blood-brain barrier is deficient.

Among other effects, microbial food metabolites can modulate the activation of microglia, these nerve cells which are essential for the survival of neurons are implicated in Parkinson's disease. Microglia respond to signals from inside the brain, but also receive information from the periphery, including the gut microbiome (Abdel88 Haq et al. 2019). Microglia from germ-free adult mice show an immature gene expression profile and do not respond adequately to immunostimulants (Erny et al. 2015; Thion et al. 2018). However, if these germ-free mice are fed a mixture of short-chain fatty acids, microglial maturation is restored (Erny et al. 2015).

The gut microbiota is a virtual organ that produces a myriad of molecules needed by the brain and other organs. Humans and microbes are in a symbiotic relationship, humans feed the microbes, and microbes in turn provide essential molecules.

The phyla Bacteroidetes and Firmicutes represent approximately 80% of total human gut microbiota. The genera of the Firmicutes phylum include Clostridium, Lactobacillus, Bacillus, Clostridium, Enterococcus, and Ruminicoccus. The phylum Bacteroidetes mainly includes the genera Bacteroides and Prevotella.

The phylum Actinobacterium is dominated by the genus Bifidobacterium. Bifidobacteria and lactobacilli are generally considered beneficial bacteria and are frequently sold as probiotic supplements. Strains of the genus Clostridium or lipopolysaccharide taxa such as Enterobacteriaceae have been associated with disease states in many neurodegenerative diseases including ALS (Charcot's disease).

Similarly but somewhat controversially, the Firmicutes/Bacteroidetes ratio, which explores the relationship between the two dominant phyla, has been associated with various neurodegenerative pathologies.

So, the intestinal microbiome is altered in Parkinson's disease. It is found in mice models of Parkinson's disease (the mice have been genetically engineered to carry a disease resembling that of Parkinson's) that the fecal levels of short-chain fatty acids are different in mice with Parkinson's disease and mice. healthy. It is the intestinal bacteria that transform dietary fiber into short-chain fatty acids by fermentation.

The authors designed personalized high-fiber diets, each containing 20% ​​of a prebiotic blend of two or three dietary fibers designed to support the growth of 5 distinct gut bacterial taxa and stimulate the production of short-chain fatty acids based on of faecal fermentation in vitro.

The scientists then observed broad changes at the microbial phylum and genus level after administration of a prebiotic diet, displaying an increase in Bacteroidetes and a decrease in Firmicutes in mice fed a prebiotic diet, resulting in a lower Firmicutes ratio. /Bacteroidetes (F/B) that has been associated with general features of metabolic health.

Interestingly, Bacteroidetes have been shown to be reduced in Parkinson's patients compared to age-matched controls, suggesting that the prebiotic may counteract this effect (Unger et al. 2016). Additionally, they observed a decrease in proteobacteria, a phylum often increased in dysbiosis and inflammation and elevated in fecal samples from patients with Parkinson's disease (Keshavarzian et al. 2015; Shin, Whon, and Bae 2015).

A fiber-rich prebiotic diet attenuates motor deficits and reduces α-synuclein aggregation in the substantia nigra of mice.

Meanwhile, the gut microbiome of ASO mice adopts a health-correlated profile upon prebiotic treatment, which also reduces microglial activation.

Single-cell RNA-seq analysis of microglia from the substantia nigra and striatum reveals increased pro-inflammatory signaling and reduced homeostatic responses in ASO mice compared to their wild-type counterparts on a standard diet.

Prebiotic feeding reverses pathogenic microglial states in ASO mice and promotes expansion of microglia's disease-associated protective macrophage (DAM) subsets. Microglia are dependent on colony stimulating factor 1 receptor (CSF1R) signaling for development, maintenance and proliferation (Elmore et al. 2014).

To test the opposite effect: If depletion of microglia eliminated the beneficial effects of prebiotics, the authors added PLX5622 to the diet of mice aged 5 to 22 weeks and quantified the number of IBA1+ microglia in various brain regions. PLX5622 is a brain-penetrating CSF1R inhibitor that can deplete microglia with no observed effects on behavior or cognition (Elmore et al. 2014).

Depletion of microglia using a CSF1R inhibitor effectively eliminated the beneficial effects of prebiotics and restored motor deficits in ASO mice despite a prebiotic diet.

These studies reveal a novel microglia-dependent interaction between diet and motor Parkinson's disease in mice, findings that may have implications for neuroinflammation and Parkinson's disease.

Prebiotics present a potentially promising therapeutic approach, as diet contributes significantly to the composition of the microbiome and epidemiological evidence has linked high fiber diets to reduced risk of developing Parkinson's disease (Boulos et al 2019).

While increased vegetable intake and adherence to a Mediterranean diet are associated with a lower risk of Parkinson's disease, people consuming a low-fiber, highly processed Western diet have an increased risk of being diagnosed with Parkinson's disease. (Alcalay et al. 2012; Gao et al. 2007; Molsberry et al. 2020).

Several ongoing clinical trials are exploring the beneficial effects of probiotics and prebiotics on Parkinson's disease outcomes. Acting on the diet or the microbiome can help relieve the symptoms of Parkinson's disease.

Depuis longtemps des patients disent que des régimes alimentaires peuvent soulager des symptomes pour des maladies telles que Alzheimer ou Parkinson. Nombre de malade de la SLA prennent des suppléments en quantité et genre très variés. Ces affirmations ont longtemps été moquées par les scientifiques, pourtant ceux-ci commencent maintenant à changer de point de vue.

Les auteurs d'un nouvel article scientifique ont donc étudié si un régime riche en fibres influence la fonction microgliale chez des souris modèles de la maladie de Parkinson qui surexpriment l'α-synucléine. Ces souris sont appelée souris ASO (α-synuclein overexpressing).

La maladie de Parkinson est une maladie éventuellement caractérisée par une pathologie de l'α-synucléine et/ou un déficit en dopamine résultant de la dégénérescence de la substantia nigra (une région du mésencéphale).

Bien que la maladie de Parkinson soit principalement classée comme un trouble cérébral, 70 à 80 % des patients présentent des symaladie de Parkinsontômes gastro-intestinaux, principalement de la constipation, mais également des douleurs abdominales et une augmentation de la perméabilité intestinale qui se manifestent généralement dans les stades prodromiques (Forsyth et al. 2011 ; Yang et al 2019).

Braak a postulé il y a près de 20 ans que l'agrégation l'α-synucléine peut commencer dans le tractus gastro-intestinal ou le bulbe olfactif, et finalement atteindre le tronc cérébral, la substantia nigra et le néocortex via le nerf vague (Braak et al. 2003). De plus en plus d'éléments corroborent le potentiel de propagation de l'intestin au cerveau de la pathologie l'α-synucléine chez rongeurs (S. Kim et al. 2019 ; B. Liu et al. 2017 ; Svensson et al. 2015).

Le nerf vague, un long nerf sinueux, est une voie majeure de signalisation d'informations bidirectionnelles entre l'intestin et le cerveau. La vagotomie est la section chirurgicale du nerf pneumogastrique, ou nerf vague, au niveau de l'abdomen. La vagotomie été utilisée pendant des décennies et la plupart des patients qui ont subi une telle chirurgie et qui sont encore en vie sont maintenant des personnes âgées. Une étude de registre suédoise a étudié le risque de maladie de Parkinson chez les patients ayant subi une vagotomie et a émis l'hypothèse que la vagotomie tronculaire est associée à un effet protecteur.

Les scientifiques ont constaté que le risque de maladie de Parkinson était en effet diminué chez les patients ayant subi une vagotomie tronculaire complète, alors qu'il n'y avait pas de réduction du risque chez ceux qui avaient subi une vagotomie sélective. Le risque de maladie de Parkinson est également diminué après une vagotomie tronculaire par rapport à la population générale. Ces résultats épidémiologiques sont importants et soutiennent l'hypothèse selon laquelle la maladie de Parkinson commence dans l'intestin et non initialement dans le cerveau. Cela fournit une preuve supplémentaire de l'implication du nerf vague dans le développement de la maladie.

De nombreux composants chimiques (de nos jours, nous disons "moléculaires" pour que cela sonne important) importants sont produits dans l'intestin et se retrouvent dans le cerveau via la circulation sanguine. Beaucoup d'entre eux sont fabriqués ou ont leur production régulée par des microbes intestinaux.

Ceux-ci comprennent les acides gras à chaîne courte, le tryptophane, la leptine et la ghréline. Les acides gras à chaîne courte comprennent le butyrate, le propionate et l'acétate. Le butyrate est un inhibiteur connu des histone désacétylases (HDAC) et, ce faisant, agit comme un régulateur épigénétique. Les cytokines, molécules clés de régulation immunitaire produites au niveau de l'intestin, peuvent voyager via la circulation sanguine et influencer la fonction cérébrale, en particulier dans les régions du cerveau où la barrière hémato-encéphalique est déficiente.

Entre autres effets, les métabolites microbiens alimentaires peuvent moduler l'activation de la microglie, or ces cellules nerveuses qui sont indispensables à la survie des neurones sont impliquées dans la maladie de Parkinson. La microglie répond aux signaux provenant de l'intérieur du cerveau, mais reçoit également des informations de la périphérie, y compris du microbiome intestinal (Abdel88 Haq et al. 2019). La microglie de souris adultes exemptes de germes présente un profil d'expression génique immature et ne répond pas adéquatement aux immunostimulants (Erny et al. 2015 ; Thion et al. 2018). Cependant, si l'on nourrit ces souris exemptes de germes avec un mélange d'acides gras à chaîne courte, la maturation microgliale est restaurée (Erny et al. 2015).

Le microbiote intestinal est un organe virtuel qui produit une myriade de molécules dont le cerveau et d'autres organes ont besoin. Les humains et les microbes sont dans une relation symbiotique, les humains nourrissent les microbes, et à leur tour, les microbes fournissent des molécules essentielles aux humains.

Les phylums Bacteroidetes et Firmicutes représentent environ 80 % du microbiote intestinal humain total. Les genres du phylum Firmicutes comprennent Clostridium, Lactobacillus, Bacillus, Clostridium, Enterococcus et Ruminicoccus. Le phylum Bacteroidetes comprend principalement les genres Bacteroides et Prevotella. Le phylum Actinobacterium est dominé par le genre Bifidobacterium. Les bifidobactéries et les lactobacilles sont généralement considérés comme des bactéries bénéfiques et sont fréquemment vendus comme suppléments probiotiques. Des souches du genre Clostridium ou des taxons de lipopolysaccharides tels que les Enterobacteriaceae ont été associées à des états pathologiques dans beaucoup de maladies neurodégénératives y compris la SLA (maladie de Charcot).

Bien que ce soit quelque peu controversé, de façon siilaire le ratio Firmicutes/Bacteroidetes, qui explore la relation entre les deux phylums dominants, a été associé à diverses pathologies neurodégénératives.

Or le microbiome intestinal est altéré dans la maladie de Parkinson. On constate chez les souris modèles de la maladie de Parkinson (on a par génie génétique infligé à ces souris une maladie ressemblant à celle de Parkinson) que les niveaux fécaux des acides gras à chaîne courte sont différent chez les souris malades de Parkinson et les souris saines. Or ce sont les bactéries intestinales qui transforment par fermentation les fibres alimentaires en acides gras à chaîne courte.

Les auteurs ont donc conçus des régimes personnalisés riches en fibres, chacun contenant 20 % d'un mélange prébiotique de deux ou trois fibres alimentaires conçu pour favoriser la croissance de 5 taxons bactériens intestinaux distincts et stimuler la production d'acides gras à chaîne courte sur la base d'une fermentation fécale in vitro.

Les chercheurs ont alors observé de vastes changements au niveau du phylum microbien et du genre après l'administration d'un régime prébiotique, affichant une augmentation des Bacteroidetes et une diminution des Firmicutes chez les souris nourries avec un régime prébiotique, entraînant une baisse du rapport Firmicutes/Bacteroidetes (F/B) qui a été associé à des caractéristiques générales de la santé métabolique.

Curieusement, il a été démontré que les Bacteroidetes sont réduits chez les patients parkinsoniens par rapport aux témoins du même âge, ce qui suggère que le prébiotique peut contrer cet effet (Unger et al. 2016). De plus, ils ont observé une diminution des protéobactéries, un phylum souvent augmenté dans la dysbiose et l'inflammation et élevé dans les échantillons fécaux de patients atteints de maladie de Parkinson (Keshavarzian et al. 2015 ; Shin, Whon et Bae 2015).

Un régime prébiotique riche en fibres atténue les déficits moteurs et réduit l'agrégation de l'α-synucléine dans la substantia nigra des souris.

Parallèlement, le microbiome intestinal des souris ASO adopte un profil corrélé à la santé lors du traitement prébiotique, ce qui réduit également l'activation microgliale.

L'analyse ARN-seq unicellulaire de la microglie de la substantia nigra et du striatum révèle une signalisation pro-inflammatoire accrue et des réponses homéostatiques réduites chez les souris ASO par rapport à leurs homologues de type sauvage suivant un régime standard. L'alimentation prébiotique inverse les états microgliaux pathogènes chez les souris ASO et favorise l'expansion des sous-ensembles de macrophages protecteurs associés à la maladie (DAM) de la microglie.

La microglie dépend de la signalisation du récepteur du facteur 1 stimulant les colonies (CSF1R) pour le développement, le maintien et la prolifération (Elmore et al. 2014).

Pour tester l'effet inverse: Si l'épuisement de la microglie à élimine les effets bénéfiques des prébiotiques, les auteurs ont ajouté PLX5622 au régime alimentaire de souris âgées de 5 à 22 semaines et quantifié le nombre de microglies IBA1+ dans diverses régions du cerveau. PLX5622 est un inhibiteur pénétrant dans le cerveau du CSF1R qui peut épuiser la microglie sans effets observés sur le comportement ou la cognition (Elmore et al. 2014).

L'épuisement de la microglie à l'aide d'un inhibiteur de CSF1R a effectivement éliminé les effets bénéfiques des prébiotiques et rétablit les déficits moteurs des souris ASO malgré un régime prébiotique.

Ces études révèlent une nouvelle interaction dépendante de la microglie entre l'alimentation et les symaladie de Parkinsontômes moteurs chez la souris, des découvertes qui pourraient avoir des imaladie de Parkinsonlications pour la neuroinflammation et la maladie de Parkinson.

Les prébiotiques présentent une approche thérapeutique potentiellement prometteuse, car le régime alimentaire contribue de manière significative à la composition du microbiome et des éléments épidémiologiques ont établi un lien entre les régimes riches en fibres et le risque réduit de développer la maladie de Parkinson (Boulos et al. 2019). Alors qu'une consommation accrue de légumes et l'adhésion à un régime méditerranéen sont associées à un risque plus faible de maladie de Parkinson, les personnes consommant un régime occidental pauvre en fibres et hautement transformé présentent un risque accru de diagnostic de maladie de Parkinson (Alcalay et al. 2012 ; Gao et al. 2007 ; Molsberry et al. 2020). Plusieurs essais cliniques en cours explorent les effets bénéfiques des probiotiques et des prébiotiques sur les résultats liés à la maladie de Parkinson. Agir sur le régime alimentaire ou le microbiome, peut aider à soulager les symptômes de la maladie de Parkinson.