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Parkinson's disease

For roughly 15 years, it has been hypothesized that Parkinson’s disease does not originate exclusively in the brain, but also in the intestines. However, the potential biological mechanisms involved remain to be elucidated.

Parkinson’s disease affects 6.3 million people worldwide1, the majority over 50 years old. It is caused by neuron loss in the substantia nigra, which controls movement. Motor symptoms gradually develop, such as slowness of movement, muscle rigidity and tremors, but also sleeping disturbances, depressive episodes and gastrointestinal disorders2.

The primary risk factor is age, but genetic predisposition3 and environmental causes, like exposure to pesticides4, have also been identified. A hypothesis has been germinating over the past 15 years about a potential role of the intestinal microbiota in the development of the disease.

An emerging hypothesis

The idea was originally advanced after observing a connection between chronic infection with Helicobacter pylori bacteria and the risk of developing Parkinson’s disease5. Dysbiosis was also observed more frequently in Parkinson’s disease patients, notably with fewer supposedly “anti-inflammatory” bacteria and more “pro-inflammatory” bacteria6. However, a cause-and-effect relationship between abnormal intestinal microbiota and Parkinson’s disease has not yet been demonstrated.

A therapeutic hope

Currently, management focuses on limiting motor symptoms of the disease with dopamine precursors or, more rarely, deep brain stimulation7. But those treatments do not prevent disease progression. Therefore, acting very early on the microbiota through nutritional or pharmacological interventions, to lower the risk of developing the disease by correcting dysbiosis, is an option currently being considered8 .

 

Sources:
1- Dorsey ER et al. Projected number of people with Parkinson disease in the most populous nations, 2005 through 2030. Neurology. 2007;68(5):384–386. https://www.ncbi.nlm.nih.gov/pubmed/17082464
2- Clairembault T et al.  Structural alterations of the intestinal epithelial barrier in Parkinson’s disease. Acta Neuropathol Commun 2015a;3:12. https://actaneurocomms.biomedcentral.com/articles/10.1186/s40478-015-0196-0
3- Cheon SM et al. Genetics of Parkinson's disease—a clinical perspective. J Mov Disord. 2012;5(2):33–41. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4027661/pdf/jmd-5-2-33-1.pdf
4- Elbaz A et al. Professional exposure to pesticides and Parkinson’s disease. Ann Neurol 2009; 66 (4): 494-504. http://onlinelibrary.wiley.com/wol1/doi/10.1002/ana.21717/full
5- Dobbs SM et al. Link between Helicobacter pylori infection and idiopathic parkinsonism. Med Hypotheses. 2000;55:93–8. https://www.ncbi.nlm.nih.gov/pubmed/10904422
6- Keshavarzian A et al.  Colonic bacterial composition in Parkinson’s disease. Mov Disord 2015; 30: 1351-60. http://onlinelibrary.wiley.com/doi/10.1002/mds.26307/abstract
7- Bronstein J et al. (2011). Deep brain stimulation for Parkinson disease: an expert consensus and review of key issues. Arch. Neurol. Année;68:165. 10.1001/archneurol.2010.260 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4523130/pdf/nihms691775.pdf
8- Mulak A, Bonaz B. Brain-gut-microbiota axis in Parkinson's disease. World J Gastroenterol. 2015;21:10609-20. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4588083/pdf/WJG-21-10609.pdf

Multiple sclerosis

The intestinal microbiota may become a target for therapy in the fight against multiple sclerosis (MS). The results of several studies showed its involvement in the onset of immune anomalies associated with myelin loss. 

MS, an autoimmune disorder characterized by loss of the myelin sheath surrounding central nervous system (CNS) neurons, affects around 80,000 people in France and probably more than 2 million worldwide. Studies designed to clarify its pathophysiological mechanisms have largely focused on immunity and the brain, but its etiology remains an enigma. 

Intestinal infections suspected

Genetic and environmental factors are suspected. Among them, intestinal infections have attracted particular attention because they provoke immune-system dysfunction. More broadly, a new avenue of investigation is exploring the potential links between MS and the intestinal microbiota, which stimulates autoantigens to induce autoimmune demyelinization1

A different microbiota

Clinical study results showed associations between gut flora and MS, with patients having, for example, Methanobrevibacter and Akkermansia overrepresentations and Butyricimonas underrepresentation, with modified expressions of genes involved in dendritic cell maturation and several immune-signaling pathways2. Using mouse models, researchers demonstrated that the gut flora is required for MS to develop. Segmented filamentous bacteria in the microbiota induce the production of MS-associated proinflammatory T-lymphocytes in the brain and, conversely, gut flora changes promote attenuation of those lymphocytes’ cytokine production3

A step towards the use of probiotics?

In practice, consuming the yeast Candida kefyr alleviates MS severity in mice, by reducing the level of inflammation4 . A recent review on the topic proposes the intestinal microbiota as a potential target for MS treatment and prevention5 .

 

Sources:
1. Berer K et al. Commensal micro- biota and myelin autoantigen cooperate to trigger autoimmune demyelination. Nature. 2011;479:538-41. http://www.nature.com/nature/journal/v479/n7374/full/nature10554.html
2.Sushrut Jangi et al. Alterations of the human gut microbiome in multiple sclerosis. Nature Communications 2016 online.  http://www.nature.com/articles/ncomms12015
3. Lee YK et al. Proinflammatory T-cell responses to gut microbiota promote experimental autoimmune encephalomyelitis. Proc Natl Acad Sci USA. 2011;108:4615-22. https://www.ncbi.nlm.nih.gov/pubmed/20660719
4. Takata K et al. Dietary yeasts reduce inflammation in central nerve system via microflora. Ann Clin Transl Neurol. 2015;2:56-66.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4301675/
5. Glenn Justin D. Emerging Concepts on the Gut Microbiome and Multiple Sclerosis. Journal of Interferon & Cytokine Research 2016 May. Volume 36 Issue 6 http://online.liebertpub.com/doi/abs/10.1089/jir.2015.0177?journalCode=jir

Anxiety disorders

The discovery of a role of the intestinal microbiota in anxiety disorders that affect hundreds of millions of individuals worldwide represents hope for research into new treatments.

Anxiety disorders (phobias, post-traumatic stress, obsessive-compulsive, etc.), characterized by excessive chronic anxiety, affect 14% of the European population1.

The possible involvement of the microbiota 

For 10 years, researchers have been evaluating the gut-flora influence on brain biochemistry and the results of a growing number of studies suggest a link between intestinal microbiota and anxiety disorders3,4,5,6,7,8. For example, a Canadian study published in 2011 analyzed the impact of intestinal microbiota transplants between different strains of mice (NIH Swiss and BALB/c) on their tendency to explore their environment less (fear or anxiety behavior). The findings showed that the “tendency to explore or not” behavior is transferable via the intestinal microbiota9.

Multiple pathways of action

Several potential pathways of action have already been identified. Some effects pass through the activation of the vagus nerve10, which acts on receptors for the neurotransmitter GABA, involved in the pathophysiology of anxiety disorders11 . Pathways via the blood (transportation of bacterial molecules that can pass through the blood–brain barrier), enteroendocrine pathways (stimulation of neuropeptide production by endocrine cells in the intestinal epithelium) and immune pathways (influence the production of pro- and anti-inflammatory cytokines) may also be involved12

A step towards new treatments?

Currently, treatments for anxiety disorders are primarily psychotherapy and medications that act directly on the brain, like anxiolytics and antidepressants. Increasing numbers of researchers foresee the possibility of adding probiotics to this therapeutic arsenal13 . However, the efficacy of this approach remains to be proven.

 

Sources:
1- Wittchen, H.-U. et al. (2011). The size and burden of mental disorders and other disorders of the brain in Europe 2010. European Neuropsychopharmacology, Année;21(9);655-679. https://www.ncbi.nlm.nih.gov/pubmed/21896369
2- Diaz Heijtz R et al. Normal gut microbiota modulates brain development and behavior. Proc Natl Acad Sci USA 2011;108:3047-52. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3041077/pdf/pnas.201010529.pdf
3- Clarke G et al. The microbiome-gut-brain axis during early life regulates the hippocampal serotonergic system in a sex-dependent manner. Mol Psychiatry 2013;18:666-73. https://www.ncbi.nlm.nih.gov/pubmed/?term=The+microbiome-gut-+brain+axis+during+early+life+regulates+the+hippocampal+seroto-+nergic+system+in+a+sex-dependent+manner
4- Nishino R et al. Commensal microbiota modulate murine behaviors in a strictly contamination-free environment confirmed by culture-based methods. Neurogastroenterol Motil 2013;25:521-8. https://www.ncbi.nlm.nih.gov/pubmed/?term=Commensal+microbiota+modulate+murine+behaviors+in+a+strictly+contamination-+free+environment+confirmed+by+culture-based+methods
5- Crumeyrolle-Arias M et al. Absence of the gut microbiota enhances anxiety-like behavior and neuroendocrine response to acute stress in rats. Psychoneuroendocrinology 2014;42:207-17. https://www.ncbi.nlm.nih.gov/pubmed/?term=Absence+of+the+gut+microbiota+enhances+anxiety-like+behavior+and+neu-+roendocrine+response+to+acute+stress+in+rats.
6- Neufeld KM et al. Reduced anxiety-like behavior and central neurochemical change in germ-free mice. Neurogastroenterol Motil 2011;23:255-64. https://www.ncbi.nlm.nih.gov/pubmed/?term=Reduced+anxiety-like+behavior+and+central+neurochemical+change+in+germ-free+mice
7- Desbonnet L et al. Gut microbiota depletion from early adolescence in mice: Implications for brain and behaviour. Brain Behav Immun 2015;48:165-73.  https://www.ncbi.nlm.nih.gov/pubmed/25866195
8- Savignac HM et al. Bifidobacteria exert strain-specific effects on stress-related behavior and physiology in BALB/c mice. Neurogastroenterol Motil 2014;26:1615-27. https://www.ncbi.nlm.nih.gov/pubmed/?term=Bifidobacteria+exert+strain-specific+effects+on+stress-related+behavior+and+phy-+siology+in+BALB%2Fc+mice
9- Bercik P et al. The intestinal microbiota affect central levels of brain-derived neurotropic factor and behavior in mice. Gastroenterology 2011;141:599-609.  https://www.ncbi.nlm.nih.gov/pubmed/?term=The+intestinal+microbiota+affect+central+levels+of+brain-derived+neurotropic+factor+and+behavior+in+mice
10- Bravo JA et al. Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve. Proc Natl Acad Sci USA 2011;108:16050-5. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3179073/pdf/pnas.201102999.pdf
11- Kumar K et al. Therapeutic potential of GABA(B) receptor ligands in drug addiction, anxiety, depression and other CNS disorders. Pharmacol Bio- chem Behav 2013;110:174-84. https://www.ncbi.nlm.nih.gov/pubmed/?term=Therapeutic+potential+of+GABA(B)+receptor+ligands+in+drug+addiction%2C+anxiety%2C+depression+and+other+CNS+disorders
12- Collins SM et al. The interplay between the intestinal microbiota and the brain. Nat Rev Microbiol. 2012;10:735–42. doi: 10.1038/nrmicro2876. https://www.ncbi.nlm.nih.gov/pubmed/23000955
13- Lye Huey Shi et al. (2016). Beneficial properties of probiotics. Tropical Life Sciences Research Année;27(2):73–90. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5031164/pdf/tlsr-27-2-73.pdf

Mood disorders

Mood disorders, depression and bipolar disorder affect people of all ages and sometimes cause severe mental distress. Effective treatments exist and ongoing research is evaluating the impact of the intestinal microbiota on these disorders.

According to the World Health Organization (WHO), depression affects more than 350 million people worldwide. It sometimes causes severe mental distress that can lead to suicide and is the first cause of professional and social disability in the world. More women than men are affected1. Mood disorders include depressive and bipolar disorders. 

Perturbed stress responses

Life events, like the loss of a spouse, a job or a separation, are associated with an increased risk of mood disorders. However, vulnerability to depression, which is partly genetic, exists for each individual2 . Thus, each person with a parent who suffers from depression has a two to four times higher risk of having a depressive episode in his/her lifetime. Defective regulation of the stress-response system, with abnormally high secretion of cortisol, the stress hormone, can also induce a depressive state. Lastly, a microbiota–intestine–brain axis communicates via multiple pathways (parasympathetic nervous system, immune, blood) and participates in the pathophysiology of mood disorders3 . Recent research on the intestinal microbiota yielded findings showing associations between dysbiosis and depression.

What treatments? 

Therapy is based on antidepressants combined with cognitive behavioral therapy for depressive disorders and mood-stabilizing drugs2,4 . A microbiota role may be promising. Results of a recent randomized, double-blind, placebo-controlled study showed that daily intake by healthy volunteers of a combination of probiotics—Lactobacillus helveticus and Bifidobacterium longum—improved mood and lowered anxiety levels5.

 

Sources:
1 – OMS, avril 2016, la dépression http://www.who.int/mediacentre/factsheets/fs369/fr/
2 – INSERM, dépression, août 2014, http://www.inserm.fr/thematiques/neurosciences-sciences-cognitives-neurologie-psychiatrie/dossiers-d-information/depression
3 – Cryan JF, Dinan TG. Mind-altering microorganisms: the impact of the gut microbiota on brain and behaviour. Nat Rev Neurosci. 2012;13:701-12.
4 - Haute Autorité de Santé (HAS), décembre 2010, prise en charge d'un trouble bipolaire, http://www.has-sante.fr/portail/upload/docs/application/pdf/2011-01/ald_23_gp_troublebipolaire_web.pdf
5 -  Messaoudi M et al. Assessment of psychotropic-like properties of a probiotic formulation (Lactobacillus helveticus R0052 and Bifidobacterium longum R0175) in rats and human subjects. Br J Nutr. 2011;105:755-64. https://www.ncbi.nlm.nih.gov/pubmed/20974015

 

Schizophrenia

Recent hypotheses suggest that an alteration in the microbiota that sustains inflammation could favor schizophrenia. Resolving intestinal dysbiosis could potentially become a new treatment option.

Schizophrenia, which affects around 0.7% of the world population, is characterized by a wide range of symptoms, such as an alteration in social relationships, cognitive problems, delirium, and hallucinations. The disease results from complex interactions between genes and environmental factors, like maternal infections during fetal development or the consumption of cannabis1.

The role of immunity

The role of an immune imbalance and particularly of a significant inflammation in the development of the disease is being increasingly recognized. As such, the possibility that pro-inflammatory intestinal dysbiosis might be responsible is beginning to be explored2

The responsibility of the microbiota

Disruptions in the composition of gastrointestinal microbiota have been found in schizophrenic patients3 , as well as an increase in intestinal permeability – particularly through an increase in circulating CD14 levels (marker for bacterial translocation)4,5.

A step towards new treatments?

20 to 30% of schizophrenic patients do not respond or barely respond to currently available antipsychotic treatments1. Action on the gut-brain axis, particularly by rebalancing the microbiota to reduce inflammation, is starting to be considered6. Studies have shown that the administration of probiotics can have an immunomodulating effect, by acting on the plasma concentrations of neurotrophic factors7 , but for the moment no treatment of this type has demonstrated clinical effectiveness.
 

Sources:
1- Inserm. Schizophrénie [en ligne]. Dossier réalisé en collaboration avec Marie-Odile Krebs. Mai 2014. Disponible à l'adresse : http://www.inserm.fr/thematiques/neurosciences-sciences-cognitives-neurologie-psychiatrie/dossiers-d-information/schizophrenie
2- Ellul P. et al. Focus sur la schizophrénie : infections, auto-immunité et dysbiose intestinale, L'INFORMATION PSYCHIATRIQUE, 10/2016 (Volume 93), p. 797-802. https://www.cairn.info/load_pdf.php?ID_ARTICLE=INPSY_9210_0797
3- Sherwin E et al. May the Force Be With You: The Light and Dark Sides of the Microbiota-Gut-Brain Axis in Neuropsychiatry. CNS Drugs 2016 ; 30 : 1019-41. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5078156/pdf/40263_2016_Article_370.pdf
4- Severance EG et al. Seroreactive marker for inflammatory bowel disease and associations with antibodies to dietary proteins in bipolar disorder. Bipolar Disord 2014 ; 16 : 230-40. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4075657/pdf/nihms591287.pdf
5- Nemani K et al. Schizophrenia and the gut-brain axis. Prog Neuropsychopharmacol Biol Psychiatry 2015 ; 56 : 155-60. https://www.ncbi.nlm.nih.gov/pubmed/?term=Nemani+K%2C+Hosseini+Ghomi+R%2C+McCormick+B%2C+Fan+X.+Schizophrenia+and+the+gut-brain+axis.+Prog+Neuropsychopharmacol+Biol+Psychiatry+2015+%3B+56+%3A+155-60.
6- Dickerson FB et al. Effect of probiotic supplementation on schizophrenia symptoms and association with gastrointestinal functioning: a randomized, placebo-controlled trial. Prim Care Companion CNS Disord. 2014; 16(1)10.4088/PCC.13m01579. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4048142/
7- Tomasik J, Yolken RH, Bahn S, Dickerson FB. Immunomodulatory Effects of Probiotic Supplementation in Schizophrenia Patients: A Randomized, Placebo-Controlled Trial. Biomark Insights. 2015 Jun 1;10:47-54. doi: 10.4137/BMI.S22007. https://www.ncbi.nlm.nih.gov/pubmed/26052224

Alzheimer’s disease

Alzheimer’s disease is a neurodegenerative disease that seems to start well before symptoms first appear. There is currently no treatment, but there are options with potential.

According to the WHO1, Alzheimer’s disease affects more than 35 million people around the world. This number is expected to almost double every 20 years, reaching 115.4 million in 20502.

Memory loss: the first visible symptom of the disease

In addition to the characteristic memory loss, Alzheimer’s disease can also cause speech and comprehension difficulties, attention and concentration problems, loss of dexterity (apraxia), and, in some cases, problems recognizing objects or faces (agnosia). Cognitive symptoms get worse over time and behavioral symptoms start to appear, such as anxiety, apathy, irritability, sleeping disorders, disinhibition, and agitation2

From a scientific perspective

Two kinds of lesions are characteristic of Alzheimer’s disease: the abnormal accumulation of beta-amyloid peptide plaque deposits and neurofibrillary degeneration. Although the causes of these phenomena remain unknown, the involvement of intestinal microbiota is being studied. Certain intestinal bacteria seem to produce amyloid peptides similar to those observed in the brains of these patients, which accelerate cerebral inflammation3 involved in the disease.

Risk factors identified

Several genetic and environmental risk factors have been identified2: high blood pressure, high cholesterol, tobacco use, sedentary lifestyle, unbalanced diet, and lack of cognitive stimulation.

Promising prospects for therapy

A diagnosis of Alzheimer’s disease, established during a specialized memory consultation, relies on various exams: neuropsychological exam, MRI, lumbar puncture2, etc. 
Although there is currently no treatment, immunotherapy4 appears to be a promising option. Changing the microbiota by affecting diet and adding probiotics and prebiotics may prevent or reduce the risk of cognitive decline3,5
 

Sources:
1. La démence. OMS. Avril 2016. http://www.who.int/mediacentre/factsheets/fs362/fr/ 
2. L'association pour la recherche sur Alzheimer http://alzheimer-recherche.org/wp-content/uploads/2015/01/FRA-Broch-instit-2015.pdf 
3. Pistollato F et al. M. Role of gut microbiota and nutrients in amyloid formation and pathogenesis of Alzheimer disease. Nutr Rev. 2016 Oct;74(10):624-34. doi: 10.1093/nutrit/nuw023
4. L'immunothérapie pour soigner la maladie d'Alzheimer. Inserm, décembre 2016 http://presse.inserm.fr/limmunotherapie-pour-traiter-la-maladie-dalzheimer/26111/ et Interleukin-2 improves amyloid pathology, synaptic failure and memory in Alzheimer’s disease mice, Brain, 20 décembre 2016 http://brain.oxfordjournals.org/content/early/2016/12/20/brain.aww330 
5. Microbiote intestinal et santé. Inserm. http://www.inserm.fr/thematiques/physiopathologie-metabolisme-nutrition/dossiers-d-information/microbiote-intestinal-et-sante

Autism-Spectrum disorders

Previously called pediatric schizophrenia, autism-spectrum disorders (ASDs) now include autistic disorders and other childhood psychoses. ASDs often have gastrointestinal comorbidities.

Appearing most often during the first 5 years of life, ASDs include autistic disorders, Asperger’s syndrome, the Landau–Kleffner syndrome (also called infantile acquired aphasia), and pervasive developmental disorder not otherwise specified (PDD-NOS). Their prevalence in the world is 1/160 children, with 4 boys for 1 girl1. ASDs share variable degrees of difficulty interacting socially, communicating and acquiring language, a narrow range of interests and acting out repetitive activities, specific to each person2.

Ongoing study of the intestinal microbiota 

Numerous factors, particularly environmental and genetic, probably contribute to making a child susceptible to ASDs1. It is widely accepted that ASDs are associated with neurodevelopmental disorders; however, the real causes are not clear3. Conversely, recent results showed frequent ASD comorbidity with gastrointestinal symptoms4 and increased intestinal permeability5 . Dysbiosis was found in mice that reproduce ASD behavioral anomalies. Oral administration of a Bacteroides fragilis strain to those mice attenuated the microbiota dysbiosis and lessened the severity of most behavioral abnormalities6 .

Therapeutic treatment

No curative therapy exists for ASDs, but early management with psychosocial interventions, like behavioral therapy, can limit communication and social behavior difficulties. Correction of digestive ecosystem imbalances by adding probiotics, prebiotics, and a controlled diet might limit ASD behavioral anomalies3,6,7.

 

Sources:
1 – Troubles du spectre autistique, OMS, février 2016  http://www.who.int/mediacentre/factsheets/autism-spectrum-disorders/fr/
2 – Pro aide autisme, une association de loi 1901, nouveaux critères diagnostiques du DSM 5 http://proaidautisme.org/wp-content/uploads/2014/04/Changes_to_DSM5_FR.pdf
3 - Van De Sande, M.M.H., van Buul, V.J. and Brouns, F.J.P.H. (2014) ‘Autism and nutrition: the role of the gut–brain axis’, Nutrition Research Reviews, Année;27(2):199–214. doi: 10.1017/S0954422414000110.
4 - Krajmalnik-Brown R. Gut bacteria in children with autism spectrum disorders: challenges and promise of studying how a complex community influences a complex disease. Microb Ecol Health Dis. 2015;26:26914. https://www.ncbi.nlm.nih.gov/pubmed/25769266
5 - Navarro, F., Liu, Y., & Rhoads, J. M. (2016). Can probiotics benefit children with autism spectrum disorders? World Journal of Gastroenterology. Année;22(46):10093–10102. http://doi.org/10.3748/wjg.v22.i46.10093
6 - Hsiao EY et al. Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders. Cell. 2013;155:1451-63. https://www.ncbi.nlm.nih.gov/pubmed/24315484
7 - New clinical study to focus on gut, autism connection sur le site du Baylor College of Medicine https://www.bcm.edu/news/pathology-and-immunology/clinical-study-focus-on-gut-autism-connection (consulté le 13/02/2017)

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