Meer dan een buikgevoel: zouden je darmbacteriën de sleutel kunnen zijn tot het ontwikkelen van een nieuwe behandeling voor de ziekte van Parkinson?

Hilke
De Rouck

De ziekte van Parkinson is de op één na meest voorkomende neurodegeneratieve aandoening na dementie en kent momenteel geen genezing. De huidige standaardbehandeling, levodopa, verliest na verloop van tijd vaak effectiviteit en veroorzaakt bij de meeste patiënten ongewenste bijwerkingen zoals onwillekeurige bewegingen. Dit benadrukt de dringende noodzaak voor effectievere behandelingen voor Parkinsonpatiënten. Recentelijk zijn de darmbacteriën naar voren gekomen als veelbelovende therapeutische doelen. In mijn thesis, in samenwerking met het bedrijf MRM Health, onderzocht ik het therapeutisch potentieel van specifieke bacteriesoorten, met name Prevotella, op het fenotype en de pathologie van de ziekte van Parkinson in muizen. Ontdek in dit fascinerende onderzoek hoe deze bacteriën de ziekte van Parkinson mogelijk kunnen beïnvloeden.

Communicatie tussen hersenen en darmen ondanks anatomische scheiding 

Ons spijsverteringskanaal herbergt een diverse microbiële gemeenschap die cruciaal is voor onze gezondheid. Wanneer deze darmmicrobiota uit balans raakt, een toestand die we dysbiose noemen, wordt dit niet alleen geassocieerd met gastro-intestinale aandoeningen, maar ook met ziekten die andere organen aantasten. Darmbacteriën kunnen bijvoorbeeld het centrale zenuwstelsel beïnvloeden, inclusief onze hersenen. Er is een tweerichtingscommunicatie tussen het centrale zenuwstelsel en het darmmicrobioom, bekend als de microbiota-darm-hersenas. Deze verbindt de hersenen met de darmen via routes zoals het immuunsysteem en de bloedsomloop, waarbij neuroactieve stoffen, metabolieten en hormonen een rol spelen. Bij dysbiose raken deze paden verstoord, wat kan leiden tot veranderingen in de hersenbarrières en ontstekingen in de hersenen. Darmdysbiose biedt daarom nieuwe mogelijkheden voor de behandeling van neurologische aandoeningen. Een opmerkelijk voorbeeld is de ziekte van Parkinson, waar steeds meer bewijs suggereert dat veranderingen in de darmflora bijdragen aan het ontstaan en de progressie van de ziekte.

De darmen en het microbioom spelen een belangrijke rol bij Parkinson

Parkinson wordt tegenwoordig gediagnosticeerd op basis van bekende motorische symptomen zoals trage of oncontroleerbare bewegingen, spierstijfheid en trillingen in rust. Hoewel deze symptomen vaak bekend zijn, is het minder bekend dat de ziekte ook gepaard gaat met niet-motorische symptomen. Patiënten ervaren bijvoorbeeld constipatie, vermoeidheid en geurverlies. Verschillende van deze niet-motorische symptomen, zoals constipatie, kunnen zich jaren voor de motorische symptomen manifesteren, wat het belang van de darmen bij Parkinson benadrukt. Gastro-intestinale-stoornissen, waaronder constipatie, komen maar liefst bij meer dan 80% van de patiënten voor. 

Een typisch kenmerk van de ziekte van Parkinson is de misvouwing, aggregatie en verspreiding van α-synucleïne in de hersenen. Opmerkelijk is dat α-synucleïne aggregaten ook in het spijsverteringskanaal van Parkinsonpatiënten zijn gevonden, wat de Braak-hypothese ondersteunt dat α-synucleïne pathologie zich van de darmen naar de hersenen kan verspreiden. Echter, niet bij alle patiënten verloopt deze verspreiding op dezelfde manier, wat heeft geleid tot een alternatieve hypothese die de ziekte van Parkinson onderverdeelt in twee subtypes: brain-first en body-first. Bij body-first patiënten begint de α-synucleïne pathologie in de darmen en verspreidt zich naar de hersenen, terwijl bij brain-first patiënten de pathologie juist in de hersenen begint.

Ander bewijs voor het belang van de darmen in Parkinson is dat de samenstelling van darmbacteriën van patiënten significant verschilt van dat van gezonde individuen. Bovendien is darmdysbiose in verband gebracht met het uitlokken of verergeren van ziekteprogressie in muizen. Een beter begrip van de microbiota-darm-hersenen verband bij de ziekte van Parkinson kan de mogelijkheid bieden om nieuwe behandelingen te ontwikkelen met behulp van middelen die gericht zijn op de veranderde darmsamenstelling. 

Intestinale dysbiose bij de ziekte van Parkinson en mogelijke interventies

De samenstelling van darmbacteriën bij Parkinsonpatiënten verschilt aanzienlijk van die bij gezonde mensen. Patiënten hebben minder bacteriën die korte-keten vetzuren produceren en meer bacteriën die met darmbarrièredisfunctie worden geassocieerd. Een verstoorde darmmicrobiota kan de ziekte verergeren, terwijl herstel van de microbiota de ziekte mogelijk kan vertragen. Bijgevolg zou het aanpakken van de dysbiose van het darmmicrobioom mogelijk een nieuwe behandelingsmogelijkheid bieden om PD te bestrijden. Fecale microbiota-transplantatie kan de darmmicrobiota aanpassen en de microbiota-darm-hersenas, en daarmee de neurodegeneratiecascade bij Parkinson, beïnvloeden. Aangezien zo’n transplantatie echter arbeidsintensief is en risico's met zich meebrengt, richt dit masterproefschrift zich op het onderzoeken van specifieke bacteriestammen als alternatief.

Parkinsonpatiënten hebben een bacteriële darmflora die verschilt van die van gezonde mensen.

Het therapeutisch potentieel van Prevotella-supplementatie bij Parkinson: eerste aanwijzingen van onze muizenstudie en toekomstige richtingen

Een opvallend verschil in darmbacteriën bij Parkinsonpatiënten vergeleken met gezonde individuen is een afname van Prevotella bacteriën. Prevotella, gramnegatieve bacteriën, zijn verantwoordelijk voor de productie van mucus en korte-keten vetzuren. Verminderde Prevotella-niveaus kunnen de darmbarrière doorlaatbaarder maken en de gevoeligheid voor darmontsteking vergroten, wat de progressie van Parkinson mogelijk kan verergeren. In mijn master thesis heb ik onderzocht of het verrijken van het microbioom met Prevotella bacteriën in een muismodel voor de ziekte van Parkinson invloed heeft op het fenotype en de pathologie van Parkinson, zowel in de vroege als late stadia van de ziekte. Hiervoor gebruikte ik twee Prevotella 'cocktails' met een verschillende samenstelling.

Heeft het verrijken van de darmen met Prevotella bacteriën invloed heeft op het fenotype (motorische afwijkingen en constipatie) en de pathologie (α-synucleïne aggregatie en neuroinflammatie) van de ziekte van Parkinson?

In mijn thesis vertoonde één Prevotella-cocktail een lichte, veelbelovende trend in het verlagen van pathologische α-synucleïne-niveaus in de hersenen in de vroege stadia van Parkinson. Deze resultaten zijn echter onvoldoende om te concluderen dat Prevotella-bacteriën een therapeutisch effect hebben in beide stadia van de ziekte. Verder onderzoek is nodig om onze bevindingen te valideren door meer parameters te analyseren en de resultaten te bevestigen in onafhankelijke muisgroepen, idealiter met grotere steekproeven.

Naar schatting zullen tegen 2040 wereldwijd 14,2 miljoen mensen lijden aan Parkinson. Dit onderstreept het dringende maatschappelijke belang van onderzoek naar nieuwe behandelingen voor deze neurodegeneratieve ziekte. Het aanpakken van dysbiose in de darmen is een veelbelovende strategie, met het potentieel om in de toekomst een bacteriepil te ontwikkelen die vele Parkinson patiënten kan helpen.

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Universiteit of Hogeschool
Universiteit Gent
Thesis jaar
2024
Promotor(en)
Prof. Dr. Roosmarijn Vandenbroucke
Thema('s)
Kernwoorden