Dokument: Der Einfluss des oralen Mikrobioms auf die Pathophysiologie der Alzheimer-Krankheit

Titel:	Der Einfluss des oralen Mikrobioms auf die Pathophysiologie der Alzheimer-Krankheit
Weiterer Titel:	The influence of the oral microbiome on the pathophysiology of Alzheimer's disease
URL für Lesezeichen:	https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=72549
URN (NBN):	urn:nbn:de:hbz:061-20260330-095312-0
Kollektion:	Dissertationen
Sprache:	Deutsch
Dokumententyp:	Wissenschaftliche Abschlussarbeiten » Dissertation
Medientyp:	Text
Autor:	Weber, Christian Matthias [Autor]
Dateien:	[Dateien anzeigen] Adobe PDF [Details] 2,84 MB in einer Datei [ZIP-Datei erzeugen] Dateien vom 13.03.2026 / geändert 13.03.2026
Beitragende:	Privatdozent Dr. med Dr. phil Finzer, Patrick [Gutachter] Prof. Dr. med Supprian, Tillmann [Gutachter] Prof. Dr. med. Dr. phil Thome, Johannes [Gutachter]
Stichwörter:	Alzheimer, Mikrobiom
Dokumententyp (erweitert):	Dissertation
Dewey Dezimal-Klassifikation:	600 Technik, Medizin, angewandte Wissenschaften » 610 Medizin und Gesundheit
Beschreibungen:	Thema der vorliegenden Dissertation ist die Untersuchung eines möglichen Zusammenhangs zwischen dem oralen Mikrobiom und der Entstehung einer Demenz bei Alzheimer-Krankheit. Die zu Grunde liegende Hypothese lautet, dass Patienten mit einer Demenz bei Alzheimer-Krankheit Unterschiede im oralen Mikrobiom zeigen, die sich als orale Dysbiose beschreiben lassen. Zur Prüfung dieser Hypothese wurden zwischen Juni 2021 und März 2023 insgesamt 51 Probanden über die Gedächtnissprechstunde der psychiatrischen Ambulanz am Universitätsklinikum Düsseldorf rekrutiert. Bei den Probanden handelt es sich um 26 Patienten mit klinisch und biochemisch diagnostizierter Demenz bei Alzheimer-Krankheit und 25 kognitiv gesunde Kontroll-Probanden. Als Kontrollen wurden dabei die jeweiligen Lebenspartner gewählt, um möglichst vergleichbare Lebensumstände zu garantieren. Nach Prüfung der Einschlusskriterien, Einwilligung und Aufklärung wurden die Probanden gemeinsam zu einem einmaligen Untersuchungstermin einbestellt. Bei diesem Termin wurde die orale Hygiene anamnestisch eruiert, anschließend erfolgte die Entnahme von drei Proben: Ein Abstrich von der rechten Wangeninnenseite, ein Abstrich im supragingivalen Bereich des ersten Molars des rechten Unterkiefers, sowie eine salivare Probe (eine weitere salivare Probe wurde ebenfalls für eine spätere, weiterführende Analyse entnommen, die jedoch nicht Gegenstand der vorliegenden Arbeit ist). Ein Patient war dabei nicht dazu in der Lage, ausreichend Speichel zu sammeln, weswegen jeweils 51 Abstriche und 50 salivare Proben im weiteren Verlauf zur Verfügung standen. Anschließend wurden die vorhandenen Zähne nach FDI-Schema (Fédération Dentaire Internationale) gezählt und es erfolgte eine Untersuchung des Zahnfleischrands mit Hilfe des modifizierten Sulkus-Blutungs-Index (SBI). Die beiden Abstriche und die Saliva-Probe wurden anschließend mikrobiologisch untersucht. Die mikrobiologischen Untersuchungen umfassten verschiedene Methoden aus der Gruppe der Next-Generation-Sequencing-Technologien (NGS): Nach initialer Extraktion der DNA (Deoxyribonucleic Acid) aus allen mikrobiologischen Proben wurden 50 Saliva-Proben zunächst mittels Oxford-Nanopore-Technologie metagenomisch sequenziert (Whole-genome-sequencing). Nach Bestimmung des DNA-Gehalts erwiesen sich die Wangenabstriche als am wenigsten geeignet für eine weiterführende Analyse und wurden daher nicht sequenziert. Die 50 Saliva- und 51 supragingivalen Proben wurden hingegen mittels Oxford-Nanopore-Technologie taxonomisch im Hinblick auf das 16S rRNA-Gen (Ribonucleic Acid) untersucht (Full-Length-16S-Sequenzierung). Um darüber hinaus einen Methodenvergleich zu ermöglichen, wurden dieselben 101 Proben zusätzlich am Biologisch-Medizinischen Forschungszentrum (BMFZ) des Universitätsklinikums Düsseldorf mittels Illumina-Technologie ebenfalls auf das 16S rRNA-Gen hin untersucht (Short-Read-16S-Sequenzierung). Die rechnergestützte Infrastruktur und Unterstützung erfolgte durch das Zentrum für Informations- und Medientechnologie der Heinrich-Heine-Universität Düsseldorf. Die bioinformatische, taxonomische Klassifizierung der metagenomischen Daten erfolgte mit Kraken2 und Bracken, die der Full-Length-16S- und Short-Read-16S-Daten mit Emu. Die statistische Auswertung der mikrobiellen Daten erfolgte durch Bestimmung der Bray-Curtis-Dissimilarität und Principal Coordinate Analysis (PCoA), sowie die Analyse mittels Linear Discriminant Analysis Effect Size (LEfSe) und Analysis of Compositions of Microbiomes with Bias Correction 2 (ANCOM-BC2). Die Alpha-Diversität wurde durch Bestimmung von Simpson- und Shannon-Index ermittelt. Bezogen auf die klinischen Parameter zeigten die Kontrollprobanden einen signifikant höheren Mini-Mental-Status-Test (MMST; p < 0,01), eine höhere Zahl von Ausbildungsjahren (p = 0,03) und ein höheres Körpergewicht (p = 0,03). Alle weiteren klinischen Parameter zeigten keinen Unterschied zwischen den Gruppen. Die Alpha-Diversität war in beiden Gruppen vergleichbar, mit Ausnahme eines signifikant höheren Shannon-Index in der Patientengruppe in der Short-Read-16S-Sequenzierung der Saliva-Proben (p = 0,03). Die PCoA zeigte auf Spezies-Ebene eine visuelle Auftrennung von Patienten und Kontrollen in salivaren und supragingivalen Proben, wobei der Effekt für die salivaren Proben am ehesten in der metagenomischen Sequenzierung und für die supragingivalen Proben am ehesten in der Short-Read-16S-Sequenzierung identifiziert werden konnte. Für beide Probenarten und alle drei Sequenzierungsmethoden konnten in LEfSe und ANCOM-BC2 zahlreiche Taxa identifiziert werden, deren Abundanz einen statistisch signifikanten Unterschied zwischen Patienten und Kontrollprobanden aufwiesen. Bakterien-Spezies, die dabei wiederkehrend identifiziert werden konnten, wurden als besonders robust eingestuft. Zu den vielversprechendsten Kandidaten zählten dabei unter anderem Prevotella nigrescens, Lactobacillus rhamnosus, Schwartzia succinivorans, Olsenella uli, Lactobacillus vaginalis, Lactobacillus oris, Prevotella maculosa, Lancefieldella rimae, Lactobacillus paracasei, Prevotella oralis und Lactobacillus gasseri mit höheren Abundanzen in der Patientengruppe, sowie Aggregatibacter aphrophilus, Granulicatella adiacens, Haemophilus sputorum, Streptococcus parasanguinis, Lachnoanaerobaculum saburreum, Veillonella dispar und Kingella oralis mit höheren Abundanzen in der Kontrollgruppe. Anhand dieser Taxa ließ sich ein Trend hin zu mehr Karies- und Parodontitis-assoziierten Taxa in der Patientengruppe identifizieren. Darüber hinaus konnte gezeigt werden, dass die Ergebnisse der drei Sequenzierungsmethoden auf Genus-Ebene eine deutliche Korrelation und bezogen auf die identifizierten Taxa nach entsprechender Filterung eine konstante Schnittmenge, aber auch distinkte Unterschiede zeigen. Die genannten Ergebnisse erlauben eine Annahme der Ausgangshypothese, da signifikante Unterschiede zwischen dem oralen Mikrobiom von Alzheimer-Patienten und gesunden Kontrollprobanden identifiziert werden konnten. Die robustesten Ergebnisse zeigten dabei diverse Bakterien-Spezies, die mit oralen Pathologien in Verbindung gebracht werden können, ohne dass sich ein Unterschied im Hinblick auf den klinischen Status der Mundgesundheit feststellen ließ. Dieser Umstand könnte als Hinweis auf einen ökologischen Wandel im Sinne einer oralen Dysbiose betrachtet werden. The subject of the present dissertation is the investigation of a possible relationship between the oral microbiome and the development of dementia in Alzheimer's disease. The underlying hypothesis is that patients with dementia in Alzheimer's disease show differences in the oral microbiome, which can be described as an oral dysbiosis. To test this hypothesis, a total of 51 subjects were recruited between June 2021 and March 2023 via the memory consultation of the psychiatric outpatient clinic at the University Hospital Düsseldorf. The subjects were 26 patients with clinically and biochemically diagnosed dementia in Alzheimer's disease and 25 cognitively healthy control subjects. The respective life partners were chosen as controls in order to guarantee comparable living conditions as far as possible. After review of the inclusion criteria, informed consent and clarification, the subjects were called together for a single examination appointment. At this appointment, oral hygiene was elicited by anamnesis, followed by collection of three samples: A swab from the inner right cheek, a swab from the supragingival area of the first molar of the right mandible, and one salivary sample (another salivary sample was also taken for a later, further analysis, which is not the subject of the present work). One patient was not able to collect sufficient saliva, which is why 51 swabs and 50 salivary samples were available in the further course. Subsequently, the teeth present were counted according to the FDI (Fédération Dentaire Internationale) scheme and an examination of the gingival margin was performed using the modified Sulcus Bleeding Index (SBI). The two swabs and the saliva sample were then examined microbiologically. The microbiological investigations included various methods from the group of Next-Generation Sequencing (NGS) technologies: After initial extraction of DNA (Deoxyribonucleic Acid) from all microbiological samples, 50 saliva samples were first metagenomically sequenced using Oxford Nanopore technology (whole-genome sequencing). After determining the DNA content, the cheek swabs proved to be the least suitable for further analysis and were therefore not sequenced. The 50 saliva and 51 supragingival samples, on the other hand, were taxonomically examined with regard to the 16S rRNA gene (ribonucleic acid) using Oxford nanopore technology (full-length 16S sequencing). In addition, to enable a comparison of methods, the same 101 samples were also analyzed for the 16S rRNA gene at the Biological Medical Research Center (BMFZ) of the University Hospital Düsseldorf using Illumina technology (short-read 16S sequencing). The computer-based infrastructure and support was provided by the Center for Information and Media Technology at Heinrich Heine University Düsseldorf. The bioinformatic, taxonomic classification of the metagenomic data was carried out with Kraken2 and Bracken, that of the full-length and short-read 16S data with Emu. Statistical evaluation of the microbial data was performed by determining Bray-Curtis Dissimilarity and Principal Coordinate Analysis (PCoA), and analysis using Linear Discriminant Analysis Effect Size (LEfSe) and Analysis of Compositions of Microbiomes with Bias Correction 2 (ANCOM-BC2). Alpha diversity was determined by the Simpson and Shannon indices. In terms of clinical parameters, the control subjects showed a significantly higher Mini-Mental Status Test (MMST; p < 0.01), a higher number of years of education (p = 0.03) and a higher body weight (p = 0.03). All other clinical parameters showed no difference between the groups. Alpha diversity was comparable in both groups, with the exception of a significantly higher Shannon index in the patient group in the short-read 16S sequencing of the saliva samples (p = 0.03). PCoA showed a visual separation of patients and controls in salivary and supragingival samples at the species level, with the effect for the salivary samples most likely to be identified in metagenomic sequencing and for the supragingival samples most likely to be identified in short-read 16S sequencing. For both sample types and all three sequencing methods, numerous taxa were identified in LEfSe and ANCOM-BC2 whose abundance showed a statistically significant difference between patients and control subjects. Bacterial species that could be identified recurrently were classified as particularly robust. The most promising candidates included Prevotella nigrescens, Lactobacillus rhamnosus, Schwartzia succinivorans, Olsenella uli, Lactobacillus vaginalis, Lactobacillus oris, Prevotella maculosa, Lancefieldella rimae, Lactobacillus paracasei, Prevotella oralis and Lactobacillus gasseri with higher abundances in the patient group, and Aggregatibacter aphrophilus, Granulicatella adiacens, Haemophilus sputorum, Streptococcus parasanguinis, Lachnoanaerobaculum saburreum, Veillonella dispar and Kingella oralis with higher abundances in the control group. Based on these taxa, a trend towards more caries- and periodontitis-associated taxa in the patient group could be identified. In addition, it could be shown that the results of the three sequencing methods show a clear correlation at the genus level and, in relation to the identified taxa after appropriate filtering, show a constant intersection, but also distinct differences. These results support the initial hypothesis, as significant differences were identified between the oral microbiome of Alzheimer's patients and healthy controls. The most robust results showed diverse bacterial species that can be associated with oral pathologies, with no difference in the clinical status of oral health. This could be seen as an indication of an ecological change in terms of oral dysbiosis.
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