Browsing by Subject "gut microbiome"
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(2017)Monissa sairauksissa suoliston seinässä voidaan havaita tulehdus, läpäisevyyden kasvu ja mikrobiston muutoksia verrattuna terveisiin verrokkeihin. Tästä syystä suoliston mikrobiston muokkaamisella ja anti-inflammatorisilla bakteerilajeilla on potentiaalia kyseisten sairauksien hoidossa sekä preventiossa. Tulehduksen hoidossa tehokkaaksi menetelmäksi on osoittautunut mm. ulosteensiirrot, mutta sen anti-inflammatorisesta vasteesta vastaavat mekanismit ovat vielä osittain epäselviä. Tämän tutkielman kirjallisuuskatsauksessa tarkasteltiin suoliston mikrobiston ja läpäisevyyden häiriöiden vaikutuksia terveyteen ja erityisesti nivelreumaan. Nivelreumapotilailla on tyypillisesti kohonnut suoliston läpäisevyys, mutta sen merkitys sairauden etenemisessä ja patogeneesissä on vielä tuntematon. Suoliston mikrobiston häiriöt ja läpäisevyyden muutokset saattavat aiheuttaa immuunireaktion, joka voi johtaa nivelen rakenteisiin kohdistuvan autoimmuniteetin puhkeamiseen. Kokeellisessa osiossa tutkittiin suolistosta eristettyjen potentiaalisesti anti-inflammatoristen Propioni acnes –bakteerin ja toistaiseksi tuntemattoman linjan (27cc1) bakteerin vaikutuksia suoliston läpäisevyyteen. Koe suoritettiin Caco2-enterosyyttisolulinjalla ja sen muodostaman epiteelin läpäisevyyttä arvioitiin TER (transepithelial electrical resistance) -mittauksilla. Valituilla bakteereilla ei havaittu kokeissa merkittävää vaikutusta epiteelin läpäisevyyteen in vitro.
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(2024)Parkinson’s disease (PD) is a prevalent neurodegenerative disease characterized by movement disorders, such as bradykinesia, akinesia, and tremor. The degeneration of dopaminergic neurons in the central nervous system (CNS) is the most central aspect of the pathophysiology of PD-related movement disorders. The treatment of PD motor symptoms is based on increasing the diminished dopaminergic signalling in the CNS. This can be achieved by using medications such as dopamine agonists and monoamine oxidase B inhibitors. Levodopa, which acts as a precursor of dopamine in the body, is currently considered the most effective treatment for PD motor symptoms. Unlike dopamine, levodopa can cross the blood-brain barrier. Thus, levodopa must reach the CNS before being metabolized into dopamine to achieve the desired therapeutic effect. Dopa decarboxylase (DDC) inhibitors and catechol-O-methyltransferase inhibitors have been co-administered alongside levodopa to reduce its peripheral metabolism. However, when administered orally, levodopa is also metabolized in the gut by tyrosine decarboxylase, an enzyme produced by gut bacteria. Inhibi tion of bacterial tyrosine decarboxylase (TyrDC) could increase the effectiveness of levodopa treatment and reduce the needed levodopa dosage. The aim of this study was to synthesize and assess the biological activity of novel analogues of previously identified hit compounds which are dual inhibitors of TyrDC and DDC. Our goal was also to gain a deeper understanding of the structure-activity relationships of these compounds. Some of the compounds synthesized in this study were able to inhibit both TyrDC and DDC. Unfortunately, they were also either toxic towar ds human cells, and/or lacked efficacy in a bacterial cell-based assay used to determine the inhibition of levodopa metabolism. However, the data generated in this study can be utilized to design and synthesize new analogs to discover more efficacious and safer TyrDC and DDC dual inhibitors.
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(2019)The gut microbiome of mammals plays many important roles in the host, including preventing colonization of pathogens, maintaining intestinal homeostasis, helping digest nutrients and even affecting host behavior. The composition of mammalian gut microbiota varies greatly between individuals, species and in time. When a mammal is born, it acquires its first, mostly anaerobic, gut microbiota through maternal transmission in the birth canal. After the initial transmission of bacteria, host genotype, especially genes related to immunity, become an important factor that helps determine which species get to stay in the gut and prosper. In adulthood age, sex, diet, disease and contact with others all become important shapers of microbiome composition. Since microbial communities are comparable to any macroecological communities, they can be explained through ecological theories. For example, community assembly theory can help distinguish the effects of input (e.g. transmission) from selective processes (e.g. filtering host genotype) on gut microbiome composition. Community assembly can lead to multiple stable equilibria determined by which species colonized the area first (“priority effect”), emphasizing the importance of early transmission, such as that maternal transmission birth. Metacommunity theory on the other hand, views a large ecosystem as a mosaic of patches and can be helpful in describing the composition of the microbiome in adult individuals. In this thesis, I use community assembly theory and metacommunity theory as a framework to explore determinants of individual gut microbiome composition in wild European wood mice (Apodemus sylvaticus). Specifically, I set out to investigate how much of the gut microbial community variation was accountable for host relatedness and how much of this effect is due maternal transmission (input) versus host genotype (filtering). To find out more about what affects the composition of the gut microbiome in wild animals, I collected both tissue and microbiome samples from wood mice in the Wytham woods research area near Oxford, Great Britain. In addition to the data collected in Wytham, I was given another similarly collected dataset from Silwood Park. My study questions were: What proportion of gut microbiome composition in wood mice is determined by host genotype? Do mothers affect their offspring’s microbiome more than fathers through maternal transmission of bacteria? DNA extractions and mouse genotyping were done by me in the MES laboratory at the University of Helsinki. Sequencing of microbial DNA was done by my co-supervisor at Royal Veterinary College in London. Microbiome similarity was compared to host genetic relatedness using Mantel test and likelihood ratio tests on linear models with dyadic data (comparing relatedness and microbiome similarity of each pair). According to the results, related individuals had a significantly more similar microbiome in Wytham, but not in Silwood. In both populations, microbiome similarity was also affected significantly by age and home range area. The general trend was, that mother-pup and fullsib pairs had more similar microbiome than unrelated pairs (though this effect was significant only in Wytham) and father-pup pairs had a more different microbiome than unrelated pairs (though this effect was significant only in Silwood). All data combined, mice had significantly more similar microbiome with their mother than father. The higher similarity between mother-pup pairs and full siblings can be explained by maternal transmission and postnatal physical contact. Since the father’s effect is purely genetic, their microbiome differing from their offspring even more than from unrelated individuals could be explained by lack of physical contact and different age. Alternatively, females could even be choosing to mate with males with different immunogenotypes, and thus more different microbiome from themselves than expected by chance. Based on my results, transmission of bacteria during and shortly after birth is a key factor shaping microbiome composition and it might even account for the “genetic” effect seen in previous studies.
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