Mikrobioomi väärtus terviseuuringutes

Väitekirja elektrooniline versioon ei sisalda publikatsiooneTehnoloogia areng on andnud inimesele võimaluse uurida ümbritsevat maailma nurkade alt, mille jaoks veel mõned kümnendid tagasi võimalused puudusid. Üks selliseid teadusvaldkondi on inimese mikrobioomi ehk meie kehal ja kehas elavate mikroorganismide nagu näiteks bakterite ja viiruste uurimine. On teada, et mikrobioomil on oluline funktsioon inimese tervisele ning mikrobioomi kooslust omakorda mõjutavad suurel määral meie elustiil, toitumisharjumused, ümbritsev keskkond ning tervislik seisund. Just seosed haigustega on tekitanud huvi mikrobioomi kasutamiseks meditsiinilistes rakendustes. Doktoritöö eesmärk oli uurida, millised faktorid lisaks teadaolevatele on seotud meie soolestiku mikrobioomi kooslusega ning kuidas on mikrobioomi andmeid võimalik kasutada haiguste diagnoosimiseks ning haigusriskide hindamiseks. Esiteks uurisime teist tüüpi diabeeti ning näitasime, et mikrobioom aitab senisest täpsemalt ennustada muutusi veresuhkru regulatsiooni kirjeldavates parameetrites, milleks olid eelkõige insuliini eritamisega seotud näitajaid. Järgmiseks eesmärgiks oli kirjeldada Eesti populatsiooni soolestiku mikrorbioomi profiiili ning tuvasatada mikrobioomi kooslust mõjutavad faktorid. Eesti Geenivaramu terviseandmestikku kasutades tuvastasime, et antibiootikumide pikaajalisel korduval kasutamisel on akkumuleeruv mõju mikrobioomi kooslusele olenemata sellest, kas antibiootikume on kasutatud viimase kuue kuu jooksul. Analüüsides pikaajalise antibiootikumide mõju arvesse võtmine võimaldas omakorda täpsustada haigusspetsiifilisi muutusi mikrobioomis. Lisaks uurisime, kas soolestiku mikrobioomi abil inimeste grupeerimine võimaldaks ka kasutust kliinilistes rakendustes. Selgus, et selliselt mikrobioomi kooslust lihtsustades on võimalik küll anda hinnang inimese üldisele elustiilile, kuid tõendid haiguste diagnoosimisel või haiguste riski hindamiseks pole piisavalt tugevad. Kokkuvõttes on mikrobioomi uurimisel meditsiinis suur potentsiaal, mis võimaldab täiendada olemasolevaid võimalusi haiguste diagnoosimiseks ning riskide hindamiseks, kuid see eeldab täiendavaid teadmisi ja uuringuid.The technological revolution allows us to study the world beyond the limits that were holding us back only a couple of decades ago. One of such fields is the study of the human microbiome. Tiny microorganisms making up the microbiome such as bacteria and viruses have been known to intervene with our health for centuries, but the whole microbial ecosystem has turned out to be more complex than previously thought. The extent of the role of the microbiome to our own functioning and well-being is just starting to unravel. Nevertheless, microbiome has been associated with a large variety of intrinsic and extrinsic factors, including various complex diseases. This evidence is leading a slow but steady progress towards clinical applications such as using microbiome for improving disease diagnostics or estimating the risk of developing a condition. This thesis aimed to expand the understanding of the factors influencing our gut microbiome composition and assess the possibility and challenges in using the microbiome composition for the clinical applications. Firstly, we identified novel microbial biomarkers for identifying the progression of type 2 diabetes (T2D), which can be used to improve the current risk estimation. Secondly, using the comprehensive health data available in the Estonian Biobank, we characterized the profile of the gut microbiome in the Estonian population and identified various factors affecting the microbiome. Our study indicated that the long-term antibiotics usage has an accumulative effect on the gut microbiome composition independent of recent usage. The novelty of this result has a significant impact on the microbiome field and the future analysis need to account for such drug effects. Lastly, we considered dividing the subjects into a few distinct clusters based on their microbiome composition and evaluated the clinical applicability of such representation. We showed that although this approach is desirable in its simplicity, it is not sufficient for clinical applications. In conclusion, the microbiome science is heading towards clinical applications, but exploratory analysis is still needed. Nevertheless, the challenges ahead do not overshadow the enthusiasm.https://www.ester.ee/record=b551831

Mikrobioomi andmete analüüs

Inimese soolestikus on suur hulk erinevaid baktereid, mis täidavad organismi jaoks mitmeid olulisi funktsioone. Käesoleva magistritöö eesmärk on uurida, kas teist tüüpi diabeedi eelses seisundis indiviidide soolestiku bakterikoosluses on muudatusi võrreldes tervete indiviidide bakterikooslusega. Võrreldakse bakterikoosluse puhul huvitavaid α- ning β - mitmekesisuse näitajaid. Seejärel uuritakse Mendeli randomiseerimise skeemi abil, missugune võiks olla bakterikoosluse liigirikkuse põhjuslik mõju prediabeedile.Lisaks uuritakse, kas leidub üksikuid baktereid, mis esinevad tervete ja prediabeetikute mikrobioomides erineva sagedusega kasutades selleks kompositsionaalsete andmete analüüsimiseks mõeldud meetodeid. Kirjeldatakse kopositsionaalsete andmete jaoks mõeldud seose tugevuse näitajat uurimaks, kas soolestiku mikrobioomis on liike, mis esinevad soolestiku keskkonnas enamasti koos. Lisaks modelleeritakse prediabeedi esinemist logistilise regressiooni ning regulariseeritud logistilise regressiooniga

Geneetiliste mõjude hindamine kinnitava faktoranalüüsiga

Genoomikapõhise personaalse meditsiini väljatöötamiseks soovitakse inimese genotüübiandmete põhjal ennustada haiguste tekkimise riske. Geneetiliste mõjude hindamisel kasutatakse enim ühenukleotiidsete polümorfismide (SNP) markereid, mis on inimese geneetilise varieeruvuse põhilisemaid avaldumisviise. DNA-ahelal lähestikku paiknevad SNP-d on omavahel tugevasti korreleeritud, seetõttu kasutatakse geeni mõju hindamisel enamasti ainult piirkonna kõige olulisemat markerit. Käesoleva bakalaureusetöö eesmärk on anda ülevaade struktuurivõrrandite mudelitest ning rakendada metoodika ühte erijuhtu - kinnitavat faktoranalüüsi, hindamaks geenipiirkonna mõju, kasutades kõiki piirkonnas mõõdetud geneetilisi markereid

Machine Learning Reveals Time-Varying Microbial Predictors with Complex Effects on Glucose Regulation

The incidence of type 2 diabetes (T2D) has been increasing globally, and a growing body of evidence links type 2 diabetes with altered microbiota composition. Type 2 diabetes is preceded by a long prediabetic state characterized by changes in various metabolic parameters. We tested whether the gut microbiome could have predictive potential for T2D development during the healthy and prediabetic disease stages. We used prospective data of 608 well-phenotyped Finnish men collected from the population-based Metabolic Syndrome in Men (METSIM) study to build machine learning models for predicting continuous glucose and insulin measures in a shorter (1.5 year) and longer (4 year) period. Our results show that the inclusion of the gut microbiome improves prediction accuracy for modeling T2D-associated parameters such as glycosylated hemoglobin and insulin measures. We identified novel microbial biomarkers and described their effects on the predictions using interpretable machine learning techniques, which revealed complex linear and nonlinear associations. Additionally, the modeling strategy carried out allowed us to compare the stability of model performance and biomarker selection, also revealing differences in short-term and long-term predictions. The identified microbiome biomarkers provide a predictive measure for various metabolic traits related to T2D, thus providing an additional parameter for personal risk assessment. Our work also highlights the need for robust modeling strategies and the value of interpretable machine learning.IMPORTANCE Recent studies have shown a clear link between gut microbiota and type 2 diabetes. However, current results are based on cross-sectional studies that aim to determine the microbial dysbiosis when the disease is already prevalent. In order to consider the microbiome as a factor in disease risk assessment, prospective studies are needed. Our study is the first study that assesses the gut microbiome as a predictive measure for several type 2 diabetes-associated parameters in a longitudinal study setting. Our results revealed a number of novel microbial biomarkers that can improve the prediction accuracy for continuous insulin measures and glycosylated hemoglobin levels. These results make the prospect of using the microbiome in personalized medicine promising

Friedrich Puksoo 114. sünniaastapäeva tähistav ettekandepäev "Raamatu aeg"

● Pagulasraamat eesti kultuuripildis / Anne Valmas ● Raamatukaubandusest Eestis 19. saj. II poolel / Signe Jantson ● Helmi Masing - elutee tähiseid / Marje Aasmets ● Raamatuloolane Kyra Robert / Gerli Kangur ● Veel üks katse portreteerida Udo Ivaskit / Malle Erme

Friedrich Puksoo päev 1997

• Friedrich Puksoo - Eesti raamatukogunduse rajajaid / Marje Aasmets • Tartu Ülikooli Raamatukogu komplekteerimise põhimõtetest 1920.-30. aastatel / Kersti Pedak • Saksa 17. sajandi raamat Tartu Ülikooli Raamatukogus / Kiira Schmidt • Baltica leide Briti Raamatukogus / Tiiu Reimo • Estica - mis see praegu on ja kuidas seda Tartus õpetada / Peeter Olesk • Tartu Ülikooli Raamatukogu fotokogu / Sulo Lembine

The Gut Microbiome in Polycystic Ovary Syndrome (PCOS) and its Association with Metabolic Traits

This work was funded by Estonian Research Council grants PUT 1371 (to E.O.), EMBO Installation grant 3573 (to E.O.) … E.O. was supported by European Regional Development Fund Project No. 15-0012 GENTRANSMED and Estonian Center of Genomics/Roadmap II project No 16-0125. S.A. was supported by the Spanish Ministry of Economy, Industry and Competitiveness (MINECO) and European Regional Development Fund (FEDER): grants RYC-2016-21199 and ENDORE (SAF2017-87526-R); and by FEDER/Junta de Andalucía-Consejería de Economía y Conocimiento: MENDO (B-CTS-500-UGR18).Purpose: Despite gut microbiome being widely studied in metabolic diseases, its role in polycystic ovary syndrome (PCOS) has been scarcely investigated. The aim of our study was to test for possible associations between gut microbiome and PCOS in late fertile age women and investigate whether changes in the gut microbiome correlate with PCOS-related metabolic parameters. Methods: We compared the 16S rRNA sequenced gut microbiome of 102 PCOS women with 201 age- and body mass index (BMI) matched non-PCOS women. Clinical and biochemical characteristics of the participants were assessed at ages 31 and 46 and analyzed in the context of gut microbiome data at the age of 46. Results: Bacterial diversity indices did not differ significantly between PCOS and controls. We identified four genera whose balance helps to differentiate between PCOS and non-PCOS. In the whole cohort, the abundance of two genera from the order Clostridiales was correlated with several PCOS-related markers. When investigating the gut microbiome composition in PCOS women with different BMI and glucose tolerance groups, prediabetic PCOS women had significantly lower alpha diversity and markedly increased abundance of genus Dorea compared to women with normal glucose tolerance. Conclusions: Our data indicate that PCOS and non-PCOS women at late fertile age with similar BMI do not signficantly differ in gut microbiota. However, there are significant microbial changes in PCOS individuals depending on their metabolic health. Further studies are needed in order to further understand these changes in more detail.Estonian Research Council grants PUT 1371EMBO Installation grant 3573European Regional Development Fund Project No. 15-0012 GENTRANSMEDEstonian Center of Genomics/Roadmap II project No 16-0125Spanish Ministry of Economy, Industry and Competitiveness (MINECO) European Regional Development Fund (FEDER) RYC-2016-21199 and ENDORE (SAF2017-87526-R)FEDER/Junta de Andalucía-Consejería de Economía y Conocimiento: MENDO (B-CTS-500-UGR18

The Gut Microbiome in Polycystic Ovary Syndrome and Its Association with Metabolic Traits

Context: Despite the gut microbiome being widely studied in metabolic diseases, its role in polycystic ovary syndrome (PCOS) has been scarcely investigated. Objective: Compare the gut microbiome in late fertile age women with and without PCOS and investigate whether changes in the gut microbiome correlate with PCOSrelated metabolic parameters. Design: Prospective, case-control study using the Northern Finland Birth Cohort 1966. Setting: General community. Participants: A total of 102 PCOS women and 201 age- and body mass index (BMI)matched non-PCOS control women. Clinical and biochemical characteristics of the participants were assessed at ages 31 and 46 and analyzed in the context of gut microbiome data at the age of 46. Intervention(s): None Main outcome measure(s): Bacterial diversity, relative abundance, and correlations with PCOS-related metabolic measures. Results: Bacterial diversity indices did not differ significantly between PCOS and controls (Shannon diversity P =.979, unweighted UniFrac P =.175). Four genera whose balance helps to differentiate between PCOS and non-PCOS were identified. In the whole cohort, the abundance of 2 genera from Clostridiales, Ruminococcaceae UCG-002, and Clostridiales Family XIII AD3011 group, were correlated with several PCOS-related markers. Prediabetic PCOS women had significantly lower alpha diversity (Shannon diversity P =.018) and markedly increased abundance of genus Dorea (false discovery rate = 0.03) compared with women with normal glucose tolerance. Conclusion: PCOS and non-PCOS women at late fertile age with similar BMI do not significantly differ in their gut microbial profiles. However, there are significant microbial changes in PCOS individuals depending on their metabolic health.Peer reviewe

Novel Early Pregnancy Multimarker Screening Test for Preeclampsia Risk Prediction

Preeclampsia (PE) is a common pregnancy-linked disease, causing preterm births, complicated deliveries, and health consequences for mothers and offspring. We have previously developed 6PLEX, a multiplex assay that measures PE-related maternal serum biomarkers ADAM12, sENG, leptin, PlGF, sFlt-1, and PTX3 in a single test tube. This study investigated the potential of 6PLEX to develop novel PE prediction models for early pregnancy. We analyzed 132 serum samples drawn at 70–275 gestational days (g days) from 53 pregnant women (PE, n = 22; controls, n = 31). PE prediction models were developed using a machine learning strategy based on the stepwise selection of the most significant models and incorporating parameters with optimal resampling. Alternative models included also placental FLT1 rs4769613 T/C genotypes, a high-confidence risk factor for PE. The best performing PE prediction model using samples collected at 70–98 g days comprised of PTX3, sFlt-1, and ADAM12, the subject's parity and gestational age at sampling (AUC 0.94 [95%CI 0.84–0.99]). All cases, that developed PE several months later (onset 257.4 ± 15.2 g days), were correctly identified. The model's specificity was 80% [95%CI 65–100] and the overall accuracy was 88% [95%CI 73–95]. Incorporating additionally the placental FLT1 rs4769613 T/C genotype data increased the prediction accuracy to 93.5% [AUC = 0.97 (95%CI 0.89–1.00)]. However, 6PLEX measurements of samples collected at 100–182 g days were insufficiently informative to develop reliable PE prediction models for mid-pregnancy (accuracy <75%). In summary, the developed model opens new horizons for first-trimester PE screening, combining the easily standardizable 6PLEX assay with routinely collected antenatal care data and resulting in high sensitivity and specificity