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[pt] A contaminação de solos por hidrocarbonetos é uma real preocupação ambiental em muitas partes do mundo devido a crescente dependência econômica dos derivados do petróleo, principalmente os combustíveis fósseis que estão frequentemente sujeitos a vazamentos e derramamentos acidentais. Estudos capazes de entender os mecanismos de biodegradação dos componentes da gasolina no solo não saturado se fazem necessários, pois auxiliam no processo de tomada de decisões em relação ao gerenciamento e controle da propagação em subsuperfície. No Brasil, o etanol é utilizado como aditivo oxigenado à gasolina e alguns autores sugerem para solo saturado que, por ser mais degradável, ele atrasa a degradação dos outros componentes mais tóxicos desse combustível. O trabalho anterior realizado por esse grupo de pesquisa para solo não saturado obteve conclusões semelhantes às já constatadas para solo saturado. No entanto, os mecanismos de degradação na zona não saturada ainda foram pouco estudados e compreendidos. Este estudo tem como objetivo analisar a degradação do contaminante em blocos não saturados indeformados de solo arenoso e siltoso, oriundos do município de Duque de Caxias – RJ, submetidos a um pulso de contaminante. Dois blocos, um arenoso (BA) e outro argiloso (BS), foram contaminados pela solução de dois porcento de Benzeno, quatro porcento de Tolueno em Heptano (BT); outros dois blocos, também um arenoso (EA) e outro argiloso (ES), foram submetidos à mesma solução adicionados etanol a vinte porcento (BTE). Foram realizados ensaios com a finalidade de monitorar a atividade degradadora total do meio, carbono disponível, perfil metabólico da microbiota, concentração dos contaminantes, além de medições da umidade volumétrica através do uso do Time Domain Reflectometer (TDR). A atividade microbiana inicial, antes da contaminação, apresentou valores baixos. Logo após a contaminação dos blocos, àqueles sujeitos a etanol apresentaram ausência de atividade enquanto os sujeitos apenas à mistura BT mostraram um aumento, contrariando as expectativas. As atividades microbianas oscilaram ao longo de todo o experimento o que pode indicar uma adaptação da microbiota às novas condições do meio. Com base nos resultados dos ensaios e monitoramentos realizados, podemos sugerir que o principal fator determinante para alteração da atividade foi à composição do solo. O contaminante não exerceu a influência esperada e vista nos estudos anteriores. / [en] The soil contamination by hydrocarbons is a real environmental concern in many parts of the world due to growing economic dependence on petroleum, mostly fossil fuels are often subject to leaks and accidental spills. Studies able to understand the mechanisms of biodegradation of gasoline components in unsaturated soil are necessary because they help in making decisions regarding the management and control of the propagation process in the subsurface. In Brazil, ethanol is used as an oxygenate gasoline additive and some authors suggest that for saturated soils, being more degradable, it delays the degradation of other more toxic components of this fuel. The previous study by this research group to unsaturated soil obtained similar results to those already observed for saturated soil. However, the mechanism of degradation in the unsaturated zone have few studies. This study aims to analyze the degradation mechanisms of the contaminant in unsaturated blocks of sand and silt soil from the city of Duque de Caxias - RJ, subjected to a pulse of contaminant. Two blocks, one sandy (BA) and silty (BS), were contaminated by two percent solution of benzene, four percent toluene in heptane (BT); other two blocks, also sandy (EA) and silty (ES), underwent the same solution added to twenty percent ethanol (BTE). Analyzes were performed to monitor the overall activity of the degrading medium, available carbon, the microbiota metabolic profile, concentration of the contaminants were performed as well as measurements of the water content through the use of Time Domain Reflectometer (TDR). The initial microbial activity before the contamination, showed low values. Soon after contamination of the blocks, those subjected to ethanol showed no activity while subject to BT mixture showed an increase, contrary to expectations. Microbial activities ranged throughout the experiment which may indicate an adaptation of microbes to new environmental conditions. Based on the results of testing and monitoring conducted, we suggest that the main determinant for changing the activity factor was the composition of the soil. The contaminant did not exert the expected influence and seen in previous studies

Immunotherapy has emerged as one of the four “standard” cancer therapies, alongside surgery, chemotherapy, and radiotherapy. Immune checkpoint inhibitor (ICI) therapy is an immunotherapy that blocks inhibitory immune checkpoint interactions, allowing T cells and other immune cells to kill tumor cells. In the tumor microenvironment, there is often overexpression of immune checkpoint proteins, whose binding interaction with cytotoxic T cells and other immune cells results in the dampening of the antitumor response. Programmed cell death protein 1 (PD-1) and T-lymphocyte-associated protein 4 (CTLA-4) are the two most targeted immune checkpoint proteins. Antibodies against PD-1 and CTLA-4, as well as other checkpoint proteins, are approved for clinical use as well as in clinical trials. While ICIs have changed the treatment landscape for many cancers, particularly those with significant immunogenicity, only 20-40% of patients respond to ICI therapy. Many factors are behind the lack of response and resistance, and significant efforts are aimed at improving the response to ICI therapy. One major area is modulating the gut microbiome, as it is well-established that microbial dysbiosis is associated with various human diseases. The concept is that by modulating the microbiome, we might be able to return it to a composition more similar to that seen in healthy individuals or provide microorganisms beneficial to clinical response. In the case of ICI therapy, it is proposed that there is a connection between certain microbial species and the immune system via metabolites and other signaling effects. The microbiome can be manipulated through many methods, including fecal microbiota transplantation (FMT), transferring bacterial isolates or consortia, probiotics, antibiotics, and soluble dietary fiber. For clinical insights, it is important to consider how the pre-treatment microbiome of patients may affect their response to ICI therapy, as well as how their microbiomes can be manipulated to enhance their response. Initial clinical trials have been promising, but this is an emerging field with additional work to be done. Particularly, a better understanding of the microorganisms involved in the response to ICI therapy and the mechanism by which they communicate with the immune system is essential. Future studies will need to be much larger to reduce noise between studies and to allow for emerging computational techniques to be applied.

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The human gut microbiota contributes to host metabolic processes. Diverse microbial metabolic enzymes can affect therapeutic agents, resulting in chemical modifications that alter drug efficacy and toxicology. These interactions may result in ineffective treatments and dose-limiting side effects, as shown by bacterial modifications of the cardiac drug digoxin and chemotherapy drug irinotecan, respectively. Yet, few drug-microbiome interactions have been characterized. Here, a platform is developed to screen for drug-microbiome interactions, validated by the isolation of a gut bacterium capable of inactivating the antineoplastic drug doxorubicin. Two hundred gut strains isolated from a healthy patient fecal sample were cultured in the presence of antibiotic and antineoplastic drugs to enrich for resistance and possible inactivation. Raoultella planticola was identified for its ability to inactivate doxorubicin anaerobically through whole cell and crude lysate assays. This activity was also observed in other Enterobacteriaceae and resulted in doxorubicin inactivation by the removal of its daunosamine sugar, likely mediated by a molybdopterin-dependent enzyme. Other potential drug-microbiome interactions were identified in this screen and can be analyzed further. This platform enables the identification of drug-microbiome interactions that can be used to study drug pharmacology, improve the efficacy of therapeutic treatments, and advance personalized medicine. / Thesis / Bachelor of Science (BSc) / The collection of microbes in the human intestinal tract, referred to as the gut microbiome, can modify therapeutic agents and change the efficacy of drug treatments. Identifying these interactions between drugs and the microbiome will help the study of drug metabolism, provide explanations for treatment failure, and enable more personalized health care. For this project, a platform was developed to isolate gut bacteria from human fecal samples and characterize bacteria that are capable of inactivating various antibiotics and anticancer drugs. Through this platform, the gut bacterium Raoultella planticola was found to inactivate doxorubicin, a commonly used anticancer drug. These results suggest that doxorubicin may be inactivated in the gut and demonstrates how this platform can be used to identify drug-microbiome interactions.

The global pandemic of diet-related non-communicable diseases and the fact that global food production represents one of the largest contributors to greenhouse gas emissions, have identified unhealthy and unsustainably food chains as a major societal health challenge and a risk to ecosystem stability. This thesis aimed to investigate if digestion of nutritious, less highly processed foods could lead to health-promoting changes in the gut microbiota. Our modern Western-style diet (MWD) is characterized by high intake of extremely processed foods, which contain significant concentrations of inflammatory advanced glycation end-products (AGE) implicated in metabolic disease development. Novel observations in this thesis showed that chronic exposure to dietary AGE modulated gut microbiota (GM) community structure rendering it more similar to the GM previously observed in diabetic/obese mice. Further, I demonstrated that elevated systemic inflammatory markers could be mediated by AGE induced changes in GM composition. Measuring the potential of whole plant foods to improve gut health, a local broccoli ecotype (Broccolo of Torbole, BR) and Moringa oleifera were investigated using in vitro models of the human GM and intestinal epithelium. BR significantly reduced bacterial richness and evenness, increased Escherichia-Shigella relative abundance and decreased Alistipes and Ruminococcus 1. The GM extensively metabolized BR polyphenols and increased concentrations of short chain fatty acids. However, BR did not impact on intestinal permeability, using a Caco-2 monolayer model and trans-epithelial electrical resistance (TEER). This thesis provided novel insights on the fate of Moringa glucosinolates and polyphenols during faecal fermentation and on their potential beneficial activity on gut health, with glucomoringin significantly increasing TEER. Microbial communities are also involved in healthy and sustainable food production. Characterizing the successional development of local organic sauerkraut production, this thesis established a culture collection of sauerkraut lactic acid bacteria of potential future biotechnological evaluation and measured metabolite production during sauerkraut fermentation. Sauerkraut water improved immune response of a Caco-2-peripheral blood mononuclear cell (PBMC) in vitro model of the gut associated immune system upon inflammatory LPS challenge. Finally, since sustainable diets rely on sustainable and nutritious foods, I analyzed the role of the GM in improving the sustainability of farmed trout. Novel sustainable feeds containing poultry by-products (P) or insect protein (Hermetia illucens (H) meal), were investigated for their potential impact on fish growth performance, GM composition and inflammatory biomarkers. P increased the relative abundance of protein-degraders Paeniclostridium and Bacteroidales, while H increased chitin-degraders Actinomyces and Bacillus. This study also provided evidence of feed-chain microbiome transmission of Actinomyces from insect H feed to trout GM. The analysis of gut microbiomes therefore represents an innovative strategy to define healthy reference diets, to characterize the potential health effects of local and traditionally produced foods, to identify new sustainable and nutritious crops, and to drive the urgently needed transformation of the global food system. In order to obtain more sustainable, healthy and nutritious food production systems a better understanding and management of microbiomes along the food chain has never been more important.

Tannins represent a heterogeneous group of high-molecular-weight polyphenols that are ubiquitous among plant families, especially in cereals, as well as in many fruits and vegetables. Hydrolysable and condensed tannins, in addition to phlorotannins from marine algae, are the main classes of these bioactive compounds. Despite their low bioavailability, tannins have many beneficial pharmacological effects, such as anti-inflammatory, antioxidant, antidiabetic, anticancer, and cardioprotective effects. Microbiota-mediated hydrolysis of tannins produces highly bioaccessible metabolites, which have been extensively studied and account for most of the health effects attributed to tannins. This review article summarises the effect of the human microbiota on the metabolism of different tannin groups and the expected health benefits that may be induced by such mutual interactions. Microbial metabolism of tannins yields highly bioaccessible microbial metabolites that account for most of the systemic effects of tannins. This article also uses explainable artificial intelligence to define the molecular signatures of gut-biotransformed tannin metabolites that are correlated with chemical and biological activity. An understanding of microbiota–tannin interactions, tannin metabolism-related phenotypes (metabotypes) and chemical tannin-metabolites motifs is of great importance for harnessing the biological effects of tannins for drug discovery and other health benefits.

Probiotics are live microorganisms that can confer health benefits to the host. They have long been consumed through fermented foods. While the specific mechanisms of probiotics are largely unclear, there is evidence that their beneficial effects may be attributed to the microbes’ ability to modify the gastrointestinal (GI) environment, to modulate host immune response, or to produce natural products that directly inhibit pathogens in the gut. With the increasing awareness of the important functions that the gut microbiota plays in affecting host heath, probiotics may no longer just stay as simple dietary supplements, but become a promising approach to disease management. With recent advances in synthetic biology, novel functions can be introduced into these “good” microbes to provide additional benefits. Genetically engineered bacteria have been developed to specifically target pathogens or effectively deliver therapeutics to the GI tract. However, there are significant limitations to the existing systems developed. For example, the engineered pathogen sensors largely rely on the similarity between the host and the pathogens, the therapeutics delivery systems are usually constrained by the molecular structures, and the majority of the works have been limited to laboratory settings. In this dissertation, I present a system we have developed based on a food-grade probiotic, Lactococcus lactis, and demonstrate a synthetic biology methodology that could be applied to build biosensors of other pathogens or environmental signals, as well as a generalizable peptide delivery vehicle to the GI tract. I will present my work in three parts. (1) The discovery of an effective antagonistic effect of L. lactis against the infectious diarrheal disease cholera, and elucidation of the mechanism with an infant mouse model. (2) The development of a diagnostic circuit in L. lacits that enables in situ detection of the pathogen and easy readout through fecal sample analysis. (3) The design of a generalizable therapeutic peptide delivery system utilizing the endogenous secretion pathway of L. lacits. Overall, my work exploits the natural and engineered benefits of the probiotic L. lactis and demonstrates its use in the intestinal disease diagnosis and therapy. / 2019-02-20T00:00:00Z

Background and aims: The association of plasma trimethylamine N-oxide (TMAO) with atherosclerotic cardio- vascular disease (ASCVD), diabetes mellitus (DM) and its determinants, as well as the role of TMAO as a predictor for short and long-term mortality, is still under discussion. We investigated associations between four plasma metabolites of the TMAO pathway and different clinical manifestations of atherosclerosis, diabetes determinants, and risk of short and long-term mortality in patients with stable ASCVD, acute myocardial infarction (AMI), cardiogenic shock (CS), and DM in three independent cohorts. Methods: TMAO and its dietary precursors were simultaneously quantified by liquid chromatography-tandem mass spectrometry in a total of 2655 participants of the German Leipzig Research Center for Civilization Dis- eases (LIFE)-Heart study, LIFE-Adult study, and the European Culprit Lesion Only PCI versus Multivessel PCI in Cardiogenic Shock (CULPRIT-SHOCK) multicenter trial. Associations with ASCVD manifestations, metabolic syndrome, 30-day mortality of patients with AMI and CS, and long-term mortality of subjects with suspected coronary artery disease (CAD) were analyzed. Results: TMAO plasma levels were not independently associated with stable ASCVD. Elevated TMAO plasma concentrations were independently associated with obesity (odds ratio, 1.23; p < 0.01) and DM (odds ratio, 1.37; p < 0.001) in LIFE-Heart. The latter association was confirmed in LIFE-Adult. We found no association of TMAO plasma levels with short-term mortality in patients with AMI and CS. However, TMAO plasma levels were in- dependent predictors of long-term mortality in patients with suspected CAD (hazard ratio, 1.24; p < 0.05). Conclusions: Potential proatherogenic mechanisms of TMAO seem to have no short-term effect in AMI. Presented associations with diabetes mellitus and obesity suggest that TMAO might have a functional role in metabolic syndrome.

京都大学 / 新制・課程博士 / 博士(農学) / 甲第24678号 / 農博第2561号 / 新制||農||1100(附属図書館) / 学位論文||R5||N5459(農学部図書室) / 京都大学大学院農学研究科応用生物科学専攻 / (主査)教授 佐藤 健司, 教授 菅原 達也, 教授 舟場 正幸 / 学位規則第4条第1項該当 / Doctor of Agricultural Science / Kyoto University / DGAM