Abstract
Accumulating evidence suggests that intestinal microbial imbalance, or dysbiosis, and the associated changes in microbe-host interactions might contribute to the prevalence of disease. Dysbiosis is associated with a loss of beneficial bacteria and has triggered research into the potential preventive and therapeutic applications of probiotic bacteria in health and disease.
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Part of the beneficial effects of probiotic bacteria can be explained by their direct interaction with cells of the host. Probiotic bacteria express specific microbe-associated molecular patterns (MAMPs) which can be recognized by the host via pattern recognition receptors (PRRs). This thesis describes the interactions between microbes and host with a focus on MAMP-PRR interactions. It further elaborates on the potential role of host-factors that modulate these processes. MAMPs, recognized by PRRs such as Toll-like receptors (TLR) and NOD-like receptors (NLR), initiate host immune responses. In contrast to work done with pathogens, PRR-MAMP interactions have not been studied in great detail for probiotic bacteria, especially regarding non-TLR/NLR PRRs. The existence of PRRs that function as co-receptors for TLR2 suggests that the quality and amplitude of the immune response may be modulated by the action of these non-TLR/NLR PRRs. One of these PRRs is DC-SIGN, a member of the PRR family of C-type lectins. Inhibition of DC-SIGN activity in co-cultures of probiotic bacteria and host cells demonstrated strain-dependent effects on both the level and the type of host-effector molecules released. The immune system is classically divided into an innate and adaptive immune system. Cells from both the innate and adaptive immune system line the intestinal tissues and are among the first cells to encounter probiotic bacteria. Data presented in this thesis show that probiotic bacteria can induce a variety of immune responses. Probiotic bacteria were shown to strain-dependently induce tolerance in innate cells to a secondary activation with a pathogen. In addition, probiotic bacteria strain-dependently induced the development of adaptive regulatory T-cells both in-vitro and in-vivo. Much remains unknown on how the immune system discriminates between closely related species of probiotic bacteria. To address this question more specifically, future research should focus on identifying probiotic-expressed MAMPs and map their interactions with host-expressed PRRs. This thesis aimed to highlight another aspect that plays a role in the immune response induced by probiotic bacteria. In the in-vivo situation, host-microbe interactions take place in tissues and therefore soluble factors present in these tissues should be considered for their effect on host-microbe interactions. Extracellular vesicles are cell-derived nano-sized vesicles which can be found in any bodily fluid and were observed to differentially modulate MAMP-induced TLR activity. Similar observations were made when lipoproteins, made of dietary fats by epithelial cells, were co-incubated with microbes and cells. Identification of the precise interactions between probiotic bacteria and cells, taking into account both the PRR-MAMP interactions and the way host-factors modulate PRR-induced cellular responses, would improve the strategy to select specific probiotic bacteria for future in-vivo and clinical testing, and would increase our understanding of the strain-specific attributes of current probiotic bacteria.
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