Investigation of mechanisms underpinning host-microbial interactions in the gastrointestinal tract

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Udayan, Sreeram
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University College Cork
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Research in the areas of microbiome science and immunology have identified different members of a host’s microbiota, particularly bacteria, as having critical roles in shaping the development and function of both intestinal and extra-intestinal immunity as reviewed in the introductory chapter (Chapter I) to this thesis. However in comparison to the vast numbers and diversity of bacteria that constitute the microbiota of a host, only the role of some of the bacterial members has been addressed in these contexts. Thus the aim of this thesis research was to investigate and further understand the molecular and cellular mechanisms underpinning host-bacterial interactions in both the gastrointestinal tract and in extra-intestinal tissues. In the first study (Chapter II) we identified the relative contributions of different pattern recognition receptors to the triggering of macrophage cytokine responses by the widely studied Gram-positive commensal bacteria Lactobacillus salivarius and Bifidobacterium breve. L. salivarius induced macrophage cytokine responses that were TLR2 independent but MyD88 and Clec4e receptor dependent unlike B. breve responses which were completely TLR2 dependent. Thus pattern recognition receptors may contribute differently in triggering cytokine responses by different commensal bacteria. In the second study (Chapter III) we developed an aseptic and stringent culture based method to identify, recover, characterize and archive a library of bacteria that disseminate to systemic tissues in mice. This approach could now be applied in research studies targeted at studying systemic dissemination using small animal models. In the third study (Chapter IV) we use the developed method to show that systemic dissemination of gut commensal bacteria occurs in WT and MyD88-/- mice at steady-state in the absence of any observable barrier defects and/or inflammatory pathologies. L. johnsonii was the most prominent bacteria that were recovered from systemic tissues of these mice. Furthermore, MyD88-/- mice had an increased degree of systemic dissemination and dramatically higher L. johnsonii abundance (accompanied by reduced overall microbial diversity) in their gastrointestinal tissues, but not stool, in comparison to WT mice. Systemic dissemination of L. johnsonii was a reflection of its overall relative abundance in the gastrointestinal tracts of specific pathogen free mice. Lastly L. johnsonii were able to persist and replicate inside dendritic cells in vitro which suggests that the bacteria we have isolated may be endosymbionts of mice. We also recovered bacterial strains other than L. johnsonii that were previously shown by others to have important immunomodulatory and systemic effects from host systemic tissues and sorted cells isolated from small intestine, colon and systemic tissues of different mice models at steady-state. Overall our research sheds new light into the basic mechanisms underpinning host-bacterial interactions in the gastrointestinal tract and in extra-intestinal tissues and we hope that these findings will be beneficial to modulate microbiota mediated extra-intestinal effects in health and disease in future.
Host , Microbiome , Gastrointestinal tract , Host-microbial interactions , Pattern recognition receptor , Systemic dissemination
Udayan, S. 2019. Investigation of mechanisms underpinning host-microbial interactions in the gastrointestinal tract. PhD Thesis, University College Cork.