Understanding how bacterial products from the microbiota enter the host and influence immune cells at systemic sites.

Abstract

Humans are colonised by live microbial communities on virtually all environmentally exposed surfaces. The major reservoir resides in the gastrointestinal tract and these colonising microbes are known as our microbiota. The relationship with our microbiota is complex. They influence many aspects of intestinal physiology mainly through their regulation of the intestinal immune system. Studies have now demonstrated that the microbiota also provides systemic benefits, by regulating the innate immune system at extra-intestinal sites. These systemic influences can occur via the dissemination of immunologically active molecules from the intestine to systemic tissues. Exactly how the microbiota exerts an influence on tissues outside of the intestine, is however, poorly understood. In this thesis, I have investigated how immunologically active cell wall molecules from the microbiota gain entry into the host, where they are deposited, how they regulate lung immunity, and how the host controls their activity to prevent pathological inflammation. We demonstrated that stimulation capability of products did not significantly affect their ability to cross the epithelial barrier, but that host processing of commensal cell wall by lysozyme promoted the entry of these molecules into the host. We found cell wall peptidoglycan deposited in many host tissues, including the bone marrow and lungs. Lysozyme susceptible cell wall demonstrated a significant increase in its capability to traverse the intestinal epithelium and enter the bloodstream, with a subsequent significant increase in deposition into host tissues such as liver and spleen. The increase in cell wall peptidoglycan in circulation due to the activity of lysozyme had a protective effect for the host by promoting resistance to pulmonary infection by K. pneumoniae. We went on to find that after entry into the bloodstream, commensal-derived cell wall products had their stimulation capacity significantly diminished by serum albumin. Collectively, our data reveal the host and commensal factors which influence the entry and activity of commensal-derived bacteria on systemic immunity. These results uncover how the microbiota could be manipulated as a novel means to enhance host resistance to pulmonary infection.