Functional analysis of the molecular cross-talk between methanogenic archaea and the human immune system

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Although the functional importance of the microbiota in human s health and disease has been confirmed in numerous studies and reports, methanoarchaea as a stable part of the gut microbiota have frequently been overlooked in reports addressing and elucidating the interdependency between members of the microbiome and components of the immune system. During the previous funding period we performed the first comprehensive study of the inflammatory response of human immune cells to methanoarchaea, which demonstrated that Methanosphaera stadtmanae is capable to induce a markedly higher inflammatory cytokine response than Methanobrevibacter smithii. Based on our results of the first funding period we hypothesize that M. stadtmanae has the potential to promote inflammatory processes in the human gut and may thus represent a so far overlooked contributor to pathological conditions in the human gut. In contrast, M. smithii appears to have evolved mechanism to suppress inflammatory processes in the gut and moreover might have immunmodulatory influence in the human gut ecosystem. Our data obtained further strongly argue for the presence of a specific archaea-associated pattern recognition receptor in humans. Finally, we demonstrated that methanoarchaea are prone to the lytic effects of antimicrobial peptides (AMPs) like bacteria and are capable to regulate their release by human immune cells. Accordingly, archaeal strains may influence the overall human immune homeostasis to comparable extents as has been shown for bacteria. Consequently we now aim to (1) identify the involved methanoarchaeal-associated molecular patterns as well as the respective human pattern-recognition receptors and mediators involved in signaling processes, (2) analyze the immunomodulating processes of methanoarchaea within the human intestine by comparing transcriptome changes upon contact of methanoarchaea with human epithelial and peripheral blood cells, (3) evaluate a potential correlation between the presence of M. stadtmanae and inflammatory gut diseases by monitoring the total cell numbers in intestinal biopsy and stool samples of healthy and diseased individuals, (4) elucidating the cellular stress responses of M. stadtmanae and M. smithii to AMPs and cytokines released by human cells, and (5) analyze the ability of M. smithii and M. stadtmanae to form biofilms on human epithelia under various conditions.Generally, these studies will expand our recent discoveries on the molecular and immunological level and evaluate the hypothesized contribution of M. stadtmanae to pathological conditions in the human gut and thus will emphasize the functional importance of methanoarchaea as a part of the human microbiota.