Abstract
Abstract Studies on TLR and NLR knock out mice have suggested these pattern recognition receptors (PRRs) drastically affect gut mucosal immunity and composition of the gut microbiome, which may give rise to diseases such as colorectal cancer. We have identified several coding SNPs in TLR5 and different NLR (including the so far enigmatic group of development-associated NLRs) to be associated with different parameters of colorectal cancer, and for TLR5 have observed a functional effect in human blood immune cells. With a view to further elucidating the underlying mechanisms of these SNPs in colorectal cancer, we have begun to investigate the role of these PRR variants on gut immune activation levels and microbiome diversity in humans. Our hypothesis is that functional TLR and NLR variants are associated with different immune potential in the gut, shaping or being shaped by the host microbiome. We have built-up, genotyped and started to assay a cohort of 125 healthy volunteers and established stool assays for sIgA and cytokine levels by ELISA, cellular contents by flow cytometry analysis and PRR stimulating potential. Additionally, a functional characterization of coding NLR SNPs in cellular model systems is being carried out. Our studies dissect the functional impact and relationship of host genetic factors and the microbiome in humans, which may reveal novel targets in the diagnosis or treatment of colorectal cancer or other gut-related diseases.
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