Microbiome-host crosstalk is crucial for gut homeostasis and its dysregulation is a hallmark of diseases such as colorectal cancer (CRC) and inflammatory bowel disease (IBD). Despite its key relevance for a holistic understanding of the human superorganism and its (patho-)physiology, how local host-microbiome interactions form specific niches in the gut and how these niches function at the cellular and molecular level remains unexplored, mainly due to a lack of suitable technologies. To fill this gap, we propose to jointly reconstruct the host transcriptional and microbiome compositional landscape of the human gut across a large number of healthy individuals as well as IBD and CRC patients. For this, we will leverage a combination of novel spatial profiling technologies for unbiased transcriptome sequencing and microbiome profiling at single-cell resolution in situ. First, we will spatially delineate local niches formed of specific microbes and host cells. To dissect this complex crosstalk into specific interactions, we will secondly use in vitro and in vivo models to introduce perturbations either on the host or the microbiome side. Finally, we will integrate the resulting data to deconvolute host-microbiome circuits computationally and to predict functional niches, in particular host responses to pathogens of relevance in IBD and CRC. Interesting predictions will be tested in organoid and animal models. Developing a spatially resolved computational model of the gut ecosystem will allow us to predict early local events in disease onset; from these we will identify and validate prognostic IBD and CRC biomarkers for future clinical translation. This work will revolutionize our understanding of intestinal host-microbiome interactions by adding a first-ever functionally resolved spatial dimension with clinical relevance for the future diagnosis and treatment of intestinal disorders.