Eduardo Javier Villablanca Bradanovic

Inflammatory bowel disease (IBD), including Crohn’s disease and ulcerative colitis (UC), affects millions worldwide, with rising incidence placing a growing burden on healthcare systems. UC is highly heterogeneous, with diverse clinical presentations, and current anti-inflammatory treatments often fail, emphasizing the need for alternative therapies.Our research aims to redefine UC through a forward-looking, data-driven approach. For the first time, our lab has classified UC patients into two molecularly distinct subtypes: UC1 and UC2. UC1 patients show increased tissue injury and poor response to biological therapies, while UC2 patients exhibit enhanced mucosal healing and better therapeutic outcomes. We hypothesize that these subtypes reflect differences in tissue damage and regenerative capacity, which could guide personalized treatment strategies. To validate and expand this classification, we will apply multi-omics approaches across independent patient cohorts and large datasets. By combining single-cell RNA sequencing, spatial biology (including transcriptomics, proteomics, and metabolomics), and ex vivo and in vivo models, we will generate a comprehensive functional atlas of UC endotypes and mucosal healing.This integrative strategy aims to identify novel druggable targets to promote mucosal regeneration, particularly for UC1 patients who lack effective treatments, advancing personalized medicine in UC.

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.