Atreya, R. | Search bioRxiv

bioRxiv2024

Integrated multi-model analysis of intestinal inflammation exposes key molecular features of preclinical and clinical IBD

BackgroundInflammatory bowel disease (IBD) is a chronic inflammatory condition of the intestine with a complex and multifaceted pathogenesis. While various animal models exist to study specific disease mechanisms relevant to human IBD, a comprehensive comparative framework linking these to IBD pathophysiology is lacking. ObjectiveIn our study, we aimed at providing a framework that delineates common and unique features encountered in 13 widely used mouse models comparing them with human IBD to identify translatable pathways in model-cohort pairs. Another aim of our study was to provide an explorable resource for looking up gene and pathway level changes in mouse models assisting in hypothesis testing and minimizing animal burden abiding by the 3R principals. DesignWe employed comparative transcriptomic analyses with curated and a priori statistical correlative methods between mouse models versus established as well as own patient datasets at both bulk and single cell levels. ResultsWe identify IBD-related pathways, ontologies, and cellular processes that are translatable between mouse models and patient cohorts. Moreover, we identify, known and novel IBD-associated subcellular mechanisms and how they are recapitulated in specific mouse models. ConclusionOur findings provide a valuable resource for selecting the most appropriate experimental paradigm to model unique features of IBD pathomechanisms, allowing analysis at the tissue, cellular, and subcellular levels. What is already known on this topicPreclinical modelling of IBD is key to the discovery of pathomechanisms and the evaluation of therapeutic approaches. However, individual models do not recapitulate the complexity of the disease and comprehensive studies comparing modelling paradigms with human IBD are lacking. What this study addsOur study provides a comparative analysis of thirteen commonly used intestinal inflammation models, identifying core-conserved pathways between mouse models and IBD patient cohorts. In addition, our study shows how specific pathways involved in IBD are recapitulated in specific mouse models and introduces a web tool to analyse the models. How this study might affect research, practice or policyBy identifying conserved and discrepant pathways between specific mouse models and IBD patient cohorts, our analysis platform provides an invaluable resource for translational IBD research.

systems biology↗

bioRxiv2024

Intestinal interstitial fluid isolation provides novel insight into the human host-microbiome interface

AimsThe gastrointestinal (GI) tract is composed of distinct subregions which exhibit segment-specific differences in microbial colonization and (patho)physiological characteristics. Gut microbes can be collectively considered as an active endocrine organ. Microbes produce metabolites, which can be taken up by the host and can actively communicate with the immune cells in the gut lamina propria with consequences for cardiovascular health. Variation in bacterial load and composition along the GI tract may influence the mucosal microenvironment and thus be reflected its interstitial fluid (IF). Characterization of the segment-specific microenvironment is challenging and largely unexplored because of lack of available tools. Method and ResultsHere, we developed methods, namely tissue centrifugation and elution, to collect IF from the mucosa of different intestinal segments. These methods were first validated in rats and mice, and the tissue elution method was subsequently translated for use in humans. These new methods allowed us to quantify microbiota-derived metabolites, mucosa-derived cytokines, and proteins at their site-of-action. Quantification of short-chain fatty acids showed enrichment in the colonic IF. Metabolite and cytokine analyses revealed differential abundances within segments, often significantly increased compared to plasma, and proteomics revealed that proteins annotated to the extracellular phase were site-specifically identifiable in IF and were differentially expressed when compared to matched serum, all suggesting local synthesis. ConclusionCollection of IF from defined segments and the direct measurement of mediators at the site-of-action in rodents and humans bypasses the limitations of indirect analysis of fecal samples or serum, providing direct insight into this understudied compartment.

microbiology↗