Project
Development of a human immune- and microbiota-competent gut-on-a-chip
The goal of this project is to establish a gut-on-a-chip model in which the three major components of the human intestine (epithelium, immune cells and microbes) are co-cultured in a physiologically relevant way. By creating a model in which cells can interact in a manner more representative of the in vivo situation compared to classical co-culture models, their responses to drugs, food components, inflammatory triggers, etc. will also be more realistic, making this organ-on-a-chip model highly relevant as a predictive tool for compound screenings.
Backgrond
Compounds currently on the market for improving gut health or inhibiting intestinal inflammation for human pathologies like inflammatory bowel disease (IBD) have gone through decade-long screening processes. This pre-clinical selection, however, is still mainly done using immortalised cell lines and animal models, both of which fail to capture the complexity of the human gut and therefore its interaction with these compounds. This leads to significant drug lead failure during clinical trials which limits the number of new drugs that become available.
Description
The “INIMINI-health project” aims to address this unmet need for more physiologically relevant pre-clinical intestinal models by establishing a gut-on-a-chip system encompassing epithelial cells, immune cells and a microbiota component. To this end, we are using the commercially available 3-lane OrganoPlate® microfluidic system by Mimetas, an industry-leading expert in the development of organ-on-a-chip technology. This system allows for a barrier-free cell co-culture through the use of a collagen matrix. A passive perfusion flow by means of a rocker ensures a faster and more physiological way of differentiating the epithelial cells, compared to the traditional static transwell-based differentiation. The industrial collaborative partners of the project will deliver various different compounds; i.e. anti-inflammatory drugs (Galapagos), anti-inflammatory bacterial supernatantia (Winclove), postbiotics (Cargill) and citrus flavanones (BioActor), which will be used to benchmark the model. Galapagos is a clinical-stage biotechnology company specialized in the discovery and development of small molecule medicines with novel modes of action and has extensive experience in target finding using preclinical research models. Cargill is one of the top 10 largest food and ingredient companies worldwide and therefore with a large potential for health impact of food innovations. BioActor and Winclove are small-to-medium enterprises with innovative ingredients and nutraceutical products. Together with technology partner Agilent, we will optimise the use of their fluorescent soluble oxygen sensors for metabolic analysis in the organ-on-chip model.
Results
At this point, the in vitro co-culture of Caco-2 intestinal epithelial cells and THP-1-Lucia monocytic immune cells in the Mimetas microfluidic chip is established. The next step is to use this immune-competent gut model to screen various compounds provided by our collaborating partners. Relevant read-outs will be intestinal epithelial integrity, cytokine secretion and metabolic profiling using a soluble oxygen sensor. We are hoping to increase the physiological relevance of this model by introducing PBMC’s instead of a monocytic cell line as the immune cell component. In order to create the microbiota-competent chip, we will use the probiotic strain Lactobacillus acidophilus W37, provided by Winclove.