Coupling organoids and Organ-on-Chip technologies to study host-microbiome interactions in health and disease.

The large intestine hosts 95% of the human bacterial load also known as the gut microbiome. To maintain homeostasis, the intestinal mucosa produces a thick bi-layered mucus gel and a complex network of cytokines to segregate and in parallel facilitate the communication between the host and the trillions of inhabiting bacteria. The compromised integrity of the intestinal epithelial barrier when coupled with the unbalanced diversity and abundance of the microbial species, or dysbiosis, triggers detrimental and complex diseases such as Inflammatory Bowel Disease and Colorectal Cancer. However, because of its location in the body, this is a difficult system to study in vivo, limiting scientific advances to animal models or cell lines.

Here, we combined advancements in organoids and Organs-On-Chip technologies and developed the Colon Intestine-Chip to address the need for human-relevant models to study intestinal epithelial barrier function (Apostolou et al., CMGH, 2021, https://doi.org/10.1016/j.jcmgh.2021.07.004) and the host-microbiome interactions in health and disease. Organoids isolated from colonic biopsies have been co-cultured with tissue-specific microvascular endothelial cells and successfully expanded in a columnar epithelial monolayer, that preserves the distinct cellular and molecular signature of the human tissue. The Colon Intestine-Chip was applied to in vitro model the “leaky gut syndrome”, and captured alterations of the paracellular permeability, cytokines secretion and transcriptomic profiling of the cells within the chip driven by prototype (IFNγ) or pleiotropic (IL-22) cytokines. Lastly, employing elements of the tissue microenvironment, such as the periodical exposure of epithelial cells to Air-Liquid Interface (pALI), we established a mucus layer with thickness relevant to the human tissue, providing the necessary microhabitat and substrate to delineate the effect of commensal bacterial strains on intestinal epithelium.

In the presentation, we report the development of a microphysiological human platform that can be leveraged to study how the complex host-microbiome interactions shape intestinal physiology and assess the efficacy and safety of novel drugs for gastrointestinal diseases at a patient-specific level.