An immunocompetent intestine-on-chip model as platform for the dissection of host-microbiota interaction

An alteration of the intestinal community called dysbiosis is associated with a range of conditions such as neurological diseases, diabetes, and inflammatory bowel diseases (IBD). Recently, organ-on-chip (OoC) platforms have been established, which mimic organ-specific physiological microenvironments. By making use of microfluidic technologies and biocompatible materials, microphysiological systems (MPS) facilitate the co-culture of human host cells and microbes such as bacteria, fungi, archaea, protozoa, as well as viruses. Therefore, MPS provide the opportunity to study the interaction of host cells and microbiota and unravel underlying mechanisms. A microfluidic intestine-on-chip model was established, which comprised an epithelial and endothelial layer, and monocyte-derived macrophages and DCs. The characterization revealed that monocytes differentiated into CD68++ CX3CR1+ macrophages and CD68+ CD103+ dendritic cells, with a distinct location within the intestinal tissue. Macrophages and DCs demonstrated to be largely unresponsive to luminal LPS administration but elicited a strong inflammatory response after endothelial LPS stimulation. Furthermore, the intestinal model allowed stable colonization with the probiotic strain L. rhamnosus, which is also tolerated by macrophages and DCs, as well as by recruited PBMCs. The intestinal model facilitated microbial interaction studies with the opportunistic pathogen C. albicans. The presence of L. rhamnosus limited the growth of the fungi, reduced tissue damage and translocation into the endothelial layer. The platform allows detailed analysis of host-microbiota interactions and accompanying immune responses. In addition, the model facilitated studying the interplay of commensal bacteria and opportunistic pathogens under physiologically relevant conditions. The intestine-on-chip model proved to be a valuable tool suitable for future investigation of diseases associated with intestinal inflammation.



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