Thinking outside the mouse: ex-vivo dissections of host-microbiome cross talks

Investigations of host-environment interactions in the gut would greatly benefit from a culture system that preserves cellular architecture yet allows tight experimental control. We have devised a microfabricated organ culture system that viably preserves the multicellular architecture of the mouse intestine, with luminal flow to control environmental parameters and permit experimental perturbation with microbes, drugs or nutrients. Using this system, we have recently identified differential involvement of the enteric nervous system in bifurcating pro- or anti-inflammatory responses to the gut microbiota (Yissachar et al., Cell 2017). We now utilize this system to study the potential role of the gut microbiota in chemotherapy-induced gut inflammation (mucositis). We show that chemotherapy administration disrupts the gut microbial community and that chemotherapy-disrupted microbiome rapidly alters gut permeability, independently of the drug. We thus suggest that chemotherapy-induced microbial dysbiosis may contribute to the initiation or maintenance of gastrointestinal mucositis. Further investigations of the underlying mechanisms may eventually facilitate the use of microbial-based perturbations to ameliorate mucositis in cancer patients.