On-chip gut permeability assay reveals barrier-modulating microbiome following chemotherapy

In the intestine, the epithelial layer separates between the microbial luminal content and the host tissues. Impairments in epithelial barrier integrity may lead to increased gut permeability and bacterial translocation into the gut tissue. Such ‘leaky gut’ condition is associated with autoimmune diseases, inflammation, and cancer. Recent studies suggest that the gut microbiota may impact epithelial integrity, barrier functions and downstream immunological responses. Yet specific associations between microbial species, their barrier-modulating properties and their mechanisms of action are mostly missing.

Here, we aim to identify specific barrier-modulating gut microbes and to characterize their mechanisms of action, in cancer patients undergoing chemotherapy.

To address this, we developed an organ culture-based method for measuring gut permeability, constituting an intermediate experimental approach between simplified in vitro assays and complex in vivo studies. This novel on-chip gut permeability assay tracks real-time changes in gut permeability in multiple gut tissues under comparable and tightly regulated conditions, in response to luminal stimulation (including purified microbes and whole microbiota samples of murine or human origin).

Using this system, we found that transfer of post-chemotherapy microbiota to a healthy gut tissue rapidly disrupts gut barrier functions and increases gut permeability compares with pre-chemotherapy microbiota. Using computational analysis and next generation sequencing we now isolate specific bacterial strains that might directly affect gut permeability (barrier stabilizers or disruptors). We expect that this study will promote new therapeutic approaches to restore the balance between gut bacteria and the immune system during chemotherapy, ameliorate intestinal inflammation, and boost anti-cancer therapy.