A tripartite of immune-, epithelial-, and nervous-systems in the homeostatic regulation of the gut

Various cell types in the intestinal mucosa are constantly exposed to complex signals emanating from the lumen, including the microbiota and its metabolites. How these bilateral interactions in turn influences intestinal homeostasis is an important question in order to understand microbiota-host interactions. This thesis has attempted to address this question in the following papers. Deletion of the diet- and microbiota-regulated aryl hydrocarbon receptor in CD11c+ cells was found to result in aberrant intestinal epithelium morphogenesis and increased susceptibility of these mice to chemically induced colitis (Paper I). Our data highlight a possible gateway of communication between the host and its environment, through the AhR in intestinal antigen presenting cells, consequently regulating intestinal epithelial cell biology and function.

In the second paper, we studied the impact of the microbiota on the development of the enteric nervous system (ENS). The ENS controls many aspects of gut physiology, including mucosal immunity. The major cellular component of the ENS is the enteric glia cell (EGC). Our data showcased that the migration and expansion of EGC networks in the lamina propria towards the lumen are under the influence of the microbiota. The postnatal expansion of mucosal EGC networks was found to coincide with the same period where the microbiota increases in number and diversity. Moreover, this microbiota-driven mechanism is an active process that can be impaired following the exposure to antibiotics, which abrogate signalling pathways mediating the host-microbe cross talk.

In the final manuscript, we developed a co-culture model system to study EGC functions further, in relation to intestinal epithelial barrier functions. Using genetic labeling techniques and live cell imaging, we observed close associations of EGCs with co-cultured intestinal epithelial organoids ex vivo, reminiscent of the contacts reported between these two cell types in vivo.

In conclusion, this thesis open more questions than answers especially as it addresses the issue of cross communication between different biological systems required for the development of complex organisms. The new player here is the microbiome and how it constantly affects the response of different cell types, including cell-to-cell communications, important for cellular adaptation to environmental cues. Future work will address the precise molecular and cellular mechanisms underlying the interplay between the microbiota and host-tissues to establish and maintain intestinal homeostasis.

List of scientific papers

I. Chng SH, Kundu P, Dominguez-Brauer C, Teo WL, Kawajiri K, Fujii- Kuriyama Y, Tak WM, Pettersson S. Ablating the aryl hydrocarbon receptor (AhR) in CD11c+ cells perturbs intestinal epithelium development and intestinal immunity. Sci Rep. 6, 23820, 2016.
https://doi.org/10.1038/srep23820

II. Kabouridis PS, Lasrado R, McCallum S, Chng SH, Snippert HJ, Clevers H, Pettersson S, Pachnis V. Microbiota controls the homeostasis of glial cells in the gut lamina propria. Neuron. 85 (2): 289-95, 2015.
https://doi.org/10.1016/j.neuron.2014.12.037

III. Chng SH, Bon-Frauches AC, Pettersson S and Pachnis V. Establishing a coculture system to study enteric glial cell functions. [Manuscript]