Role of ALPK1 in intestinal homeostasis – GUT-ALPK1

The human gut is colonized by trillions of microbes that constitute the microbiota and exert diverse functions often associated with beneficial physiological effects for their host. The vast repertoire of microbiota-derived molecules has an overall beneficial impact on the organism by maintaining the intestinal homeostasis notably by favouring the maintenance of the intestinal barrier, the functions of intestinal epithelial cell (IECs) as well as the development and maturation of the mucosal immune cells. In this process, innate immunity elicited by the microbiota, mediates a protective physiological response by clearing pathogens, repairing damaged tissues, increasing barrier functions, promoting IEC differentiation and proliferation as well as the development and maturation of the sub-epithelial immune cells such as T cells. These processes are initiated through the activation of innate immune receptors, also called pattern recognition receptors (PRRs), that recognise a wide range of microbial ligands. By sensing microbiota-derived metabolites, PRRs, expressed by IECs, have emerged as key regulators of intestinal epithelium development and intestinal homeostasis and as such in chronic inflammatory diseases such as inflammatory bowel disease (IBD).
Recently, ALPK1, by recognizing its ligand ADP-H, has been described as a PRR initiating pro-inflammatory responses and pathogen clearance. The role of ALPK1 and its ligand ADP-H produced by pathogenic bacteria as initiators of TIFA oligomerization and phosphorylation and NF-kB activation has been established by numerous studies. Although many advances have been made in understanding the role of the microbiota and PRRs in intestinal homeostasis and how the dysregulation of this axis leads to pathophysiological conditions such as IBD, no study has assessed the role of ALPK1 in this context.
By using organoids, ALPK1 knock-out mice and in vivo colitis approaches, our preliminary results suggest a role for ALPK1 pathway in the development, differentiation and functions of IECs and in regulating intestinal physiopathology. Moreover, we also showed that ALPK1 is highly expressed in inflamed tissues from IBD patients compared to uninflamed and control tissues and that members of the microbiota can activate the ALPK1 pathway positioning this signalling axis as a potential new hub for the host-microbiota dialogue and intestinal homeostasis.
Based on this growing body of evidence, we thus propose that ADP-H/ALPK1 is a central signalling pathway allowing integration of microbiota derived cues to finely tune the intestinal homeostasis. The global objective of the GUT-ALPK1 project is thus to analyse the role of this signalling axis in the maintenance of intestinal homeostasis at steady state and at pathophysiological conditions and to decipher the mechanisms involved. In order to address these objectives, we will use transdisciplinary approaches, whereby unique knockout animal models will be combined with cutting-edge organoid approaches, and human transcriptomic analysis. In this project we will characterize the impact of ALPK1 on intestinal homeostasis, we will identify the ADP-H transport mechanisms, we will assess the implication of this signalling axis in the development of colitis and we aim to transpose these findings in humans.