Modulation of the enteric nitrergic pathway by O-GlcNAcylation and role of the gut microbiota’s “bacterial mediators”

The student will be affiliated with two laboratories, the Unit in Biological Sciences and Biotechnology (US2B) and The Enteric Nervous System in gut and brain disorders (TENS) laboratory and will operate at both locations.

The student will be co-supervised by Dr. F. Pennarubia (US2B) and Dr. M. Caillaud (TENS).

Subject description

The enteric nervous system (ENS) plays a central role in digestive physiology, regulating digestive functions such as intestinal permeability and motility. The activity of the SNE is primarily regulated by two neurotransmitters, acetylcholine and nitric oxide (NO), which ultimately induce muscle contraction and relaxation, respectively, thereby contributing to the regulation of intestinal motility. The function of the nitric oxide pathway depends on the regulation of its key proteins, particularly nNOS and PSD95. These two proteins are subject to post-translational modifications (PTMs), such as phosphorylation, which are known to modulate their activity.

However, recent research suggests that another PTM appears to be involved in NO production, the O-GlcNAcylation. O-GlcNAcylation is a glycosylation consisting in the transfer of an O-linked N-acetylglucosamine (GlcNAc) onto a serine (Ser), threonine (Thr) or tyrosine (Tyr) residue. It's a dynamic PTM under the control of the O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) which catalyzes the addition and removal of O-GlcNAc, respectively. O-GlcNAcylation will modulate numerous cellular processes (transcription, epigenetics, cell signaling, etc.) by influencing the localization, stability, and interaction of proteins.

Alterations in the NO pathway have been identified in gastrointestinal (GI) disorders associated with changes in the composition of the gut microbiota (dysbiosis). Data obtained at the TENS laboratory show that the application of “mediators” from the gut microbiota of patients with GI disorders on enteric neuron cultures increase NO production. Furthermore, the collaboration between the TENS and US2B laboratories suggests that this change in NO production may be dependent on an alteration in O-GlcNAcylation.

The objective of this internship is to understand the role of O-GlcNAcylation in the dysregulation of NO production by dysbiotic gut microbiota.

Objective 1: Investigate the role of O-GlcNAcylation on key proteins in the nitrergic pathway and its consequences for NO production

Objective 2: Investigate the effect of gut microbiota “mediators” on the enteric neurons O-GlcNAcylation profile

• Master's student

• Skills and knowledge in biochemistry, molecular biology, and cell biology

• Knowledge of glycobiology and/or neurobiology would be an asset

• Laboratory experience (Master's internship or other)