Periodic Reporting for period 1 - CeleSte (Commensal microbiota regulation of neuro-immune networks)
Reporting period: 2020-11-01 to 2022-10-31
The enteric nervous system (ENS), neuronal and glial cells, development and function can be influenced by the microbiota. Germ-free mice have defective maturation of enteric glial and neuronal cells, being this dysfunction central to the pathophysiology of gastrointestinal diseases. Production of neuroregulatory molecules by these neuronal cells involved microbial product sensing although the identity of commensal microorganisms and the sensing molecular pathways are unknown. By using neuronal-specific mutants and neurosphere-derived organoids, the present project aims to understand how glial- and neuron-derived regulators are influenced by particular commensal microorganisms and how this active neuronal sensing impacts of defined neuroimmune cell units, notably on the glial-ILC3 and neuron-ILC2 interactions. Deciphering these new pathways of ENS-microbial crosstalk will improve our understanding of this equilibrium and will contribute to the development of new therapeutic strategies in gastrointestinal diseases.
In this project, we have been exploring how nervous cells perceive, integrate and respond to commensal microorganisms or their products. Initially, we have explored the presence of the different pattern recognition receptors and their adaptors in the enteric neurons and glial cells. We have found that enteric nervous cells mainly rely on MYD88-mediated sensing in comparison to other sensing mechanisms, interestingly nervous MYD88 expression is comparable to its expression by other immune cells. This was true for in vitro generated neurosphere-derived neurons and glial cells and neurons and glial cells purified from the intestine.
In parallel, we have analyzed the nervous cells-mediated microbial sensing impact on the enteric immune system functionality, particular on the innate lymphoid cells (ILC)-type 2 function. Notably, we found that neuronal-MYD88-sensing of commensal microorganisms or their signals is essential for neuron-derived regulators, particular the cholinergic (Chat+) neurons function. This neuronal sensing promotes the intestinal ILC2 functionality at the level of cytokines production. In contrast, glial cells MYD88-mediated sensing of microbiota suppresses ILC2 activity.
Moreover, this active neuronal and/or glial cells MYD88-sensing of commensal microorganisms impacts on the ENS functionality, particularly the intestinal motility. Our results indicate that the intestinal motility is inhibited by glial cells-mediated microbial sensing whereas is promoted by adrenergic (Th+) neuron-mediated commensals detection and not affected by cholinergic (Chat+) neuron-mediated microbial sensing.
These results will be included in future peer-reviewed articles for their exploitation and dissemination.
In parallel, we have analyzed the nervous cells-mediated microbial sensing impact on the enteric immune system functionality, particular on the innate lymphoid cells (ILC)-type 2 function. Notably, we found that neuronal-MYD88-sensing of commensal microorganisms or their signals is essential for neuron-derived regulators, particular the cholinergic (Chat+) neurons function. This neuronal sensing promotes the intestinal ILC2 functionality at the level of cytokines production. In contrast, glial cells MYD88-mediated sensing of microbiota suppresses ILC2 activity.
Moreover, this active neuronal and/or glial cells MYD88-sensing of commensal microorganisms impacts on the ENS functionality, particularly the intestinal motility. Our results indicate that the intestinal motility is inhibited by glial cells-mediated microbial sensing whereas is promoted by adrenergic (Th+) neuron-mediated commensals detection and not affected by cholinergic (Chat+) neuron-mediated microbial sensing.
These results will be included in future peer-reviewed articles for their exploitation and dissemination.
In this reporting period we have analyzed the impact on neuronal MYD88-mediated sensing of microbiota on their described relation with the innate lymphoid cells. We anticipate that at the end of the project we are going to have identified neuronal molecular pathways that are important modulator of a broad spectrum of immune cells, not only innate lymphoid cell, upon microbiota sensing.
Uncovering these new molecular pathways of neuronal-microbial crosstalk will contribute to the identification of new therapeutic targets that are dysregulated in gastrointestinal diseases.
Uncovering these new molecular pathways of neuronal-microbial crosstalk will contribute to the identification of new therapeutic targets that are dysregulated in gastrointestinal diseases.