Florent Fioriti


Peptidoglycan : A key elicitor of the gut- brain axis

The gut microbiota plays a crucial role in maintaining host health, with recent research highlighting the intricate interplay between gut-derived bacterial metabolites and host physiology. Among these metabolites, peptidoglycan (PGN) has been identified as a potential molecule that can modulate host brain functions and behavioral parameters. However, the mechanisms underlying PGN’s impact on the gut-brain axis are not well known. Previous genetic studies of my host lab strongly suggested that PGN can infiltrate the brains of Drosophila, hence modifying some neuronally-controlled behaviors. The goal of my thesis was to biochemically demonstrate that gut derived-PGN can indeed reach the fly brain and to identify its impact of gene expression. Using high-resolution mass spectrometry, I showed that PGN released by gut-associated bacteria can rapidly be detected in the central nervous system (CNS), providing the first direct evidence that brain cells can perceive PGN following its translocation from the gut to the hemolymph, the insect blood.

To further investigate the molecular and cellular mechanisms through which PGN affects the CNS, I combined whole-genome transcriptome analyses, comprehensive genetic assays, and reporter gene systems. The findings reveal that bacterial infection primarily elicits a PGN dose- dependent NF-κB humoral immune response in glial cells forming the outer cell layer of the blood-brain barrier (BBB). This immune response highlights the ability of the BBB to recognize and respond to gut-derived bacterial metabolites, providing a potential avenue for communication between the gut and the brain.

In addition to this immune response, I was able to illustrate an overproduction of neurotransmitter transporters, which appears to be both dependent on the quantity of PGN and the activation of the IMD pathway in glial cells. This observation suggests a potential intersection between immune response mechanisms and the control of neurotransmitter systems. The full functional consequences of this interaction remain undefined and necessitate further investigation.

Towards the end of the thesis, I explored the impact of bacterial infection on a fly model for Alzheimer’s disease. I discovered that an intestinal infection could exacerbate the symptoms of Alzheimer’s disease, and that this exacerbation is proportional to the bacterium’s ability to produce PGN, which is intrinsically linked to its capacity to activate the NF-κB pathway in the brain.

In summary, this thesis provides direct evidence establishing gut-derived PGN as an important mediator of the gut-brain axis in Drosophila, offering novel insights into the complex interactions between gut microbiota and host physiology. The findings provide a foundation for future studies on the molecular pathways and cellular processes modulated by PGN.