Farnesol regulation of the Immune-Gut-Brain Axis in the context of CNS inflammatory demyelination 2267098

Abstract Introduction Experimental models and clinical evidence suggest multifactorial and bidirectional interactions between the gut and the central nervous system (CNS). A third player, the immune system, has recently been identified in these interactions, with research showing a link between the gut microbiome and inflammatory conditions, including those affecting the CNS. In this study, we make the case that farnesol, a naturally produced isoprenoid intermediate of the mevalonate pathway, plays a key signaling player that links the gut and its microbiota, the immune system, and the CNS. Interestingly, farnesol has been studied extensively as a quorum-sensing regulator of fungal biofilms and for its antibacterial effects. Methods Using experimental autoimmune encephalomyelitis (EAE) and in vitro systems, we tested the effects of orally administering farnesol using corn oil as a delivery vehicle on the integrity of the intestinal barrier, the gut mucosal immune compartment, and the microbiome and mycobiome composition, quantified ex vivo and in vitro by 16S rRNA and ITS sequencing, respectively. Results C57BL/6 mice induced with EAE, treated with farnesol, showed reduced disease severity, linked to effects on the gut barrier integrity and modifications on the phenotype of monocyte-derived macrophages, reduced proinflammatory cytokine production, such as TNF-α, and the composition of the gut microbiome and mycobiome of EAE mice. Furthermore, farnesol directly impacts the microbial composition when cultured in vitro. Importantly, corn oil administration resulted in significant modifications in gut microbes. Conclusion Our study indicates that farnesol should be considered as a significant modulator of the immune-gut-brain axis. Furthermore, corn oil should not be an optimal delivery method. Corn oil-free delivery methods based on lipidic micelles are now being tested in our laboratory. Funding Source National Institutes of Health (Grant number R15AI191202) Topic Categories Therapeutic Approaches to Autoimmunity (THER)