View Program - 63rd Annual Drosophila Research Conference

Peroxisomes are metabolic organelles that contribute to maintain the healthy metabolic status of the cell.Emerging evidence suggests that peroxisomes contribute in different ways to the function, development and survival of different tissues. Recent studies demonstrated that the peroxisome is essential in intestinal epithelial cells for the metabolic status of the organism, to regulate tissue inflammation and to maintain host-commensal/pathogen interactions in the gut. Considering the importance of gut-derived signaling for interorgans communication such as the gut-brain axis, we performed transcriptomic and metabolomic analyses to determine whether peroxisome metabolism in the gut controls secretion of trophic factors that contribute to neuronal health in adult flies. Integration of metabolomic and peptidomic analyses of the hemolymph integrated to transcriptomic and metabolomic analyses of control guts and peroxisome-depleted guts, revealed that peroxisomes modulate the production and secretion of gut-specific neuropeptides and inflammatory lipids in the circulation and in turn affect the gut-brain communications. Alteration of peroxisomal β-oxidation causes lipotoxicity in enterocytes triggers systemic release of inflammatory lipids (Cer22/Cer18) and inhibits the secretion of trophic neuropeptides such as Bursicon and Npl1 that are necessary to promote metabolic adaptation and stress responses in the organism. The transcriptional inhibition of these genes and the accumulation of inflammatory lipids together lead to brain inflammation, locomotor defects and reduce animal lifespan. Treatment with the free fatty acids scavenger, Niacin, rescues the described phenotypes in adult flies that have depleted peroxisomes in the enterocytes. Conversely, treatment with the established inhibitor of peroxisomal β-oxidation Thioridazine, or feeding an high fat diet lead to brain inflammation, dopaminergic neurons death, locomotion defects and reduces lifespan in control flies.
Considering that emerging evidence suggests that changes in diet-gut-brain axis influence the metabolic and inflammatory status of the neurons that is linked to Neurodegenerative Diseases (NDs) and that mild mutations in peroxisome genes are associated to the onset of NDs, we believe this work advanced our understanding of the the impact of peroxisomal metabolism on gut-brain axis, neuro-inflammation and the onset of NDs.

Peroxisome metabolism in enterocytes regulates the diet-gut-brain axis and lead to neurodegeneration