Swiss Cheese Gene Is Important for Intestinal Barrier, Microbiome, and Lipid Metabolism Regulation in Drosophila Gut

Mutations in the human patatin-like lysophospholipase domain containing the 6 gene <i>PNPLA6</i> encode an evolutionarily conserved (lyso)phospholipase, leading to the development of a complex hereditary spastic paraplegia 39 (SPG 39) and a number of rare severe syndromes in humans. Diseases disrupt the functioning of the nervous and reproductive systems and the gastrointestinal tract. The study aims to investigate the role of the <i>Drosophila melanogaster swiss cheese</i> gene, an ortholog of the human <i>PNPLA6</i> gene, in gut function. We showed that the <i>swiss cheese</i> gene knockout leads to changes in the morphology of the midgut, disruption of the septate junction structure and the intestinal barrier permeability, and a decrease in the lipid droplet number in enterocytes. As a result of such disturbances, intestinal stem cells (ISCs) proliferation is activated, and the gut microbiome is altered. Ectopic expression of human <i>PNPLA6</i> leads to the recovery of the intestinal barrier in the fly gut. The example of <i>Drosophila</i> demonstrates the important role of evolutionarily conserved (lyso)phospholipase in intestinal homeostasis.