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

## TL;DR

The Swiss Cheese gene in fruit flies is crucial for gut health, affecting the intestinal barrier, microbiome, and lipid metabolism.

## Contribution

The study reveals the Swiss Cheese gene's role in gut function and shows human PNPLA6 can restore gut barrier integrity in flies.

## Key findings

- Swiss Cheese gene knockout disrupts midgut morphology and intestinal barrier permeability.
- Loss of Swiss Cheese leads to fewer lipid droplets in enterocytes and altered gut microbiome.
- Human PNPLA6 ectopic expression recovers the intestinal barrier in Drosophila.

## Abstract

Mutations in the human patatin-like lysophospholipase domain containing the 6 gene PNPLA6 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 Drosophila melanogaster swiss cheese gene, an ortholog of the human PNPLA6 gene, in gut function. We showed that the swiss cheese 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 PNPLA6 leads to the recovery of the intestinal barrier in the fly gut. The example of Drosophila demonstrates the important role of evolutionarily conserved (lyso)phospholipase in intestinal homeostasis.