Infection-Induced Elevation of Gut Glycosaminoglycans Fosters Microbiota Expansion in Drosophila melanogaster

While host genetics influence the composition of intestinal microbial communities, host genetic factors controlling the abundance of intestinal commensals remain to be determined. Here, we performed a genome-wide association (GWA) study in the fruit fly Drosophila melanogaster to identify host genetic variants linked to the abundance of Lactiplantibacillus plantarum – a major gut commensal of fruit flies. Our GWA study uncovered significant association between polymorphisms in genes involved in heparan sulfate synthesis and L. plantarum load. RNAi mediated knockdown of some of these genes resulted in reduced heparan sulfate synthesis and L. plantarum abundance. Mechanistically, heparan sulfate facilitates adhesion of L. plantarum to host epithelium and promotes biofilm formation. We further showed that infection induces heparan sulfate synthesis by the host via activation of the Nf-kB immune signaling cascade. Increased availability of heparan sulfate during infection results in the expansion of L. plantarum population in the gut and protection of the host from intestinal pathogens via colonization resistance. Furthermore, heparan sulfate is required for infection-induced expression of immune effectors and for prevention of intestinal dysplasia. These findings underscore heparan sulfate as a crucial modulator of intestinal homeostasis, pivotal in microbiota control, intestinal defense, and epithelial renewal.