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. We perform a genome-wide association study in Drosophila melanogaster to identify host genetic variants linked to the abundance of the gut commensal Lactiplantibacillus plantarum. Polymorphisms in genes involved in heparan sulfate synthesis are strongly associated with L. plantarum abundance. RNAi knockdown of these genes reduces both heparan sulfate synthesis and commensal load. Upon infection, host heparan sulfate synthesis is induced via activation of the nuclear factor κB immune signaling pathway, increasing L. plantarum populations and conferring colonization resistance against pathogens. Furthermore, heparan sulfate is required for infection-induced immune effector expression and 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.