Dr. Aranzazu Arias-Rojas

U.S.A.

Infection-induced elevation of gut glycosaminoglycans fosters microbiota expansion in Drosophila melanogaster

Aranzazu Arias-Rojas1,4, Marko Rubinić 1,2
, Jasmin Albiez1,5,6, Dagmar Frahm1, Robert
Hurwitz3, Igor Iatsenko1,*
1 Research group Genetics of host-microbe interactions, Max Planck Institute for Infection
Biology, Charitéplatz 1, 10117 Berlin, Germany
2 Humboldt-Universität zu Berlin, Faculty of Life Sciences, 10099 Berlin, Germany
3 Protein Purification Core Facility, Max Planck Institute for Infection Biology, Berlin,
Germany
4 Present address: Broad Institute of MIT and Harvard, Cambridge, MA, USA
5 Present address: Swiss Tropical and Public Health Institute, Allschwil, Switzerland
5 Present address: University of Basel, Basel, Switzerland

Abstract

Background

Host genetics plays a critical role in shaping the composition of intestinal microbial communities. However, the specific host genetic factors that regulate the abundance of individual commensal bacteria remain largely unknown. Lactiplantibacillus plantarum is a major gut commensal in Drosophila melanogaster, providing a powerful model to investigate the genetic determinants that govern host–microbe interactions.

Methods

To identify host genetic variants influencing microbial abundance, a genome-wide association (GWA) study was conducted in Drosophila melanogaster using L. plantarum load as a quantitative trait. Candidate genes identified through this analysis were functionally validated using RNA interference (RNAi) to knock down their expression. Additional assays examined heparan sulfate synthesis, bacterial adhesion to host epithelium, and biofilm formation. The impact of infection and immune signaling pathways on heparan sulfate production and L. plantarum dynamics was also evaluated.

Results

The GWA study revealed a strong association between polymorphisms in genes involved in heparan sulfate biosynthesis and L. plantarum abundance. RNAi-mediated knockdown of these genes reduced heparan sulfate levels and led to a corresponding decrease in L. plantarum colonization. Mechanistically, heparan sulfate was found to facilitate bacterial adhesion to intestinal epithelial surfaces and promote biofilm formation. Upon infection, activation of the NF-κB signaling cascade increased heparan sulfate synthesis in the host, leading to expansion of the L. plantarum population. This expansion conferred colonization resistance against intestinal pathogens and contributed to maintaining intestinal homeostasis. Furthermore, heparan sulfate was required for infection-induced expression of immune effectors and prevention of intestinal dysplasia.

Conclusions

This study identifies heparan sulfate as a key host factor modulating the gut microbiota. By promoting L. plantarum adhesion and biofilm formation, heparan sulfate enhances colonization resistance and supports epithelial integrity during infection. These findings establish heparan sulfate as a central regulator of host–microbiota interactions, integrating immune signaling, microbial control, and epithelial renewal to maintain intestinal homeostasis.