Sex-associated gut microbiome and host transcriptome responses to dietary phytochemicals in Drosophila

Abstract Dietary phytochemicals can influence host physiology and gut microbial communities. However, how phytochemicals are associated with coordinated changes in intestinal responses and microbiome across sexes remains poorly understood. Here, we used Drosophila melanogaster to investigate how curcumin, capsaicin, resveratrol, and thymoquinone are associated with gut microbiome and intestinal transcriptomic responses in females and males. Integrative analysis revealed that the gut transcriptome and microbiome were most strongly associated with phytochemical-enriched diets, while sex represented the major axis of variation. Supplementation was associated with changes in the relative abundance of bacterial taxa that differed between sexes. Females showed more pronounced treatment-associated changes within Lactobacillaceae and marked enrichment of Enterococcus under thymoquinone, whereas males maintained Acetobacter -rich communities, particularly under capsaicin and resveratrol. Curcumin-fed females showed reduced expression of genes involved in carbohydrate digestion and trehalose metabolism, consistent with lower glucose, whereas curcumin-fed males showed activation of xenobiotic detoxification pathways dominated by cytochrome P450 genes. Capsaicin was associated with P450-related changes in females and increased expression of IMD-associated genes, including DptB , in males, coinciding with an Acetobacter -rich microbiome. These findings highlight biological sex as an important variable in diet-microbiome-host interactions and suggest that phytochemical responses reflect the interplay among compound identity, gut microbial communities, and sex-associated host physiology.