ABSTRACTThe termite gut accomplishes key physiologic functions that underlie termite symbiosis and sociality. However, potential candidate functions of the host-symbiont holobiome have not yet been explored across seemingly divergent processes such as digestion, immunity, caste differentiation, and xenobiotic tolerance. This study took a meta-analysis approach for concurrently studying host and symbiont gut metatranscriptome responses of the lower termite Reticulitermes flavipes, which has ancestral characteristics and hosts a diverse mix of eukaryotic and bacterial symbionts. Thirteen treatments were compared from 5 categories (dietary, social, hormonal, immunological, and xenobiotic), revealing 3 main insights. First, each of the 5 tested colonies had distinct magnitudes of transcriptome response, likely as a result of unique symbiont profiles, which highlights the uniqueness of individual termite colonies. Second, after normalization to standardize colony response magnitudes, unique treatment-linked metatranscriptome topologies became apparent. Third, despite colony and topology differences, 4 co-opted master genes emerged that were universally responsive across diverse treatments. These master genes encode host functions related to protein translation and symbiont functions related to protein degradation and pore formation in microbial cell walls. Three of the 4 master genes were from co-evolved protist symbionts, highlighting potentially co-evolved roles for gut symbiota in coordinating functional responses of the collective host-symbiont holobiome. Lastly, for host genes identified, these results provide annotations of recent termite genome sequences. By revealing conserved domain genes, as well as apparent roles for gut symbiota in holobiome regulation, this study provides new insights into co-opted eusocial genes and symbiont roles in termite sociobiology.