Functional divergence of the gut microbiome associated with lifestyle and helminth infection in Indigenous Peninsular Malaysian.

Gut microbiome catalogs from Indigenous Southeast Asian populations remain underrepresented. Here, we integrated metagenomic and metatranscriptomic data from Indigenous Orang Asli (OA) in Peninsular Malaysia and urban residents of Kuala Lumpur (KL), together with immune profiling, to investigate gut microbial activity and functions associated with lifestyle and helminth infection. Prevotella showed significantly higher transcriptional activity in OA, whereas Bacteroides was more active in KL, corresponding to distinct immune signatures. Microbial genome-wide association studies (mGWAS) revealed Prevotella copri_A variants were linked to lifestyle and host immunity, while Blautia strain variation was associated with helminth infection. Malaysian metagenome-assembled genomes (MAGs) uncovered 307 novel species, predominantly within Clostridia. Among these, the novel HGM13006 species were enriched with genes for starch and sucrose metabolism, and the novel Ruminococcus_D species in flagellar assembly and chemotaxis. Together, these findings provide function-level insights into gut microbiome variation associated with lifestyle and helminth infection in an indigenous population.