MULTI-OMICS INVESTIGATION OF THE GUT MICROBIOME–PARASITE–HOST AXIS: LINKING MICROBIAL DYSBIOSIS, IMMUNOMETABOLISM, IMMUNE REGULATION, AND THERAPEUTIC OUTCOMES

Abstract

Intestinal parasitic infections disrupt the gut microbiome–host axis, but the underlying immunometabolic mechanisms and post-treatment outcomes remain poorly characterized in endemic South Asian populations. This prospective longitudinal study (N=300) conducted in Islamabad, Pakistan, integrated shotgun metagenomics, LC MS/MS metabolomics, and host peripheral blood mononuclear cell (PBMC) transcriptomics to comprehensively map the gut microbiome–parasite–host axis. Patients with confirmed Giardia duodenalis, Entamoeba histolytica, or soil-transmitted helminth infections were evaluated at baseline and 8 weeks post-standard pharmacological treatment, alongside age-matched healthy controls. Infection induced severe microbial dysbiosis, marked by a 26.5% reduction in alpha diversity and the targeted depletion of short-chain fatty acid (SCFA)-producing taxa, notably Faecalibacterium prausnitzii. This ecological shift caused a >2-fold collapse in fecal butyrate and secondary bile acids, which strongly correlated with impaired regulatory T cell (Treg) function, reduced IL-10 production, and the hyperactivation of pro-inflammatory NLRP3 and IFN-γ pathways. Crucially, while standard anthelmintic and antiprotozoal therapy achieved a 95% parasitological cure rate, it failed to restore microbiome resilience (score: 0.68) or resolve systemic immunometabolic inflammation, resulting in persistent post-infectious gastrointestinal symptoms in 23.3% of the cohort. These findings demonstrate that parasite eradication alone is insufficient for holistic mucosal recovery. We conclude that intestinal parasitoses drive profound, multi-layered immunometabolic disruption mediated by microbiome depletion, highlighting the urgent need to integrate adjunctive microbiome-targeted therapies into standard clinical protocols in endemic regions.