BACKGROUND: The association between Kyoto Encyclopedia of Genes and Genomes (KEGG) metabolic pathways and immunologic non-response among people living with HIV (PLHIV) on antiretroviral therapy (ART) is not well documented. This study aimed to characterize KEGG metabolic pathways among HIV-infected men who have sex with men (MSM) with different immunologic responses. METHODS: We recruited HIV-uninfected MSM (healthy controls, HC) and HIV-infected MSM on ART >
24 months in Guangzhou, June-October 2021. HIV-infected MSM with HIV viral load <
20 copies/mL were grouped into poor immunological responders (PIR) (CD4 + T cell count <
350 cells/µL) and good immunological responders (GIR) (CD4 + T cell count ≥ 350 cells/µL). Stool samples were collected. Bacterial 16S ribosomal DNA sequencing was performed on stool samples, and KEGG metabolic pathways of gut microbiota were imputed from 16S rDNA sequences. RESULTS: A total of 51 HC, 41 PIR, and 56 GIR were enrolled. The median time since HIV diagnosis for PIR and GIR was 4.6 and 4.2 years. KEGG metabolic pathways were significantly different among HC, PIR, and GIR groups. Retrograde endocannabinoid signaling, pantothenate and CoA biosynthesis, bile secretion, non-homologous end-joining, and gastric cancer were the top five important KEGG metabolic pathways associated with the immunologic responses. Specifically, retrograde endocannabinoid signaling performed best in discriminating PIR and GIR. CONCLUSIONS: This study presented a comprehensive landscape of KEGG metabolic pathways in PLHIV with different treatment outcomes. These results suggest the potential of KEGG metabolic pathways as novel disease progression markers and therapeutic targets.