Virome remodeling rewires epigenetic and metabolic pathways linked to infection-associated colorectal cancer risk

Background Colorectal cancer (CRC) incidence is rising in sub-Saharan Africa, coinciding with the high prevalence of immune-modulating infections such as HIV and helminths. The gut virome, a critical yet understudied component of the microbiome, may influence oncogenic processes through epigenetic and metabolic alterations. However, the interplay between gut viral communities, HIV-helminth co-infection, and CRC risk remains poorly characterized in African populations. This study aimed to investigate gut virome-associated epigenetic and metabolic signatures linked to CRC susceptibility among South African adults, with a focus on HIV and helminth co-infection dynamics. Methods Untargeted shotgun metagenomic sequencing was performed on stool DNA samples from 62 adults stratified into five groups: uninfected controls (n = 10), HIV-only (n = 14), helminth-only (n = 15), HIV-helminth co-infected (n = 13), and CRC-confirmed patients (n = 10). Bioinformatic analyses were used to identify differentially abundant viral genes and to functionally annotate epigenetic and metabolic pathways associated with infection status and CRC occurrence. Results and discussion Adenine-specific DNA methylase (COG2189) emerged as one of the most significantly enriched epigenetic markers across all infected and CRC groups, CRC (7.0 ± 1.26, q = 2.98e-06), helminth-only (7.1 ± 1.16, q = 1.30e-07), HIV-only (6.2 ± 1.21, q = 1.28e-05), and co-infected 6.5 ± 1.21, q = 6.11e-06), suggesting a shared viral epigenomic mechanism potentially contributing to tumorigenesis. Additionally, diverse metabolism-related genes were differentially abundant, particularly those linked to butyrate metabolism, oxidative stress response, and polyamine biosynthesis, metabolic pathways known to influence tumor initiation, immune evasion, and disease progression. These findings indicate that the gut virome may play an intermediary role in modulating host epigenetic and metabolic landscapes in infection-driven CRC risk. Conclusion This study identifies novel gut virome-associated epigenetic and metabolic functional signatures that may serve as early, non-invasive biomarkers of CRC susceptibility in HIV- and helminth-endemic populations. Integrating such molecular indicators into cancer surveillance and prevention frameworks could enhance early detection strategies and precision cancer care in underrepresented, high-infection burden African regions.