Dysbiosis of the enteric DNA virome correlates with the development of cachexia in a murine Lewis lung carcinoma (LLC) model

Cachexia, a multifaceted wasting syndrome, profoundly impacts quality of life and survival rates in cancer patients. Gut inflammation is identified as a key player among the contributing factors for its development. Consequently, numerous studies have sought to characterize changes in gut microbiota of cachectic individuals, given the well-established roles of the gut microbiota in controlling and/or triggering both local and systemic inflammation in their hosts. Most of these investigations have applied mouse models of tumor-induced cachexia to show correlations between alterations in bacterial and fungal abundance in the digestive tract and the onset of cancer cachexia (CC). However, the role of viral dysbiosis in CC development remains unexplored. The present study aims to address this gap by characterizing the gut virome during the progression of murine cancer cachexia. Although our approach was limited to DNA viruses, our findings reveal that cachectic animals with Lewis lung carcinoma exhibited a subtle yet statistically significant modulation in composition (R² = 0.17622; p = 0.05). A linear discriminant analysis effect size (LEfSe) analysis revealed that the dysbiosis observed in the gut virome of CC animals was mostly characterized by a significant enrichment in giant viruses of the family Phycodnaviridae (LDA score, 4.2582; p-value, 0.004; pwr_app, 0.9984) and significantly decreased populations of bacteriophages of the families Microviridae (LDA score, 4.3458; p-value, 0.0127; pwr_app, 0.9065) and Inoviridae (LDA score, 3.3028; p-value, 0.0017; pwr_app, 0.9992). This cachexia-associated viral dysbiosis shares similarities with virome alterations documented in other conditions linked to gut inflammation, including, ulcerative colitis, Crohn's disease, and Clostridioides difficile infection. These new insights suggest the potential contributions of viral communities to the pathophysiology of CC and other inflammation-driven diseases.