Abstract
BACKGROUND: Although previous observational studies have highlighted a possible association between the gut microbiota (GM) and head and neck cancer (HNC), the causal relationships remain unclear, particularly regarding the role of plasma proteins as potential mediators. Clarifying these connections is essential for uncovering the underlying mechanisms of HNC progression and may lead to new therapeutic strategies. MATERIALS AND METHODS: First, we examined the causal link between the GM and HNC via a two-sample Mendelian randomization (MR) approach. We then investigated the causative relationships between plasma proteins and HNC via the same two-sample MR technique. The coefficient product approach was then used to clarify the role of plasma proteins in the causative pathway between the GM and HNC. Finally, sensitivity investigations were performed to assess the robustness and coherence of the results. RESULTS: MR analyses revealed the protective effects of one family and six genera on HNC (Lachnospiraceae, Parabacteroides, Phascolarctobacterium, Alistipes, Sutterella, Roseburia and Alloprevotella). In contrast, three genera (Ruminococcus, Prevotella and Bacteroides) were significantly positively associated with HNC risk. Through further examination, researchers discovered 18 plasma proteins that have a causal relationship with HNC. Notably, the mediation MR illustrated that the causal protective effect of OTU97_86 (Phascolarctobacterium) on HNC (total effect IVW: OR = 0.879, 95% = 0.810-0.954, p = 0.002) was mediated by Proteasome subunit alpha type-1 (PSMA1) (- 0.020, 95% CI = - 0.039 ~ - 0.001, p = 0.036), accounting for 15.25% of the total effect. Similarly, the causal effect of OTU99_35 (Ruminococcus) on HNC risk (total effect IVW: OR = 1.109, 95% CI = 1.027-1.198, p = 0.008) was mediated by the protein FAM107B (0.015, 95% CI = 0.001-0.029, p = 0.031), accounting for 14.69% of the total effect. CONCLUSION: MR and mediation analysis revealed that specific GMs influence HNC risk through plasma proteins: Phascolarctobacterium protects against HNC via PSMA1, whereas Ruminococcus increases HNC risk through FAM107B. These pathways suggest that Phascolarctobacterium is a potential preventative factor and that Ruminococcus is a risk factor. This highlights the possibility of using specific GM and plasma proteins as biomarkers or therapeutic targets for HNC prevention, diagnosis, and treatment.