Microbiota-Derived Proteins Shape T Cell Responses in Healthy and Colorectal Cancer Subjects

<b>Background/Objectives:</b> <i>Fusobacterium nucleatum</i> and <i>Akkermansia muciniphila</i> are key components of the human microbiota, influencing health and disease. <i>F. nucleatum</i> is associated with colorectal cancer (CRC) and poor prognosis through its pro-inflammatory and pro-tumorigenic activity, whereas <i>A. muciniphila</i> is linked to metabolic benefits and anti-inflammatory effects. This study aimed to evaluate the immunomodulatory impact of protein extracts from these bacteria on peripheral T cell responses in healthy individuals and CRC patients. <b>Methods</b>: Peripheral blood mononuclear cells (PBMCs) were exposed to bacterial extracts, individually or in combination, and T cell subsets were analyzed by polychromatic flow cytometry. <b>Results</b>: In healthy donors, <i>F. nucleatum</i> increased Th0, Th2, and Tc9 cell frequencies while reducing Th1, Th1/Th17, and Treg cells. Conversely, <i>A. muciniphila</i> promoted a pro-inflammatory-associated T cell phenotype characterized by higher Th0, Th2, Th17, and Tc17 cells. Combined exposure enhanced Th0, Th17, and Tc17 cells while decreasing Th9 cells. In CRC patients, bacterial extracts induced no significant changes in T cell subsets. <b>Conclusions</b>: These findings indicate that <i>F. nucleatum</i> skews immune responses toward humoral and mucosal defense, whereas <i>A. muciniphila</i> enhances T cell polarization toward subsets usually associated with pro-inflammatory immune responses in healthy subjects. Further studies are needed to clarify their systemic immunological roles and interactions within the tumor microenvironment of CRC.