Short-Chain Fatty Acid Sodium Butyrate Suppresses Protective Humoral Immunity by Inhibiting Follicular T Helper Cell Differentiation

Abstract

The gut microbiome and its metabolites are critical regulators of intestinal homeostasis, with emerging evidence highlighting their influence on humoral immune responses and vaccine efficacy. The development of effective humoral immunity depends on the magnitude and quality of germinal centers (GCs), which are driven by follicular T helper (Tfh) cells. Here, we investigate the role of short-chain fatty acids (SCFAs) in shaping humoral immunity, with a particular focus on Tfh cells. In ex vivo assays, we found that sodium butyrate, not sodium acetate or sodium propionate, directly suppresses Tfh cells differentiation and helper functions. Using antigen-specific and influenza virus infection models, we further demonstrate that sodium butyrate impairs Tfh cell differentiation, leading to diminished GC B cell responses and compromised humoral immunity during systemic infection. Notably, mice treated with sodium butyrate succumbed to virus infection, underscoring its effect on impairing protective immunity. Mechanistically, our findings reveal that sodium butyrate mediates these suppressive effects on Tfh cells via histone deacetylase (HDAC) inhibition. Together, our findings establish sodium butyrate as a negative regulator of humoral immunity by directly suppressing the Tfh-cell differentiation and Tfh-derived GC responses. These insights provide a mechanistic link between gut microbiome-derived metabolites and humoral immunity, with potential implications for vaccine efficacy and therapeutic interventions.