The effect of butyrate on human macrophages
Butyrate is a short-chain fatty acid produced by gut microbiota during the fermentation of dietary fibers. Its concentration varies across regions of the body, especially in the gut. Butyrate plays diverse biological roles, particularly in immune regulation, often through epigenetic mechanisms such as histone modification.This thesis investigates the immunomodulatory and epigenetic effects of butyrate on human monocyte-derived macrophages. We show that low concentrations (0.1 mM) suppress pro-inflammatory cytokines via PPAR-γ signaling and histone acetylation, while high concentrations (10 mM) enhance inflammation and induce cell death. These effects involve GPCRs, CD36, and SRC kinase signaling.We also found that butyrate causes global histone acetylation by butyrylating the histone acetyltransferase p300. This disrupts its bromodomain interaction with acetylated histones, impairing site-specific regulation. Molecular dynamics simulations reveal a shift toward widespread, non-specific acetylation—highlighting a novel epigenetic mechanism.Moreover, we examined how extracellular pH affects butyrate uptake. Acidic pH promotes cellular entry and intracellular acidification, while basic pH enhances histone acetylation. These results suggest that pH modulates butyrate’s activity.Lastly, we explore CD36’s dual role in cancer. It promotes tumor growth and immune suppression via fatty acid uptake but can also enhance anti-tumor immunity through CD8⁺ T cell activation and antigen presentation. Its function depends on the ligand and cellular context.Together, these findings emphasize the context-dependent effects of butyrate and CD36, and their therapeutic potential in inflammation, metabolism, and cancer.