Sodium Butyrate: A Microbiota-Derived Short-Chain Fatty Acid Regulating Inflammation, Gut Barrier Function, and Colorectal Cancer Progression.

Colorectal cancer (CRC) is a polyetiologic disease related to genetic changes, chronic inflammation, dysregulation of the intestinal barrier, diet and gut microbiota dysbiosis. Butyrate is a short-chain fatty acid (SCFA) produced by the microbiota that plays a crucial role in energy metabolism, epithelial homeostasis and mucosal immunity. Sodium butyrate (NaB), the sodium salt of butyric acid, has therefore been the subject of experimental investigation and appears to be a therapeutic option of potential interest. This review critically explores the biological, pharmacological and translational significance of butyrate and NaB in CRC. It details the origins and physicochemical properties, pharmacokinetics, effects on the intestinal barrier, and interactions with the intestinal microbiota, alongside immunomodulatory actions, molecular pathways underlying anti-cancer efficacy, clinical evidence, and patent holdings, and further explores prospective formulation and delivery methods. Butyrate/NaB exerts pleiotropic effects via inhibition of HDAC and activation of free fatty acid receptors (FFARs), such as GPR41/FFAR3, GPR43/FFAR2 and GPR109A/HCAR2.These processes regulate various inflammatory and oncogenic signaling pathways, including NF-κB, NLRP3, Wnt/β-catenin, PI3K/Akt, MAPK, and STAT3, as well as mitochondrial metabolism, oxidative stress, cell-cycle progression, apoptosis, epithelial-mesenchymal transition, and immune-cell function. Additionally, butyrate helps preserve gut barrier function and can influence CRC biology by interacting with the tumour microenvironment, microbial metabolism, and epithelial cells. There is extensive preclinical evidence of the barrier-protective, anti-inflammatory, immunomodulatory, and anticancer properties of butyrate/NaB in cell- and animal-based models. The strength of evidence, however, depends on the model, concentration/dose, duration of treatment and endpoint. The mechanistic and preclinical results should therefore not be interpreted as being equivalent to actual clinical efficacy. There is limited available human evidence for specific therapeutic uses of CRC. Various factors limit its translational application, including rapid metabolism, a short biological half-life, and low systemic exposure, as well as inherent butyrate fluctuations, formulation challenges, and a scarcity of stringent clinical trials tailored to CRC. Colon-targeted delivery systems, microencapsulation, nanotechnology-based delivery systems, microbiome-directed interventions, patient selection by biomarkers, and rational combination strategies may overcome these limitations. Butyrate/NaB offers a promising multitarget strategy for CRC research; however, further investigation into its mechanisms, pharmacokinetics, dosing, formulation, and large-scale clinical trials is necessary to validate its therapeutic efficacy and define its translational potential.