The Anticancer Mechanisms of Short-Chain Fatty Acids and Their Clinical Application Prospects

Short-chain fatty acids (SCFAs) are lipid substances composed of 2 to 6 carbon atoms, mainly including acetate, propionate, and butyrate. These substances are important metabolic products produced by gut microbiota through the fermentation of dietary fiber. In recent years, numerous studies have shown that SCFAs not only play a key role in gut health but also exhibit significant biological effects in the prevention and treatment of various cancers.

Metabolic Processes of Short-Chain Fatty Acids

Mechanism for SCFA Production

A large number and diverse types of microbial communities reside in the human gut, forming a complex ecosystem. When dietary fibers enter the digestive tract, they are almost undigested due to humans lacking enzymes to break down cellulose. However, specific bacterial groups in the colon can ferment these dietary fibers into SCFAs through various metabolic pathways.

Different intestinal microbiota utilize different metabolic pathways to produce SCFAs. Bacteroides and Bifidobacterium species convert dietary fibers into acetate via acetyl-CoA pathway; while other bacteria like Faecalibacterium generate propionate through succinate pathway; And some others like Roseburia produce butyrate via phosphotransbutyrylase/butyryl-CoA transferase pathway. These metabolic processes provide energy for gut microbes while importantly producing SCFAs with broad biological activity.

Absorption and Distribution of SCFAs

After being produced in the colonic lumen, due to their unique physicochemical properties, SCFAs are primarily absorbed through specific transport mechanisms. Since acetate, propionate, and butyrate have pKa values at 4.76, 4.87, and 4.82 respectively—existing mainly as ions under intestinal pH—they are rarely absorbed by simple diffusion methods. The main absorption routes involve medium-affinity transport mediated by monocarboxylate transporter 1 or high-affinity transport mediated by sodium-coupled monocarboxylate transporter 1.

Research indicates that there is a clear regional difference in how SCFAs are absorbed within the intestine: both cecum and proximal colon serve as primary sites for absorption where concentrations peak; whereas as one moves distally along the intestine towards rectum concentrations gradually decrease—a distribution characteristic potentially related to differences observed in left vs right-sided colorectal cancer incidence rates. Unabsorbed SCFAs may enter systemic circulation via portal vein exerting physiological effects throughout body systems.

Direct Anticancer Mechanisms of Short-Chain Fatty Acids

n G Protein-Coupled Receptor Mediated Signaling Pathways n nSCFAs can be specifically recognized by G protein-coupled receptors (GPCRs) on cancer cell surfaces activating downstream signaling pathways leading anticancer actions currently identified include GPCR41,GPR43,and GPR109A among which acetate ,propionate ,and butyrate act as agonists toward GPCR41 & GPR43 whilst Butyrate uniquely activates GPR109A . nSCFA’s promote apoptosis within cancer cells predominantly via two mechanisms : death receptor apoptotic pathway & mitochondrial apoptotic route ;in death receptor path way ,SCFA increases secretion tumor necrosis factor-alpha(TNF-alpha),upregulating Fas ligand(Fas-L); meanwhile mitochondrial route reduces expression anti-apoptotic protein Bcl-2 facilitating activation caspase cascade response .For instance,in HepG2 liver carcinoma cell line Propionic acid significantly increased TNFa secretion inducing apoptosis upon activating GPCR41 .In terms regulating cell cycle,SFCAS induce blockages utilizing multiple mechanisms demonstrated reducing cyclins/CDK expressions upregulating CDK inhibitor P21 causing impediments cellular proliferation notably these effects partly independent from P53 suggesting potential therapeutic avenues even against P53 mutant cancers.SCFAS additionally markedly inhibit metastatic invasion capabilities seen during epithelial-mesenchymal transition(EMT)—a critical step involving decreased E-cadherin expression cytoskeletal rearrangements—in breast cancer cells where it was found regulate phosphorylation levels large tumor suppressor gene1(YAP).This reverses EMT process inhibiting metastasis further illustrating complexity interactions between diet derived metabolites immune responses oncogenesis! ... [Content continues] ...