SCFAs’ pleiotropic role in pathogenesis and salutogenesis: mechanisms in exacerbation and regulation of inflammation and fibrosis from gut to host

Short-chain fatty acids (SCFAs) are essential gut microbiota metabolites with significant effects that are well recognized for their anti-inflammatory benefits, yet their pro-inflammatory and pleiotropic properties have received little attention in literature. SCFAs produced by gut bacteria from one to five carbons engage with a network of G-protein-coupled receptors such as FFAR2/GPR43, FFAR3/GPR41, Olfr78 and monocarboxylate transporters (MCT-1-MCT-4) to influence host physiology. Through established signalling pathways including Mitogen-Activated Protein Kinase (MAPK), mTOR and G<i>α</i>i/G<i>α</i>q, SCFAs serve as acetyl CoA precursors that facilitate lipogenesis, gluconeogenesis and cholesterol synthesis while also activating NF<i>κ</i>B and reactive oxygen species pathways (e.g. succinate), potentially resulting in vascular inflammation. While SCFAs typically suppress inflammation through histone deacetylase inhibition and immune regulation, pro-inflammatory roles emerge in specific settings. Within immune compartments, SCFAs exhibit cell-specific effects, from priming cell-driven pro-inflammatory roles in one type of immune cell to suppression of inflammatory mediators in others. Moreover, SCFAs can lead to fibrotic remodelling, an intensified form of inflammation in both intestinal and distant tissues. This review aims to demonstrate the complex biphasic bridge between aggravation and resolution influenced by factors such as cell type, study methodologies, receptors, dose dependency, age, metabolic changes and inherent properties and concludes with the significance of particular and accurate research approaches to mimic the true environment and observe SCFA effects employing humanized mice, gut-on-chip systems and organoids for more precise and relevant results.