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

## TL;DR

Short-chain fatty acids (SCFAs) have both harmful and beneficial effects on inflammation and fibrosis, depending on factors like cell type and dose, and understanding these dual roles is crucial for accurate research.

## Contribution

This paper highlights the underappreciated pro-inflammatory and pleiotropic roles of SCFAs alongside their well-known anti-inflammatory effects.

## Key findings

- SCFAs can trigger vascular inflammation via pathways like NFκB and reactive oxygen species.
- SCFAs show cell-specific effects, promoting inflammation in some immune cells while suppressing it in others.
- SCFAs contribute to fibrotic remodelling in both gut and distant tissues.

## Abstract

SCFAs exert dual roles in health and disease by modulating immune responses, inflammation, and fibrosis across organs, influencing salutogenesis and pathogenesis through dose, cell-specific, and contextual factors.

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 Gαi/Gαq, SCFAs serve as acetyl CoA precursors that facilitate lipogenesis, gluconeogenesis and cholesterol synthesis while also activating NFκB 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.