The Role of Short-Chain Fatty Acids and Bile Acids in Intestinal and Liver Function, Inflammation, and Carcinogenesis.

Alexander Visekruna,Maik Luu

doi:10.3389/fcell.2021.703218

Abstract

During the past decade, researchers have investigated the role of microbiota in health and disease. Recent findings support the hypothesis that commensal bacteria and in particular microbiota-derived metabolites have an impact on development of inflammation and carcinogenesis. Major classes of microbial-derived molecules such as short-chain fatty acids (SCFA) and secondary bile acids (BAs) were shown to have immunomodulatory potential in various autoimmune, inflammatory as well as cancerous disease models and are dependent on diet-derived substrates. The versatile mechanisms underlying both beneficial and detrimental effects of bacterial metabolites comprise diverse regulatory pathways in lymphocytes and non-immune cells including changes in the signaling, metabolic and epigenetic status of these. Consequently, SCFAs as strong modulators of immunometabolism and histone deacetylase (HDAC) inhibitors have been investigated as therapeutic agents attenuating inflammatory and autoimmune disorders. Moreover, BAs were shown to modulate the microbial composition, adaptive and innate immune response. In this review, we will discuss the recent findings in the field of microbiota-derived metabolites, especially with respect to the molecular and cellular mechanisms of SCFA and BA biology in the context of intestinal and liver diseases.

Highlights

The triangular interdependency between gut microbiota, diet and immune cells is substantially connected to the functionality of a symbiotic cellular network and to the host’s health status
We examine recent work investigating the modes of action by which two major groups of bacterial metabolites, short-chain fatty acids (SCFA) and bile acids (BAs), impact on liver- and gut-associated inflammatory and cancerous diseases
Based on experiments with physiological amounts of isotope-labeled SCFAs, den Besten and colleagues demonstrated that 62% of the infused propionate in the murine cecum was involved in whole body glucose production, accounting for 69% of total glucose synthesis

Summary

INTRODUCTION

The triangular interdependency between gut microbiota, diet and immune cells is substantially connected to the functionality of a symbiotic cellular network and to the host’s health status. Recent studies have shown that enhanced histone H3 acetylation at the Foxp locus and increased acetylation of the Foxp protein itself can be modulated by butyrate, stabilizing the genetic integrity of Tregs (Arpaia et al, 2013; Furusawa et al, 2013) Besides their HDAC-inhibitory properties, SCFAs are able to increase the activation of mammalian target of rapamycin (mTOR), a central regulator of cell growth and energy homeostasis (Sengupta et al, 2010). The nuclear acetyl-CoA served as a substrate for histone acetyltransferases (HATs) which facilitate the conjugation of acetyl groups to histones, thereby regulating gene expression and the production of cytokines such as IL-10 and IFN-γ (Wellen et al, 2009; Zhao et al, 2016; Bantug et al, 2018; Luu et al, 2019) These data strongly support the concept of a metabolic-epigenetic crosstalk in which cellular metabolism-derived molecules serve as source for posttranslational modifications (PTMs) (Figure 2A). These findings suggest a link between microbiota and epigenetic regulation opening the venue for investigating new PTMs based on microbial metabolites

SCFAS IMPACT ON INTESTINAL HOMEOSTASIS AND INFLAMMATION

SCFAS IN DEVELOPMENT OF COLORECTAL CANCER AND STEM CELL RENEWAL

Findings

CONCLUSION AND FUTURE DIRECTIONS