Short Chain Fatty Acids (SCFAs)-Mediated Gut Epithelial and Immune Regulation and Its Relevance for Inflammatory Bowel Diseases

Abstract

Ulcerative colitis (UC) and Crohn's disease (CD), collectively known as Inflammatory Bowel Diseases (IBD), are caused by a complex interplay between genetic, immunologic, microbial and environmental factors. Dysbiosis of the gut microbiome is increasingly considered to be causatively related to IBD and is strongly affected by components of a Western life style. Bacteria that ferment fibers and produce short chain fatty acids (SCFAs) are typically reduced in mucosa and feces of patients with IBD, as compared to healthy individuals. SCFAs, such as acetate, propionate and butyrate, are important metabolites in maintaining intestinal homeostasis. Several studies have indeed shown that fecal SCFAs levels are reduced in active IBD. SCFAs are an important fuel for intestinal epithelial cells and are known to strengthen the gut barrier function. Recent findings, however, show that SCFAs, and in particular butyrate, also have important immunomodulatory functions. Absorption of SCFAs is facilitated by substrate transporters like MCT1 and SMCT1 to promote cellular metabolism. Moreover, SCFAs may signal through cell surface G-protein coupled receptors (GPCRs), like GPR41, GPR43, and GPR109A, to activate signaling cascades that control immune functions. Transgenic mouse models support the key role of these GPCRs in controlling intestinal inflammation. Here, we present an overview of microbial SCFAs production and their effects on the intestinal mucosa with specific emphasis on their relevance for IBD. Moreover, we discuss the therapeutic potential of SCFAs for IBD, either applied directly or by stimulating SCFAs-producing bacteria through pre- or probiotic approaches.

Keywords: IBD; IECs; SCFAs; dysbiosis; immune cells; intestinal mucosa.

Figures

Figure 1

Schematic representation of carboydrates fermentation pathways that lead acetate, propionate and butyrate production. The main enzymes involved in the butyrate production are indicated as (a) butyrate kinase and (b) butyryl CoA:acetate CoA transferase. Figure adapted from den Besten et al. (35).

Figure 2

SCFAs in healthy (A) and inflamed (B) colonic mucosa. In healthy mucosa, (1) bacterial fermentation of dietary fiber (DF) by SCFAs-producing bacteria (e.g., F. prausnitzii), increases luminal content of butyrate (green), propionate (blue) and acetate (purple) (2), forming a gradient along the crypt. In lamina propria (LP) macrophages under acute inflammatory stimulus (4), butyrate inhibits histone deacetylases (HDACs) thus; NF-κB-induced pro-inflammatory mediators (e.g. TNF-α, IL-6, IL-12 and iNOS) expression whereas increases anti-inflammatory mediators (e.g., IL-10). In colonocytes (5), butyrate is β-oxidized to Acetyl-CoA and constitutes the main source of energy by entering the TCA cycle. Alternatively, butyrate initiates signaling pathway activation (or repression) by GPCRs and/or directly inhibits HDACs, thus activating (e.g., HIF-1, STAT3 and SP1) or repressing (e.g., NF-κB) transcription factors (TFs), increasing epithelial barrier function, antimicrobial peptides (AMPs) production, cell proliferation and decreasing inflammation. In inflamed mucosa as IBD, (1) a decreased fermentation of DF by low levels of SCFAs-producing bacteria (e.g., F. prausnitzii) (2), reduces SCFAs luminal content (3). In LP inflammatory macrophages (4), butyrate-GPCRs activation and -HDACs inhibition are downregulated, thus, there is uncontrolled NF-κB-induced pro-inflammatory mediators' expression (e.g. TNF-α, IL-6, IL-12 and iNOS) and decrease of anti-inflammatory mediators (e.g., IL-10), although it appears that the inflammation increasesthe GPCRs and transporters expression. In inflamed colonocytes (5), butyrate uptake and oxidation are decreased and GPCRs and transporters are also downregulated. This contributes to decreased epithelial barrier integrity, AMPs production, cell proliferation and increased inflammation.