Gut microbiota-derived short chain fatty acids are potential mediators in gut inflammation

Abstract

Gut inflammation is a challenging concern in humans and animals, which disturbs normal growth and leads to severe bowel diseases. Short chain fatty acids (SCFA) are the gut microbiota metabolites produced from fermentation of non-digestible carbohydrates, and have been reported to modulate gut inflammation. SCFA have been implicated as the potential therapeutic bioactive molecules for gut inflammatory diseases, and could be an alternative to antibiotic growth promoters (AGP). In this review, the existing knowledge about the types of SCFA, the related gut microbes producing SCFA, the roles of SCFA in maintaining gut homeostasis, and how SCFA modulate gut inflammation is summarized. The therapeutic application of SCFA in the treatment of inflammatory bowel disease (IBD) is also highlighted.

Keywords: Gut homeostasis; Gut inflammation; Gut microbiota; Inflammatory bowel disease; Short chain fatty acid.

Graphical abstract

Fig. 1

The synthesis pathways of different SCFA. SCFA synthesis depends upon the type of substrate, and the preference of every bacterium for available substrates is probably distinct. Based on substrate type, SCFA synthesis might be classified into 4 categories. Different bacteria use sugars (as demonstrated in section 1), carbon chain elongation (section 2), amino acids (section 3) or other substrates (section 4) for SCFA synthesis following different pathways. Propanediol and succinate pathways are represented in section 1 (Top left) of the figure. Thiolase-mediated butyryl-CoA, propionyl-CoA, and acetyl–CoA pathways are represented in section 2 (Top right) of the figure. Aminotransferase, thioesterase, dehydrogenase, and transacylase enzymes pathway using different amino acids as a basic source is represented in section 3 (Bottom left) of the figure. Wood–Ljungdahl and pyruvate decarboxylation to Acetyl–CoA pathways, and other types of substrates are represented in section 4 (Bottom right) of the figure. SCFA = short chain fatty acids; C = carbon; CoA = coenzyme A.

Fig. 2

Overall and gut-specified functions of SCFA. In humans and animals, after ingestion, the feed interacts with several types of digestive enzymes/gastric secretions, which help in nutrients digestion. However, some proportion of the nutrients remains undigested. Gut microbiota helps digest the remaining undigested carbohydrates and produces SCFA, i.e., acetate, propionate, and butyrate. Overall, these SCFA help in nutrients digestion, drug metabolism, toxin elimination, immunity training, and neurological/endocrinological functions regulation. Specifically, these SCFA protect the gut from inflammation, maintain gut barrier integrity, facilitate epithelial cells in nutrient absorption, and prevent entry of harmful entities and infectious agents. SCFA = short chain fatty acids.

Fig. 3

Schematic presentation of gut eubiosis and homeostasis. Intact gut epithelium maintains eubiosis and homeostatic balance. Most of the pathogens remained in the gut lumen, whereas the commensal bacteria elicited the underlying mechanisms via producing SCFA and triggering innate and adaptive immune regulation. SCFA via their GPR and (correlated) TLR modulate the immune regulation. During innate immune regulation (the left grey colour representation in the figure), SCFA, especially butyrate, induced apoptosis via activating the neutrophils and macrophages. On the other hand, activation of natural killer and dendritic cells, differentiation of macrophages and dendritic cells, and recruitment of neutrophils and macrophages were reduced. Th1-mediated cytokine productions from macrophages and dendritic cells, and neutrophilic induced cytotoxic effects and cytokine secretion were also reduced. During adaptive immune regulation (the right grey colour representation in the figure), SCFA, via GPR/TLR receptors activated B cells, Naïve T cells, and T regulatory cells (Treg). Treg were either directly activated by propionate or were indirectly activated by butyrate via Naïve T cells. B cells produced IgA, which inhibits bacterial invasion through the gut epithelium. Treg suppressed inflammatory and allergic responses, and its differentiation ameliorated colitis. Additionally, butyrate via HDAC modulated proliferation and recruitment of T cells (Th1, Th2, Th17), induced apoptosis, thus regulated cytokine production. SCFA properly maintain the gut eubiosis and homeostasis via both innate and adaptive immune regulation. SCFA = short chain fatty acids; GPR = G protein-coupled receptors; TLR = Toll-like receptors; Th1 = T helper type 1 cells; Th2 = T helper type 2 cells; Th17 = T helper type 17 cells; Treg = T regulatory cells; IgA = immunoglobulin A; HDAC = histone deacetylases.

Fig. 4

Schematic outlining of the main players in gut dysbiosis and inflammation. Gut dysbiosis depicts a decreased biodiversity and is accompanied by loss of beneficial bacteria, with defective barrier functions leading to leaky gut, impaired anti-microbial response, and enhanced bacterial adhesion and translocation. After damaging gut barrier, the gut became a leaky gut, which allowed the pathogens’ intrusion into lamina propria via crossing damaged barriers. Here, these pathogens produced toxins and secreted LPS and LTA. These toxins, LPS and LTA, together initiated inflammation, endotoxemia and thus caused metabolic diseases. These factors increased pro-inflammatory cytokines production, impaired anti-inflammatory cytokine secretion, and hence insufficient immune response led to the non-homeostatic condition. These factors also triggered the underlying cell signalling cascade. Although SCFA rushed to overcome the dysbiosis, however, SCFA could not elicit a proper anti-inflammatory state due to sudden invasion of pathogens. Gut-associated lymphoid tissue (GALT) also interactively released T cells and collaboratively competed with an intruded pathogenic storm. LPS = lipopolysaccharide; LTA = lipoteichoic acid; SCFA = short chain fatty acids.

Fig. 5

A probable cellular mechanism of SCFA-related immune response in gut homeostasis. GPR and TLR work in appropriate correlation. Bacterial PAMP, i.e., toxins, LPS and LTA, stimulated TLR and underlying signalling pathways. They promoted the secretion of pro-inflammatory cytokines, i.e., IL-1β, TNF-α, IL-6, etc. As a result, inflammation is initiated. SCFA, i.e., acetate, propionate, and butyrate, intricately correlate with TLR, i.e., TLR2, TLR3, TLR4, TLR9 and TLR10 via GPR, i.e., GPR41, GPR43, and GPR109A. GPR are inter-connected with SCFA via G proteins, which are heterotrimeric and comprise 3 subunits, alpha (α), beta (β), and gamma (γ). This demonstration explains the stimulation of TLR by PAMP, activation of GPR by SCFA, correlation and trans-membrane signalling activities of GPR and TLR, initiation of pro-inflammatory cytokines-mediated inflammation and other malfunctions, stimulation of anti-inflammatory activity to overcome inflammation, and activation of PPAR, MAPK, NF-κB, and NLRP3 inflammasome pathways and relevant transcription/genes expression in overall immune regulation via SCFA. GPR = G protein-coupled receptors; TLR = toll-like receptors; PAMP = pathogen-associated molecular patterns; LPS = lipopolysaccharide; LTA = lipoteichoic acid; IL-1β = interleukin 1β; TNF-α = tumor necrosis factor α; IL-6 = interleukin 6; SCFA = short chain fatty acids; TLR2 = toll-like receptor 2; TLR3 = toll-like receptor 3; TLR4 = toll-like receptor 4; TLR9 = toll-like receptor 9; TLR10 = toll-like receptor 10; GPR41 = G protein-coupled receptor 41; GPR43 = G protein-coupled receptor 43; GPR109A = G protein-coupled receptor 109 A; PPAR = peroxisome proliferator-activated receptors; MAPK = mitogen activated protein kinase; NF-κB = nuclear factor-kappa B; NLRP3 = NOD (nucleotide-binding oligomerization domain) LRR (leucine-rich repeat) and pyrin domain-containing 3.

Fig. 6

Overall scheme and correlation of all possible factors in inflammation (gut dysbiosis) and homeostasis (gut eubiosis). PAMP = pathogen-associated molecular patterns; LPS = lipopolysaccharide; LTA = lipoteichoic acid; SCFA = short chain fatty acids; TLR = Toll-like receptors; MAPK = mitogen activated protein kinase; NF-κB = nuclear factor-kappa B.