The Divergent Immunomodulatory Effects of Short Chain Fatty Acids and Medium Chain Fatty Acids

Abstract

Fatty acids are derived from diet and fermentative processes by the intestinal flora. Two to five carbon chain fatty acids, termed short chain fatty acids (SCFA) are increasingly recognized to play a role in intestinal homeostasis. However, the characteristics of slightly longer 6 to 10 carbon, medium chain fatty acids (MCFA), derived primarily from diet, are less understood. Here, we demonstrated that SCFA and MCFA have divergent immunomodulatory propensities. SCFA down-attenuated host pro-inflammatory IL-1β, IL-6, and TNFα response predominantly through the TLR4 pathway, whereas MCFA augmented inflammation through TLR2. Butyric (C4) and decanoic (C10) acid displayed most potent modulatory effects within the SCFA and MCFA, respectively. Reduction in TRAF3, IRF3 and TRAF6 expression were observed with butyric acid. Decanoic acid induced up-regulation of GPR84 and PPARγ and altered HIF-1α/HIF-2α ratio. These variant immune characteristics of the fatty acids which differ by just several carbon atoms may be attributable to their origins, with SCFA being primarily endogenous and playing a physiological role, and MCFA exogenously from the diet.

Allicin Ameliorates Intestinal Barrier Damage via Microbiota-Regulated Short-Chain Fatty Acids-TLR4/MyD88/NF-κB Cascade Response in Acrylamide-Induced Rats

“…TLR4, existing in the form of a homodimer and signaling through MyD88, is thought to exhibit conservatism evolutionarily in its sentinel role to regulate essential bodily function. SCFAs in the host intestine are in line with the conservative signal receptor characteristic of TLR4, inhibiting large-scale inflammation response in response to local TLR4. , To investigate whether TLR4/MyD88/NF-κB mediates the anti-inflammatory effect of SCFAs, the expression levels of pathway proteins and downstream cytokines were assessed. After treatment with allicin, protein levels of the TLR4/MyD88/NF-κB pathway and TNF-α, IL-1β, IL-6, and IL-18 levels decreased dramatically, while the IL-10 level increased, indicating that intestinal inflammation was evidently suppressed.…”

Regulatory role of short-chain fatty acids in inflammatory bowel disease

“…In patients with IBD, butyrate inhibits the TLR2-mediated release of inflammatory factors [ 74 , 75 ]. Butyric acid also reduces adapter protein expression level [ 76 ]. In addition, increased level of TLR4 signaling also reduces the abundance of SCFA-producing flora in the gut, which is highly relevant to the development of IBD [ 75 ].…”

Roles of gut microbiota and metabolites in overweight and obesity of children

“…found that caprylic acid (C8:0) downregulated the serum levels of interleukin-1β (IL-1β) and interferon γ (IFNγ) and increased the abundance of Lachnoclostridium , Roseburia , and Prevotella_9 , activating GPR43 and improving intestinal permeability ( 113 ). Capric acid (C10:0) can upregulate GPR84 and peroxisome proliferator-activated receptor γ (PPARγ) ( 114 ). Dodecanoic acid (C12:0), also known as lauric acid, can improve insulin sensitivity ( 100 ).…”