Short-Chain Fatty Acids Suppress Inflammatory Reactions in Caco-2 Cells and Mouse Colons

Abstract

Short-chain fatty acids (SCFAs), such as acetate, propionate, and butyrate, play an important role in the maintenance of intestinal homeostasis. In the present study, anti-inflammatory effects of SCFAs were examined in human intestinal Caco-2 cells and mouse colonic cultures. Stimulation of Caco-2 cells with tumor necrosis factor (TNF)-α induced interleukin (IL)-8 (TNF-α, 17.1 ± 7.2 vs Control, 1.00 ± 0.26, P < 0.01) and IL-6 expression (TNF-α, 21.7 ± 10.0 vs Control, 1.00 ± 0.28, P < 0.01) through the activation of nuclear factor κB p65, spleen tyrosine kinase, and mitogen-activated protein kinase pathways. Pretreatment of cells with acetate (5 mM, IL-8 1.23 ± 0.40, IL-6 2.19 ± 0.92, P < 0.01 ), propionate (2.5 mM, IL-8 2.45 ± 2.10, IL-6 2.19 ± 0.92, P < 0.01), or butyrate (0.625 mM, IL-8 1.44 ± 0.70, IL-6 2.31 ± 0.32, P < 0.01) suppressed inflammatory responses induced by TNF-α. Pharmacological inhibition of monocarboxylate transporter (MCT)-1 attenuated the suppression of inflammatory signals by SCFAs. High expression levels of CXC motif chemokine ligand 2 (CXCL2, an IL-8 homologue, DSS, 31.7 ± 9.8 vs Control, 1.00 ± 0.70, P < 0.01) and IL-6 (DSS, 17.5 ± 7.2 vs Control, 1.00 ± 0.68, P < 0.01) were observed in BALB/c mouse colonic cultures exposed to dextran sodium sulfate, whereas treatments with mixtures of SCFAs decreased these elevated expression levels (CXCL2 4.14 ± 2.88, IL-6 0.58 ± 0.28, P < 0.01). Our results suggest that SCFAs transported by MCT-1 suppress TNF-α-induced inflammatory signaling in intestinal cells.

Intestinal enteroids recapitulate the effects of short-chain fatty acids on the intestinal epithelium

“…Short chain fatty acids have also been shown to have anti-inflammatory activity in immune cells [5,7], however, effects on intestinal host cells are not well understood. Interleukins (ILs) are secreted cytokines that regulate immune responses and can function in a pro-or antiinflammatory manner.…”

“…Short chain fatty acids are also known to exhibit effects on cellular proliferation and immune response [5]. Previous literature has shown that BUT decreases cellular proliferation and increases antimicrobial peptide expression, cytokine/ chemokine production, as well as tight junction proteins [6,7]. BUT has been the most widely studied SCFA and has been reported to have specific health benefits [8].…”

Cryptotanshinone from Salvia miltiorrhiza Bunge (Danshen) inhibited inflammatory responses via TLR4/MyD88 signaling pathway

“…Inflammation is a complicated process which is regulated by a series of inflammatory mediators and cytokines [1]. Accumulating evidences have confirmed that pro-inflammatory cytokines, such as TNF-α and IL-6, are able to induce inflammatory responses and aggravate the development of inflammation [28]. In response to LPS, proinflammatory cytokines, such as TNF-α and IL-6, are often overproduced.…”

Targeting the Pregnane X Receptor Using Microbial Metabolite Mimicry

“…We have also shown that FKK5 and FKK6 interact directly with PXR LBD and result in its activation. Thus, to determine the effect of FKK5 and FKK6 on the PXR-TLR4-NF-κB signaling pathway, we used PXR-transfected Caco-2 cells and exposed these cells to FKK5 and 6 since undifferentiated Caco-2 cells inherently have low PXR expression (not detected) but relatively higher TLR4 expression and are excellent in vitro models for the study of enterocyte function [36][37][38][39] . FKK5 and FKK6 down-regulates TLR4 (0.39-fold and 0.49-fold, respectively) but up-regulates CYP3A4 (3.7-fold and 3.29-fold, respectively) and MDR1 (5.12-fold and 6.45-fold, respectively) mRNA expression ( Fig.…”

“…To further characterize the anti-inflammatory effects of FKK5 and 6 on human intestinal cells and tissue, we first determined their effects on Caco-2 cell monolayers. These cells were well-established models to study intestinal cell differentiation and physiology, specifically under conditions of inflammatory stimuli 38 . Differentiated Caco-2 cells via long term culture have heightened PXR expression 40 .…”