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Abstract

Nuclear factor-kappa B (NF-kappaB) is a critical transcription factor for the inducible expression of multiple genes involved in inflammation. NF-kappaB is sequestered in the cytoplasm by inhibitory IkappaB proteins. Extracellular stimuli, notably interleukin-1beta (IL-1beta) and tumor necrosis factor alpha (TNF-alpha) activate NF-kappaB nuclear translocation via IkappaB phosphorylation and degradation. Since previous reports suggest that the short chain fatty acid butyrate has antiinflammatory properties, the effects of butyrate on NF-kappaB nuclear translocation in human epithelial cells (HeLa229) were tested. In cells pretreated with butyrate, a time- and dose-dependent inhibition of IL-1beta-mediated NF-kappaB nuclear translocation was observed. However, IkappaB alpha phosphorylation and degradation occurred rapidly in both butyrate pretreated and nonpretreated cells, respectively. These data indicate that inhibition of IL-1beta-induced NF-kappaB activation by butyrate does not require an intact IkappaB alpha protein.

Butyrate inhibits IL-1β-induced inflammatory gene expression by suppression of NF-κB activity in pancreatic beta cells

“…Accumulating evidence indicates that the gut microbiota plays a role in metabolic health and T2D ( 32 , 63 ). Specifically, butyrate, a short-chain fatty acid produced by certain gut bacteria, has anti-inflammatory properties ( 39 , 40 , 41 , 42 , 43 , 44 , 45 ) and affects glucose metabolism ( 32 , 38 , 64 ). Recently, we showed that butyrate protected beta cells from cytokine-induced dysfunction ( 52 ).…”

“…The anti-inflammatory properties of butyrate prompted us to examine the effect of butyrate on activation of the transcription factor NF-κB, which is required for Nos2 expression ( 25 , 69 , 70 ) and involved in the regulation of several other inflammatory associated genes ( 71 ). Regulation of NF-κB activity occurs at multiple levels including, subcellular localization, posttranslational modifications of proteins as well as gene accessibility, and butyrate has been shown to modulate NF-κB activation at different levels in other cell types ( 39 , 40 , 41 , 42 , 43 , 44 , 45 , 67 , 72 ).…”

“…As diet supplementation with butyrate in animal models of diabetes has shown promising results on circulating glucose levels, these results suggest that butyrate may play a role in glucose homeostasis ( 35 , 36 , 37 , 38 ). In various cell types, butyrate inhibits inflammation, NF-κB activation, and iNOS in vitro ( 39 , 40 , 41 , 42 , 43 , 44 , 45 ). Two main mechanisms have been suggested: (1) inhibition of histone deacetylases (HDACs) leading to increased acetylation of histones and nonhistone proteins and (2) binding to the free fatty receptor 2 (FFAR2) and FFAR3 ( 46 ).…”

Butyrate Protects Pancreatic Beta Cells from Cytokine-Induced Dysfunction

“…Other studies have also reported on the anti-inflammatory properties of butyrate, which are thought to be mediated through inhibition of NFκB [37][38][39][40]. In vivo downregulation of chemokines such as Cxcl1 and Cxcl10 may be important to reduce the recruitment and activation of immune cells, thereby reducing islet inflammation and improving beta cell function [41]. One of the most downregulated genes was nitric oxide synthase 2 (Nos2), encoding the iNOS enzyme.…”

Microbial metabolism of dietary components to bioactive metabolites: opportunities for new therapeutic interventions

“…Similarly, propionate modulates PPAR-γ activity in intestinal cells, one effect of which is to increase expression of epithelial Kruppel-like factor 4 [ 42 ], a tumor suppressor transcription factor that may be important in preventing colorectal cancer. Butyrate also inhibits the NF-κB pathway (a prototypical proinflammatory signaling pathway that expresses genes for cytokines, chemokines and adhesion molecules) [ 43 – 47 ]. All three SCFAs are used as energy substrates, with propionate serving as a substrate for gluconeogenesis while acetate and butyrate serve as substrates for fatty acid synthesis.…”