Dietary resistant starch type 4-derived butyrate attenuates nuclear factor-kappa-B1 through modulation of histone H3 trimethylation at lysine 27

Abstract

Indigestible resistant starches (RS) are substrates for gut-microbial metabolism and have been shown to attenuate intestinal inflammation but the supporting evidence is inconsistent and lacks mechanistic explanation. We have recently reported dietary RS type 4 (RS4) induced improvements in immunometabolic functions in humans and a concomitant increase in butyrogenic gut-bacteria. Since inflammation is a key component in metabolic diseases, here we investigated the effects of RS4-derived butyrate on epigenetic repression of pro-inflammatory genes in vivo and in vitro. RS4-fed mice, compared to the control-diet group, had higher cecal butyrate and increased tri-methylation of lysine 27 on histone 3 (H3K27me3) in the promoter of nuclear factor-kappa-B1 (NFκB1) in the colon tissue. The H3K27me3-enrichment inversely correlated with concentration dependent down-regulation of NFκB1 in sodium butyrate treated human colon epithelial cells. Two additional inflammatory genes were attenuated by sodium butyrate, but were not linked with H3K27me3 changes. This exploratory study presents a new opportunity for studying underlying H3K27me3 and other methylation modifying mechanisms linked to RS4 biological activity.

Consumption of transglycosylated starch down-regulates expression of mucosal innate immune response genes in the large intestine using a pig model

“…As a type of soluble fibre, resistant starch (RS) has been reported to decrease large intestinal inflammation by down-regulating the expression of inflammatory mediators, such as pro-inflammatory TNF- α and NF- κ B ( 1 , 9 ) , and enhancing the expression of nuclear transcription factor PPAR- γ ( 10 ) . In being resistant to digestion by mammalian enzymes in the small intestine, RS is highly fermentable for amylolytic bacteria in the hindgut ( 11 ) .…”

“…In being resistant to digestion by mammalian enzymes in the small intestine, RS is highly fermentable for amylolytic bacteria in the hindgut ( 11 ) . The beneficial effect of RS on host physiology may, therefore, encompass SCFA-derived attenuation of intestinal inflammation ( 1 , 9 , 12 ) . For the five RS types, most evidence for immunomodulatory abilities exists for RS2 (granular and high amylose starches) and RS3 (retrograded starch) ( 1 , 10 ) , whereas less has been reported about anti-inflammatory properties of RS4 ( 1 , 9 ) .…”

Dietary Phenethyl Isothiocyanate Protects Mice from Colitis Associated Colon Cancer

“…It is generally accepted that inflammation-related molecules and pathways are useful targets for the prevention and treatment of cancer [ 23 , 24 , 25 ]. Furthermore, dietary factors can modulate in vivo epigenetic signatures and, therefore, susceptibility to diseases [ 5 , 26 ]. Of particular interest, in the context of inflammatory gene expression modulation by dietary agents is the tri-methylation of H3 at lysine 27 (H3K27me3), which is frequently associated with transcriptional repression and gene silencing [ 27 , 28 ].…”

“…RNA extraction, purification, cDNA synthesis and real-time PCR were performed as previously described by our group [ 5 , 26 ]. All samples were run in duplicate.…”

Diet and Microbes in the Pathogenesis of Lupus

“…Interestingly, when Foxp3 is acetylated, the transcription factor becomes more stable and has greater propensity to bind DNA yielding a more stable and effective Treg population [182]. In addition to the regulation of Treg differentiation, butyrate has also been shown to increase the tri-methylation of lysine 27 on histone 3 (H3K27me3) in the promoter of nuclear factor-κB1 (NF-κB1) in colon tissue resulting in repression of inflammation [183]. In our lupus mouse studies, we found a marked depletion of lactobacilli in our lupus animals and increases in Lachnospiraceae compared to age-matched health controls.…”