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

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 the 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 the 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.

Impact of dietary resistant starch type 4 on human gut microbiota and immunometabolic functions.

Dietary modulation of the gut microbiota impacts human health. Here we investigated the hitherto unknown effects of resistant starch type 4 (RS4) enriched diet on gut microbiota composition and short-chain fatty acid (SCFA) concentrations in parallel with host immunometabolic functions in twenty individuals with signs of metabolic syndrome (MetS). Cholesterols, fasting glucose, glycosylated haemoglobin, and proinflammatory markers in the blood as well as waist circumference and % body fat were lower post intervention in the RS4 group compared with the control group. 16S-rRNA gene sequencing revealed a differential abundance of 71 bacterial operational taxonomic units, including the enrichment of three Bacteroides species and one each of Parabacteroides, Oscillospira, Blautia, Ruminococcus, Eubacterium, and Christensenella species in the RS4 group. Gas chromatography-mass spectrometry revealed higher faecal SCFAs, including butyrate, propionate, valerate, isovalerate, and hexanoate after RS4-intake. Bivariate analyses showed RS4-specific associations of the gut microbiota with the host metabolic functions and SCFA levels. Here we show that dietary RS4 induced changes in the gut microbiota are linked to its biological activity in individuals with signs of MetS. These findings have potential implications for dietary guidelines in metabolic health management.