Individual short-chain fatty acids differentially reprogram transcriptional states in colorectal cancer cells

Short-chain fatty acids (SCFAs) produced by the gut microbiota contribute to intestinal function, immune responses and host metabolism, yet how individual SCFAs shape intracellular gene expression states remains incompletely defined. Here, we used intestinal epithelial-derived colorectal cancer cells to characterize early responses to sodium butyrate, propionate, valproate, acetate and 3-hydroxybutyrate using RNA sequencing. RNA-seq showed that SCFA treatment altered transcriptional states, with distinct effects among SCFA species. Functional analyses suggested a tendency toward suppression of stimulus-responsive signalling pathways across colorectal cancer cell lines, together with downregulation of pathways involved in RNA processing and post-transcriptional regulation. In addition, intron retention increased after SCFA treatment. Although the magnitude depended on treatment conditions, reproducible intron retention patterns were detected in specific cell lines, consistent with potential alterations in RNA maturation processes. Analyses of H3K27me3 and RT-qPCR further suggested that some SCFA-induced expression changes were transient, whereas others were partially sustained in association with altered epigenetic profiles. Collectively, these datasets provide a foundation for understanding how microbiota-derived SCFAs influence cellular states in colorectal cancer cell lines through transcriptional changes and increased intron retention.