The Anti-inflammatory Immune Regulation Induced by Butyrate Is Impaired in Inflamed Intestinal Mucosa from Patients with Ulcerative Colitis

Altered gut microbiota composition and reduced levels of short-chain fatty acids, such as butyrate, have been identified as key components of ulcerative colitis (UC). We aimed to determine and compare effects of butyrate on the intestinal immune profile of UC patients with active disease and non-inflamed controls. Biopsies were cultivated during 6 h with or without butyrate. Cytokines were measured in supernatants and mRNA gene expression was analyzed in biopsies using Qiagen RT(2) Profiler PCR Arrays. The intestinal immune profile of cultured biopsies, as determined by mRNA gene expression and secreted cytokines, differed between inflamed UC samples and controls. Principal component analysis revealed that addition of butyrate differently regulated mRNA expression in inflamed biopsies from UC and non-inflamed biopsies from controls. Highly discriminant and predictive orthogonal partial least squares discriminant analyses identified 29 genes for UC (R2 = 0.94, Q2 = 0.86) and 23 genes for controls (R2 = 0.90, Q2 = 0.71) that were most regulated by butyrate. UC displayed more up-regulation of genes as compared with controls, and controls displayed the most prominent down-regulations. Ingenuity Pathway Analysis identified a down regulation of the Neuroinflammation Signaling pathway and predicted inhibition of the categories Inflammatory response, cellular movement, and cellular development as top diseases and functions, respectively, for controls but not for UC. In conclusion, butyrate has a different effect on gene regulation and more potently down-regulates gene expression of inflammatory pathways in non-inflamed controls than in inflamed tissue of UC patients. These discrepancies may at least partly explain why anticipated anti-inflammatory effects of local butyrate induction or supplementation are not always obtained. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s10753-019-01133-8) contains supplementary material, which is available to authorized users.