Butyrate Does Not Protect Against Inflammation-induced Loss of Epithelial Barrier Function and Cytokine Production in Primary Cell Monolayers From Patients With Ulcerative Colitis

Abstract

Background and Aims In vitro studies using immortalised cancer cell lines showed that butyrate has an overall positive effect on epithelial barrier integrity, but the physiological relevance of cancer cell lines is limited. We developed epithelial monolayers from human tissue samples of patients with ulcerative colitis [UC] to assess the effect of butyrate on epithelial barrier function. Methods A protocol to establish monolayers from primary epithelial cells of UC patients [n = 10] and non-UC controls [n = 10] was optimised. The monolayers were treated with 8 mM sodium butyrate ± tumour necrosis factor alpha [TNFα] and type II interferon [IFNγ] for 48 h. Changes in transepithelial electrical resistance were monitored. Barrier gene expression levels were measured. Inflammatory proteins in the supernatant of the cells were quantified with OLINK. Results We demonstrated that primary monolayer cultures can be grown within 1 week of culture with robust resistance values and polarised tight junction expression. Butyrate treatment of the cultures increased resistance but was detrimental in combination with TNFα and IFNγ. The combined treatment further induced even higher IL8 mRNA and inflammatory protein secretion than for the inflammatory mediators alone. The observed effects were similar in cultures from patients and non-UC controls, suggesting that there were no patient-specific responses responsible for these findings. Conclusions We found that butyrate does not protect against inflammation-induced barrier dysfunction and even worsens its effects in primary epithelial monolayers of UC patients and controls. The basic mechanisms of butyrate should therefore be reconsidered in future studies, in particular in patients with active inflammation and pre-existing barrier defects as is known for UC.

Intestinal Inflammation Modulates the Epithelial Response to Butyrate in Patients With Inflammatory Bowel Disease

“…Ours is the first study to compare the intrinsic ability of human epithelial organoids from UC and CD patients to uptake, metabolize, and respond to butyrate, along with the complex SCFA mixtures extracted from fecal samples. We clearly show that organoids from noninflamed IBD mucosa respond to butyrate similarly to controls, which is consistent with recent observations by Vancamelbeke et al, 42 who found no differences in the response of control and UC cultures to butyrate, alone or in combination with TNFɑ/IFNγ. On the other hand, we confirmed in both ex vivo epithelial cultures and whole mucosal samples that the inflammatory milieu, in particular the presence of TNFɑ, does impact butyrate uptake and oxidation.…”

NCoR1 Protects Mice From Dextran Sodium Sulfate–Induced Colitis by Guarding Colonic Crypt Cells From Luminal Insult

“…This finding is concordant with recent publications in which butyrate or butyrate-producing fermentable fiber are found to exacerbate the severity of experimental colitis. 39,[50][51][52][53] These observations also coincide with current practices to exclude fermentable oligosaccharides, disaccharides, monosaccharides, and polyols from the diet of IBD patients. 54,55 Caloric intake regulates tissue homeostasis and health.…”

Probiotic Lactobacillus casei: Effective for Managing Childhood Diarrhea by Altering Gut Microbiota and Attenuating Fecal Inflammatory Markers

“…have been associated with the production of butyrate, which is the major energy source of colonic epithelial tissue and may be involved in immune regulation and intestinal-barrier function [37,38,39,40]. In contrast, recent studies [41,42] have shown that butyrate is not universally beneficial for intestinal health. Lachnospiraceae and Ruminococcaceae differ with respect to their average numbers of carbohydrate-active genes and gene families, particularly glycoside hydrolases and carbohydrate-binding modules, which are more abundant and more diverse in Lachnospiraceae and Ruminococcaceae [43].…”