Inflammation‐Induced Downregulation of Butyrate Uptake and Oxidation Is Not Caused by a Reduced Gene Expression

Boesmans, Leen; Ramakers, Meine; Arijs, Ingrid; Windey, Karen; Vanhove, Wiebe; Schuit, Frans; Rutgeerts, Paul; Verbeke, Kristin; Preter, Vicky De

doi:10.1002/jcp.24725

Cited by 11 publications

(9 citation statements)

References 29 publications

(51 reference statements)

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“…52 Compared with most other studies that are using concentrations ranging from 50 ng/ml to 100 ng/ml, the TNFα and IFNγ concentrations in our study were rather low since we wanted to limit profound epithelial damage in this condition due to cell viability decreases. 29,53 When using double concentrations [50 ng/ml] of the cytokines, the gene expression alterations showed similar trends with higher relative changes, but also more extreme TEER decreases [Supplementary Figures 1 and 2]. Because the epithelial cells were derived from non-inflamed areas in the UC patients, we did not expect to see high baseline inflammatory marker expression levels.…”

Section: Discussionmentioning

confidence: 94%

“…Primary intestinal epithelial cultures were treated with a physiological concentration of 8 mM sodium butyrate [Sigma-Aldrich, St Louis, MO, USA] dissolved in 200 µl 50% HM medium for 48 h. To further evaluate its effect in the presence of inflammatory stimuli, this condition was repeated in combination with 25 ng/ml recombinant human TNFα [Invivogen, Toulouse, France] and 25 ng/ml IFNγ [Invitrogen] in 600 µl 50% HM medium. The concentrations of the inflammatory stimuli were based on literature 29–34 and a pilot study in our laboratory with 50 ng/ml of the components [Supplementary Figures 1 and 2, available as Supplementary data at ECCO-JCC online]. Cells grown in 50% HM were used as negative control condition.…”

Section: Methodsmentioning

confidence: 99%

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

Vancamelbeke

Laeremans

Vanhove

et al. 2019

Journal of Crohn's and Colitis

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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.

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Section: Discussionmentioning

confidence: 94%

Section: Methodsmentioning

confidence: 99%

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

Vancamelbeke

Laeremans

Vanhove

et al. 2019

Journal of Crohn's and Colitis

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“…The finding that butyrate gene counts changes between t0 and t12 weeks was not fully paralleled by butyrate stool output may be due to various reasons, including differential gene expression, incomplete coverage of butyrate production genes, differential butyrate uptake in responders and non-responders (Boesmans et al, 2015), or trivial technical effects, all of which should be taken into account for future studies.…”

Section: Discussionmentioning

confidence: 99%

Microbial shifts and signatures of long-term remission in ulcerative colitis after faecal microbiota transplantation

et al. 2017

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Faecal microbiota transplantation (FMT) may contribute towards disease remission in ulcerative colitis (UC), but it is unknown which factors determine long-term effect of treatment. Here, we aimed to identify bacterial signatures associated with sustained remission. To this end, samples from healthy donors and UC patients-grouped into responders and non-responders at a primary end point (week 12) and further stratified by sustained clinical remission and relapse assessed at ⩾1-year follow-up were analysed, comparing the efficacy of FMT from either a healthy donor or autologous faeces. Microbiota composition was determined with a 16S rRNA gene-based phylogenetic microarray on faecal and mucosal samples, and functional profiles were predicted using PICRUSt with quantitative PCR verification of the butyrate production capacity; short-chain fatty acids were measured in faecal samples. At baseline, UC patients showed reduced amounts of bacterial groups from the Clostridium cluster XIVa, and significantly higher levels of Bacteroidetes as compared with donors. These differences were reduced after FMT mostly in responders. Sustained remission was associated with known butyrate producers and overall increased butyrate production capacity, while relapse was associated with Proteobacteria and Bacteroidetes. Ruminococcus gnavus was found at high levels in donors of failed FMT. A microbial ecosystem rich in Bacteroidetes and Proteobacteria and low in Clostridium clusters IV and XIVa observed in UC patients after FMT was predictive of poor sustained response, unless modified with a donor microbiota rich in specific members from the Clostridium clusters IV and XIVa. Additionally, sustained response was associated with restoration of the butyrate production capacity.

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“…Previous work in colorectal cancer cell lines utilized radiolabelled butyrate and measured its conversion to 14 CO 2 after a given incubation or exposure time. [Thibault et al, ; Boesmans et al, ]. Both tumor necrosis factor alpha (TNF‐α) and interferon gamma (IFN‐γ) were demonstrated to suppress butyrate oxidation.…”

Section: Discussionmentioning

confidence: 99%

Characterization of the Pro‐Inflammatory Cytokine IL‐1β on Butyrate Oxidation in Colorectal Cancer Cells

Johnstone

Bennett

Standifer

et al. 2017

J of Cellular Biochemistry

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Cancer, in part, is driven, by alterations in cellular metabolism that promote cell survival and cell proliferation. Identifying factors that influence this shift in cellular metabolism in cancer cells is important. Interleukin-1β (IL-1β) is a pro-inflammatory cytokine that has been reported to be elevated in colorectal cancer patients. While much is known toward the effect of dietary nutrients on regulating inflammation and the inflammatory response, which includes cytokines such as IL-1β, far less is understood how cytokines impact nutrient fate to alter cancer cell metabolism. Butyrate, a nutrient derived from the fermentation of dietary fiber in the colon, is the preferential exogenous energetic substrate used by non-cancerous colonocytes, but is used less efficiently by colorectal cancer cells. To test whether IL-1β alters colonocyte energy metabolism, we measured butyrate oxidation in HCT116 colorectal cancer cells with and without IL-1β. We hypothesize that IL-1β will push cancerous colonocytes away from the utilization and oxidation of butyrate. In this study, we demonstrate that pretreatment of colorectal cancer cells with IL-1β diminished butyrate oxidation and NADH levels. This effect was blocked with the interleukin receptor antagonist A (IL-1RA). Moreover, IL-1β suppressed basal mitochondrial respiration and lowered the mitochondrial spare capacity. By using inhibitors to block downstream targets of the interleukin-1 receptor pathway, we show that p38 is required for the IL-1β-mediated decrease in butyrate oxidation. These data provide insight into the metabolic effects induced by IL-1β in colorectal cancer, and identify relevant targets that may be exploited to block the effects of this cytokine. J. Cell. Biochem. 118: 1614-1621, 2017. © 2016 Wiley Periodicals, Inc.

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Inflammation‐Induced Downregulation of Butyrate Uptake and Oxidation Is Not Caused by a Reduced Gene Expression

Cited by 11 publications

References 29 publications

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

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

Microbial shifts and signatures of long-term remission in ulcerative colitis after faecal microbiota transplantation

Characterization of the Pro‐Inflammatory Cytokine IL‐1β on Butyrate Oxidation in Colorectal Cancer Cells

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