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

In ulcerative colitis (UC) the butyrate metabolism is impaired, leading to energy-deficiency in the colonic cells. The effect of inflammation on the butyrate metabolism was investigated. HT-29 cells were incubated with pro-inflammatory cytokines (TNF-α and/or IFN-γ) for 1 and 24 h. Cells were additionally stimulated with butyrate to investigate its anti-inflammatory potential. Butyrate uptake and oxidation were measured using (14)C-labeled butyrate. Gene expression of the butyrate metabolism enzymes, interleukin 8 (IL-8; inflammatory marker) and villin-1 (VIL-1; epithelial cell damage marker) was measured via quantitative RT-PCR. Significantly increased IL-8 expression and decreased VIL-1 expression after 24 h incubation with TNF-α and/or IFN-γ confirmed the presence of inflammation. These conditions induced a decrease of both butyrate uptake and oxidation, whereas the gene expression was not reduced. Simultaneous incubation with butyrate counteracted the reduced butyrate oxidation. In contrast, 1 h incubation with TNF-α induced a significant increased IL-8 expression and decreased butyrate uptake. Incubation with TNF-α and/or IFN-γ for 1 h did not induce cell damage nor influence butyrate oxidation. The inflammation-induced downregulation of the butyrate metabolism was not caused by a reduced gene expression, but appeared consequential to a decreased butyrate uptake. Increasing the luminal butyrate levels might have therapeutic potential in UC.

The financial impact of SBRT for oligometastatic disease: A population-level analysis in Belgium.

INTRODUCTION: There is a steady rise in Stereotactic Body RadioTherapy (SBRT) utilization in oligometastatic disease (OMD). This may generate important financial consequences for radiotherapy budgets. The National Institute for Health and Disability Insurance of Belgium (NIHDI) initiated a coverage with evidence development (CED) project for innovative radiotherapy, including SBRT, in 2011. A cost calculation and budget estimation for SBRT in the OMD setting was carried out. MATERIALS AND METHODS: Predictive growth scenarios for future uptake of SBRT for OMD in Belgium were developed using demographics and CED data. The provider cost of SBRT for OMD in Belgium was calculated using the Time-Driven Activity-Based Costing (TD-ABC) model developed by ESTRO-HERO, alimented with national data on resources, treatments and operational parameters, and compared to the new reimbursement. Combining these, the future financial impact of this novel treatment indication for healthcare providers and payers in Belgium was evaluated. RESULTS: The number of 428 OMDs treated with SBRT in Belgium in 2017 is expected to increase between 484 and 2073 courses annually by 2025. A provider cost of €4360 per SBRT was calculated (range: €3488-€5654), whereas the reimbursement covers between €4139 and €4654. Large variations in potential extra provider costs by 2025 ensue from the different scenarios, ranging between €1,765,993 and €9,038,754. Provider costs and reimbursement show good agreement. CONCLUSION: Although the financial impact of SBRT for OMD in Belgium is forecasted to remain acceptable, even in extreme scenarios, further clinical trials and real-life clinical and financial monitoring with prospective data gathering are necessary to refine the data.

Butyrate Producers as Potential Next-Generation Probiotics: Safety Assessment of the Administration of Butyricicoccus pullicaecorum to Healthy Volunteers.

Advances in gut microbiota research have triggered interest in developing colon butyrate producers as niche-specific next-generation probiotics, targeted at increasing colon butyrate production and countering disease-associated microbiota alterations. Crucial steps in the development of next-generation probiotics are the design of formulations with a reasonable shelf life as well as the safety demonstration of an intervention in healthy volunteers. One such potential next-generation butyrate-producing probiotic is Butyricicoccus pullicaecorum 25-3T, with demonstrated safety in in vitro as well as animal models. Here, we examined the strain's safety, tolerability, and impact on microbiota composition and metabolic activity in healthy volunteers in a randomized, double-blind, placebo-controlled crossover study in 30 healthy volunteers. The study design consisted of two 4-week intervention periods (108 CFU B. pullicaecorum [treatment] or maltodextrin [placebo] per day) with a 3-week washout in between. We assessed adverse events, blood parameters (primary endpoints), and fecal microbiota composition and metabolite profiles (secondary endpoints). The number of reported adverse events during the B. pullicaecorum treatment was similar to that of placebo intervention, as were observed changes in blood chemistry parameters, bowel habits, and fecal calprotectin concentrations. Administration of the strain did not induce any disruptive effect in microbiota composition or metabolic activity. In this first human intervention trial with a butyrate-producing Clostridium cluster IV isolate, we demonstrated B. pullicaecorum 25-3T administration to be both safe and well tolerated by healthy participants. This safety study paves the way for the further development of the strain as a next-generation probiotic. IMPORTANCE This study is the first to determine the safety and tolerance in humans of a butyrate-producing Clostridium cluster IV next-generation probiotic. Advances in gut microbiota research have triggered interest in developing colon butyrate producers as next-generation probiotics. Butyricicoccus pullicaecorum 25-3T is one such potential probiotic, with demonstrated safety in vitro as well as in animal models. Here, we produced an encapsulated B. pullicaecorum formulation that largely preserved its viability over an 8-month storage period at 4°C. Administration of this formulation to healthy volunteers allowed us to establish the intervention as safe and well tolerated. The probiotic intervention did not cause disruptive alterations in the composition or metabolic activity of health-associated microbiota. The results presented pave the way for the exploration of the impact of the strain on microbiota alterations in a clinical setting.

Modulating the microbiota in inflammatory bowel diseases: prebiotics, probiotics or faecal transplantation?

Crohn's disease (CD) and ulcerative colitis (UC) are the two major phenotypes of inflammatory bowel diseases (IBD) which constitute a spectrum of chronic, debilitating diseases characterised by a relapsing inflammation of the intestinal mucosal lining. Evidence from a variety of disciplines implicates the intestinal microbiota in the pathogenesis of idiopathic IBD and their complications, including pouchitis. Many studies have reported a dysbiosis in IBD, characterised by a decrease in diversity, a decreased abundance of some dominant commensal members (such as Clostridium IV and XIVa) and an increase in detrimental bacteria (such as sulphate reducing bacteria and Escherichia coli). Therapies such as prebiotics and probiotics aim to selectively manipulate the intestinal microbiota and have been evaluated as an attractive therapeutic option with few side effects. The multispecies product VSL#3 was found effective in preventing and maintaining remission in pouchitis, whereas both VSL#3 and E. coli Nissle were effective in maintaining remission in UC. A more drastic approach to restore the composition of the microbiota and correct the underlying imbalance is a faecal microbiota transplantation (FMT). FMT has been successfully applied to treat patients with even recalcitrant Clostridium difficile infection. Particularly in UC, the majority of studies suggest that FMT may be an effective treatment option although the evidence is still limited. It is anticipated that our increasing knowledge on the composition and function of the intestinal microbiota components will allow in the future for a better selection of highly performing bacteria with specific functions required for specific benefits.

Impaired islet function in commonly used transgenic mouse lines due to human growth hormone minigene expression.

The human growth hormone (hGH) minigene is frequently used in the derivation of transgenic mouse lines to enhance transgene expression. Although this minigene is present in the transgenes as a secondcistron, and thus not thought to be expressed, we found that three commonly used lines, Pdx1-Cre(Late), RIP-Cre, and MIP-GFP, each expressed significant amounts of hGH in pancreatic islets. Locally secreted hGH binds to prolactin receptors on ß cells, activates STAT5 signaling, and induces pregnancy-like changes in gene expression, thereby augmenting pancreatic ß cell mass and insulin content. In addition, islets of Pdx1-Cre(Late) mice have lower GLUT2 expression and reduced glucose-induced insulin release and are protected against the ß cell toxin streptozotocin. These findings may be important when interpreting results obtained when these and other hGH minigene-containing transgenic mice are used.