The Effects of Prebiotic Supplementation with OMNi-LOGiC® FIBRE on Fecal Microbiome, Fecal Volatile Organic Compounds, and Gut Permeability in Murine Neuroblastoma-Induced Tumor-Associated Cachexia.

Beate Obermüller,Holger Till,Reingard Grabherr,Bernhard Kienesberger,Ingeborg Klymiuk,Daniela Sperl,Georg Singer,Angela Horvath,Vanessa Stadlbauer,Peter Gierschner,Hans-Jürgen Gruber,Christoph Castellani,Maria D Semeraro,Wolfram Miekisch

doi:10.3390/nu12072029

Abstract

Malignant diseases can cause tumor-associated cachexia (TAC). Supplementation with prebiotic non-digestible carbohydrates exerts positive metabolic effects in experimental oncologic diseases. The aim of this project was to assess the effect of prebiotic supplementation with OMNi-LOGiC® FIBRE on intestinal microbiome, bacterial metabolism, gut permeability, and inflammation in a murine model of neuroblastoma (NB)-associated TAC. For this study, 2,000,000 NB cells (MHH-NB11) were implanted into athymic mice followed by daily supplementation with water or 200 mg prebiotic oligosaccharide (POS) OMNi-LOGiC® FIBRE (NB-Aqua, n = 12; NB-POS, n = 12). Three animals of each tumor group did not develop NB. The median time of tumor growth (first visibility to euthanasia) was 37 days (IQR 12.5 days) in the NB-Aqua group and 37 days (IQR 36.5 days) in the NB-POS group (p = 0.791). At euthanasia, fecal microbiome and volatile organic compounds (VOCs), gut permeability (fluorescein isothiocyanate-dextran (FITC-dextran), and gut barrier markers were measured. Values were compared to sham animals following injection of culture medium and gavage of either water or OMNi-LOGiC® FIBRE (SH-Aqua, n = 10; SH-POS, n = 10). Alpha diversity did not differ significantly between the groups. Principal coordinate analysis (PCoA) revealed clustering differences between Aqua and POS animals. Both NB and POS supplementation led to taxonomic alterations of the fecal microbiome. Of 49 VOCs, 22 showed significant differences between the groups. NB animals had significantly higher gut permeability than Aqua animals; POS did not ameliorate these changes. The pore and leak pathways of tight junctions did not differ between groups. In conclusion, our results suggest that NB-induced TAC causes increased gut permeability coupled with compositional changes in the fecal microbiome and VOC profile. Prebiotic supplementation with OMNi-LOGiC® FIBRE seemed to induce modifications of the fecal microbiome and VOC profile but did not improve gut permeability.

Highlights

The metabolic competition for nutrients between host and tumor has increasingly moved into the focus of science in the past years
We demonstrated in a murine neuroblastoma model that prebiotic supplementation with significant differences of the expression of pro-apoptotic Bax and Bcl2 (Figure 6e,f)
OMNi-LOGiC® FIBRE was associated with compositional changes in the fecal microbiome

Summary

Introduction

The metabolic competition for nutrients between host and tumor has increasingly moved into the focus of science in the past years. Depending on the underlying type of cancer, TAC affects up to three-quarters of oncologic patients [2]. The causes of TAC are complex and the underlying molecular mechanisms have still not been elucidated in detail [3]. An interaction between host and tumor involving the secretion of pro-inflammatory cytokines from both cancer cells and the host immune system has been shown to be involved. These soluble mediators include tumor necrosis factor alpha (TNF-α), interferon gamma (INF-γ), and a variety of interleukins (IL-6, IL-8, IL-1β, and others) [4,5,6]. The tumor itself may release catabolic substances such as proteolysis-inducing factor, anemia-inducing substance, activin, or myostatin, thereby further fueling the progression of TAC [4,7]

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