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SHR Neuro Cancer Cardio Metab Microb Lipid

Modification of the intestinal microbiome to improve metabolism, gut barrier function and inflammation in neuroblastoma

Abstract: BACKGROUND: Malignant tumors may lead to a catabolic state with loss of muscle and adipose tissue. The full picture of catabolism is termed cachexia and is associated with significant morbidity and mortality of cancer patients. Although the full picture is rarely observed up to 50% of children with cancer suffer from significant malnourishment. Additionally to tumor-induced catabolism, side-effects of chemotherapy may be problematic for the patients. In this regard up to 60% of children suffer from gastrointestinal mucositis presenting with nausea, vomiting, diarrhea or constipation and abdominal pain. In the worst case, mucositis may lead to bacterial translocation with life-threatening inflammatory response. Clinically this may require a reduction of the dosage or the number of chemotherapy cycles resulting in reduced effectivity. Up to now the therapy of mucositis is only symptomatic. Recent research of the applicant has shown a significant reduction of Lactobacilli in mice with neuroblastoma (a malignant childhood tumor). The dysbiosis was associated with catabolism, increased gut permeability and inflammation. Astonishingly, chemotherapy alone also lead to a significant reduction of Lactobacilli compared to sham mice, which may be linked to the development of mucositis clinically. Overall, the intestinal microbiome seems to play an essential role in the development of tumor-associated catabolism and chemotherapy-induced mucositis.
AIM: The aim of this project is to determine if manipulation of the intestinal microbiome with prebiotics, probiotics and bacteriocins (also referred to as lantibiotics) exerts beneficial effects on inflammation, gut permeability and metabolism in a murine model of neuroblastoma. Additionally, a human work package should determine if the changes in the intestinal microbiome observed in mice can also be seen in children with neuroblastoma.
METHODS: An established neuroblastoma model will be used to cause cachexia in mice. Additionally, a group of animals will receive chemotherapy. One work package will analyze the effect of Omni-Logic® Apfelpektin (a prebiotic containing pectin oligosaccharides) and Omni-Biotic® AAD (a probiotic) on these mice. The main focus will be on the intestinal microbiome, bacterial metabolism , gut permeability , mucositis , inflammation and metabolism. Additionally, data gained on microbial alterations by tumor and chemotherapy will be used to select specific bacteriocins and bacterial metabolites to influence the microbiome. These substances will be prepared for in vivo testing and applied to the same animal model. A basic science human work package will address the question if there are differences in the intestinal microbiome and the volatile organic compound profile between children with neuroblastoma and healthy controls. Furthermore, serial investigations in children with neuroblastoma will assess whether of not these patients show alterations of the intestinal microbiome under chemotherapy.
INNOVATIONS: In this project cutting edge technology will be used to gain information about the main research topics. Especially the examination of volatile organic compounds in relation to the other tests is novel in this research field and provides non-invasive information about bacterial metabolism and indirectly on the patients’ inflammatory system and metabolism. The pre- and probiotics tested in this project are available on the market. If they lead to a reduction of tumor- or chemotherapy-induced disturbances of inflammatory system, gut barrier or metabolism in this project they may be easily used as supportive measures in the anti-cancer therapy of the future. The use of bacteriocins has presently not been tested in this context. If these substances would prove effective then this project would be a first important milestone towards human application of bacteriocins.

Project Leader:: Castellani Christoph

Duration:: 01.09.2018-30.06.2022

Programme:: BRIDGE

Type of Research: basic research

Staff: Castellani, Christoph, Project Leader; Lammer, Thomas, Co-worker; Kuesz, Anna, Co-worker; Singer, Georg, Co-worker; Sperl, Daniela Ingrid, Co-worker; Klymiuk, Ingeborg, Co-worker; Obermüller, Beate, Co-worker; Brunnader, Lars, Co-worker; Mittl, Barbara, Co-worker; Kienesberger, Bernhard, Co-worker

MUG Research Units: Center for Medical Research (ZMF); Core Facility Molecular Biology; Department of Paediatric and Adolescent Surgery; Division of Paediatric Haematology-Oncology; Vice-Rector's Office for Teaching and Studies

Project partners: Medical University of Rostock, Germany
Contact person: Dr. Wolfram Miekisch, Inst. für Anästhesie und Intensivmedizin;; University of Natural Resources and Applied Life Sciences, Vienna, Austria
Contact person: Prof. Dr. Reingard Grabherr;

Funded by: Institut Allergosan pharmazeutische Produkte Forschungs- und Vertriebs GmbH, Gmeinstraße 13, 8055 Graz, Austria; Österreichische Forschungsförderungsgesellschaft mbH (FFG/mit peer review), Sensengasse 1, 1090 Wien, Austria

Project results published: > Insights into the Composition of a Co-Culture of 1... Nutrients. 2022; 14(6):; > Die Wirkung des Neuroblastoms auf die Darmwandbarr... https://webserver.mcn-nuernberg.de/chirurgie2019/timetable/abstract.php?id=369. 2019; -136. Kongress der deutschen Gesellschaft für Chirurgie ; MÄR 26-29, 2019; Munich, GERMANY.