Integrated In Vitro and In Silico Modeling Delineates the Molecular Effects of a Synbiotic Regimen on Colorectal-Cancer-Derived Cells
| Autor: | Joëlle V. Fritz, Almut Heinken, Joanna Baginska, Ines Thiele, Thomas Sauter, Kacy Greenhalgh, Maria Irene Pires Pacheco, Pit Ullmann, Pranjul Shah, Paul Wilmes, Elisabeth Letellier, Tamara Jean Rita Bintener, Rashi Halder, Serge Haan, Audrey Frachet, Javier Ramiro-Garcia |
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| Přispěvatelé: | Fonds National de la Recherche Luxembourg, Horizon 2020 |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Synbiotics Colorectal cancer In silico medicine.medical_treatment gut microbiome colorectal cancer Pharmacology Biology General Biochemistry Genetics and Molecular Biology law.invention 03 medical and health sciences Probiotic 0302 clinical medicine Downregulation and upregulation law medicine Humans Computer Simulation Microbiome Intestinal Mucosa lcsh:QH301-705.5 Cells Cultured 2. Zero hunger Lacticaseibacillus rhamnosus Prebiotic Probiotics modeling medicine.disease 3. Good health Gastrointestinal Microbiome Regimen 030104 developmental biology Prebiotics lcsh:Biology (General) gut-on-a-chip Host-Pathogen Interactions prebiotic symbiotic Caco-2 Cells Colorectal Neoplasms nutritional therapy 030217 neurology & neurosurgery probiotic |
| Zdroj: | Cell Reports Cell Reports, Vol 27, Iss 5, Pp 1621-1632.e9 (2019) |
| ISSN: | 2211-1247 |
| DOI: | 10.1016/j.celrep.2019.04.001 |
| Popis: | By modulating the human gut microbiome, prebiotics and probiotics (combinations of which are called synbiotics) may be used to treat diseases such as colorectal cancer (CRC). Methodological limitations have prevented determining the potential combinatorial mechanisms of action of such regimens. We expanded our HuMiX gut-on-a-chip model to co-culture CRC-derived epithelial cells with a model probiotic under a simulated prebiotic regimen, and we integrated the multi-omic results with in silico metabolic modeling. In contrast to individual prebiotic or probiotic treatments, the synbiotic regimen caused downregulation of genes involved in procarcinogenic pathways and drug resistance, and reduced levels of the oncometabolite lactate. Distinct ratios of organic and short-chain fatty acids were produced during the simulated regimens. Treatment of primary CRC-derived cells with a molecular cocktail reflecting the synbiotic regimen attenuated self-renewal capacity. Our integrated approach demonstrates the potential of modeling for rationally formulating synbiotics-based treatments in the future. The authors would like to thank Dr. Christian Jäger at the LCSB Metabolomics Platform for helpful discussions and metabolite quantification, and Martine Schmitz for RT-PCR validation analysis. We thank the contributing surgeons from the Centre Hospitalier Emile Mayrisch in Esch-sur-Alzette and the nurses of the Clinical and Epidemiological Investigation Center of the Luxembourg Institute of Health for collecting samples for research purposes. The authors wish to thank Frutarom for providing the SoyLife prebiotic. K.G. was supported by an AFR PhD fellowship from the Luxembourg National Research Fund (FNR; AFR/PHD/9964547 ). This work was supported by a Luxembourg Personalised Medicine Consortium pump-prime grant (PerPreProBioCRC) and a proof-of-concept grant ( PoC/15/11014639 ) from the FNR , awarded to P.W. The project was also supported through an internal research project grant (IRP; MiDiCa) from the University of Luxembourg to S.H. and P.W., and two CORE Junior grants ( C14/BM/8066232 and C16/BM/11282028 ) awarded to J.F. and E.L., respectively. This work was further supported by an ATTRACT Programme grant ( FNR/A12/01 ) awarded to I.T., a European Research Council (ERC) grant under the European Union’s Horizon 2020 research and innovation programme (grant agreement No. 757922 ) awarded to I.T., and an FNR grant ( PRIDE15/10675146/CANBIO ) to T.B. peer-reviewed |
| Databáze: | OpenAIRE |
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