@article{3815b2c0ac764ad4b050b002997893b8,
title = "Integrated In Vitro and In Silico Modeling Delineates the Molecular Effects of a Synbiotic Regimen on Colorectal-Cancer-Derived Cells",
abstract = "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 use of specific diets that promote the growth of beneficial microorganisms together with such microorganisms may help treat such diseases as colorectal cancer. Greenhalgh et al. show that one such synbiotic regimen induces downregulation of pro-carcinogenic and drug resistance genes as well as metabolic changes that affect the growth of cancer cells.",
keywords = "colorectal cancer, gut microbiome, gut-on-a-chip, modeling, nutritional therapy, prebiotic, probiotic, symbiotic",
author = "Kacy Greenhalgh and Javier Ramiro-Garcia and Almut Heinken and Pit Ullmann and Tamara Bintener and Pacheco, {Maria Pires} and Joanna Baginska and Pranjul Shah and Audrey Frachet and Rashi Halder and Fritz, {Jo{\"e}lle V.} and Thomas Sauter and Ines Thiele and Serge Haan and Elisabeth Letellier and Paul Wilmes",
note = "Funding Information: The authors would like to thank Dr. Christian J{\"a}ger 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. Conceptualization, K.G. E.L. S.H. and P.W.; Methodology, K.G. E.L. S.H. and P.W.; Formal Analysis, K.G. J.R.G. and A.H.; Investigation, K.G. J.B. A.F. J.V.F. P.S. and P.U.; Writing – Original Draft, P.W. and K.G.; Writing – Review & Editing, J.R.G. A.H. M.P.P. T.B. P.U. J.B. A.F. R.H. J.V.F. E.L. T.S. I.T. and S.H.; Funding Acquisition, K.G. E.L. J.F. T.B. S.H. I.T. T.S. and P.W.; Supervision E.L. J.V.F. J.B. T.S, S.H. I.T. and P.W. The authors P.W. and K.G. have a corresponding patent application (EP18206858), which is currently pending. Funding Information: The authors would like to thank Dr. Christian J?ger 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. Conceptualization, K.G. E.L. S.H. and P.W.; Methodology, K.G. E.L. S.H. and P.W.; Formal Analysis, K.G. J.R.G. and A.H.; Investigation, K.G. J.B. A.F. J.V.F. P.S. and P.U.; Writing ? Original Draft, P.W. and K.G.; Writing ? Review & Editing, J.R.G. A.H. M.P.P. T.B. P.U. J.B. A.F. R.H. J.V.F. E.L. T.S. I.T. and S.H.; Funding Acquisition, K.G. E.L. J.F. T.B. S.H. I.T. T.S. and P.W.; Supervision E.L. J.V.F. J.B. T.S, S.H. I.T. and P.W. The authors P.W. and K.G. have a corresponding patent application (EP18206858), which is currently pending. Funding Information: The authors would like to thank Dr. Christian J{\"a}ger 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{\textquoteright}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. Publisher Copyright: {\textcopyright} 2019 The Author(s)",
year = "2019",
month = apr,
day = "30",
doi = "10.1016/j.celrep.2019.04.001",
language = "English",
volume = "27",
pages = "1621--1632.e9",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "5",
}