Integrated in vitro and in silico modelling delineates the molecular effects of a synbiotic regimen on colorectal-cancer derived cells.

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 integrated the multi-omic results with in silico metabolic modelling. 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. Our integrated approach demonstrates the potential of modelling for rationally formulating synbiotics-based treatments in the future.

通过调控人体肠道微生物组，益生元（prebiotics）与益生菌（probiotics，二者的组合被称为合生元（synbiotics））可用于治疗结直肠癌（colorectal cancer, CRC）等疾病。当前受方法论局限，仍无法明确此类疗法的潜在协同作用机制。本研究对团队已有的HuMiX肠道芯片（HuMiX gut-on-a-chip）模型进行拓展，在模拟益生元干预的培养条件下，将结直肠癌来源的上皮细胞与模式益生菌进行共培养，并将多组学（multi-omic）检测结果与计算机模拟代谢建模（in silico metabolic modelling）进行整合分析。相较于单独使用益生元或益生菌的治疗方案，合生元干预方案可下调促致癌通路及耐药相关基因的表达，并降低癌代谢物（oncometabolite）乳酸的水平。本研究采用的整合分析方法证实，建模技术在未来合理设计基于合生元的治疗方案中具备可观的应用潜力。