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See detailIntegrated In Vitro and In Silico Modeling Delineates the Molecular Effects of a Synbiotic Regimen on Colorectal-Cancer-Derived Cells
Greenhalgh, Kacy UL; Ramiro Garcia, Javier UL; Heinken et al

in Cell Reports (2019), 27

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 ... [more ▼]

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 combina- torial 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 prebi- otic or probiotic treatments, the synbiotic regimen caused downregulation of genes involved in procarci- nogenic 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 ca- pacity. Our integrated approach demonstrates the potential of modeling for rationally formulating synbi- otics-based treatments in the future. [less ▲]

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See detailA study of the molecular mechanisms underlying the response of human colorectal adenomacarcinoma enterocytes to prebiotics and probiotics
Greenhalgh, Kacy UL

Doctoral thesis (2018)

The human gastrointestinal tract (GIT) microbiome plays essential roles in maintaining human health. A variety of diseases including colorectal cancer (CRC) are associated with microbial dysbiosis ... [more ▼]

The human gastrointestinal tract (GIT) microbiome plays essential roles in maintaining human health. A variety of diseases including colorectal cancer (CRC) are associated with microbial dysbiosis. Administration of microbial isolates associated with health benefits (e.g. prebiotics) together with specific dietary components (e.g., probiotics) may find application as supportive therapeutic options in the treatment and management of CRC. Although microbiome-modulating therapeutics hold great promise, such approaches are presently not formally integrated into treatment plans. To obtain better understanding of combined pre- and probiotic regimens in relation to CRC, the present study was dedicated to investigate the effects of selected prebiotics on the proliferation of CRC primary cells and conventional CRC-cell lines, the effects of prebiotics on the growth and metabolism of selected probiotic strains, and the combinatorial/synbiotic effects of selected pre- and probiotics on CRC proliferation. In addition, this work established the in vitro gut-on-a chip HuMiX model with a simulated high-fibre medium for co-culturing human and microbial cells in HuMiX. Furthermore, the anti-carcinogenic combinatorial effects of dietary fiber (e.g., prebiotics), and GIT bacteria (e.g., probiotics) were evaluated using human GIT transcriptomes and metabolomes in HuMiX. An integrated in vitro and in silico modeling approach was finally established to decipher the complex cross-talk between gut bacteria, dietary components and human host cells. My results demonstrate that in stark contrast to the individual pre- or probiotic treatments, the synbiotic regimen of the probiotic Lactobacillus rhamnosus GG and dietary fiber results in the down-regulation of genes involved in pro-carcinogenic pathways and drug resistance (e.g., ABC transporters) and reduced levels of the oncometabolite lactate. Distinct ratios of organic and short-chain fatty acids are produced during the simulated regimens. Treatment of primary CRC-derived cells with a molecular cocktail reflecting the synbiotic regimen attenuated self-renewal capacity. The developped integrated in vitro and in silico modelling approach provides mechanistic insights into the interplay between pre- and probiotics and elucidation of the microbiota-host relationship. In summary, my dissertation work illustrates the potential of HuMiX to be used for nutritional studies and more precisely for studying the underlying mechanisms of the effects that dietary components (e.g., dietary fiber) and probiotics have on CRC-derived cells. Thereby, this dissertation work highlights the potential for formulating efficacious dietary supplements including synbiotics in the context of therapeutic regimens for microbiome-linked diseases in the future. [less ▲]

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See detailEngineering Solutions for Representative Models of the Gastrointestinal Human-Microbe Interface
Mac Giolla Eain, Marc UL; Baginska, Joanna UL; Greenhalgh, Kacy UL et al

in Engineering (2017)

Host-microbe interactions at the gastrointestinal interface have emerged as a key component in the governance of human health and disease. Advances in micro-physiological systems are providing researchers ... [more ▼]

Host-microbe interactions at the gastrointestinal interface have emerged as a key component in the governance of human health and disease. Advances in micro-physiological systems are providing researchers with unprecedented access and insights into this complex relationship. These systems combine the benefits of microengineering, microfluidics, and cell culture in a bid to recreate the environmental conditions prevalent in the human gut. Here we present the human-microbial cross talk (HuMiX) platform, one such system that leverages this multidisciplinary approach to provide a representative in vitro model of the human gastrointestinal interface. HuMiX presents a novel and robust means to study the molecular interactions at the host-microbe interface. We summarize our proof-of-concept results obtained using the platform and highlight its potential to greatly enhance our understanding of host-microbe interactions with a potential to greatly impact the pharmaceutical, food, nutrition, and healthcare industries in the future. A number of key questions and challenges facing these technologies are also discussed. [less ▲]

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See detailGeneration of genome-scale metabolic reconstructions for 773 members of the human gut microbiota
Magnusdottir, Stefania UL; Heinken, Almut Katrin UL; Kutt, Laura et al

in Nature Biotechnology (2016)

Genome-scale metabolic models derived from human gut metagenomic data can be used as a framework to elucidate how microbial communities modulate human metabolism and health. We present AGORA (assembly of ... [more ▼]

Genome-scale metabolic models derived from human gut metagenomic data can be used as a framework to elucidate how microbial communities modulate human metabolism and health. We present AGORA (assembly of gut organisms through reconstruction and analysis), a resource of genome-scale metabolic reconstructions semi-automatically generated for 773 human gut bacteria. Using this resource, we identified a defined growth medium for Bacteroides caccae ATCC 34185. We also showed that interactions among modeled species depend on both the metabolic potential of each species and the nutrients available. AGORA reconstructions can integrate either metagenomic or 16S rRNA sequencing data sets to infer the metabolic diversity of microbial communities. AGORA reconstructions could provide a starting point for the generation of high-quality, manually curated metabolic reconstructions. AGORA is fully compatible with Recon 2, a comprehensive metabolic reconstruction of human metabolism, which will facilitate studies of host–microbiome interactions. [less ▲]

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See detailThe human gut microbiome in health: establishment and resilience of microbiota over a lifetime
Greenhalgh, Kacy UL; Wilmes, Paul UL; Meyer, Kristen Michelle et al

in Environmental Microbiology (2016), 18(7), 21032116

With technological advances in culture-independent molecular methods, we are uncovering a new facet of our natural history by accounting for the vast diversity of microbial life which colonizes the human ... [more ▼]

With technological advances in culture-independent molecular methods, we are uncovering a new facet of our natural history by accounting for the vast diversity of microbial life which colonizes the human body. The human microbiome contributes functional genes and metabolites which affect human physiology and are, therefore, considered an important factor for maintaining health. Much has been described in the past decade based primarily on 16S rRNA gene amplicon sequencing regarding the diversity, structure, stability and dynamics of human microbiota in their various body habitats, most notably within the gastrointestinal tract (GIT). Relatively high levels of variation have been described across different stages of life and geographical locations for the GIT microbiome. These observations may prove helpful for the future contextualization of patterns in other body habitats especially in relation to identifying generalizable trends over human lifetime. Given the large degree of complexity and variability, a key challenge will be how to define baseline healthy microbiomes and how to identify features which reflect deviations therefrom in the future. In this context, metagenomics and functional omics will likely play a central role as they will allow resolution of microbiome-conferred functionalities associated with health. Such information will be vital for formulating therapeutic interventions aimed at managing microbiota-mediated health particularly in the GIT over the course of a human lifetime. [less ▲]

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See detailA microfluidics-based in vitro model of the gastrointestinal human-microbe interface.
Shah, Pranjul UL; Fritz, Joëlle UL; Glaab, Enrico UL et al

in Nature communications (2016), 7

Changes in the human gastrointestinal microbiome are associated with several diseases. To infer causality, experiments in representative models are essential, but widely used animal models exhibit ... [more ▼]

Changes in the human gastrointestinal microbiome are associated with several diseases. To infer causality, experiments in representative models are essential, but widely used animal models exhibit limitations. Here we present a modular, microfluidics-based model (HuMiX, human-microbial crosstalk), which allows co-culture of human and microbial cells under conditions representative of the gastrointestinal human-microbe interface. We demonstrate the ability of HuMiX to recapitulate in vivo transcriptional, metabolic and immunological responses in human intestinal epithelial cells following their co-culture with the commensal Lactobacillus rhamnosus GG (LGG) grown under anaerobic conditions. In addition, we show that the co-culture of human epithelial cells with the obligate anaerobe Bacteroides caccae and LGG results in a transcriptional response, which is distinct from that of a co-culture solely comprising LGG. HuMiX facilitates investigations of host-microbe molecular interactions and provides insights into a range of fundamental research questions linking the gastrointestinal microbiome to human health and disease. [less ▲]

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