Faculty
Medical Sciences
Supervisor Name
Dr. Michael Silverman
Keywords
microbiome, FMT, trimethylamine, atherosclerosis
Description
Faecal microbiota transplantation (FMT) involves the administration of donor faecal matter to a diseased recipient with the goal of remodeling the host microbiome to provide health benefits. In recent years, FMT has emerged as a potential therapy for a variety of microbiome-associated diseases such as atherosclerosis. Trimethylamine (TMA) is an atherosclerosis-linked metabolite generated by the gut microbiota from dietary precursors which is then oxidized to trimethylamine N-oxide (TMAO) by the liver, contributing to increased gut permeability. It has been shown that FMT may alter or restore the gut microbiome of recipients to reduce plasma TMAO levels. Despite its potential, the FMT donor screening procedure for potentially transmissible conditions is a lengthy, costly, and often unsuccessful process. Current studies suggest that a successful FMT may rely on the selection of a donor microbiome capable of restoring the specific components lacking in the diseased state. However, appropriate in vitro donor models are limited and the components of the donor microbiome critical to FMT success remain unknown. To identify the response of donor gut microbiome samples to a given treatment, the group previously modified an in vitro model (MiPro) to simultaneously evaluate the responses of numerous individual samples. To test this in vitro model, a sample population of atherosclerosis patients with high plasma TMAO receiving FMT intervention (n=2) and FMT donors (n=4) was utilized to characterize the effects of microbiome samples on barrier integrity and potentially identify desirable donor characteristics. Quantitative polymerase chain reaction (qPCR) was used to monitor changes in TMA-production gene abundance as a marker of atherosclerosis disease severity in FMT recipients. Using a cell co-culture model of the human intestinal barrier, the effect of the donor microbiome on intestinal permeability measured by transepithelial electrical resistance (TEER) and confocal imaging of tight junctions was then assessed. Differences in co-culture barrier integrity were observed following treatment with filtered donor MiPro effluent. These findings suggest that the novel in vitro model has the potential to predict donor microbiota resilience and identify desirable donor characteristics in future iterations. This could allow for the optimization of future FMT therapies for atherosclerosis and other microbiome-associated diseases.
Acknowledgements
This USRI project would not have been possible without the guidance and support of Dr. Michael Silverman and Dr. Jeremy Burton, the entire Burton lab, the USRI program, and the Schulich School of Medicine and Dentistry.
Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-Share Alike 4.0 License.
Document Type
Poster
Functional Characterization of a High-Throughput In Vitro Model to Predict Faecal Microbiota Transplantation (FMT) Donor Success
Faecal microbiota transplantation (FMT) involves the administration of donor faecal matter to a diseased recipient with the goal of remodeling the host microbiome to provide health benefits. In recent years, FMT has emerged as a potential therapy for a variety of microbiome-associated diseases such as atherosclerosis. Trimethylamine (TMA) is an atherosclerosis-linked metabolite generated by the gut microbiota from dietary precursors which is then oxidized to trimethylamine N-oxide (TMAO) by the liver, contributing to increased gut permeability. It has been shown that FMT may alter or restore the gut microbiome of recipients to reduce plasma TMAO levels. Despite its potential, the FMT donor screening procedure for potentially transmissible conditions is a lengthy, costly, and often unsuccessful process. Current studies suggest that a successful FMT may rely on the selection of a donor microbiome capable of restoring the specific components lacking in the diseased state. However, appropriate in vitro donor models are limited and the components of the donor microbiome critical to FMT success remain unknown. To identify the response of donor gut microbiome samples to a given treatment, the group previously modified an in vitro model (MiPro) to simultaneously evaluate the responses of numerous individual samples. To test this in vitro model, a sample population of atherosclerosis patients with high plasma TMAO receiving FMT intervention (n=2) and FMT donors (n=4) was utilized to characterize the effects of microbiome samples on barrier integrity and potentially identify desirable donor characteristics. Quantitative polymerase chain reaction (qPCR) was used to monitor changes in TMA-production gene abundance as a marker of atherosclerosis disease severity in FMT recipients. Using a cell co-culture model of the human intestinal barrier, the effect of the donor microbiome on intestinal permeability measured by transepithelial electrical resistance (TEER) and confocal imaging of tight junctions was then assessed. Differences in co-culture barrier integrity were observed following treatment with filtered donor MiPro effluent. These findings suggest that the novel in vitro model has the potential to predict donor microbiota resilience and identify desirable donor characteristics in future iterations. This could allow for the optimization of future FMT therapies for atherosclerosis and other microbiome-associated diseases.