Mixed-Bag and Compartmentalized Human Gut Microbiome Models Comparison 

Project Topic 

Comparing the metabolism of reconstructed human gut microbiota in mixed-bag and compartmentalized models. Identify the pros and cons of using each model in the simulation of metabolism. The successful evaluation of each model shall deepen the understanding of the metabolic modeling concept introduced in Module 5 Mixed-Bag and Compartmentalized Models in NCSU BIT 495 Metabolic Modeling. 

Learning Objectives 

● Understand the difference between a mixed-bag versus a compartmentalized model

● Evaluate how metabolism of dietary compounds is affected by each type of human gut microbiota model 

● Discuss additional application(s) for either type of model 

Background 

The microbes present in the human gut break down large dietary compounds such as fiber and convert them into energy precursing nutrients such as short-chain fatty acids for the host to use. For this reason, the human gut microbiome plays an essential role in human metabolism. Further research in the metabolic pathways involved will prove to be beneficial towards engineering effective processes for the mass production of vitamins and essential amino acids that the gut excretes [1]. Additionally, an imbalance (dysbiotic state) in the microbiome is shown to be associated with several metabolic diseases such as irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), ulcerative colitis (UC), and type 2 diabetes, etc [2]. The ability to break down the metabolic mechanisms and exchanges that occur between differing compositions in microbiome can aid in understanding how to develop drug therapies or even cures that specifically target the initiating mechanisms [1]. 

A case study with the premise of identifying the metabolic interaction between diet and the children’s microbiota was conducted by T. Blasco et al. (2021). Fecal matter from children exhibiting various clinical conditions was inoculated with fermented in vitro boiled lentils. It was discovered that there were a substantial amount of reactions involved in the metabolism of this dietary compound, as well as the production of a larger number of 87 metabolites produced based on diet. Metabolites produced based on clinical conditions constituted 49 out of the overall number of metabolites found, and 15 were based on both diet and clinical conditions making up an even smaller fraction of the total. Finally, degradation pathways of 179 phenolic compounds were also obtained. This was initially conducted using a mixed-bag model, but the study was repeated using a compartmentalized model where similar results were obtained for each sample with a computational duration 24-times as long [4]. 

Computational simulation through Constraint-Based Reconstruction and Analysis (COBRA) is the preferred method by many researchers to predict multi-species microbial behavior in Genome-scale Models (GEMs) of the human gut. While assuming a state-state mass balance, Flux Balance Analysis (FBA) reconstruction processes can occur either utilizing mixed-bag or compartmentalized GEMs. Mixed-bag, or “gene-soup,” modeling involves creating a “meta-GEM” that encompasses the entirety of a community’s metabolic circuitry. As a result, all biomass reactions are merged, each metabolic is copied once, and taxonomic differences cannot be made. However, this model is effective in determining the metabolic potential with a lower computational demand. Alternatively, the compartmentalized modeling is similar to the mixed-bag method as it also generates a single meta-GEM, with the exception that individually taxon-related genes, reactions, and metabolites are distinguished by pseudocompartments, and the sum of the overall biomass flux is optimized [3]. Although this modeling possesses distinguishing capabilities, this property comes at a greater computational expense [4]. 

Questions 

Which of the two modeling approaches are more popular for researching purposes?

Preference depends on the time a researcher is willing to set aside. Compartmentalized modeling is more popular for the taxon-distinguishing property [3]; however the computational time is quite extensive. 

How would the biomass flux of an overly thriving taxon affect the GEM of a community?

An overly thriving taxon makes dif erentiating the contributions between other taxons much more dif icult. In response to this issue, a “balanced growth” assumption may be made to converge between the fluxes and allow greater optimization of the overall growth in a community [3]. 

What is a potential application of either model in research towards reconstructing the human gut microbiome? 

The exact cause of UC was recently discovered to be due to the diminished microbiota diversity from missing gut microbes, specifically from the Ruminococcaceae family [5]. FBA-based compartmentalized modeling could be used to simulate growth of that specific microbe within a human gut microbiome GEM.

References 

[1] Magnúsdóttir, S., & Thiele, I. (2017, December 16). Modeling metabolism of the Human Gut Microbiome. Current Opinion in Biotechnology. Retrieved April 28, 2022, from https://www.sciencedirect.com/science/article/pii/S095816691730201X 

[2] Bull, M. J., & Plummer, N. T. (2014, December). Part 1: The human gut microbiome in health and disease. Integrative medicine (Encinitas, Calif.). Retrieved April 28, 2022, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4566439/ 

[3] Colarusso, A. V., Goodchild-Michelman, I., Rayle, M., & Zomorrodi, A. R. (2021, April 20). Computational modeling of metabolism in microbial communities on a genome-scale. Current Opinion in Systems Biology. Retrieved April 28, 2022, from  https://www.sciencedirect.com/science/article/pii/S2452310021000123 

[4] Blasco, T., Pérez-Burillo, S., Balzerani, F., Hinojosa-Nogueira, D., Lerma-Aguilera, A., Pastoriza, S., Cendoya, X., Rubio, Á., Gosalbes, M. J., Jiménez-Hernández, N., Pilar Francino, M., Apaolaza, I., Rufián-Henares, J. Á., & Planes, F. J. (2021, August 5). An extended reconstruction of human gut microbiota metabolism of dietary compounds. Nature News. Retrieved April 28, 2022, from https://www.nature.com/articles/s41467-021-25056-x 

[5] News Center. (2020, February 25). Stanford scientists link ulcerative colitis to missing gut microbes. News Center. Retrieved April 28, 2022, from https://med.stanford.edu/news/all-news/2020/02/stanford-scientists-link-ulcerative-colitis-to-miss ing-gut-micro.html