Contextualizing Whole-Body Metabolic Modeling in Microbial Co-Metabolism Networks Modeling with or without Host: A Scoping Review Protocol

Introduction: Whole-body metabolic modeling (WBMM) integrates genome-scale metabolic reconstructions of a host and its microbiome to simulate their metabolic interactions and examine the impact of microbial metabolites on host physiology. Key methods include constraint-based approaches (stoichiometric), Flux Balance Analysis (FBA), Dynamic FBA, kinetic modeling, and hybrid techniques, all of which address the complex dynamics of co-metabolism between microbiome and/or their host. The goal is to effectively manage the complexity of co-metabolism networks by comparing various strategies and emphasizing full integration of the host and microbiome. Methods: This scoping review will explore and compile information on relevant studies from Medline/PubMed, Embase, and Web of Science databases, published between January 2007 and Jun 2025. Relevant documents will be retrieved using the keywords 'microbial community metabolic model' and 'metabolomics.' The review question will be applied to include qualifying studies. This scoping review will adhere to the PRISMA-ScR guidelines. As 'Inclusion Criteria', we will include studies on the interaction between≥2 microbiomes without host and host-microbiome metabolic interactions, without any restriction on the type of microbiome or host (e.g., metabolic exchange between human/animal tissues and gut microbial communities). We will define various developed computational approaches for WBMM and microbiome metabolic modeling, such as constraint-based methods like flux balance analysis (FBA), and dynamic FBA for time-course simulations, along with kinetic. The primary outcome will be the modeling of metabolic interactions and co-metabolism networks (i.e., the reconstruction or analysis of microbiome co-metabolism and/or integrated host–microbiome metabolic networks), network topology metrics, flux distributions, and validation against experimental data. 'Study Selection' will applied through all articles obtained through a systematic search of electronic databases, during two study screening phases, including 'title and abstract screening', and full-text screening based on inclusion criteria. Studies that do not satisfy the inclusion criteria will be excluded. The full text of potentially relevant papers will be downloaded and thoroughly examined to verify their eligibility for inclusion in the scoping review. Reviewers will select each study; discrepancies will be resolved by consensus or third‐party adjudication. The process of these screening and selection phases will be illustrated in the PRISMA chart. As 'Data Extraction', a pre-designed standardized form will capture required data from the included studies on microbiome community and/or host interaction, prediction approach, metabolic Model, and primary prediction model study designs. The extraction sheet was previously evaluated by the principal investigator (PI). Study characteristics will be retrieved, for example, title, first author, publication year, country, host species, sample size, and study design. Computational approach will be summarized and compared with modeling framework and algorithms (such as FBA, dynamic FBA, kinetic), software/toolbox used; Simulation and analysis tools; Model fitting and validation; External validation; Code and Data provided; supervised ML/DL. Microbiome data will be focused, including sequencing platform, taxonomic resolution, and genome‐scale models. Integration strategy may be coupling host and microbial GEMs, compartmentalization, and transport reactions. Outcomes will be network topology metrics, flux distributions, and validation against experimental data. No restriction for languages and geographical characteristics, and the author's affiliation, Other potential data extraction form contents will include data source, predicted microbiome community-related outcome; Overfitting properly; Appropriate data source; Data integration (Gene, Transcript, Protein, metabolite); Data on validation will also be collected. Discussion: This scoping review protocol aims to summarize, map, and synthesize the current develiped computational modeling evidence on computational MM focused on metabolic interactions within the microbiome community with or without host and co-metabolism network modeling, while identifying existing research gaps to inform the design of future high-quality studies. It ultimately strives for comprehensive whole-body metabolic modeling.