Background The overall goal of this project is to advance understanding of the existing science to provide the basis for dietary modulation of the gut microbiome for potential health benefit and avoidance of harm. Identifying microbially-derived metabolites that may serve as biomarkers for health is a necessary step to understanding the role of microbiome function for health. Ultimately, knowing what metabolites (including presence and quantity) matter for health can inform development of a nutritional strategy for health benefits and the prevention of adverse health effects, such as metabolic syndrome, type 2 diabetes, and cardiovascular disease. The specific questions to be addressed in this project are: 1. What diet-related and gut-derived metabolites have been linked to specific health outcomes or are markers of health outcomes? (Phase 1) 2. For the selected metabolites from Phase 1, what types of evidence are available for the relationship of those metabolites to specific health outcomes? (Phase 2) Based on the findings from Phase 1, we have identified the following metabolites (including their salt and acid forms) for the scoping review: 1. Deoxycholate (Deoxycholic Acid) 2. Putrescine 3. Lithocholate (Lithocholic Acid) 4. Tryptamine 5. d-Alanine 6. Urolithins 7. Glycodeoxycholate (Glycodeoxycholic Acid) 8. N-Acetylmannosamine 9. Phenylacetylglutamine 10. Glycolithocholate (Glycolithocholic Acid) Methods Identifying the Research Question What types of evidence are available on the relationship between oral intake of metabolites or the precursor of metabolites and health outcomes? Identifying Relevant Studies We will search the following databases for primary studies and systematic reviews: PubMed®, EmbaseTM , and Commonwealth of Agricultural Bureau. The search strategy will include: 1. Names and synonyms of the metabolites, including their salt and acid forms. 2. Limits to the English language. 3. Exclusion of reviews. Our search strategy is presented in Appendix A. We will hand search the reference lists of included articles. Study Selection Table 1 lists our inclusion and exclusion criteria. We will pilot test our eligibility criteria on the first 100 abstracts. We will review disagreement and modify the eligibility criteria as needed. Once the eligibility criteria have been finalized, two independent reviewers will screen each abstract. Both reviewers will need to agree that the article meets at least one of the exclusion criteria to be excluded. We will track and resolve differences between reviewers regarding abstract inclusion or exclusion through consensus adjudication. We will use PICO Portal to conduct and manage screening. Articles promoted based on the abstract screen will undergo another independent screen by two reviewers using the full-text article. We will track and resolve differences between reviewers regarding article inclusion or exclusion through consensus adjudication. Table 1. Inclusion and Exclusion Criteria PICOTS Inclusion criteria Exclusion criteria Population • Human studies • Any health conditions Intervention/Exposure • For interventional studies: Oral intake of metabolites or precursor of metabolites • For observational studies: Oral intake of metabolites or precursor of metabolites or Blood/Fetal/Urine concentration of metabolites Comparison • Any comparison Outcomes • Any health outcome Timing • No limits Study design • Randomized Clinical Trials • Non-Randomized Clinical Trials • Prospective/Retrospective Cohort Studies • Case-control Studies • Reviews • Editorials • Comments • Meeting Abstracts • Case Reports Language • English Charting the Data We will develop and pilot test a standardized charting table. For each study, we plan to tag or extract the following data: study design, study location, study population, sample size, intervention/exposure type (modified by diet/supplement, level, how ascertained), health outcome (ascertainment method), and the nature of results. Collating, Summarizing, and Reporting the Results We will organize the results by metabolite. We will create tables containing all information extracted from the eligible studies. We will create summary tables or matrices summarizing the study designs, study populations, study locations, sample sizes, and the health outcomes evaluated by metabolite. We will not be abstracting details on the results or performing risk of bias assessment.   Appendix A. Search Strategy PubMed #1 Name/Synonyms of Metabolites Deoxycholic Acid[tiab] OR Desoxycholic Acid[tiab] OR Deoxycholate[tiab] OR Kybella[tiab] OR Cholanoic Acid[tiab] OR Putrescine[tiab] OR 1,4-Diaminobutane[tiab] OR 1,4 Diaminobutane[tiab] OR Tetramethylenediamine[tiab] OR 1,4-Butanediamine[tiab] OR 1,4 Butanediamine[tiab] OR Lithocholic Acid[tiab] OR Lithocholate[tiab] OR Tryptamine[tiab] OR Tryptamines[tiab] OR D-Alanine[tiab] OR D Alanine[tiab] OR Urolithins[tiab] OR Urolithin[tiab] OR Glycodeoxycholate[tiab] OR Glycodeoxycholic Acid[tiab] OR Deoxycholylglycine[tiab] OR N-Acetylmannosamine[tiab] OR 2-acetamido-2-deoxy-D-mannose[tiab] OR N-acetyl-D-mannosamine[tiab] OR Phenylacetylglutamine[tiab] OR Glycolithocholic Acid[tiab] OR Glycolithocholate[tiab] OR lithocholylglycine[tiab] #2 Language Restriction English[la] #3 Publication Type Restriction Review[pt] #4 Study Subject Animals[mh] NOT humans[mh] #5 Final Strategy #1 AND #2 NOT #3 NOT #4 Initial search yielded 13,899 records on Aug 25, 2021. Embase #1 Name/Synonyms of Metabolites (‘Deoxycholic Acid’ OR ‘Desoxycholic Acid’ OR ‘Deoxycholate’ OR ‘Kybella’ OR ‘Cholanoic Acid’ OR Putrescine OR ‘1,4-Diaminobutane’ OR ‘1,4 Diaminobutane’ OR Tetramethylenediamine OR ‘1,4-Butanediamine’ OR ‘1,4 Butanediamine’ OR ‘Lithocholic Acid’ OR Lithocholate OR Tryptamine OR Tryptamines OR ‘D-Alanine’ OR ‘D Alanine’ OR Urolithins OR Urolithin OR Glycodeoxycholate OR ‘Glycodeoxycholic Acid’ OR Deoxycholylglycine OR ‘N-Acetylmannosamine’ OR ‘2-acetamido-2-deoxy-D-mannose’ OR ‘N-acetyl-D-mannosamine’ OR Phenylacetylglutamine OR ‘Glycolithocholic Acid’ OR Glycolithocholate OR lithocholylglycine):ti,ab #2 Language Restriction English:la #3 Publication Type Restriction Review/it #4 Study Subject [Animals]/lim NOT [Humans]/lim #5 Final Strategy #1 AND #2 NOT #3 NOT #4 Initial search yielded 15,977 records on Aug 25, 2021.