Background/Objectives: Stress is increasingly recognized as an important modulator of gut microbiome composition and function through the bidirectional microbiota-gut-brain axis. Dietary, psychobiotic, and other lifestyle-oriented interventions have therefore attracted growing interest as potential strategies for simultaneously influencing stress-related outcomes and the gut microbiome. This systematic review aimed to evaluate randomized controlled trials (RCTs) investigating the effects of lifestyle-oriented and psychobiotic interventions on both stress-related outcomes and the gut microbiome in adults. Methods: A systematic literature search was conducted in PubMed, Scopus, and Cochrane CENTRAL for English-language RCTs published between 2016 and April 2026, in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines. Eligible studies included adults (≥18 years), evaluated lifestyle-oriented or psychobiotic interventions, and reported both gut microbiome-related and stress-related psychological or biological outcomes. Risk of bias was assessed using the Cochrane Risk of Bias 2 (RoB 2) tool. Owing to substantial methodological and clinical heterogeneity, findings were synthesized narratively. Results: Twenty-nine RCTs met the eligibility criteria. Interventions included psychobiotic supplementation, dietary interventions and functional foods, and other lifestyle-oriented approaches. Across intervention categories, microbiome responses were heterogeneous, and no single taxonomic or diversity signature consistently characterized trials reporting favorable stress-related outcomes. Nevertheless, recurrent changes involving Bifidobacterium/Bifidobacteriaceae, Lactobacillus/Lactobacillaceae, Faecalibacterium, Roseburia, and members of the Lachnospiraceae/Ruminococcaceae families were identified across several interventions, together with changes in SCFA-related microbial features. Changes in global microbial diversity were inconsistent, and psychological and microbiome responses did not invariably occur in parallel. Overall, the randomized evidence indicates recurrent taxonomic and functional signals rather than a uniform microbiome response across stress-targeting interventions. Substantial heterogeneity in populations, intervention characteristics, study duration, outcome measures, and microbiome assessment methods limited direct comparisons across trials. Conclusions: Current randomized evidence does not identify a uniform microbiome signature associated with successful stress-targeting interventions but suggests partial convergence involving selected bacterial taxa and functional microbial features. The lack of consistent parallel changes in psychological and microbiome outcomes precludes conclusions regarding whether microbiome alterations mediate improvements in stress-related outcomes. Larger, longer-term RCTs incorporating standardized microbiome methodologies and functional microbial analyses are needed to determine the reproducibility and mechanistic relevance of these signals.
