Modulation of the Gut Microbiota by Prebiotics, Probiotics, and Psychobiotics and Its Impact on the Gut Microbiota–Brain Axis: A Systematic Review

Background: The gut microbiota–brain axis is a highly integrated bidirectional communication network operating through neural, neuroendocrine, immune, and metabolic pathways that maintain central nervous system homeostasis and has emerged as a promising complementary therapeutic target for neurological and neuropsychiatric disorders. Objective: The objective of this study is to systematically evaluate the effects of prebiotics, probiotics, and psychobiotics on gut–brain communication and neurological and behavioral outcomes, including neuroinflammatory markers, HPA-axis parameters, and microbial metabolites. Methods: A systematic review was conducted in accordance with the PRISMA 2020 guidelines. Literature searches of PubMed, Scopus, and Google Scholar from 2020 up to March 2026 identified 81 eligible studies (48 preclinical studies, 27 randomized controlled trials, and 6 quasi-experimental clinical studies) from 7358 records. Primary outcomes were systematically categorized into four domains: (1) cognitive performance and social/adaptive behavior; (2) neuroinflammatory markers (TNF-α, IL-6, IL-1β) and barrier integrity; (3) HPA-axis parameters (cortisol/corticosterone); and (4) neuroactive microbial metabolites (short-chain fatty acids and tryptophan derivatives). Methodological quality and risk of bias were assessed independently by two reviewers using the SYRCLE tool for preclinical studies and the Joanna Briggs Institute (JBI) tools for randomized and quasi-experimental clinical trials, with summary visualizations generated using the robvis web application (version 0.3.0). Results: Neurodegenerative diseases (n = 31; 38.3%) and mood disorders (n = 29; 35.8%) were the most frequently investigated conditions. Probiotics predominated (n = 61), followed by prebiotics (n = 12) and synbiotics (n = 8). Descriptively, 92% of included studies reported improvements in at least one evaluated outcome. However, this unweighted observation reflects effect direction rather than clinical magnitude, encompassing primary and secondary endpoints across highly heterogeneous sample sizes, study designs, and risk-of-bias profiles. Conclusions: Microbiota-targeted interventions show promise as complementary strategies for neurological disorders; however, substantial methodological heterogeneity, unstandardized dosing, and the absence of quantitative meta-analysis preclude definitive clinical recommendations. Successful translation will require harmonized protocols, strain-specific functional characterization, and precision microbiota-based trials.