Next-Generation Nutraceuticals Targeting the Gut–Brain Axis: Mechanisms and Clinical Evidence

Abstract

The gut–brain axis has emerged as a key regulator of neurological and mental health, yet nutraceutical research in this field remains dominated by probiotics, while a broader range of diet-derived bioactive compounds that modulate gut–brain communication without live microbes receives far less attention. This integrative review synthesizes mechanistic and clinical evidence on non-viable, metabolite-driven nutraceutical strategies, including postbiotics, microbially transformed phytochemicals, and dietary metabolites that interact with immune, neurological, and endocrine signaling. We describe how short-chain fatty acids, indole derivatives, phenolic metabolites, and bile acid-related compounds influence neurotransmitter synthesis, neuroinflammation, hypothalamic–pituitary–adrenal axis activity, and blood–brain barrier integrity, and we integrate findings from cellular, animal, and human studies to identify host receptors, signaling cascades, and context-dependent effects shaped by host physiology and microbiome composition. Interindividual variability, a major source of inconsistent intervention outcomes, receives particular attention. Rather than cataloguing compounds, we appraise the strength, limitations, and translational significance of the available evidence, identify methodological gaps in current intervention studies, and argue that reframing gut–brain nutraceuticals as modulators of microbe–host metabolic signaling, rather than microbial replacement therapy, provides a more precise and clinically actionable paradigm. We conclude by outlining research priorities, including biomarker-driven participant stratification, dose and duration optimization, and disease-specific outcome selection, to guide the rational development of next-generation nutraceutical therapies targeting the gut–brain axis.