Beyond the brain: curcumin as a multi-target neuropharmacological modulator of the gut-brain axis in major depressive disorder and Parkinson's disease.

Abstract

Curcumin, the principal polyphenol of Curcuma longa, has been proposed as a multi-target neuropharmacological agent for neuropsychiatric and neurodegenerative disorders. We propose that major depressive disorder (MDD) and Parkinson's disease (PD) share a convergent gut-brain axis dysfunction, and that curcumin can serve as a pharmacological probe to test whether this convergent pathway is causally relevant. This narrative review evaluates that hypothesis. We conducted a structured literature search across PubMed, Scopus, Web of Science, Google Scholar, and CNKI using predefined search terms. This is a narrative review with a structured search strategy rather than a systematic review; no formal risk-of-bias assessment or meta-analysis was performed. From 2256 identified records, 112 primary studies were selected for synthesis after dual screening and consensus resolution. Findings should be interpreted as hypothesis-generating rather than as a quantitative synthesis. We propose a differential metabolite-sensitivity threshold model as a testable hypothesis: shared dysbiosis-related metabolic and inflammatory disturbances may affect serotonergic function earlier than dopaminergic function because depressed mood manifests at modest neurotransmitter deficits, whereas nigrostriatal dopaminergic neurons possess substantial compensatory reserve. Preclinical studies indicate that curcumin exerts prebiotic-like effects, promotes short-chain fatty acid-producing bacteria, suppresses NF-κB-dependent neuroinflammation, restores BDNF signaling, inhibits α-synuclein aggregation, and improves depressive- and PD-like behaviors. These actions map onto convergent gut-brain pathways involving short-chain fatty acid deficiency, tryptophan-kynurenine imbalance, monoaminergic precursor depletion, and neuroinflammation. This model generates four testable predictions: (P1: functional dysbiosis convergence; P2: temporal precedence of depressed mood; P3: curcumin's multi-node modulation; and P4: clinical benefit with adequate bioavailability). Preclinical evidence supports functional convergence (P1), temporal asymmetry (P2), and curcumin's multi-target actions (P3), but clinical benefit in MDD-PD comorbidity (P4) remains untested. However, curcumin's clinical translation remains limited by poor oral bioavailability (~ 1% for standard extracts) and the absence of randomized trials in MDD-PD comorbidity. We conclude that the convergent gut-brain hypothesis is plausible, partially supported, and directly testable, and we specify the minimal studies required to confirm or falsify it.

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