Neuroimmune mechanisms of the gut-brain axis in treatment-resistant depression: Implications for microbiome-based therapeutic strategies.

Treatment-resistant depression (TRD) represents a major clinical challenge characterised by inadequate response to conventional antidepressant therapies and high relapse rates. Emerging evidence suggests that TRD may extend beyond monoaminergic dysfunction and may involve dysregulation of the HPA axis, neuroinflammation, impaired neuroplasticity, and disruption of the gut-brain axis (GBA). Gut dysbiosis has been associated with treatment resistance through alterations in monoamine turnover, immune signalling, intestinal barrier integrity, and drug-microbiome interactions affecting antidepressant bioavailability. This review integrates emerging evidence supporting targeted modulation of the GBA as a mechanistically informed strategy for TRD. Specific microbial strains (e.g., Christensenella minuta, Akkermansia muciniphila, Bifidobacterium breve CCFM1025), microbial metabolites (e.g., indole-3-propionic acid, indole-3-lactic acid, anserine), and phytochemicals (e.g., curcumin, matrine, salidroside) are discussed for their proposed roles in modulating neuroendocrine signalling, neuroinflammation, and synaptic plasticity. The review also highlights emerging peripheral biomarkers, including the kynurenine/tryptophan ratio, serum metabolomics, and lymphocyte serotonin transporter clustering, as candidate tools for stratified psychiatry. Most of the evidence discussed in this review comes from animal studies, in vitro systems, and computational analyses, while direct evidence in patients with treatment-resistant depression remains limited. These findings provide important mechanistic insights into gut-brain axis dysfunction but require further validation in human TRD populations. Biomarker-guided and endotype-based approaches targeting the gut-brain axis may offer a useful framework for future research, although their clinical utility has yet to be established.