Associations between dietary vitamin K1 and K2 intake and incident dementia: findings from the Danish Diet, Cancer, and Health cohort.

Major depressive disorder (MDD), generalized anxiety disorder, bipolar disorder (BD), and posttraumatic stress disorder (PTSD) collectively constitute one of the most urgent global health crises of the 21st century, with the World Health Organization estimating that mood and anxiety disorders together affect more than 580 million people worldwide and represent the single largest contributor to years lived with disability []. Despite this escalating epidemiological pressure, conventional pharmacotherapy anchored in the monoamine hypothesis, primarily selective serotonin reuptake inhibitors (SSRIs) and serotonin–norepinephrine reuptake inhibitors (SNRIs), has reached an unmistakable efficacy plateau, with delayed onset of action, modest initial remission rates, and substantial gastrointestinal and metabolic adverse effects continuing to undermine clinical utility. Approximately one-third of patients with MDD fail to achieve remission after two or more adequate antidepressant trials, fulfilling current criteria for treatment-resistant depression (TRD) []. Moreover, the persistent neurobiological hallmarks of TRD, such as chronic low-grade neuroinflammation, aberrant synaptic plasticity, hippocampal volumetric loss, and sustained hypothalamic-pituitary-adrenal (HPA) axis hyperactivity, argue compellingly for therapeutic strategies that move beyond the narrow synaptic monoamine framework toward systemic, multiorgan pathophysiology. Within this context, biological psychiatry has undergone an intense paradigm shift over the past decade, recognizing the gastrointestinal tract and its resident microbial ecosystem as a profound modulator of central nervous system (CNS) function through the microbiota-gut-brain axis (MGBA) []. The human gut harbors more than 100 trillion microorganisms whose collective metagenome significantly exceeds the host genome and engage in continuous bidirectional crosstalk with the CNS through neural, endocrine, immune, and metabolic pathways. Compelling causal evidence has emerged from fecal microbiota transplantation (FMT) experiments in which the transfer of microbiota from depressed patients into germ-free or antibiotic-treated rodents was found to induce depression- and anxiety-like phenotypes accompanied by neuroinflammation and diminished hippocampal brain-derived neurotrophic factor (BDNF) expression []. Correspondingly, a 2025 meta-analysis of randomized controlled trials (RCTs) encompassing 681 participants reported that FMT significantly alleviated depressive symptoms compared with placebo [], strengthening the translational relevance of microbiota-targeted interventions in human psychiatric disease. Among the myriad bioactive metabolites elaborated by the gut microbiota, short-chain fatty acids (SCFAs), including predominantly acetate, propionate, and butyrate generated through anaerobic fermentation of dietary fiber, have emerged as one of the most extensively investigated mediators in MGBA signaling, exerting pleiotropic neuroactive, immunomodulatory, and epigenetic effects through histone deacetylase (HDAC) inhibition, free fatty acid receptor activation, and direct modulation of microglial polarization, blood-brain barrier (BBB) integrity, and tryptophan–kynurenine flux [,]. Recent mechanistic studies have substantially extended this picture. In parallel, a 2025 systematic review of 19 RCTs reported symptom amelioration across the included trials, although with substantial heterogeneity in strain, dose, and duration after psychobiotic intervention [], and a 2026 meta-analysis reported an SCFA-deficit signature in individuals with MDD compared with that in healthy controls [].