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Gut microbiota alterations are associated with the onset of depression; however, the underlying mechanisms remain unclear. Activation of hippocampal AMP-activated protein kinase (AMPK) in ulcerative colitis mice with disrupted gut microbiota balance produces antidepressant effects. However, the relationship between hippocampal AMPK and antibiotic treatment (ABX)-induced depression-like behavior remains unclear. Therefore, we aimed to investigate whether 5-aminoimidazole-4-carboxamide 1-β-d-ribofuranoside (AICAR), an AMPK activator, is associated with the prevention of ABX-induced depression-like behaviors. ABX mice exhibited depression-like behaviors, as evidenced by prolonged immobility and reduced sucrose preference. In the hippocampus of the ABX mice, Iba1 and pro-inflammatory microglial markers were upregulated, whereas brain-derived neurotrophic factor (BDNF), CD206, arginase-1, and interleukin-10 were downregulated. Additionally, levels of AMPK phosphorylation, cAMP response element binding protein (CREB), and tropomyosin-related kinase B (TrkB) were decreased. AICAR administration attenuated these behavioral and molecular alterations. Phosphorylated AMPK was colocalized with the neuronal marker-NeuN-and microglial marker-Iba1. AICAR ameliorated the reduction in hippocampal neuron proliferation and survival and reduced microglial activation-associated morphological changes in the hippocampus. These findings suggest that AICAR administration is associated with antidepressant-like effects, potentially involving enhanced neurogenesis and attenuation of neuroinflammation in the hippocampus of ABX mice. Together, this study highlights the significance of hippocampal AMPK phosphorylation in depression associated with gut microbiota alterations, and suggests a potential target for therapeutic interventions. Show less

The gut microbiome and the central nervous system are intricately connected through a bidirectional communication system that plays a vital role in maintaining gut homeostasis and overall health. Disruptions in this interaction are linked to gastrointestinal and neuropsychiatric disorders, including anxiety. This review aims to provide a comprehensive analysis of the gut microbiota's role in anxiety and evaluate the therapeutic potential of prebiotics. This review synthesizes recent literature from databases including PubMed, Scopus, Web of Science, and Google Scholar, focusing on the gut microbiota's role in anxiety and the therapeutic potential of prebiotics. The microbiota-gut-brain axis communicates through multiple pathways, including the vagus nerve, immune signaling, microbial metabolites, and the hypothalamic-pituitary-adrenal (HPA) axis. Prebiotics modulate these pathways by enhancing beneficial microbial populations and influencing the production of neuroactive compounds. Key molecular targets implicated in this communication include brain-derived neurotrophic factor (BDNF), glucocorticoid receptors, and shortchain fatty acids, which modulate neurotransmitters such as GABA and serotonin, and influence neuroinflammatory pathways implicated in anxiety pathophysiology. The findings highlight the immunological, neurochemical, and endocrine mechanisms through which the gut microbiota interacts with neurophysiological systems. These mechanisms underscore the pharmacological potential of prebiotics in the management of psychiatric illnesses. The interplay between the gastrointestinal microbiota and neurophysiological systems provides key pharmacological insights into the potential of prebiotics as a therapeutic approach for managing psychiatric illnesses, detailing their mechanistic pathways and translational applications in clinical practice. Show less

The global rise in mental health conditions has prompted interest in interventions that act beyond conventional psychopharmacology. Psychobiotics, broadly understood as live microorganisms or microbe-derived products that interact with the microbiota-gut-brain axis, have been suggested to exert neuroactive effects through neural, immune, endocrine and metabolic routes. This narrative review synthesizes recent preclinical, mechanistic and early clinical observations. Experimental studies show that selected strains can modulate cytokine signalling, influence stress-responsive systems such as the hypothalamic-pituitary-adrenal axis, and support synaptic plasticity via factors such as brain-derived neurotrophic factor. A limited number of human trials using well-characterized Lactobacillus and Bifidobacterium strains have reported improvements in affective and stress-related outcomes, but these effects are generally small to moderate, more apparent in adjunctive than stand-alone use, and dependent on strain, dose, population and intervention length (typically 4-12 weeks). Evidence on neurodevelopmental conditions (e.g., autism spectrum disorder, attention-deficit/hyperactivity disorder) remains preliminary, based on small and heterogeneous samples. Across studies, key constraints include methodological heterogeneity, incomplete strain-level reporting, and gaps in mechanistic resolution that make it difficult to link microbial shifts to psychiatric benefit. Emerging microbiome- and metabolomics-informed approaches may help identify likely responders and improve translational precision, but they are not yet ready for routine clinical application. Overall, psychobiotics should currently be viewed as a promising adjunct within integrative mental health care, warranting larger, standardized trials with clearly defined strains, doses and mechanistic endpoints. Show less