Gut microbiota modulation by ketamine compounds: a preclinical systematic review with clinical sample data

Background

Treatment-resistant depression (TRD) remains a major clinical challenge and highlights the need for mechanistically novel interventions. Ketamine and its enantiomers exert rapid antidepressant effects through glutamatergic, neuroplastic, inflammatory, and stress-related pathways. In parallel, the microbiota-gut-brain axis has emerged as a relevant interface between peripheral immune-metabolic regulation and central nervous system function. Preclinical evidence suggests that ketamine compounds may influence gut microbiota composition, but human longitudinal data, particularly for intranasal esketamine in TRD, are lacking. This study integrated a systematic review of preclinical evidence with original clinical observations in patients receiving intranasal esketamine.

Methods

A systematic review was conducted across PubMed, Web of Science, Medline, and PsycArticles/Info, from inception to July 2025, to identify animal or human studies investigating ketamine, esketamine, arketamine, or related metabolites and gut microbiota outcomes. Eligible studies reported alpha diversity, beta diversity, taxonomic composition, metagenomic, or metabolomic findings. In parallel, nine patients with TRD treated with intranasal esketamine according to standard clinical practice were evaluated longitudinally. Fecal samples were collected within 48 hours before treatment initiation and after two months. Microbiota composition was assessed through 16S rRNA sequencing of the V3-V4 regions. Alpha diversity indices, dominant phyla, and compositional patterns were analyzed using non-parametric statistics. Principal component analysis (PCA) explored global microbial variation, whereas linear discriminant analysis (LDA) identified taxa contributing to baseline versus post-treatment separation. Clinical symptoms were assessed using MADRS, HAMA, and BPRS.

Results

Sixteen studies met inclusion criteria, all conducted in rodent models; no eligible human study was identified. Across preclinical studies, alpha diversity findings were heterogeneous, with most studies reporting no significant changes in richness or evenness, while occasional increases or decreases were observed according to model, dose, enantiomer, and sequencing strategy. Beta diversity changes were more consistent, with several studies showing separation between ketamine-treated and control animals, indicating microbial community restructuring. Recurrent taxonomic patterns included reductions in Proteobacteria and enrichment of short-chain fatty acid producing taxa, especially within Lachnospiraceae and Ruminococcaceae.

In the clinical cohort, intranasal esketamine was not associated with significant changes in alpha diversity indices or in the abundance of Actinobacteriota, Bacteroidota, Firmicutes, or Verrucomicrobiota. Proteobacteria showed a significant post-treatment reduction, partially mirroring preclinical findings. PCA did not reveal a uniform global compositional shift, suggesting substantial inter-individual variability. Conversely, LDA identified significant separation between baseline and post-treatment samples, indicating subtle but structured microbial restructuring. Post-treatment enriched taxa mainly belonged to Lachnospiraceae and Ruminococcaceae lineages, including Lachnoclostridium, Eubacterium, Enterocloster, and Dorea. Baseline-enriched taxa included Acidaminococcus, Mediterraneibacter gnavus, Bacteroides fragilis, and Bacteroides stercoris. No significant associations emerged between microbiota changes and clinical outcome measures.

Conclusions

Ketamine-related compounds may modulate gut microbiota through selective taxonomic restructuring rather than broad diversity changes. These preliminary clinical findings suggest intranasal esketamine may reduce pro-inflammatory Proteobacteria and enrich taxa associated with short-chain fatty acid production, supporting further controlled studies integrating microbiota, metabolomic, inflammatory, and clinical response data. Although exploratory, these findings provide a translational framework for investigating psychopharmacomicrobiomic mechanisms underlying rapid antidepressant response in TRD and for identifying future microbial biomarkers of esketamine efficacy and tolerability.

References

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