Pleiotropic modulation of the gut-brain-lung axis by ketamine and its enantiomers

Ketamine, a potent N-methyl-D-aspartate receptor (NMDAR) antagonist, is widely used for anesthesia and analgesia and, because of its rapid antidepressant effects, in psychiatry. Increasing evidence suggests that ketamine and its enantiomers-(R)-ketamine (arketamine) and (S)-ketamine (esketamine)-also modulate systemic immunity and provide organ protection, partly through interactions with the gut microbiota, microbial metabolites, and intestinal immune-cell trafficking. However, these gut-mediated pathways must be distinguished from ketamine's well-established direct central and peripheral actions. In this review, we summarize how ketamine engages the gut-brain and gut-lung axes, emphasizing anti-inflammatory, immunoregulatory, and barrier-protective effects, while critically evaluating the evidence for causality in gut-organ communication. Along the gut-brain axis, ketamine is associated with restoration of microbial balance, normalization of short-chain fatty acid levels, and reduced migration of gut-derived γδ T17 and Th17 cells to the central nervous system, correlating with attenuated neuroinflammation and depressive-like behaviors. Through the gut-lung axis, ketamine has been reported to limit bacterial translocation and mesenteric lymph-associated inflammatory signaling and reduces pulmonary infiltration of pro-inflammatory cells, suggesting potential relevance in acute lung injury and other respiratory disorders. We also discuss enantiomer-specific effects: arketamine appears to provide more sustained neuroprotection and may be associated with fewer adverse effects than esketamine. Overall, these findings suggest the broad therapeutic potential of ketamine and its enantiomers for neuropsychiatric and inflammatory diseases, while underscoring the need for careful evaluation of long-term safety, optimal dosing, microbiota-targeted adjunctive strategies, and causal studies to distinguish direct pharmacological actions from indirect, microbiota-mediated effects.