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

Abstract

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.

Introduction

Racemic ketamine has long been used for anesthesia, analgesia, and sedation [1], and clinical trials have established its rapid antidepressant effects in treatment-resistant patients with major depressive disorder (MDD) [2–4]. By non-competitively blocking N-methyl-D-aspartate receptors (NMDARs)—particularly on inhibitory interneurons—ketamine transiently enhances cortical glutamatergic transmission, activates synaptogenic signaling cascades, and produces antidepressant effects within hours that can persist for days [5]. Beyond psychiatry, ketamine and its (S)-enantiomer, esketamine, are increasingly used for acute pain control and perioperative management [6].

Recent studies have expanded the understanding of ketamine beyond its central nervous system actions, revealing important effects on systemic inflammation and organ protection, partly associated with interactions involving the gut microbiota, microbial metabolites, and gut-derived immune-cell trafficking [7–9]. Much of this work focuses on two major gut-organ communication pathways: the gut–brain and gut–lung axes [10–14]. The gut–brain axis regulates central nervous system (CNS) function through neural, immune, and metabolic signaling, whereas the gut–lung axis describes how gut-derived microbes, metabolites, and immune cells influence pulmonary immunity and pathology [7, 8, 13]. Dysregulation of these axes can promote neuroinflammation and lung injury, contributing to disorders such as depression, chronic obstructive pulmonary disease (COPD), and acute respiratory distress syndrome (ARDS) [7, 8, 15–18]. In parallel, alterations in microbial metabolites have been linked to metabolic, cardiovascular, and neurodegenerative diseases [19, 20], and accumulating evidence suggests that ketamine and its enantiomers can reshape gut microbial communities and their metabolic outputs [21, 22].

Given ketamine’s anti-inflammatory and immunoregulatory properties [8, 23, 24], this review systematically examines how ketamine and its enantiomers influence the gut–brain and gut–lung axes, with particular emphasis on changes in gut microbiota composition, microbial metabolites, and intestinal immune-cell migration.

It is important to note that ketamine exerts direct effects on neurons, glia, and immune cells through NMDAR antagonism and other receptor systems, while gut-mediated mechanisms represent parallel and interacting pathways that can amplify or modulate its systemic actions. For example, ketamine-induced shifts in gut microbiota and microbial metabolites may alter systemic inflammation and immune-cell trafficking, thereby influencing neuroinflammation and pulmonary injury. Conversely, ketamine’s central actions—such as modulation of vagal activity—can affect gut motility, permeability, and immune responses, forming a bidirectional regulatory loop. Accordingly, this review distinguishes ketamine’s direct pharmacological effects from its indirect, gut-mediated actions, while highlighting how these mechanisms interact to shape its overall therapeutic profile.

Pharmacological characteristics of ketamine

Ketamine produces rapid antidepressant effects primarily through non-competitive antagonism of NMDARs, leading to enhanced synaptic plasticity and increased release of neurotrophic factors such as brain-derived neurotrophic factor (BDNF) [25]. By preferentially inhibiting NMDARs on inhibitory interneurons, ketamine disinhibits glutamatergic pyramidal neurons, triggers activity-dependent synaptogenesis, and rapidly improves depressive symptoms.

However, its clinical application is constrained by several adverse effects, including acute psychotomimetic and dissociative symptoms, transient cognitive impairment, cardiovascular stimulation, and potential for abuse and dependence [26] (Fig. 1). These safety concerns have made optimization of dosing, formulation, and enantiomer selection major priorities in ketamine research. Nevertheless, despite regulatory limitations, off-label ketamine use for depression remains widespread in the United States (US) and other countries, reflecting both its unique rapid efficacy and the unmet need in treatment-resistant depression [27].

Fig. 1. Distinct mechanistic pathways of ketamine enantiomers.

Ketamine enantiomers exert therapeutic effects through multiple, partially overlapping mechanisms. Both (R)-ketamine (arketamine) and (S)-ketamine (esketamine) antagonize NMDARs, modulate monoaminergic neurotransmission, and suppress inflammatory signaling. However, arketamine’s antidepressant actions preferentially depend on activation of the ERK pathway and enhancement of 5-HT release in the prefrontal cortex, whereas esketamine relies mainly on NMDAR blockade and downstream mTOR signaling. Beyond central nervous system effects, both enantiomers reduce systemic inflammation—lowering TNF-α and IL-6—and confer organ protection in models such as CLP–induced sepsis and ALI. 5-HT 5-hydroxytryptamine (serotonin), ALI acute lung injury, BDNF brain-derived neurotrophic factor, CLP cecal ligation and puncture, ERK extracellular signal-regulated kinase, IL-6 interleukin-6, NMDAR N-methyl-D-aspartate receptor, TNF-α tumor necrosis factor-alpha.

NMDAR antagonism

Ketamine’s primary mechanism of action is antagonism of NMDARs [28]. These ionotropic glutamate receptors play a central role in learning, memory, and synaptic plasticity [29]. By blocking NMDARs, ketamine alters NMDAR-dependent glutamatergic signaling, producing its characteristic anesthetic and analgesic effects [30]. The same mechanism also contributes to its rapid antidepressant action, likely by initiating downstream neuroplastic processes and synaptic remodeling [31]. In addition, NMDAR blockade can influence other neurotransmitter systems, including dopamine, thereby broadening ketamine’s clinical utility in both acute pain management and mood disorders [32, 33].

However, the relationship between NMDAR antagonism and antidepressant efficacy is not straightforward. Other NMDAR antagonists, such as the high-affinity blocker MK-801, have failed to show consistent antidepressant effects in clinical trials [34–36]. This discrepancy indicates that simple receptor blockade is insufficient and points to critical pharmacological differences, including ketamine’s unique binding kinetics (e.g., trapping blockade), subunit selectivity, and its concurrent actions at non-NMDAR targets, such as opioid receptors (discussed below) [12, 37]. Thus, while NMDAR antagonism is a key initiating event, ketamine’s distinctive antidepressant profile likely arises from the combination of its specific NMDAR interactions and its broader pleiotropic actions.

Opioid receptor activation

Beyond NMDAR antagonism, ketamine shows moderate affinity for the μ-opioid receptor (MOR) [38, 39], and MOR activation contributes to its well-established analgesic effects [6]. Whether opioid signaling is also required for ketamine’s antidepressant action remains controversial. In patients with treatment-resistant depression (TRD), pretreatment with the opioid antagonist naltrexone attenuated ketamine’s antidepressant response in one study [40], and a randomized crossover trial similarly implicated opioid receptor involvement [41].

In contrast, several preclinical and clinical studies suggest that opioid signaling is not universally required. In chronic social defeat stress (CSDS) and lipopolysaccharide (LPS) models of depression, naltrexone failed to block ketamine’s antidepressant-like effects in mice [42]. Likewise, two clinical studies in depressed patients with comorbid alcohol use disorder reported no effect of naltrexone on ketamine’s antidepressant efficacy [43, 44]. In rats, naltrexone abolished ketamine’s behavioral benefits, yet direct opioid receptor activation alone did not reproduce ketamine’s effects, suggesting a permissive rather than sufficient role for opioid signaling [45]. Another study further showed that ketamine’s antidepressant-like effects depend on endogenous β-endorphin–driven MOR activation within the medial prefrontal cortex [46].

Taken together, these findings indicate that opioid signaling may be necessary in specific neural circuits or experimental contexts but is not uniformly required across species, models, or clinical populations. Its contribution therefore appears context-dependent and remains unresolved [47, 48]. Given that esketamine has a higher affinity for MOR than racemic ketamine [38, 39], future studies should determine whether opioid blockade similarly modulates esketamine’s antidepressant efficacy in patients with TRD.

Monoaminergic modulation

Ketamine’s antidepressant actions also involve modulation of monoaminergic systems. It rapidly increases brain levels of serotonin (5-HT), noradrenaline, and dopamine, changes that likely contribute to its mood-elevating effects [49]. These increases may occur indirectly, as NMDAR blockade reduces glutamate-driven inhibitory control over monoaminergic neurons, thereby enhancing their firing and transmitter release. In parallel, ketamine activates the mammalian target of rapamycin (mTOR) signaling pathway, a central regulator of synaptic growth and plasticity, which promotes rapid synaptogenesis and functional recovery in mood-related circuits [50]. Together, monoaminergic enhancement and mTOR-dependent synaptic remodeling act in concert with NMDAR antagonism to produce ketamine’s rapid and robust antidepressant effects.

Anti-inflammatory effects

Beyond its actions on neurotransmission, ketamine exerts dose- and context-dependent anti-inflammatory effects that likely contribute to both its antidepressant and organ-protective properties. Growing evidence indicates that ketamine and its enantiomers reduce inflammatory signaling, which may be particularly relevant because inflammation is increasingly recognized as a key contributor to depression [9, 21, 51, 52]. In patients with TRD, baseline serum interleukin (IL)-6 levels predict clinical response to ketamine, suggesting that inflammatory status modulates treatment efficacy [53]. Experimentally, ketamine reduces circulating pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α) and IL-6, suppresses microglial activation, and decreases reactive oxygen species production in the CNS, thereby alleviating depression-like behaviors [54, 55]. These anti-inflammatory actions also support neuroprotection by limiting neuroinflammation and promoting neuronal survival [56]. In addition, ketamine may indirectly dampen systemic inflammation by reshaping gut microbiota composition and diversity, linking its immunomodulatory effects to gut-mediated pathways [57].

Two enantiomers of ketamine

Arketamine

Arketamine, the R-enantiomer of ketamine, has lower affinity for NMDARs yet produces more robust and longer-lasting antidepressant effects than esketamine in many preclinical models. It rapidly relieves depressive symptoms and upregulates brain-derived neurotrophic factor (BDNF), thereby promoting synaptic plasticity and synaptogenesis [58]. Unlike esketamine, arketamine increases serotonin release in the prefrontal cortex through largely NMDAR-independent mechanisms [59]. It also suppresses lipopolysaccharide (LPS)-induced inflammation and depression-like behavior by downregulating CD38 signaling, reducing cyclic ADP-ribose and intracellular calcium, and inhibiting microglial and astrocytic activation [60]. In socially isolated mice, arketamine—but not esketamine—restored anterior insular cortex activity and improved cognitive function [61]. Early clinical studies suggest that single or repeated intravenous infusions of arketamine can rapidly improve mood, with benefits lasting for weeks [62–64], although larger controlled trials are still required to confirm its efficacy in depressed patients.

Beyond its antidepressant actions, arketamine shows strong anti-inflammatory and organ-protective properties. It attenuates disease severity in models of experimental autoimmune encephalomyelitis, ulcerative colitis, sepsis-induced multi-organ injury, and ischemic brain damage [65–67]. In our own studies, arketamine reduced lethal inflammation and organ injury in a cecal ligation-puncture sepsis model [68] and reversed LPS-induced neurofunctional deficits by suppressing neuroinflammation [69]. It also increases microglial transforming growth factor-β1 (TGF-β1) expression, further dampening inflammatory responses in the brain [70]. Moreover, arketamine alleviates depression-like behaviors in the CSDS model, an effect associated with remodeling of gut microbiota composition [71, 72]. Although these studies demonstrated correlations between microbial shifts and behavioral improvement, direct causal testing (e.g., fecal microbiota transplantation [FMT]) has not yet been performed.

Recent work further suggests that gut–brain communication is central to arketamine’s actions. Specific gut microbial profiles may enhance its neuroprotective effects in cuprizone-treated mice [22]. Mechanistically, this benefit was linked to vagus nerve–dependent signaling, because subdiaphragmatic vagotomy abolished arketamine’s protective effects, indicating a microbiota–vagus–brain pathway. As understanding of these mechanisms grows, combination strategies—such as pairing arketamine with psychotherapy—are being explored to maximize therapeutic outcomes [73].

Our recent study also revealed an immune-gut-brain mechanism. Chronic restraint stress promoted migration of CD8α⁺ γδ T17 cells from the small intestine to the meninges and brain, increased hippocampal IL-17A, and impaired PINK1/Parkin-mediated mitophagy. Arketamine corrected stress-induced dysbiosis, reduced γδ T-cell trafficking, lowered IL-17A levels, restored mitophagy, and alleviated depression-like behaviors [15], highlighting its capacity to regulate immune–microbiota–brain interactions.

However, clinical findings are not uniformly positive. A small pilot trial (n = 10) found that arketamine was no more effective than placebo in TRD, underscoring the influence of study design, dosing, and patient selection on outcomes [74]. These mixed results emphasize the need for larger, well-controlled trials and optimized dosing strategies to define the true clinical potential of arketamine.

Esketamine and its major metabolite (S)-norketamine

Esketamine also shows clear antidepressant efficacy, although its underlying mechanisms differ in important ways from those of arketamine. Unlike arketamine—whose antidepressant actions depend largely on ERK (extracellular signal–regulated kinase) signaling—esketamine requires activation of the mTOR pathway to produce rapid mood-elevating effects [75, 76]. By modulating glutamatergic transmission and enhancing synaptic plasticity, esketamine helps restore dysfunctional neural circuits. In addition, acute changes in sleep architecture may contribute to its antidepressant response [77]. Compared with arketamine, esketamine appears to rely more strongly on direct NMDAR antagonism and less on serotonergic modulation [59]. Clinically, repeated esketamine dosing alleviates depressive symptoms and may reduce suicidal ideation [78]. In preclinical models, it also improves spatial working memory in chronic pain and favorably alters gut microbiota composition while reducing systemic inflammation [21]. Although these studies link microbiota changes with behavioral improvement, the relationship remains largely associative rather than causally established.

Beyond its psychiatric applications, esketamine exerts organ-protective effects. In a sepsis model, it attenuated acute lung injury (ALI) by inhibiting the migration of intestinal γδ T cells to the lung [21]. Using flow cytometry and in vivo cell tracking, this study demonstrated reduced infiltration of gut-derived γδ T17 cells into pulmonary tissue after esketamine treatment, providing direct evidence for immune-cell trafficking along the gut–lung axis. These findings highlight that esketamine’s benefits extend beyond the brain to systemic immune regulation. However, its clinical use is limited by dissociative symptoms, cardiovascular effects, and addiction potential, underscoring the need for careful patient selection and monitoring [39].

(S)-Norketamine, the primary metabolite of esketamine, has emerged as a promising alternative. It produces strong antidepressant-like effects in the CSDS model, with efficacy comparable to esketamine but without typical NMDAR-related side effects such as prepulse-inhibition deficits, psychotomimetic behaviors, or altered gamma oscillations [79]. Its low affinity for NMDARs likely explains this improved tolerability. (S)-Norketamine also reverses depressive-like behaviors in chronic corticosterone-treated mice [80] and in social isolation–reared mice [81]. Recent data further suggest that its antidepressant-like effects in LPS-treated mice are accompanied by beneficial changes in gut microbiota composition [82]. Together, these findings position (S)-norketamine as a side-effect-sparing candidate that may retain antidepressant efficacy while minimizing the liabilities associated with esketamine [83].

Gut-brain axis

Overview of the gut-brain axis: pathways relevant to ketamine action

The gut–brain axis is a bidirectional communication network linking the CNS, enteric nervous system (ENS), gut microbiota, and immune system [13, 84]. Through neural pathways—most notably the vagus nerve—as well as endocrine and immune routes, the CNS regulates digestion, gut immunity, emotional states, and neural plasticity [14, 85]. In the opposite direction, gut-derived signals such as microbial metabolites, cytokines, and immune cells feedback to influence brain function and behavior.

The gastrointestinal (GI) tract is not only responsible for nutrient absorption but also plays a central role in maintaining immune homeostasis. When intestinal barrier integrity is disrupted, bacterial components and immune mediators can translocate into the circulation, triggering systemic inflammation that ultimately affects the brain [7, 8, 15, 86] (Fig. 2). Thus, alterations in gut microbiota composition, barrier function, or immune signaling can propagate along the gut–brain axis and contribute to neuroinflammation and psychiatric symptoms—providing a critical framework for understanding how ketamine and its enantiomers may exert part of their effects through gut-mediated pathways.

Fig. 2. Integrated network of enteric glial cells in gut–brain axis communication.

EGCs act as a central communication hub within the gut–brain axis, interacting dynamically with intestinal epithelial cells, immune cells, and enteric neurons to maintain mucosal barrier integrity and regulate local and systemic immunity. EGC-derived cytokines and chemokines modulate the activity of dendritic cells, macrophages, and B cells, which in turn present antigens and shape adaptive immune responses, including differentiation of CD4⁺ and CD8⁺ T cells. Microbial signals such as IL-1 and IL-23 promote Th17 cell differentiation, whereas commensal-derived metabolites support the development of IL-22–producing ILC3s, thereby helping to balance Tregs and Th17 cells. Under inflammatory conditions, γδ T cells can polarize into IL-17–producing subsets and migrate via CCR6-dependent pathways to the CNS, contributing to neuroinflammation. PRRs on epithelial cells, including TLR5 and NOD2, detect MAMPs and activate signaling cascades (e.g., NF-κB) that enhance epithelial defense and cytokine production. Secretory IgA, IELs, and anti-inflammatory cytokines such as IL-10 further reinforce mucosal homeostasis. Together, this integrated cellular network illustrates how gut-resident cells coordinate barrier function, immune tolerance, and neuroimmune signaling along the gut–brain axis. APC antigen-presenting cell, CCR6 C-C chemokine receptor type 6, CNS central nervous system, EECs enteroendocrine cells, EGCs enteric glial cells, ENs enteric neurons, ENS enteric nervous system, GCs goblet cells, IECs intestinal epithelial cells, IELs intraepithelial lymphocytes, ILC3s group 3 innate lymphoid cells, iNKT cells invariant natural killer T cells, MAMPs microbe-associated molecular patterns, NK cells natural killer cells, PRRs pattern-recognition receptors, Tregs regulatory T cells.

Neural pathways

The ENS, together with enteric glial cells, forms an intrinsic neural network that communicates bidirectionally with the CNS and regulates intestinal motility, immunity, and barrier function [87–90]. For long-range signaling, the vagus nerve serves as the principal neural conduit between the brain and visceral organs [85].

The vagus nerve is central to the cholinergic anti-inflammatory pathway and plays a key role in shaping gut microbiota composition and systemic metabolism [85, 91]. Disruption studies highlight its importance. For example, copper-containing hemoproteins induce gut dysbiosis and subsequent brain inflammation through the subdiaphragmatic vagus nerve (SDVN); these effects are attenuated by SDVN transection, antibiotic treatment, or FMT [92]. Similarly, inflammatory signals arising from Complete Freund’s Adjuvant–induced gut imbalance exacerbate pain and cognitive deficits via the SDVN, whereas SDVN transection reverses these changes [93].

Social isolation alters vagal activity and gut microbial profiles, leading to activation of intestinal γδ T cells and their migration to the brain and lung, where IL-17A release worsens stroke injury and pneumonia; these processes are mitigated by vagotomy or γδ T-cell depletion [7]. Probiotic interventions can restore microbial balance and increase short-chain fatty acid (SCFA) production, activating gut–brain signaling through the aryl hydrocarbon receptor and indoleamine 2,3-dioxygenase pathways to promote systemic anti-inflammatory responses and protect against ischemic stroke [94]. Finally, splenic nerve transection has been shown to modulate immunity and gut microbiota through a spleen–gut–brain axis, reducing inflammation in both spleen and brain and alleviating depressive-like behavior in α7 nicotinic acetylcholine receptor–deficient mice [95].

Immune pathways

As the body’s largest immune organ, the gut-associated lymphoid tissue contains a diverse population of lymphocytes and antigen-presenting cells that maintain immune tolerance and homeostasis [96, 97]. Among these, specific T-cell subsets—particularly Th17 cells and γδ T cells—are especially important for gut–brain communication, because their differentiation in the intestine can shape inflammatory responses in distant organs, including the brain.

The small intestine is the primary site of Th17 cell differentiation. Their development is tightly regulated by microbial cues and innate immune signaling pathways such as IL-1 and IL-23 [98]. Recent work shows that synbiotic-derived metabolites can bias type-3 innate lymphoid cells (ILC3s) toward an natural cytotoxicity receptor (NCR)⁺ IL-22–producing phenotype, thereby improving the regulatory T (Treg)/Th17 balance. Under chronic stress, this microbiome–ILC3–Th17–Treg axis uniquely correlates with behavioral changes, linking gut immune modulation to chemokine-driven recruitment of immune cells into the prefrontal cortex and hippocampus [99]. These findings illustrate how intestinal immune dynamics can translate into altered brain function.

γδ T cells, although a minor fraction of intestinal T cells, are crucial for epithelial integrity, tissue repair, and antimicrobial defense. Under pathological conditions, however, they can differentiate into IL-17–producing inflammatory cells that promote tissue injury [100]. After stroke, gut-derived T cells and macrophages migrate to the CNS via lymphatic and hematogenous routes, aggravating neuroinflammation [101]. Studies in CC-Motif Chemokine Receptor-6 (CCR6)-deficient mice demonstrate that this receptor is essential for IL-17⁺ γδ T-cell trafficking from the gut to the brain, where their accumulation worsens neurological damage [102].

Beyond the gut, splenic γδ T cells also play a key role in inflammation-associated depression. Arketamine alleviates LPS-induced splenomegaly, reduces plasma IL-6 levels, normalizes splenic γδ T-cell proportions, and improves depressive-like behaviors. Importantly, these therapeutic and preventive effects are abolished by pretreatment with a γδ T-cell receptor–specific neutralizing antibody [103]. Moreover, splenic γδ T cells are required for the antidepressant and anxiolytic effects of vagotomy in LPS-induced models, highlighting a functional spleen–brain immune axis [104].

Taken together, these findings indicate that gut- and spleen-derived immune cells—particularly Th17 and γδ T cells—form critical links between peripheral immunity and brain function. Given ketamine’s anti-inflammatory actions and its capacity to modulate vagal and immune signaling, these immune pathways represent plausible mechanisms through which ketamine may indirectly influence brain function via the gut–brain and spleen–brain axes.

Microbiota-metabolite signaling

The human gut microbiota, dominated by Firmicutes, Bacteroidetes, Actinobacteria, and Proteobacteria, is distributed along the entire GI tract [105]. Microbial ligands can enter the circulation and even reach the bone marrow, where they regulate hematopoietic progenitor cells and enhance immune-cell production during systemic infection. In addition, microbial products act as microbe-associated molecular patterns (MAMPs) that engage pattern-recognition receptors (PRRs) on innate immune cells—such as monocytes, macrophages, and natural killer cells—thereby triggering cytokine release and shaping a large proportion of systemic immune responses [96, 106].

Gut microbes maintain intestinal homeostasis through multiple signaling pathways that strengthen epithelial barrier function, regulate antimicrobial peptide secretion, and modulate both innate and adaptive immunity, including intraepithelial lymphocyte activity and secretory IgA production [107, 108]. When this finely balanced system is disrupted (dysbiosis), microbial products and immune mediators can escape the gut and exert widespread systemic and neural effects.

The gut microbiota also influences emotional behavior, anxiety, and depression by regulating neurotransmitters such as dopamine and serotonin, as well as stress hormones like cortisol [109]. Through these neurochemical and immunological pathways, microbes shape neural signaling and mood [110]. In the CNS, microglia rely on mitochondrial autophagy to maintain homeostasis and control inflammation; enhanced autophagy during infection limits tissue damage and cytokine release. Because gut microbes regulate microglial metabolism and autophagy, they can indirectly modulate neuroinflammatory tone [111].

Dysbiosis has been linked to numerous neurological and systemic disorders, illustrating how gut–organ communication pathways may intersect with ketamine’s actions. These examples are provided to illustrate shared pathways rather than to imply established clinical efficacy of ketamine in these disorders. In Alzheimer’s disease (AD), altered microbial communities promote β-amyloid aggregation and tau hyperphosphorylation, driving systemic and central inflammation [112]. Patients with AD and Parkinson’s disease (PD) show reduced microbial diversity and shifts in key taxa that exacerbate oxidative stress and neuroinflammation [113, 114]. Dysbiosis can also increase intestinal permeability and disrupt the blood-brain barrier (BBB), further amplifying neural injury [115]. These mechanisms—neuroinflammation, oxidative stress, and barrier dysfunction—overlap with pathways targeted by ketamine’s anti-inflammatory and barrier-protective effects, suggesting potential therapeutic convergence.

Gut microbiota diversity is also closely linked to mental health. Patients with depression often show reduced diversity and imbalanced proportions of Bacteroidetes, Firmicutes, Proteobacteria, and Actinobacteria [116]. In contrast, richer microbial ecosystems correlate with lower anxiety and reduced hyperactivity in prefrontal brain regions [117]. Interventions such as FMT can restore microbial balance, normalize immune responses, and improve neurological and psychiatric outcomes [118]. Because depression is a primary indication for ketamine, its association with gut dysbiosis provides a strong rationale for exploring gut-mediated mechanisms in ketamine’s antidepressant actions.

Microbial metabolites represent key mediators of gut–brain communication. Among them, SCFAs—including acetate, propionate, and butyrate—help maintain intestinal barrier integrity and regulate immune-cell trafficking [119]. In the gut, SCFAs promote Treg differentiation, suppress inflammation, and preserve immune tolerance [120]. By activating G-protein–coupled receptors such as FFA2 and FFA3, SCFAs exert broad anti-inflammatory effects.

SCFAs also influence neurological disease progression. They modulate neuronal signaling, reduce neuroinflammation, and shape microglial function via the gut–brain axis [121]. For example, certain Bacteroides fragilis strains alter gut metabolites that cross the BBB to affect neurotransmitter balance; their abundance inversely correlates with depressive symptom severity [122]. Moreover, SCFAs regulate microglial function and mitochondrial autophagy, further linking the microbiota to CNS immune responses [123]. Thus, microbial metabolites form a biochemical bridge between the gut and brain.

In ischemic stroke models, commensal bacteria regulate post-stroke inflammation and recovery by controlling intestinal γδ T-cell activity and cytokine release (e.g., IL-17, interferon (IFN)-γ), effects that can be reversed by antibiotics or FMT [124]. SCFAs further guide immune-cell migration: butyrate induces Treg differentiation in gut-associated lymphoid tissue, and these Tregs can migrate to distant organs to restore immune tolerance [125]. Stroke therefore exemplifies how gut-derived immune cells and metabolites influence remote organ pathology—a pathway potentially modulated by ketamine through its immunoregulatory properties.

At the cellular level, butyrate activates peroxisome proliferator-activated receptor (PPAR)-γ in macrophages to suppress pro-inflammatory cytokines, while both butyrate and propionate expand Treg populations and maintain immune balance [126]. SCFA supplementation after stroke improves neurological recovery by reducing inflammatory T-cell responses and promoting tissue repair [127]. Beyond SCFAs, the microbiota also produces γ-aminobutyric acid (GABA) and secondary bile acids, which alleviate symptoms of AD, PD, depression, and anxiety via receptor-mediated signaling and by reducing oxidative stress and neuroinflammation [128].

Alterations in gut microbial composition and metabolite profiles are therefore tightly linked to depression and neuroinflammatory disorders (Table 1). Interventions capable of reshaping the gut microbiota—such as ketamine and its enantiomers—may exert part of their therapeutic effects through these microbiota–metabolite signaling pathways, complementing their direct neural and immune actions.

Table 1.

Summary of gut bacterial taxa, stress-related alterations, and associated conditions.

Bacterial Taxa/Group	Reported Alterations Under Stress or Disease	Associated Conditions	Pathophysiological Role/Mechanism (as described in the manuscript)	Study Type	Reference (s) from Manuscript
Bacteroidetes	Depressed patients show altered proportions	Depression	–	Clinical (patient cohort)	[116]
Bacteroides fragilis (specific strain)	Abundance inversely correlates with depressive symptom severity	Depression	Alters gut metabolites that cross the BBB to affect central neurotransmitter balance (e.g., serotonin)	Clinical (patient cohort)	[122]
Bacteroides (OTU009)	Enriched in lung microbiota of patients with ARDS	ARDS	Presence in lungs correlates positively with serum and BALF TNF-α levels	Clinical (ARDS patient cohort)	[16]
Firmicutes	Depressed patients show altered proportions	Depression	–	Clinical (patient cohort)	[116]
Proteobacteria	1. Depressed patients show altered proportions. 2. Overgrowth in gut microbiota of critically ill patients.	1. Depression. 2. Critical illness (ICU)	Drives intestinal inflammation and systemic signals that reshape lung microbiota	Clinical (patient cohort & ICU study)	[116], [143]
Actinobacteria	Depressed patients show altered proportions	Depression	–	Clinical (patient cohort)	[116]
Lachnospiraceae	Enriched in lung microbiota of ARDS patients	ARDS, Critical illness	Associated with fewer ventilator-free days and reduced survival	Clinical (ARDS patient cohort)	[17]
Enterobacteriaceae	1. Overgrowth in gut microbiota of critically ill patients. 2. Enriched in lung microbiota of ARDS patients	Critical illness (ICU), Sepsis, ARDS	1. Drives intestinal inflammation. 2. Associated with fewer ventilator-free days and reduced survival	Clinical (ICU and ARDS patient studies)	[17], [143]
Escherichia coli	Overgrowth and translocation to the lungs following intestinal fungal dysbiosis	Pulmonary infection, Sepsis	Drives accumulation of specific lung macrophages and exacerbates lung inflammation	Animal (murine model)	[144]
Ligilactobacillus, Lactococcus, Helicobacter	CRS-induced dysbiosis, decreased diversity, increased abundance of Ligilactobacillus, Lactococcus, Helicobacter	Depression (CRS model)	Promotes migration of small intestinal CD8α⁺ γδ T17 cells to meninges and brain; elevates hippocampal IL-17A; impairs PINK1/Parkin-mediated mitophagy	Animal (murine CRS model)	[15]
Gut Microbiota (General)	Reduced beneficial bacteria in germ-free mice	Ketamine’s conditioned CPP	Essential for normal dopamine release, BDNF/mTOR signaling, and the rewarding effects of ketamine in mice	Animal (CPP mouse model)	[131]
Gut Microbiota Diversity (General)	Reduced in: 1. Patients with depression, AD, or PD. 2. Critically ill patients (ARDS/Sepsis)	1. Depression, AD, PD. 2. Critical illness (ARDS/Sepsis)	Correlates with increased inflammation, barrier dysfunction, and disease severity	Clinical (multiple patient cohorts)	[16,17,112,113,116,143]

AD Alzheimer’s disease, ARDS acute respiratory distress syndrome, BALF bronchoalveolar lavage fluid, BBB blood-brain barrier; BDNF brain-derived neurotrophic factor; CPP conditioned place preference, CRS chronic restraint stress, ICU intensive care unit, mTOR mechanistic target of rapamycin, PD Parkinson’s disease, TNF-α, tumor necrosis factor-alpha.

Key cytokines in gut-brain signaling: IL-17 and IL-33

Growing evidence identifies IL-17 and IL-33 as pivotal cytokines that translate intestinal immune activity into neuroinflammatory and behavioral outcomes. IL-17, mainly produced by gut-derived Th17 and γδ T cells, has a dual role in the gut–brain axis. Although it is best known for its pro-inflammatory actions—driving neuroinflammation and disrupting the BBB—it also participates in tissue repair and microbial homeostasis, reflecting its role in the immune system’s adaptive balance between activation and regulation [100, 102]. In models of depression and stroke, IL-17⁺ γδ T cells migrate from the gut to the brain in a CCR6-dependent manner, where they directly exacerbate neuroinflammation and neuronal injury [102, 124]. These findings position IL-17 as a direct molecular messenger linking intestinal immunity to central nervous system pathology.

In contrast, IL-33 functions primarily as an “alarmin” released after epithelial injury in the gut. Through signaling via its receptor stimulation-2 (ST2), IL-33 is essential for maintaining mucosal barrier integrity and orchestrating type-2 immune responses, including activation of Tregs and type-2 innate lymphoid cells (ILC2s) [18]. Although its direct involvement in mood disorders is less clearly defined than that of IL-17, IL-33’s central role in preserving gut homeostasis makes it an important upstream regulator of gut–brain communication. By limiting intestinal barrier breakdown and systemic inflammatory spillover—processes strongly implicated in depression pathophysiology [7, 18] —the IL-33/ST2 axis may indirectly shape the inflammatory environment that influences brain function.

Together, IL-17 and IL-33 represent complementary arms of gut–brain immune signaling: IL-17 acts as an active pro-inflammatory courier from gut to brain, whereas IL-33 functions as a protective sentinel that limits inflammatory leakage at its source. Future studies should clarify how these cytokine pathways interact and whether interventions such as ketamine can modulate IL-17– or IL-33–dependent signaling to restore immune and neural homeostasis.

Modulation of the gut-brain axis by ketamine and its enantiomers

Ketamine’s therapeutic effects are thought to arise primarily from its direct actions in the brain—most notably NMDAR antagonism, which rapidly enhances glutamatergic transmission, promotes BDNF release, and drives synaptic plasticity within hours [25, 28, 31]. These central mechanisms can occur independently of the gut microbiota. Nevertheless, growing preclinical evidence suggests that the microbiome may modulate treatment outcomes by shaping individual responsiveness, supporting the durability of antidepressant effects, or influencing efficacy under conditions such as stress-induced dysbiosis [57, 71, 129]. Although several studies report associations between ketamine administration and changes in gut microbiota, these microbial shifts may arise secondary to ketamine’s primary neurochemical and anti-inflammatory actions rather than serving as the initial drivers. Thus, parallel improvements in behavior, inflammation, and microbial composition should be interpreted as largely correlative, and definitive causal roles for the microbiome require targeted experimental validation.

Preclinical work nevertheless supports meaningful gut–brain interactions in ketamine’s actions. A seminal study showed that a single dose of arketamine reversed depression-like behaviors in CSDS-exposed mice while reshaping gut microbiota, providing early correlative evidence for gut–brain involvement [71, 72]. More recently, repeated esketamine treatment in a chronic-pain mouse model improved spatial working memory, accompanied by favorable shifts in microbial communities and reduced inflammation [21]. These findings suggest that gut changes may contribute to sustaining or modulating central benefits, even if they are not the primary trigger.

In contrast, chronic or high-dose ketamine exposure can be detrimental to gut homeostasis. Long-term administration disrupts gut microbiota and weakens intestinal barrier integrity, leading to hippocampal dysfunction and subsequent depressive-, anxiety-like, and cognitive deficits [130]. Although this study documents a pathological association, it does not clarify whether dysbiosis is a cause or consequence of neural impairment. Stronger causal evidence comes from studies of reward: germ-free or antibiotic-treated mice show reduced dopamine release and suppressed hippocampal and prefrontal BDNF/mTOR signaling after ketamine, resulting in blunted place-preference behavior, whereas FMT restores these effects [131]. Similarly, in a mouse depression model, ketamine improved behavior alongside microbial changes that may enhance pharmacodynamic effects through altered BBB permeability [57], and co-administration with Dajianzhong Tang further amplified benefits by enhancing gut–brain neurotransmitter signaling [132]. Clinical observations parallel these findings: patients with TRD display reduced beneficial bacteria and increased potential pathogens, supporting a modulatory role of the microbiome in ketamine responsiveness [129] (Fig. 3).

Fig. 3. Gut dysbiosis in AD-related pathology.

Imbalances in the gut microbiota promote β-amyloid aggregation and aberrant tau phosphorylation, thereby fueling systemic and CNS inflammation. Dysbiosis also increases intestinal permeability, which compromises BBB integrity and allows peripheral immune mediators to access the brain. Microbial metabolites further shape neuroinflammatory processes. Butyrate, a major SCFA, promotes Treg differentiation in gut-associated lymphoid tissue, suppressing excessive immune activation and maintaining tolerance. In macrophages, butyrate activates PPARγ, thereby inhibiting pro-inflammatory cytokine release. SCFAs broadly regulate immune-cell differentiation through free fatty acid receptors FFA2 and FFA3, which also influence neuronal signaling and anti-inflammatory pathways. Secondary bile acids interact with TRP channels and GPCRs to modulate intestinal γδ T-cell activity, driving IL-17 and IFN-γ production that exacerbates CNS inflammation. In parallel, activation of the subdiaphragmatic vagus nerve conveys pro-inflammatory signals to the brain, contributing to neuroinflammation and demyelination, while splenic nerve–mediated aryl hydrocarbon receptor signaling further amplifies central immune activation. Importantly, ketamine enantiomers can counteract several of these pathogenic processes: esketamine improves spatial working memory in chronic-pain models, and arketamine reverses cognitive deficits and depressive-like behaviors in social-isolation and LPS-induced depression models. BBB blood–brain barrier, CNS central nervous system, GALT gut-associated lymphoid tissue, GPCRs G-protein–coupled receptors, IFN-γ interferon-γ, IL-17 interleukin-17, LPS lipopolysaccharide, PPARγ peroxisome proliferator-activated receptor-gamma, SCFAs short-chain fatty acids, Treg regulatory T cell, TRP transient receptor potential.

Ketamine’s effects in depression may also be shaped indirectly through changes in diet [133]. Severe depression is associated with appetite loss and reduced dietary diversity, which in turn worsen gut dysbiosis and systemic inflammation [134, 135]. By rapidly improving anhedonia and motivation, ketamine may restore appetite and healthier eating patterns [133, 136], secondarily fostering a more favorable microbial environment that reinforces its anti-inflammatory and neuroplastic actions.

Overall, ketamine’s antidepressant efficacy reflects an interaction between direct neuropharmacological mechanisms (e.g., NMDAR antagonism, MOR activation) and indirect gut-mediated pathways, including microbiota remodeling and normalization of microbial metabolites such as SCFAs. The gut–brain axis therefore functions as a modulatory circuit that can enhance, prolong, or individualize ketamine’s central effects, rather than acting as an isolated or primary driver of its therapeutic action.

Gut-lung axis mechanisms

Gut-lung crosstalk

The gut–lung axis refers to the bidirectional communication between the intestinal and respiratory systems that is essential for maintaining immune homeostasis and microbial balance [137, 138]. Both organs belong to the mucosal immune network and share key structural and functional features, including highly vascularized epithelia, selective barrier functions, and protective mucus layers [105]. They also arise from the embryonic foregut and retain common inflammatory and immune components, such as epithelial cells and mucosa-associated lymphoid tissues [139].

Because the lungs are continuously exposed to circulating inflammatory mediators, disorders of the respiratory and GI systems frequently coexist. Epidemiological data illustrate this overlap: Swedish registry studies show that patients with COPD have a substantially increased risk of developing ulcerative colitis and Crohn’s disease, highlighting shared pathways of chronic inflammation and immune dysregulation [140]. In turn, COPD-related impairment of gut barrier integrity—together with aggravating factors such as physical stress and hypoxia—can further increase intestinal permeability and systemic inflammation [141].

Experimental studies provide strong evidence for gut-to-lung microbial translocation and immune-cell trafficking in animal models, while clinical observations in critically ill patients offer supportive but largely associative data. Although these findings strongly suggest a functional gut–lung connection, establishing clear causality and directionality in humans remains challenging. These limitations underscore the importance of mechanistic studies to define how intestinal dysbiosis, barrier dysfunction, and immune activation translate into pulmonary pathology.

Microbiota translocation

Gut dysbiosis can initiate local intestinal inflammation and toxin release, allowing microbial products to enter the circulation and subsequently injure the lungs [142]. Clinical evidence supports this concept. In a Chinese cohort of 31 critically ill patients, bronchoalveolar lavage fluid (BALF) and fecal samples collected within 24 h of intensive care unit (ICU) admission showed that reduced gut microbial diversity and overgrowth of Proteobacteria—particularly Enterobacteriaceae—were associated with intestinal inflammation. These inflammatory signals then propagated via both the vagus nerve and the bloodstream, triggering systemic inflammation that reshaped the lung microbiota. Pathogens such as Pseudomonas aeruginosa and Staphylococcus aureus became enriched in the lungs, accompanied by immune imbalance characterized by fewer T and B cells, increased neutrophils, elevated pro-inflammatory cytokines, and reduced anti-inflammatory mediators [143].

Importantly, lung inflammation can also feedback to disrupt gut homeostasis, forming a bidirectional loop that governs mucosal immunity [143]. In a murine model, intestinal fungal dysbiosis promoted E. coli overgrowth and its translocation to the lungs during infection. This process induced accumulation of CD45⁺F4/80⁺Ly6G⁻Ly6C⁻CD11b⁺CD11c⁺ macrophages in lung tissue, and genetic deletion of Toll-like receptor 4 (TLR4) or depletion of these macrophages prevented antifungal drug-induced worsening of lung inflammation [144].

The gut microbiota profoundly shapes host immunity and influences the development of many diseases [145]. Within the gut–lung axis, dysbiosis can promote asthma and lung inflammation, while gut-derived immune cells traffic via the bloodstream to the lungs and modulate local immune responses [146–148]. In experimental ALI, antibiotic-induced depletion of gut microbes can paradoxically improve outcomes by strengthening the intestinal barrier, rebalancing immune responses, and reducing pro-inflammatory cytokines [149]. These findings highlight the dynamic and context-dependent nature of gut–lung interactions.

During sepsis, breakdown of the intestinal barrier and microbial shifts drive systemic and pulmonary inflammation, worsening ALI and ARDS. Conversely, lung injury—with its surge of inflammatory cytokines and altered lung microbiota—feeds back to the gut, inducing dysbiosis and mucosal damage. This vicious cycle amplifies inflammation and accelerates sepsis-induced ALI/ARDS [142].

Under physiological conditions, the intestinal barrier tightly regulates the passage of water, small solutes, and immunomodulatory factors while excluding microbes and macromolecules [142]. In sepsis, this barrier is disrupted, permitting bacterial translocation [142, 150]. In septic ALI/ARDS, inflammatory signaling further increases permeability through upregulation of claudin-2 and junctional adhesion molecule, downregulation of claudin-5 and zonula occludens-1, and activation of myosin light chain kinase [142].

Animal and human studies directly link gut-to-lung translocation with disease severity. In a Pseudomonas aeruginosa pneumonia–sepsis model, the small-intestinal albumin-to-plasma albumin ratio increased markedly within 40 h, indicating enhanced vascular leak, and mesenteric lymph node cultures became more frequently positive, confirming worsened bacterial translocation [151]. In ARDS patients, sequencing of BALF from 68 cases versus seven controls revealed enrichment of gut-associated Bacteroides (OTU009) in the lungs, with abundance positively correlated with TNF-α levels in both serum and BALF [16]. Another prospective cohort showed that higher lung bacterial DNA loads—especially from gut-derived Lachnospiraceae and Enterobacteriaceae—were associated with fewer ventilator-free days, lower extubation rates, and reduced survival. Together, these findings identify gut-to-lung microbial translocation as a major driver of ARDS pathogenesis and highlight the lung microbiota as a potential therapeutic target [17].

Metabolite signaling

Gut microbes influence lung health not only through immune modulation but also via the production of bioactive metabolites. SCFAs, bile acids, and tryptophan-derived metabolites can travel from the gut to the lungs through the bloodstream or via vagal pathways, where they regulate fibroblast activity and tissue remodeling [152]. For instance, butyrate and other SCFAs activate G-protein-coupled receptor 43 (GPR43) on pulmonary fibroblasts, suppressing their activation and reducing collagen deposition, thereby exerting anti-fibrotic effects [153]. In contrast, secondary bile acids such as deoxycholic acid activate farnesoid X receptor (FXR) and takeda G protein-coupled receptor 5 (TGR5) signaling in fibroblasts, promoting collagen synthesis and accelerating pulmonary fibrosis [154].

Tryptophan metabolites also shape lung inflammation. Kynurenine activates lung macrophages through the kynurenine pathway, inducing pro-inflammatory cytokines such as IL-6 and TNF-α, which further drive fibrotic and inflammatory processes [155]. In a model of severe acute pancreatitis–associated lung injury, gut-derived SCFAs (butyrate, propionate, and acetate) strengthened intestinal barrier function, reduced systemic inflammation, promoted a healthier microbiome, and ultimately protected lung function [156]. By regulating oxidative stress, apoptosis, autophagy, pyroptosis, and ferroptosis, microbiota-derived metabolites may therefore critically influence the development and progression of ALI and ARDS [9].

Immune cell migration

Immune cells originating in the gut—particularly Th17 and γδ T cells—can migrate to the lungs via CCR6-dependent pathways, amplifying pulmonary inflammation and shaping the severity of ARDS [157]. During early inflammation, γδ T17 cells rapidly release IL-17, triggering strong pro-inflammatory cytokine cascades in lung tissue [8]. After sepsis, activation of Wnt/β-catenin signaling in alveolar macrophages upregulates C-C motif chemokine ligand 1 (CCL1) through lymphoid enhancer-binding factor 1 (LEF1), which promotes the migration of memory γδ T17 cells from the small intestine to the lungs. Their subsequent IL-17A secretion markedly worsens ALI [8].

Neural modulation also influences this process. Interventions such as recombinant human atrial natriuretic peptide (rhANP) or small-intestinal vagotomy reduce IL-17A levels and block γδ T-cell trafficking to the brain and lungs, thereby alleviating social isolation–exacerbated stroke pneumonia and ischemic brain injury. These effects appear to be mediated, at least in part, through the splenic vagal nerve [7].

Gut dysbiosis further alters adaptive immunity by shifting the balance between regulatory T cells (Tregs) and Th17 cells—two populations that critically regulate pulmonary inflammation [157]. For example, Houttuynia cordata polysaccharide reshapes gut flora, increases SCFA production, restores the Th17/Treg balance, and alleviates lung inflammation [158]. Innate lymphoid cells (ILCs) are also influenced by microbial changes. Expansion of Proteobacteria promotes ILC2 migration and IL-33 production in the lungs. Mechanistically, the IL-33–CXCL16 axis drives ILC2 accumulation in lung tissue, while the IL-25–CCL25 pathway recruits inflammatory ILC2 to the intestine during abdominal infection or sepsis. These ILC2 subsets cooperate to regulate inflammation and maintain host defense [158].

Mesenteric lymph pathway

The intestinal lymphatic hypothesis proposes that gut-derived bacteria, toxins, and inflammatory mediators activate mucosal immunity and are transported to the lungs and systemic circulation through mesenteric lymphatics [142]. Mesenteric lymph contains hydrophilic components (fluids, cytokines, hormones), lipophilic components (dietary lipids and lipoproteins), and cellular elements (primarily lymphocytes). After tissue injury or infection, lymph flow increases, and protein–lipid interactions further modify lymphatic function [159]. This lymph then carries bacteria, endotoxins, cytokines, and metabolites into the circulation, triggering systemic inflammation and precipitating ALI [159].

Experimental studies strongly support this pathway. Transfer of mesenteric lymph from trauma/hemorrhagic shock (T/HS) mice into healthy rats induces lung injury similar to that seen in T/HS [160]. Conversely, surgical blockade of lymph flow—such as thoracic duct or mesenteric lymph duct ligation—prevents ALI caused by intestinal ischemia–reperfusion, peritoneal infection, T/HS, and burns [160–162].

Clinical evidence also points to the importance of this route. In a non-randomized prospective study of 12 patients with severe acute pancreatitis complicated by ALI, thoracic duct drainage rapidly improved pulmonary gas exchange. All patients survived the early phase without major complications, suggesting that removal of inflammatory mediators from the lymphatic system can alleviate respiratory failure [163]. Together, these findings identify mesenteric lymph as a critical conduit through which gut-derived toxins and inflammatory signals drive lung injury.

Immunomodulatory effects of ketamine on the gut-lung axis

Ketamine has shown therapeutic potential in ALI by dampening excessive inflammation and preserving pulmonary function. It protects against high-mobility group box 1 (HMGB1)–induced ALI by inhibiting TLR4 signaling, thereby reducing inflammatory cascades and lung tissue damage [164]. In both cellular and animal models, ketamine also attenuates LPS-induced lung injury by enhancing autophagy and suppressing apoptosis through regulation of the AMP-activated protein kinase (AMPK)–mTOR pathway [165].

Esketamine similarly exerts protective effects on the lung. Shi et al demonstrated that esketamine limits ferroptosis in ALI by upregulating hypoxia-inducible factor-1α (HIF-1α) and heme oxygenase-1 (HO-1), activating the HIF-1α/HO-1 pathway [166]. In a rat model of ventilator-induced COPD, esketamine alleviated ALI by suppressing MAPK/NF-κB signaling and reducing oxidative stress [167]. These findings indicate that ketamine and esketamine protect the lung through multiple anti-inflammatory and cytoprotective pathways.

Beyond ALI, ketamine’s bronchodilatory properties have made it a valuable option for acute asthma exacerbations. Both clinical and preclinical studies report rapid symptom relief and improved airflow in children with severe asthma, without compromising safety [168] (Fig. 4). In mixed-granulocyte mouse models of asthma, ketamine reduces airway inflammation by inducing inflammatory-cell apoptosis and activating the nuclear factor erythroid 2-related factor 2 (Nrf2) antioxidant pathway [169]. Thus, ketamine’s benefits in respiratory disease extend beyond inflammation control to include direct effects on airway tone and oxidative stress.

Fig. 4. Pathogen-driven barrier disruption and lung injury pathways in sepsis.

During sepsis, enteric pathogens and dysbiosis disrupt intestinal barrier integrity, allowing translocation of bacteria, endotoxins, cytokines, and metabolites through mesenteric lymphatics and the systemic circulation. These gut-derived factors reach the lungs and trigger inflammatory cascades. In alveolar macrophages, activation of Wnt/β-catenin signaling increases LEF1–dependent expression of CCL1, which drives CCR6-dependent migration of memory γδ T17 cells from the gut to the lung. Their secretion of IL-17A amplifies pulmonary inflammation and worsens ALI. Th17 and γδ T cells further reinforce this inflammatory loop through the same chemokine axis. Interventions such as recombinant human ANP or SDV reduce IL-17A levels and prevent γδ T-cell infiltration into the lungs. Microbial metabolites also shape lung pathology. SCFAs activate GPR43 on fibroblasts to inhibit activation and collagen production, thereby limiting fibrosis, whereas secondary bile acids engage FXR and TGR5 to promote fibroblast proliferation and extracellular-matrix deposition. Tryptophan metabolites (e.g., kynurenine) activate lung macrophages through the kynurenine pathway, inducing release of IL-6 and TNF-α and further driving fibrotic remodeling. Ketamine confers protection against ALI by suppressing TLR-4 signaling and modulating the AMPK/mTOR pathway, while esketamine mitigates ferroptosis-mediated injury via activation of the HIF-1α/HO-1 axis. In addition, ketamine’s bronchodilatory properties contribute to relief of acute asthma exacerbations. ALI acute lung injury, AMPK AMP-activated protein kinase, ANP atrial natriuretic peptide, CCL1 C-C motif chemokine ligand 1, CCR6 C-C chemokine receptor 6, FXR farnesoid X receptor, GPR43 G-protein–coupled receptor 43, HIF-1α hypoxia-inducible factor-1α, HMGB1 high-mobility group box 1, HO-1 heme oxygenase-1, IL-17A interleukin-17A, LEF1 lymphoid enhancer-binding factor 1, LPS lipopolysaccharide, SCFAs short-chain fatty acids, SDV subdiaphragmatic vagotomy, TGR5 takeda G-protein–coupled receptor 5, TLR-4 toll-like receptor 4, mTOR mechanistic target of rapamycin.

Ketamine’s broad protective profile—including analgesic, anti-inflammatory, bronchodilatory, and anxiolytic effects—largely reflects its ability to suppress pro-inflammatory cytokines such as TNF-α, IL-6, and IL-8, as well as its direct relaxation of airway smooth muscle [170]. In oncology research, ketamine has also shown antitumor activity in neuroblastoma and lung cancer cells by inhibiting proliferation, inducing apoptosis, and suppressing migration [171]. Esketamine offers additional perioperative benefits: a randomized, double-blind trial found that low-dose esketamine during general anesthesia reduced postoperative atelectasis and improved respiratory mechanics [172]. In a septic rat model, esketamine infusion did not impair alveolar fluid clearance, oxygenation, acid–base balance, lung histology, or cytokine profiles, supporting its safety in critically ill patients [173].

Although ketamine’s efficacy in ALI clearly involves direct pulmonary mechanisms—such as TLR4 inhibition, autophagy modulation, and cytokine suppression [164, 165, 170]—evidence for gut-dependent mechanisms is more limited and largely correlative. For example, reduced trafficking of gut-derived γδ T17 cells to the lung has been observed after ketamine treatment [8], but it remains unclear whether this reflects a primary gut-mediated effect or a secondary consequence of systemic anti-inflammatory actions. Ketamine likely protects the lung through both direct local mechanisms and indirect gut-modulated pathways, with their relative contributions varying by disease context. Therefore, understanding ketamine’s actions requires integrated consideration of both lung-centered and gut-dependent mechanisms within the gut–lung axis (Table 2).

Table 2.

Evidence for gut-mediated effects of ketamine and its enantiomers across disease models.

Disease / Model	Gut-related changes observed	Associated outcomes	Evidence type	Causal link to gut	Supporting References
Depression (CSDS model)	Reshaping of gut microbiota	Antidepressant-like behavior (arketamine)	Correlative	Not established	[71,72]
Depression (LPS model)	Modulation of gut microbiota; ↓ splenic γδ T cells	Improved depressive-like behavior (arketamine)	Mechanistic (antibody blocking)	Partially supported	[103]
Depression (TRD patients)	Reduced beneficial bacteria; ↑ potential pathogens	Ketamine efficacy	Correlative	Not established	[129]
Chronic pain + cognitive impairment	Altered microbiota; ↓ inflammation	Improved spatial working memory (esketamine)	Correlative	Not established	[21]
Cuprizone-induced demyelination	Gut microbiota remodeling	Enhanced remyelination; neuroprotection (arketamine)	Mechanistic (vagotomy blocks effect)	Supported	[22,92]
Sepsis-induced ALI	↓ Gut-derived γδ T17 cell migration to lung	Attenuated lung injury (esketamine)	Mechanistic (cell tracking)	Supported	[8]
Acute lung injury (ARDS models)	Gut dysbiosis; bacterial translocation	Pulmonary inflammation	Correlative	Not established	[16,17,142]
Sepsis (CLP model)	Not explicitly measured (systemic inflammation focus)	Multi-organ protection; improved survival (arketamine)	Correlative (outcome-focused)	Not established	[68]
Social isolation + stroke	↑ Gut γδ T cell migration to brain/lung	Worsened stroke pneumonia	Mechanistic (vagotomy/γδ T cell depletion)	Supported	[7]
Long-term ketamine abuse (rat model)	Gut dysbiosis; barrier disruption	Hippocampal dysfunction; anxiety-like behavior	Correlative	Not established	[130]
Ketamine reward (CPP model)	↓ SCFA levels; microbiota depletion	↓ Conditioned place preference	Mechanistic (FMT restores effect)	Supported	[131]
Inflammation-induced depression (LPS model)	Beneficial shifts in gut microbiota	Antidepressant-like effect of (S)-norketamine	Correlative	Not established	[82]

ALI acute lung injury, ARDS acute respiratory distress syndrome, CLP cecal ligation and puncture, CPP conditioned place preference, CSDS chronic social defeat stress, FMT fecal microbiota transplantation, LPS lipopolysaccharide, SCFA short-chain fatty acid, TRD treatment-resistant depression.

Comparison of racemic ketamine and ketamine enantiomers

Direct comparisons between arketamine and esketamine in TRD are scarce, but studies comparing intravenous (IV) racemic ketamine with intranasal (IN) esketamine offer indirect insights. In a retrospective review of 153 patients, Meisner et al found that IV racemic ketamine produced greater symptom reduction over 4–5 weeks than IN esketamine [174]. Improvement occurred earlier with racemic ketamine—often after the first infusion—whereas esketamine typically showed significant effects after the second dose, despite similar baseline severity [174].

In a complementary letter, Tan and Hashimoto suggested that the superior or more sustained effects of racemic ketamine may partly reflect the contribution of arketamine, which appears to produce longer-lasting antidepressant actions and may engage mechanisms distinct from those of esketamine alone [175]. Although esketamine has demonstrated rapid antidepressant effects and has received regulatory approval for TRD, these emerging comparative data imply that racemic ketamine—through the combined actions of both enantiomers, particularly arketamine—may provide a faster onset and greater overall symptom reduction in some patients. Moreover, given that NMDAR-related dissociative symptoms are not required for antidepressant efficacy of ketamine or esketamine [176], it is plausible that arketamine makes an important contribution to the robust antidepressant actions of racemic ketamine [10–12, 37].

Taken together, these observations emphasize the importance of enantiomer-specific contributions when selecting ketamine-based therapies. They also highlight the need for well-controlled, prospective head-to-head trials comparing racemic ketamine, arketamine, and esketamine to clarify their relative efficacy, durability of response, safety profiles, and optimal clinical indications in patients with TRD [37].

Adverse events of ketamine enantiomers

Post-marketing pharmacovigilance studies of esketamine nasal spray indicate that, in addition to well-recognized acute reactions—such as dissociation, sedation or somnolence, dizziness/vertigo, and transient blood-pressure elevation—a range of neuropsychiatric “serious” adverse events has also been reported in spontaneous-report databases. Analyses of the FDA Adverse Event Reporting System (FAERS) have identified signals for unusual reactions including flashbacks, tachyphylaxis, autoscopy, and potential addiction liability, as well as reports related to suicidal risk [177]. Another large database study found that older adults (>65 years) showed higher reporting rates of dissociation, suicidal ideation, depression, and anxiety than younger patients [178]. More recent FAERS-based analyses further detected novel safety signals, such as homicidal ideation and substance use disorder, underscoring the need for continued and careful pharmacovigilance [179].

Large-scale real-world safety data from the U.S. Risk Evaluation and Mitigation Strategy (REMS) program, summarized by Sanacora et al, provide a more structured assessment of esketamine’s safety profile. These data show that acute adverse effects—particularly blood-pressure changes, dissociation, and nausea—are largely consistent with clinical-trial findings and generally reassuring [180]. However, although the overall suicide rate during treatment approximated that expected in treatment-resistant MDD, a substantial proportion of suicides occurred within one week of the most recent dose. This timing raises concern about possible vulnerability around dosing intervals, discontinuation, or withdrawal-related effects. At the same time, the surprisingly low numbers of reported suicide attempts and all-cause deaths suggest possible underreporting or limitations inherent to passive surveillance systems. Thus, while these data broadly support the clinical safety of esketamine, they also leave important unresolved questions regarding suicidality and the interpretation of real-world adverse-event rates [181, 182].

In contrast, the adverse-event profile of arketamine remains much less well defined because existing studies are small and lack long-term or post-marketing surveillance. Early trials suggest that arketamine may cause fewer dissociative and psychotomimetic effects than esketamine, but robust comparative safety data are not yet available. Future studies using large real-world databases, active surveillance systems, and prospective registries will be essential to clarify the long-term safety of ketamine enantiomers, particularly with respect to neuropsychiatric events, abuse liability, and suicidality-related outcomes.

Conclusion and future directions

Ketamine and its enantiomers exert pleiotropic actions that extend well beyond simple NMDAR antagonism. In addition to rapidly enhancing synaptic plasticity and neurotrophic signaling, they consistently dampen systemic and central inflammation. A growing body of preclinical work links their administration to remodeling of gut microbial communities, shifts in microbial metabolites (e.g., SCFAs and bile acids), and altered trafficking of gut-derived immune cells along the gut–brain and gut–lung axes. Together, these findings suggest that ketamine’s benefits in depression, sepsis, and respiratory disease may partly involve modulation of mucosal barrier integrity, microbial ecology, and immune-cell migration. However, these relationships are largely associative. Because the gut and brain influence each other bidirectionally [84, 105], ketamine’s central actions can secondarily reshape gut function, while gut changes can in turn modulate brain and lung pathology. Thus, current evidence supports a contributory role for gut–organ axes in ketamine’s systemic effects, but does not yet establish that barrier repair or metabolite rebalancing are primary initiating mechanisms. Notably, arketamine shows particularly long-lasting antidepressant and organ-protective effects in rodents, often accompanied by microbiota remodeling, whereas esketamine demonstrates efficacy in ALI and asthma models through anti-inflammatory, autophagy-enhancing, and anti-ferroptotic pathways.

Future research must move from correlation to causation and toward more precise therapeutic targeting. Dissecting gut-mediated from direct central effects will require causal experimental strategies, including FMT from ketamine-treated donors, antibiotic- or germ-free models to deplete microbiota, and tissue-specific genetic manipulations (e.g., intestinal epithelial or immune-cell–specific knockouts of key signaling molecules). Combining these tools with multi-omics profiling of microbiota, metabolites, and immune responses will clarify whether gut-derived signals act as drivers, amplifiers, or bystanders in ketamine’s actions. Such work will be essential for translating these insights into rational combination strategies—pairing ketamine or its enantiomers with microbiota-targeted or immune-modulating interventions—to optimize efficacy while minimizing adverse effects.

Author contributions

XZ, XZ, SY, KH and JZ contributed to the literature search and acquisition of data, drafting of the initial manuscript and critical revision of the final manuscript and approved the final version of the manuscript for publication.

Data availability

Not applicable.

Competing interests

Dr. Hashimoto is one of the editorial board members of this journal. Dr. Hashimoto is the inventor of filed patent applications on “The use of (R)-ketamine in the treatment of psychiatric diseases”, “(S)-norketamine and salt thereof as pharmaceutical”, “(R)-ketamine and derivative thereof as prophylactic or therapeutic agent for neurodegeneration disease or recognition function disorder”, “Preventive or therapeutic agent and pharmaceutical composition for inflammatory diseases or bone diseases”, and “(R)-ketamine and its derivatives as a preventive or therapeutic agent for a neurodevelopmental disorder” by the Chiba University. Dr. Hashimoto also declares that he has received research support from Otsuka (Japan). Other authors declare no conflict of interest.