1. bookVolume 76 (2022): Edition 1 (January 2022)
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Ketamine used in the therapy of depressive disorders impacts protein profile, proliferation rate, and phagocytosis resistance of enterococci

Publié en ligne: 09 Aug 2022
Volume & Edition: Volume 76 (2022) - Edition 1 (January 2022)
Pages: 333 - 338
Reçu: 03 Jan 2022
Accepté: 11 May 2022
Détails du magazine
License
Format
Magazine
eISSN
1732-2693
Première parution
20 Dec 2021
Périodicité
1 fois par an
Langues
Anglais
Abstract Introduction

A low concentration of ketamine is used to cause an anti-depressive effect. The mechanism of ketamine's action in depression is believed to result, among others, from its anti-inflammatory activity. Despite the fact that only high concentrations of ketamine inhibit bacterial growth, it is clear that even a sub-inhibitory concentration of chemicals may change bacterial properties. Considering the above, in the current study we aimed to evaluate the in vitro influence of ketamine on proliferation of enterococci and their interactions with monocytes.

Materials and Methods

The studied strains were isolated as etiological agents of infection at Medical University of Gdansk. The proliferation and metabolic activity were determined using the FACSVerse flow cytometer after addition of CFDA-SE to bacterial suspension. For the determination of phagocytosis resistance, THP-1 human monocytes cell line was used. Suspension of monocytes which engulfed CFDA-SE–stained bacteria was then stained with propidium iodide to evaluate cytotoxicity of enterococci.

Results

The result of the study showed unexpected response of bacterial cells to ketamine at an early stage of culture. In 57.7% of strains, both proliferation rate and metabolic activity were boosted. This group of strains was also less susceptible to phagocytosis than in culture without ketamine. Different response of isolates to ketamine was also visible in changes of proteins’ profile determined by MALDI-TOF.

Conclusions

The analysis of bacteria at an early stage in the growth curve demonstrated the bacterial diversity in response to ketamine and let us set the hypothesis that microbiome susceptibility to ketamine may be one of the elements which should be taken into consideration when planning the successful pharmacotherapy of depression

Keywords

Introduction

Ketamine's usage as a medicine has a long history, more than 50 years old. At first, it was used as an anesthetic and analgesic agent, but following that, its ability to block NMDA (glutamate N-methyl-D-aspartate calcium channels) receptors was discovered and the usage of the drug in psychiatry was also approved [1]. The approval of ketamine as a drug came first for hyperalgesia [2] and then for schizophrenia [3], but later on it was also used for treatment of resistant unipolar and bipolar depressions [4, 5, 6]. Its rapid action, its effectiveness in combating the symptoms, and its benign and transient adverse effects back up its common, current usage [7].

If we add the quick and effective anti-depressive action of ketamine to its well-proven immunomodulatory [8, 9] and antimicrobial potential [10, 11, 12], we need to consider a possible influence of ketamine on the gut bacteria. Even though the dosage of ketamine used in anesthesiology and anti-depressive therapy is well below its minimal inhibitory concentration (MIC) for the majority of bacteria [11], the possible influence of ketamine on bacterial growth cannot be ignored. It is widely known that even sub-inhibitory concentration of chemicals, such as antibiotics, can affect many properties of bacteria, such as virulence factors’ expression or cell morphology [13, 14, 15, 16, 17]. So far there are few published results about the potential modulation of antibacterial properties of ketamine used in the concentration range specific to therapy of depression. The knowledge about possible influence of ketamine seems to be essential, as the mechanism of action of this drug in depression is believed to result from, among other factors, its anti-inflammatory activity [18]. Even more interestingly, some data even suggest that this anti-inflammatory activity is, at least partially, the result of interaction between the drug and gut bacteria [19]. Changes of bacterial virulence – apart from expression of virulence genes and formation of biofilm – include also changes in proliferation rate and the development of so-called small colony variants (SCVs). SCVs are considered especially important in the case of chronic infections, promoting chronic low-grade inflammation, which is also commonly linked with depressive disorders [20, 21]. In the current study we aimed to evaluate the in vitro influence of ketamine on the proliferation, cytotoxicity, and phagocytosis resistance of Enterococcus when exposed to ketamine in concentrations used in depressive disorders therapy.

Materials and Methods
Determination of growth rate and metabolic activity changes

The 27 studied enterococcal strains were isolated from various clinical samples as etiological agents of infection and collected in the Department of Medical Microbiology, Medical University of Gdansk (Table 1). The isolates were identified to species level by strep ID test (BioMerieux, Poland) and classified as different strains of Enterococcus faecalis by biochemical and antibiotic resistance profiles.

Source of strains

Source Number of strains
Upper respiratory tract 6
Cervical canal 4
Vagina 4
Wound 5
Urine (> 106 cfu/mL) 4
Bedsore 3
Sperm 1

The growth rate was studied in Brain Heart Infusion Broth (BHI, Oxoid, England). Medium was inoculated with bacterial strains and cultured at 37°C in aerobic conditions with shaking (200 rpm). After 24 h, the fresh BHI was inoculated with 10 μL of bacterial suspension. Each isolate was then incubated at 37°C for 3 hours in two variants: with or without ketamine. The concentration of ketamine used in the experiment was 200 ng/mL – the maximal plasma concentration obtained from a patient undergoing anti-depression therapy 40 minutes after infusion [22].

The samples were then centrifuged and pellets were washed three times with saline. To measure metabolic activity of E. faecalis, 10 μM of CFDA-SE (carboxyfluorescein diacetate succinimidyl ester, Sigma-Aldrich, USA) were added to 200 μL of bacterial suspension of each strain. Mixtures were then incubated for 45 min at 37 °C and centrifuged. The pellets were collected and washed three times with PBS (phosphate-buffered saline, Sigma-Aldrich, USA). The number of bacterial cells and their fluorescence were determined using FACSVerse flow cytometer (Becton Dickinson, San Jose, CA, USA). Effect was measured as the ratio of number of the cells and green fluorescence intensity in culture with ketamine versus culture without ketamine.

Determination of phagocytosis resistance and cytotoxicity of the strains

For the assessment of phagocytosis, THP-1 human monocytes cell line (TIB-202™, ATCC, American Type Culture Collection) was used. The cells were cultured in RPMI-1640 medium supplemented with 2 mM L-glutamine, 100 U/mL penicillin, 100 μg/mL streptomycin, and 10% (vol/vol) heat-inactivated fetal bovine serum (FBS) (all from Sigma-Aldrich, USA). For each phagocytosis assay, the enterococcal culture stained with CFDA-SE was used.

Each phagocytic mixture contained 0.4 mL of stained enterococci (8 × 107) and 0.4 mL of monocytes (2.5 × 107). The mixture was incubated for 45 min at 37 °C. Suspension of monocytes was then stained with propidium iodide (PI, Sigma Aldrich, USA) at room temperature to determine cells’ membrane permeability and to evaluate cytotoxicity of enterococci. Emitted fluorescence was determined using a FACSVerse flow cytometer. Differences in phagocytosis effectiveness between strains treated with ketamine and without ketamine were measured as the changes in green fluorescence (for CFDA-SE) and the cytotoxicity of bacterial cells (treated with ketamine vs. not treated with ketamine) was measured as the changes in red fluorescence (for PI). The red fluorescence emitted by PI-stained monocytes not exposed to bacterial suspension was considered a baseline value for monocytes’ viability.

Determination of protein profiles in MALDI-TOF analysis

To analyze protein profiles, BHI medium was inoculated with bacterial strains and cultured at 37°C in aerobic conditions with shaking (200 rpm). After 24 h, the fresh BHI was inoculated with 10 μL of bacterial suspension. Each isolate was then incubated at 37°C for 18 hours in two variants: with or without ketamine. The samples were centrifuged, and pellets were washed three times with saline. The bacterial pellet was applied to a metal plate and dried at room temperature. Then, 1 μL of an α-cyano-4-hydroxycinnamic acid matrix solution (HCCA, Bruker Daltonics) was applied and the sample was left to dry at room temperature. Measurement of the spectrum and comparative analysis with reference spectra of bacteria were performed using MALDI-Biotyper 3.0 (Bruker Daltonics, USA). Mass spectra were collected using FlexControl software (Bruker Daltonics, USA). Then, the spectra were baseline analyzed using mMass Software, version 5.5.0. [23].

Statistical analysis

The ratio of the number of bacteria and the intensity of fluorescence, expressed as mean fluorescence per particle (green fluorescence for CFDA-SE/FSC; red fluorescence for PI/FSC), were subjected to the analysis of variance (ANOVA) with Statistica™10 software (StatSoft, Poland). The normality of distribution was verified by χ2 test, and the data were normalized by Box–Cox transformation.

Results
Ketamine impacts proliferation of enterococcal cells

Although the ketamine does not affect the formation of SCVs, Enterococcus faecalis strains show two opposite reactions when it comes to the response to ketamine. Among tested strains, there were those responding by inhibiting their metabolism as well as the strains which in the presence of ketamine boosted their metabolism considerably. In 42.3% of strains the inhibition of their metabolism, measured as CFDA-SE hydrolysis, was observed. Within this group, in 23.1% of strains also proliferation rate was lower than in culture without ketamine and susceptibility to phagocytosis mediated by THP-1 cells increased up to 1.51 times while the median cytotoxicity was usually lower.

In contrast to our expectations, the majority of strains (57.7%) increased both proliferation and cellular metabolism at tested concentration of ketamine. The increase of proliferation varied from 1.23 up to 4.5 times (median 2.45) while increase of metabolism varied from 1.24 up to 5.90 times (median 2.75) when compared to bacteria not exposed to ketamine. Correlation between induction of proliferation and metabolism rate measured by CFDA-SE hydrolysis has not been proved, but based on abovementioned criteria, we might define two groups of strains: boosted and inhibited by ketamine (Figure 1).

Fig. 1

Characteristics of two types of strains identified by response to ketamine

Ketamine affects the protein profiles in the bacterial strains

The diverse response of strains to ketamine was also visible in protein profiles analyzed by MALDI-TOF. In detailed analysis, in the spectral profiles of studied enterococci, 15 peaks were identified with m/z value of 2211, 2633, 3420, 3670, 4440, 4780, 5360 6080, 6230, 6400, 6840, 7330, 7570, 8910 and 9540. Eight of those peaks were described previously by Stępień-Pyśniak D as characteristic for Enterococcus faecalis, while others were unique for the studied collection [24].

In both groups of strains (inhibiting and intensifying the proliferation rate) and in the abovementioned study of Stępień-Pyśniak et al. [24], relative intensity of the peak was the highest at m/z 4440 and this value remained unchanged after incubation with ketamine.

In the strains responding to the exposure to ketamine by increasing the proliferation, most of the proteins increased in amount, decreased peak intensity was noticed at m/z 5360 and 6400. In the group of strains with inhibited proliferation, the intensity of peaks was lower after incubation with ketamine, with the exception of m/z value at 4439, 5360 and 9540 (Table 2).

Changes of relative values of protein peak after incubation of the enterococcal strains with ketamine. Group A+: strains increasing proliferation when cultured with ketamine; group B+ strains inhibited by ketamine; group A and B – strains cultured without ketamine. Grey bars: peaks typical for Enterococcus faecalis according to Stępień-Pyśniak D et al. [24]. Dark grey bars: the highest protein peak for all the measurements, considered as baseline for observed levels in other protein peaks (group A and B) and after the exposure to ketamine (group A+ and B+). Green color underlines the increase of peak value; the red color indicates decreased or missing peak when compared to strains not exposed to ketamine

Reference m/z Group A Group A + Group B Group B +
Stępień-Pyśniak D 2211 67 88 0 25
2663 29 0 0 17
3421 29 29 33 20
3669 26 35 24 0
4439 100 100 100 100
4778 28 37 22 17
5361 53 40 38 62
6084 14 16 15 10
6231 14 15 18 0
6403 25 24 31 26
6839 31 32 40 38
7326 42 59 42 13
7572 23 0 23 19
8911 12 15 21 12
9544 27 35 23 26
Ketamine affects susceptibility to phagocytosis in the bacterial strains

Not only proliferation rate and protein profiles were different in both groups. Susceptibility to phagocytosis was lower within groups “boosted” by ketamine strains. The ANOVA analysis proved decreased cytotoxicity and increased phagocytosis rates in the group of strains inhibited by ketamine. The changes of cytotoxicity and phagocytosis were not as evident in cases of strains with increased proliferation (Figure 2).

Fig. 2

Changes in cytotoxicity and phagocytosis in two groups of Enterococcus faecalis strains. The value 1.00 means no changes when compared with bacteria not treated with ketamine

Discussion

It is widely known that ketamine inhibits bacterial growth [10, 11], but MIC value usually is above even the concentration used for anesthetic purposes, while concentrations used in the therapy of depression are many times lower. In our study, we have identified the strains with unexpectedly heterogeneous response to subinhibitory concentration of ketamine. Bacterial response to ketamine was visible in all observed aspects – proliferation, metabolism rate, and protein profiles, and was shown to affect cytotoxicity, and the phagocytosis resistance of strains as well. That in itself is not surprising when we take into consideration bacterial (not only E. faecalis) diversity in response to many drugs and other chemical agents. When analyzing those varied responses, however, we can outline some hypothesis.

Inhibition of proliferation and metabolism together with increased susceptibility to phagocytosis can be considered as related to the reduced risk of chronic infection. For one, all those factors will affect the effective removal of bacteria from the host body by the immune cells; for another, the persistence of bacterial agents is considered an important factor affecting the development of depression [25]. Therefore, such observation may also be treated as an additional, possible explanation of ketamine's anti-depressive mode of action. This is apart, of course, from the evident inhibition of NMDA (N-methyl-D-aspartate) receptors [26]. Inversely, a significant portion of the strains seems to be resistant to ketamine and to react in the opposite way, which may be one of the possible explanations behind the varied response to ketamine when used long-term, among the patients with treatment-resistant depression. This diversity could be also explained by the changes in protein profiles. Currently it is believed that the protein profiles reflect bacterial metabolism [27]. The highest intensity peak was observed at m/z 4440 – in both groups of bacteria – inhibited and stimulated by the ketamine. What is interesting is that others also reported such occurrence [24].

The fact that Enterococcus faecalis phagocytosis mediated by THP-1 cells was diverse when exposed to ketamine suggests that the ketamine changes properties of bacteria, as the THP-1 monocytes were not incubated with ketamine. In the Toyota S et al. study, the influence of ketamine on phagocytosis was observed when concentration above 100 μg/mL was used [28]. At lower concentrations (but still much higher than those used in our experiments) ketamine inhibited phagocytosis of Escherichia coli and Staphylococcus aureus [29]. Some data suggest that the decrease in phagocytic activity is caused by the stimulation of prostaglandin E2 (PGE2) production [30]. PGE2 is one of the chemicals engaged in anti-inflammatory response – Son K-A et al. proved that PGE2 release leads to decreased production of pro-inflammatory cytokines, such as TNF-α, which in turn is responsible for superoxide generation needed for effective oxidative burst in phagocytosis [30].

Based on our results, we propose the hypothesis that micro-biome susceptibility to ketamine may be one of the elements essential for the successful pharmacotherapy of depression. Although presented results are preliminary, it is also clear that mechanisms and consequences of observed changes are the promising target for future studies, including influence of ketamine on biofilm formation and survival of bacteria within phagocytes. This study contributes to the evidence for interplay between pro- and anti-inflammatory response with microbiome dysfunction.

We have also proved that this diverse reaction of bacterial cells to ketamine may be noticed only at a very early stage of growth curve. Later on, the ketamine does not affect the bacteria in any specific way (data not shown).

Conclusions

The results of the study proved the influence of therapeutic concentration of ketamine on cytotoxicity, proliferation, and phagocytosis resistance, as well as the diversity in the response of enterococcal isolates to ketamine. Taking into consideration that such properties of bacteria are related to the risk of chronic inflammation, the abovementioned findings might be essential for therapy individualization of patients suffering from depressive disorders.

Fig. 1

Characteristics of two types of strains identified by response to ketamine
Characteristics of two types of strains identified by response to ketamine

Fig. 2

Changes in cytotoxicity and phagocytosis in two groups of Enterococcus faecalis strains. The value 1.00 means no changes when compared with bacteria not treated with ketamine
Changes in cytotoxicity and phagocytosis in two groups of Enterococcus faecalis strains. The value 1.00 means no changes when compared with bacteria not treated with ketamine

Source of strains

Source Number of strains
Upper respiratory tract 6
Cervical canal 4
Vagina 4
Wound 5
Urine (> 106 cfu/mL) 4
Bedsore 3
Sperm 1

Changes of relative values of protein peak after incubation of the enterococcal strains with ketamine. Group A+: strains increasing proliferation when cultured with ketamine; group B+ strains inhibited by ketamine; group A and B – strains cultured without ketamine. Grey bars: peaks typical for Enterococcus faecalis according to Stępień-Pyśniak D et al. [24]. Dark grey bars: the highest protein peak for all the measurements, considered as baseline for observed levels in other protein peaks (group A and B) and after the exposure to ketamine (group A+ and B+). Green color underlines the increase of peak value; the red color indicates decreased or missing peak when compared to strains not exposed to ketamine

Reference m/z Group A Group A + Group B Group B +
Stępień-Pyśniak D 2211 67 88 0 25
2663 29 0 0 17
3421 29 29 33 20
3669 26 35 24 0
4439 100 100 100 100
4778 28 37 22 17
5361 53 40 38 62
6084 14 16 15 10
6231 14 15 18 0
6403 25 24 31 26
6839 31 32 40 38
7326 42 59 42 13
7572 23 0 23 19
8911 12 15 21 12
9544 27 35 23 26

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