Therapeutic effects of Probiotic Ointment for Atopic Dermatitis

 

Mikhail Kasatkin1*, Lyudmila Smirnova2, Dmitrii Babaskin3

1Department of Sports Medicine and Medical Rehabilitation, I.M. Sechenov First Moscow State Medical University (Sechenov University), Bolshaya Pirogovskaya str., 2, Moscow, 119435, Russian Federation.

2Department of Dermatology and Venereology, I.M. Sechenov First Moscow State Medical University (Sechenov University), Bolshaya Pirogovskaya str., 2, Moscow, 119435, Russian Federation.

3Department of Pharmacy, I.M. Sechenov First Moscow State Medical University (Sechenov University), Trubetskaya Str., 8-2, Moscow, 119991, Russian Federation.

*Corresponding Author E-mail: mikh_kasatkin@rambler.ru

 

ABSTRACT:

The human microbiome is an integral part of the body, playing a crucial role in metabolism, energy homeostasis, the regulation of the immune system, and others. The study aims to examine the effect of probiotic ointment on the qualitative composition of the lesional skin microbiome in patients with atopic dermatitis. The study population consisted of 110 patients aged 20 to 45 years with mild atopic dermatitis (AD). The patients were divided into two groups. One group received four different medications: levocetirizine dihydrochloride, enterosgel, topical Tizol gel, and topical 1% hydrocortisone ointment. The other group received a similar treatment with four different medications: levocetirizine dihydrochloride, enterosgel, topical Tizol gel, and topical probiotic ointment. The treatment period was one month. After treatment, the frequency and intensity of the main AD symptoms significantly decreased. A load of S. aureus fell in the probiotic-treated group from 73.4% to 29.1% (p<.05). In the standard-treated group, the S. aureus load decreased from 78.2% to 43.6% (p<.05). The study found that the standard treatment without probiotics helped to decrease S. aureus colonisation in AD patients by 2.00 times (p<.05), whereas using the probiotic ointment reduced S. aureus colonisation by 3 times (p<.05).

 

KEYWORDS: Immune system, Normalisation of the skin Microbiome, Probiotic Ointment, skin Microbiome, topical Probiotics, Treatment period.

 

 


INTRODUCTION:

The human microbiome plays an important role in homeostasis and aids in the proper functioning of a human body1. It becomes increasingly clear that human existence is impossible without microbial life. The more types of microorganisms constitute a human microbiome, the better because taxonomic diversity is a factor that determines human health. The human body comprises millions of coexisting microorganisms, such as bacteria, viruses, and fungi2,3.

 

The human microbiome is a diverse and constitutive part of the human body. According to some estimates, our body is composed mostly of microbial cells at a ratio of 10:13. Microorganisms make up around 3 to 5 percent of the total body mass, having a higher concentration than the heart and the brain4. The largest portions of human microbiota concentrate in the gastrointestinal (GI) tract, reside on the skin and within the oral cavity, and occupy the respiratory and genitourinary systems. The GI tract, for example, consists of more than 100.000 billion microorganisms and hundreds of species of bacteria. Even though each person has a unique microbiome composition, their microbial community typically includes the following bacterial phyla or divisions: Firmicutes (genera Lactobacillus, Eubacterium, Clostridium, and Ruminococcus), Bacteroidetes (genera Bacteroides and Prevotella), Proteobacteria (Enterobacter spp.), and Actinobacteria (genera Bifidobacterium and Colinsella)4,5.

 

The human microbiota strongly affects the development and regulation of the immune system6, a complex network of cells that emerged in association with microorganisms3,6. The early precursors of the adaptive immune system emerged around 500 million years ago3.

 

Bacteria synthesise the analogues of hormones such as serotonin, dopamine, norepinephrine, histamine, and testosterone5, which enter the bloodstream through the intestinal wall and reach the brain, shaping one’s taste preferences, behaviour, habits, and more7. This process occurs within the brain-gut-microbiota axis, a communication network that enables brain-gut interaction at three levels: the motor, sensory, and neuroendocrine ones5,8. The brain-gut axis dysfunction can provoke an inflammatory bowel disease (IBD), accompanied by dysbiosis and mental disorders such as depression, anxiety, nervousness, etc.9. The human microbiome also plays a crucial role in digestion, synthesis of vitamins, and angiogenesis3,10.

 

Industrial modernization has led to an increased incidence of diseases associated with immune system hyperreactivity11,12. The human microbiome research made it possible to understand the pathogeneses of many diseases better. For instance, metabolic disturbances may associate with other conditions, such as obesity and abnormal Firmicutes and Bacteroidetes levels13. Some bacteria, namely bifidobacterium and lactobacillus, can restore the immune function and inhibit allergic reactions14. The recent studies show that mycobiota participates in developing human diseases, such as hepatitis B, cystic fibrosis, and IBD15.

 

Many inflammatory and autoimmune diseases (such as arthritis, IBD, type 2 diabetes mellitus, bronchial asthma, and systemic lupus erythematosus) can be treated by modulating and restoring the microbiota16,17. The composition and the functional potential of the human microbiome is largely influenced by diet18,19. This feature allows doctors to use pre-, pro-, and synbiotics in microbiome regulation18,19. Probiotics are biologically active supplements containing one or more types of bacteria to restore normal microflora19,20. Probiotics are widely used in clinical practice. To be effective, a probiotic must fulfill several criteria: (1) it must be resistant to hydrochloric acid, bile, and pancreatic juice to survive passage through the GI tract; (2) it must release antimicrobial compounds to fight pathogens; (3) it must adhere to the intestinal epithelium; (4) it must colonize the target organ (such as gastrointestinal tract, skin, urogenital system, etc.); (5) it must be safe; and (6) it must survive during storage under normal conditions16. The research on the potential effect of probiotics on the human body is extensive. Nevertheless, our understanding of the mechanisms of action of probiotics is blurred. The U.S. Food and Drug Administration21 did not approve any probiotics for the treatment or prevention of health disorders.

 

At present, substantial evidence exists that shows what benefits the use of probiotics might have, when applied to bowel disturbances, immune disorders, and vaginal infections. Studies report on the therapeutic effect of probiotics on rheumatoid arthritis22,23, liver cirrhosis24,25, atopic eczema26-28. Sometimes, probiotics may be prescribed to lower blood cholesterol, yet findings regarding this possibility are contradictory29-31.

 

The disturbance of the microbiome plays a direct role in certain diseases. From this perspective, it is vital to explore how it responses to different illnesses. This step may lead to a better understanding of associations between microorganisms and somatic pathologies. Today, using probiotics in the treatment of skin diseases is a hot topic in medical research. It is especially the case for atopic dermatitis (AD), the incidence of which has grown significantly over the past decade. AD affects around 15 to 20 percent of school-age children in developed countries32 and 3 percent of adults worldwide33. In the United States, for example, nearly 30 million people suffer from AD34. The total cost attributable to AD treatment in 2016 amounted to 5.4 billion dollars35. The lack of medication to achieve a long-term AD remission makes scientists seek new treatments. One of the promising remedies for AD is probiotics, which may facilitate the remission. The literature on the effect of probiotics in the treatment of AD is scarce and limited by a small sample size and an oral administration route of probiotic delivery. This study deals with the topical route of probiotic administration (application to the external surfaces). The examples include ointments, creams, and lotions, which may be applied directly to the affected skin. This work aimed to examine the therapeutic effect of probiotic ointment and the qualitative composition of the lesional skin microbiome in patients with atopic dermatitis.

 

MATERIALS AND METHODS:

Participants and Regimen:

The study population consisted of 110 adult patients (59 men and 51 women), aged 20 to 45 years, with mild AD. The exclusion criteria were as follows: (1) patients under 18 years and above 45 years of age; (2) widespread or diffuse AD, moderate to severe AD, another skin disorder, and concomitant acute disturbances; (3) patients having chronic somatic disease, mental disorders or cancer; (4) pregnancy and lactation; and (5) patients who receive antibiotic therapy three months before the study.

 

All patients were randomly assigned to one of two groups: a standard-treated group and a probiotic-treated group, 55 patients per group (Figure 1). The standard-treated group received levocetirizine dihydrochloride tablets 5 mg orally once a day and enterosgel capsules 32 g orally twice a day. Patients in this group were assigned to a hypoallergenic diet. In addition, all patients in this group were treated with topically applied Tizol gel (trice a day) and topically applied 1% hydrocortisone ointment (once a day). The probiotic-treated group received a similar treatment, but with a specially prepared probiotic ointment, instead of the 1% hydrocortisone ointment. Both treatments lasted one month. The control group consisted of 30 age-matched healthy individuals.

 

Figure 1. The study flowchart.

 

Procedures:

All procedures concerning the diagnosis and treatment of AD were carried out in accordance with the 2018 European Guidelines for Treatment of Atopic Eczema (Atopic Dermatitis)35,36.

 

Patients in both groups underwent history taking, physical examination, and microbiological examination of the skin before and after the 30-day treatment campaign. The skin examination was to identify cutaneous manifestations, such as erythema, dry skin, peeling of the skin, crusting, edema, itching, white dermographism, and hyperpigmentation.

 

The severity of AD was measured by using the SCORAD (Scoring Atopic Dermatitis). The AD severity scores were categorised into three groups: mild (<20 points), moderate (20–40 points), and severe (>40 points). The extent of AD was measured with the rule of nines. The intensity of AD was evaluated by grading the following six signs: erythema, edema/papulation, excoriations, lichenification, oozing/crusts, and dryness.

 

All patients underwent eosinophil count testing for allergic reactions and a battery of biochemical tests. This battery of tests involves the blood glucose test, the kidney function test, the liver function test, and the total protein test. The blood glucose test was to exclude carbohydrate metabolism disorders. The kidney function test involved the analysis of blood (urea and serum creatinine tests) and urine. The kidney function test and the liver function test were meant to exclude kidney and liver dysfunctions. The total protein test was to exclude concomitant kidney, liver, and heart diseases. The blood samples were taken from the cubital vein in the morning after an overnight fast of 8 hours. The biochemical screening was performed in an automatic analyzer Huma Star 600 (Germany).

 

Аll patients underwent a qualitative examination of the skin microbiota via a culture method37. The samples for microbiota analysis were collected from the affected skin of atopic patients. The non-affected skin samples were collected from the middle third of the inner forearm in healthy participants. The sampling campaign was according to the guidelines of Patrick R. Murray38 and Vadim Menshikov39.

 

The collected samples of bacteria were inoculated into the suitable culture media (HiMedia, India) within 1 hour after collection. For facultative anaerobic microflora, the following media were used: blood agar base, endo agar, HiGrome aureus agar base, HiGrome enterococci agar, and HiGrome candida differential agar. For non-clostridial anaerobic microflora, the following media were used: shaedler agar, anaerobic agar, and Bacteroides bile esculin agar. The cultures were incubated aerobically or anaerobically. The aerobic incubation at 37° C lasted 24 to 48 h. For anaerobic incubation, the culture plates were placed in anaerobic jars with Anaero-Higas pack at 37° C for 48 to 72 h. After incubation, the bacterial colonies were identified according to their morphological, biochemical, and tinctorial properties using commercial Staphylotests, Anaerotests, Nefermtests, and Enterotests (Lachema, Czech Republic).

 

Probiotic Ointment Preparation:

The probiotic ointment was prepared by adding one sachet of powdered multi-probiotic SIMBITER Forte-M to 1 g of Tizol gel. A total of 10 g of Tizol gel was used. The multi-probiotic SIMBITER Forte-M is comprised of lactobacilli (1.0x109 CFU/g), bifidobacteria (1.0x109 CFU/g), lactic acid streptococci (1.0x108 CFU/g), acetic acid bacteria (1.0x105 CFU/g), and propionic acid bacteria (1.0x108 CFU/g). The ointment preparation was carried out in a laboratory with the help of sterile porcelain containers. The final stage of preparation involves reinforcing the probiotic ointment with sea buckthorn oil. Due to antioxidant properties, this extract can protect anaerobic live bacteria against oxygen-induced damage. The ointment expires 14 days after opening and should be stored at 2° C to 8° C.

 

Ethical Statement:

All procedures involving human participants were in accordance with the following guidelines: the 1964 Helsinki Declaration, the ICH GCP (1996), and the Council of Europe Convention on Human Rights and Biomedicine.

 

All participants have signed an informed consent form to participate in the study. This form contains the name, purpose, objectives, and methods of this study, as well as treatment regimens, possible side effects, and expected results. The participants were allowed to discontinue participation in research at any time. Each participant was given a copy of the signed consent document.

 

The research protocol and the informed consent form were approved by the I.M. Biomedical Ethics Commission of the I.M. Sechenov First Moscow State Medical University and the Bioethics Commission of the Tula State University.

 

Statistical Analysis:

Statistical data processing involved the following methods: Student's t-test, Wilcoxon's T-test, Mann-Whitney U-test, Fisher's Exact Test, and Odds Ratio (OR) calculation. The difference between variables was considered significant at p<.05.

 

 

RESULTS AND DISCUSSION:

Among patients with AD, the average baseline SCORAD was 16.35 ± 0.47 points. The burden of allergic response, predominantly maternal, was reported in all cases. Of all patients examined, 102 (92.7%) had erythematous and squamous skin affected by lichenification. Other 8 (7.3%) patients had lichenoid disturbances. Neither exudation nor pruriginous abnormalities were detected. The most prevalent symptoms were the itchy dry skin (100%), localized erythema (92.7%), peeling/lichenification (95.5%), and sleep disturbances (74.5%). The above clinical manifestations are typical of AD. It also applies to the localization of skin lesions seen on the upper limbs, face, and neck. Due to the mild severity of the disease (affected body surface area, 8.10 ± 0.42%), no cases of overall health decline were detected. Eighthly-two (or 74.5%) patients with AD reported having disruptions in their sleep, mostly due to itching.

 

The above findings are consistent with clinical data from the AD literature40,41. In particular, the U.S. study of 305 patients with AD found that the most common symptoms were itchy skin, skin pain, and sleep disturbance41. In this study, patients did not report pain sensations, probably because the examined AD cases were mild, whereas the U.S. study focused more on moderate and severe cases. Furthermore, patients could not feel the pain because the itch sensation was much stronger than the pain.

 

The taxonomic analysis of skin microbiota (Table 1) revealed that patients with AD were infected by Staphylococcus aureus (77.3%), Staphylococcus epidermidis (54.5%), Peptococcus spp. (60.0%), Propionibacterium spp. (48.2%), Streptococcus pyogenes (7.3%), and Staphylococcus haemolyticus (1.8%). A total of 14 types of microorganisms were detected. The most common microorganism found in atopic individuals was S. aureus, with an average load of 47.9 ± 4.82 CFU/cm².


 

 

Table 1. Prevalence of microorganisms in atopic individuals.

Microorganism

Control (n=30)

AD (n=110)

OR

95% CI

N

%

N

%

S. aureus

9

30.0

85

77.3

7.93*

3.23-19.5

S. epidermidis

27

90.0

60

54.5

7.50*

2.15-26.19

S. haemolyticus

7

23.3

2

1.8

1.05

0.21-5.34

Str. pyogenes

0

0.0

8

7.3

р > 0.05**

Bacillus spp.

11

36.7

10

9.1

5.79*

2.16-15.53

Micrococcus spр.

20

66.7

24

21.8

7.17*

2.96-17.34

Corynebacterium spр.

8

26.7

25

22.7

1.22

0.51-3.22

Propionibacterium spp.

6

20.0

53

48.2

3.72*

1.41-9.81

Peptostreptococcus spp.

9

30.0

43

39.1

1.50

0.63-3.57

Peptococcus spp.

13

43.3

66

60.0

1.96

0.87-4.44

Enterococcus spp.

7

23.3

2

1.8

16.44*

3.21-84.28

Veillonella sрp.

4

13.3

11

10.0

1.38

0.41-4.71

Bacteroides spp.

0

0.0

17

15.5

р > 0.05**

Eubacterium spp.

3

10.0

1

0.9

12.11*

1.21-121.10

Note: * − values <0.05 are considered statistically significant compared to control; ** − exact р-values, obtained with Fisher's exact test.


 

S. aureus participates in the cutaneous adverse reactions of the body42,43. The present findings are consistent with similar studies44-47. It was found that some members of the genera Staphylococcus, Corynebacterium, and Micrococcus have a histidine decarboxylating effect, which indicates a connection between alterations of skin microbiota and AD. Furthermore, S. aureus can cause the release of histamine, one of the most important mediators of allergy44-47. Other studies highlight a correlation between the growth of Streptococcus (or Propionibacterium) on the skin and AD45,46.

 

Of all microorganisms found in healthy individuals, the most common ones were S. epidermidis (90.0%), Micrococcus (66.7%), and Peptococcus (43.3%). The least common microorganism found among healthy individuals was Eubacterium (10.0%). The average load of S. aureus in the control group was 16.8 ± 2.44 CFU/cm². A total of 12 types of microorganisms were detected. Note that the frequency of such microorganisms as S. aureus, S. epidermidis, Bacillus, Micrococcus, and Propionibacterium between the treated and the control group is statistically significant (p<.05).

 

The above findings are consistent with other studies48-50. For example, the German scholars comparing the skin microbiome of healthy individuals and patients with AD found that patients with AD had a significantly higher number of bacteria of the genus Staphylococcus. Meanwhile, the number of bacteria from the genera Corynebacterium and Dermacoccus was lower50. A similar study was conducted among 170 patients with AD in the United States. The study focused on identifying methicillin-sensitive (MSSA) or methicillin-resistant (MRSA) S. aureus. The results show a significant reduction in Streptococcus spp. and Propionibacterium spp. on MSSA-colonised lesional skin compared to non-affected skin (p<1E-3). Also, researchers found a further reduction in Streptococcus spp. (p=0.023), Propionibacterium spp. (p=0.007, respectively), and Corynebacterium spp. (p<1E-3) on MRSA-colonised lesional skin51.

 

From the results of this study, the standard therapy should include the localized delivery of remedies to the skin to restore the normal skin microbiome. This study suggests using a probiotic ointment from Tizol gel and multi-probiotic SIMBITER Forte-M. This preparation helped to reduce the localized cutaneous pathology and restore the skin microbiome composition. After the treatment, a significant decline in the SCORAD score (from 16.41 ± 0.50 to 5.19 ± 0.22, p<.05) in the probiotic-treated group was observed. Also, there was a significant decline of the SCORAD score from (16.28 ± 0.43 to 8.10 ± 0.27, p<.05) in the standard treatment group. By the end of the study, the frequency and intensity of cutaneous manifestations decreased significantly from baseline in both groups (p<.05). However, patients receiving probiotic ointment showed better results (Table 2). For instance, the itching sensation completely disappeared in 47 probiotic-treated patients versus 39 standard-treated patients (p<.05). The dryness completely disappeared in 48 probiotic-treated patients versus 40 standard-treated patients (p<.05). It also applies to other items: localised erythema (46 probiotic-treated versus 37 standard-treated patients, p<.05), peeling/lichenification (48 probiotic-treated versus 43 standard-treated patients, p<.05), and sleep disturbance (34 probiotic-treated versus 25 standard-treated patients, p<.05). Although cutaneous manifestations of AD remained in some patients, their intensity was significantly lower compared with baseline. The extent of skin lesions in probiotic-treated patients decreased significantly compared to that in standard-treated patients (3.80 times versus 2.30 times, p<.05).


 

Table 2. Changes over time in the prevalence of AD symptoms among treated patients.

Symptom

Group

Baseline

End of Treatment Period (day 30)

Р

N

%

N

%

Itchy skin

T1

55

100

16

29.1

р1<0.01, р2<0.01, р3=0.03

T2

55

100

8

14.5

Dry skin

T1

55

100

15

27.3

р1<0.01, р2<0.01, р3=0.03

T2

55

100

7

12.7

Localised erythema

T1

50

90.9

13

23.6

р1<0.01, р2<0.01, р3=0.04

T2

52

94.5

6

10.9

Peeling skin/ lichenification

T1

53

96.4

10

18.2

р1<0.01, р2<0.01, р3<0.05

T2

52

94.5

4

7.3

Sleep disturbance

T1

40

72.7

15

29.1

р1<0.01, р2<0.01, р3=0.049

T2

42

76.4

8

14.5

Note: *−values less than 0.05 are considered statistically significant compared to control; ** − values less than 0.05 are considered statistically significant compared to the standard-treated group; р1 − significance level in intragroup comparison (before/after treatment) within the standard-treated group; р2 − significance level in intragroup comparison (before/after treatment) within the probiotic-treated group; р3 − significance level in the comparative study of the standard-treated and probiotic-treated groups. T1 is the standard-treated group (n=55), whereas T2 is the probiotic-treated group (n=55).

 

Table 3. Changes over time in the prevalence of microorganisms among treated patients.

Microorganism

Control

Group

Baseline

End of Treatment Period (day 30)

Р

N

%

N

%

N

%

S. aureus

9

30.0

T1

43

78.2

24

43.6

р1<0.01*, р2<0.01*, р3=0.045**

T2

42

73.4

16

29.1

S. epidermidis

27

90.0

T1

31

56.4

42

76.4

р1=0.014*, р2<0.01*, р3>0.05

T2

29

52.7

47

85.5

S. haemolyticus

7

23.3

T1

1

1.8

4

7.3

р1>0.05, р2<0.01*, р3>0.01**

T2

1

1.8

12

21.8

Str. pyogenes

0

0.0

T1

4

7.3

1

1.8

р1>0.05, р2>0.05, р3>0.05

T2

4

7.3

0

0.0

Bacillus spp.

11

36.7

T1

6

10.9

13

23.6

р1=0.044*, р2<0.01*, р3>0.05

T2

4

7.3

16

29.1

Micrococcus spр.

20

66.7

T1

12

21.8

28

50.1

р1=0.01*, р2<0.01*, р3>0.05

T2

12

21.8

35

63.6

Corynebacterium spр.

8

26.7

T1

13

23.6

12

21.8

р1>0.05, р2>0.05, р3>0.05

T2

12

21.8

15

27.3

Propionibacterium spp.

6

20.0

T1

26

47.3

19

34.5

р1>0.05, р2=0.03*, р3>0.05

T2

27

49.1

13

23.6

Peptostreptococcus spp.

9

30.0

T1

22

40.0

18

32.7

р1>0.05, р2>0.05, р3>0.05

T2

21

38.1

14

25.5

Peptococcus spp.

13

43.3

T1

31

56.4

28

50.9

р1>0.05, р2=0.01*, р3>0.05

T2

35

63.6

23

41.8

Enterococcus spp.

7

23.3

T1

2

3.64

7

10.9

р1>0.05, р2<0.01*, р3>0.05

T2

0

0.0

10

18.2

Veillonella sрp.

4

13.3

T1

6

10.9

7

12.7

р1>0.05, р2>0.05, р3>0.05

T2

5

9.1

7

12.7

Bacteroides spp.

0

0.0

T1

8

14.5

4

7.3

р1>0.05, р2<0.01*, р3>0.05

T2

9

16.4

1

1.8

Eubacterium spp.

3

10.0

T1

1

1.8

2

3.6

р1>0.05, р2=0.02*, р3>0.05

T2

0

0.0

5

9.1

Note: * − values less than 0.05 are considered statistically significant compared to baseline; ** − values less than 0.05 are considered statistically significant compared to the standard-treated group; р1 − significance level in intragroup comparison (before/after treatment) within the standard-treated group; р2 − significance level in intragroup comparison (before/after treatment) within the probiotic-treated group; р3 − significance level in the comparative study of the standard-treated and probiotic-treated groups. T1 is the standard-treated group (n=55), whereas T2 is the probiotic-treated group (n=55).

 


By the end of the treatment, the prevalence of S. aureus among probiotic-treated patients decreased significantly compared to that among standard-treated patients (by 3.00 times versus 2.00 times, p<.05). The S. aureus load in probiotic-treated and standard-treated individuals declined 2.70 and 1.80 times, respectively (p<.05). Meanwhile, a significant increase in the prevalence of S. epidermidis, Bacillus, and Micrococcus from baseline was detected in both groups (p<.05). A crucial finding is a significant increase in the prevalence of S. epidermidis (p<.05) among patients with AD because this bacterium induces the synthesis of β-defensins 2 and 3, antimicrobial peptides that have antimicrobial activity against S. aureus, as well as antiviral activity52. The prevalence of S. haemolyticus, Enterococcus spp., and Eubacterium among probiotic-treated patients increased significantly compared to that in the standard-treated group (p<.05). Finally, there was a significant decrease in the prevalence of Propionibacterium (2.08 times, p<.05) and Peptococcus (1.52 times, p<.05) among probiotic-treated patients (Table 3).

 

There are few studies on the topical application of probiotics. The available findings, however, are in line with this work. For instance, the study of a lotion containing inactivated L. johnsonii strain NCC 533 (0.3% La1) found that three weeks of lotion-based therapy had a beneficial effect on the S. aureus load (p<.05) when compared to conventional moisturizers53. A double-blind, randomized clinical study revealed the role of S. epidermidis in skin hydration. A mixture of lyophilised S. epidermidis with a gel improved skin's lipid content and moisture-holding capacity54,55,56. In general, the results of other studies are rather contradictory. Furthermore, those studies were limited by small sample size, which requires further, more detailed, and extensive investigation.

 

CONCLUSIONS:

From research results, the most common bacteria found in the AD skin microbiome are S. aureus (77.3%), S. epidermidis (54.5%), Peptococcus spp. (60.0%), and Propionibacterium spp. (48.2%). The standard treatment for AD in conjunction with probiotic ointment seems to be more effective than the standard treatment alone. It helped to significantly reduce the prevalence and intensity of cutaneous manifestations attributable to AD. After the synergistic treatment, the skin load of different types of bacteria among atopic patients was similar to that in healthy individuals. For instance, the prevalence of S. epidermidis (p<.05), S. haemolyticus (p<.05), Bacillus (p<.05), Micrococcus (p<.05), and Enterococcus (p<.05) increased significantly, whereas the prevalence of Propionibacterium (p<.05) and Peptococcus (p<.05) decreased. The prevalence of S. aureus declined from 73.4% to 29.1% (p<.05) among probiotic-treated and from 78.2% to 43.6% (p<.05) among standard-treated patients. These findings indicate that probiotic ointment is more effective for AD than a gel.

 

DATA AVAILABILITY:

Data will be available on request.

 

CONFLICTS OF INTEREST:

The authors declare that they have no competing interests.

 

FUNDING STATEMENT:

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

 

ACKNOWLEDGMENTS:

Not applicable.

 

REFERENCES:

1.        Integrative HMP (iHMP). Research network consortium. The integrative human microbiome project. Nature. 2019; 569:641-648. doi:10.1038/s41586-019-1238-8

2.        Garud NR, Pollard KS. Population genetics in the human microbiome. Trends in Genetics. 2020; 36:53-67. doi.org/10.1016/j.tig.2019.10.010

3.        West CE, Jenmalm MC, Prescott SL. The gut microbiota and its role in the development of allergic disease: a wider perspective. Clinical and Experimental Allergy. 2015; 45:43-53. doi.org/10.1111/cea.12332

4.        Kharitonova LA, Grigoriev KI, Borzakova SN. Human microbiota: how a new scientific paradigm changes medical practice. Experimental and Clinical Gastroenterology. 2019; 161:55-63. doi.org/10.31146/1682-8658-ecg-161-1-55-63

5.        Cong X, Henderson WA, Graf J, McGrath JM. Early life experience and gut microbiome: the brain-gut-microbiota signaling system. Advances in Neonatal Care. 2015; 15:314-323. doi.org/10.1097/ANC.0000000000000191

6.        van der Meulen TA, Harmsen H, Bootsma H, Spijkervet FK, Kroese FG, Vissink A. The microbiome-systemic diseases connection. Oral Diseases. 2016; 22:719-734. doi.org/10.1111/odi.12472

7.        Rejepov DT, Vodyashkin AA, Sergorodceva AV, Stanishevskiy YM. Biomedical Applications of Silver Nanoparticles (Review). Drug Development & Registration. 2021; 10(3):176-187. doi.org/10.33380/2305-2066-2021-10-3-176-187

8.        Cryan JF, O'Riordan KJ, Cowan CS, Sandhu KV, Bastiaanssen TF, Boehme M, et al. The microbiota-gut-brain axis. Physiological Reviews. 2019; 99:1877-2013. doi.org/10.1152/physrev.00018.2018

9.        Hayley S, Audet MC, Anisman H. Inflammation and the microbiome: implications for depressive disorders. Current Opinion in Pharmacology. 2016; 29:42-46. doi.org/10.1016/j.coph.2016.06.001

10.      Benson AK. The gut microbiome—an emerging complex trait. Nature Genetics. 2016; 48:1301-1302. doi.org/10.1038/ng.3707

11.      Cianci R, Pagliari D, Piccirillo CA, Fritz JH, Gambassi G. The microbiota and immune system crosstalk in health and disease. Mediators of Inflammation. 2018; 1: 2912539. doi.org/10.1155/2018/2912539

12.      Kramer CD, Genco CA. Microbiota, immune subversion, and chronic inflammation. Frontiers in Immunology. 2017; 8:255-265. doi.org/10.3389/fimmu.2017.00255

13.      Koleva PT, Bridgman SL, Kozyrskyj AL. The infant gut microbiome: evidence for obesity risk and dietary intervention. Nutrients. 2015; 7:2237-2260. doi.org/10.3390/nu7042237

14.      Reynolds LA, Finlay BB, Maizels RM. Cohabitation in the intestine: interactions among helminth parasites, bacterial microbiota, and host immunity. The Journal of Immunology. 2015; 195:4059-4066. doi.org/10.4049/jimmunol.1501432

15.      Iliev D, Leonardi I. Fungal dysbiosis: immunity and interactions at mucosal barriers. Nature Reviews Immunology. 2017; 17:635-646. doi.org/10.1038/nri.2017.55

16.      Plaza-Diaz J, Ruiz-Ojeda FJ, Gil-Campos M, Gil A. Mechanisms of action of probiotics. Advances in Nutrition. 2019; 10:49-66. doi.org/10.1093/advances/nmy063

17.      Bortnikova VV, Karabaeva VV, Krepkova LV, Mizina PG, Babenko AN, Mikheeva NS, et al. A retrospective analysis of the clinical studies of a drug flakozid in the treatment of diseases of the hepatobiliary system. Drug Development & Registration. 2021; 10(3):100-104. doi.org/10.33380/2305-2066-2021-10-3-100-104

18.      Markowiak P, Śliżewska K. Effects of probiotics, prebiotics, and synbiotics on human health. Nutrients. 2017; 9:1021-1251. doi.org/10.3390/nu9091021

19.      Reid G, Gadir AA, Dhir R. Probiotics: reiterating what they are and what they are not. Frontiers in Immunology. 2019; 10:424-430. doi.org/10.3389/fmicb.2019.00424

20.      Sanders ME, Merenstein D, Merrifield CA, Hutkins R. Probiotics for human use. Nutrition Bulletin. 2018; 43:212-225. doi.org/10.1111/nbu.12334

21.      FDA. Dietary supplements: new dietary ingredient notifications and related issues: guidance for industry, https://www.fda.gov/regulatory-information/search-fda-guidance-documents/draft-guidance-industry-new-dietary-ingredient-notifications-and-related-issues.

22.      Lowe JR, Briggs AM, Whittle S, Stephenson MD. A systematic review of the effects of probiotic administration in inflammatory arthritis. Complementary Therapies in Clinical Practice. 2020; 40: 101207. doi.org/10.1016/j.ctcp.2020.101207

23.      Mohammed AT, Khattab M, Ahmed AM, Turk T, Sakr N, Khalil AM, et al., The therapeutic effect of probiotics on rheumatoid arthritis: a systematic review and meta-analysis of randomised control trials. Clinical Rheumatology. 2017; 36: 2697–2707. doi.org/10.1007/s10067-017-3814-3

24.      Tang Y, Huang J, Zhang WY, Qin S, Yang YX, Ren H, et al. Effects of probiotics on nonalcoholic fatty liver disease: a systematic review and meta-analysis. Therapeutic Advances in Gastroenterology. 2019; 12:1-23. doi.org/10.1177% 2F1756284819878046

25.      Zhang Q, Gao F, Yang X, Hu Y, Liu Y, Hou Y, et al. Protective effect of probiotics against esophagogastric variceal rebleeding in patients with liver cirrhosis after endoscopic therapy. Medical Science Monitor: International Medical Journal of Experimental and Clinical Research. 2020. 26: e924040. doi.org/10.12659/ MSM.924040

26.      Disamantiaji AP, Izza EF, Soelaeman MF, Sembiring T, Louisa M. Probiotics in the management of atopic dermatitis for children: a case-based review. Dermatology Research and Practice. 2020; 2020:4587459. doi.org/10.1155/2020/4587459

27.      Jiang W, Ni B, Liu Z, Liu X, Xie W, Wu IX, Li X. The role of probiotics in the prevention and treatment of atopic dermatitis in children: an updated systematic review and meta-analysis of randomised controlled trials. Pediatric Drugs. 2020; 22:535-549. doi.org/10.1007/s40272-020-00410-6

28.      Yu Y, Dunaway S, Champer J, Kim J, Alikhan A. Changing our microbiome: probiotics in dermatology. British Journal of Dermatology. 2019; 182:39-46. doi.org/10.1111/bjd.18088

29.      Sivamaruthi BS, Kesika P, Chaiyasut C. A mini-review of human studies on cholesterol-lowering properties of probiotics. Scientia Pharmaceutica. 2019; 87:26. doi.org/10.3390/ scipharm87040026

30.      Skonieczna-Żydecka K, Kaźmierczak-Siedlecka K, Kaczmarczyk M, Śliwa-Dominiak J, Maciejewska D, Janda K, et al. The effect of probiotics and synbiotics on risk factors associated with cardiometabolic diseases in healthy people—a systematic review and meta-analysis with meta-regression of randomised controlled trials. Journal of Clinical Medicine. 2020; 9:1788-1823. doi.org/10.3390/jcm9061788

31.      Selezneva AI, Smirnov VA, Goryachkin VV, Chadova NN, Polyakov SV, Shestakov VN, et al. The integrated model of quality management system of laboratory studies of medicines (review). Drug Development & Registration. 2021; 10(3):148-165. doi.org/10.33380/2305-2066-2021-10-3-148-165

32.      Suaini H, Tan CP, Loo EX, Tham EH. Global differences in atopic dermatitis. Pediatric Allergy and Immunology. 2020; 32:23-33. doi.org/10.1111/pai.13335

33.      Yong MYA, Tay YK. Atopic dermatitis. Dermatologic Clinics. 2017; 35: 395-402. doi.org/10.1016/j.det.2017.02.012

34.      Adamson AS. The economics burden of atopic dermatitis. In Management of Atopic Dermatitis 2017; 79–92. Springer, Cham. doi.org/10.1007/978-3-319-64804-0_8

35.      Wollenberg A, Barbarot S, Bieber T, Christen‐Zaech S, Deleuran M, Fink‐Wagner A, et al. Consensus‐based European guidelines for treatment of atopic eczema (atopic dermatitis) in adults and children: part II. The Journal of the European Academy of Dermatology and Venereology. 2018; 32:850-878. doi.org/10.1111/jdv.14888

36.      Wollenberg A, Szepietowski J, Taieb A, Ring J. Corrigendum: consensus‐based European guidelines for treatment of atopic eczema (atopic dermatitis) in adults and children: part I. The Journal of the European Academy of Dermatology and Venereology. 2019; 33: 1436. doi.org/10.1111/jdv.14891

37.      Pokatilov B. Colonisation and adhesion by microbes of the skin of patients in a surgical hospital in an ecologically unfavorable environment. Dissertation for the degree of candidate of sciences abstract, Volgograd 1993.

38.      Murray PR, Rosenthal KS, Pfaller MA. Medical microbiology. Elsevier/Saunders, Philadelphia, USA 2013.

39.      Menshikov VV. Clinical and laboratory research methods. Labora, Moscow 2009.

40.      Gerbens LAA, Chalmers JR, Rogers NK, Nankervis H, Spuls PI, Harmonising Outcome Measures for Eczema (HOME) initiative. Reporting of symptoms in randomised controlled trials of atopic eczema treatments: a systematic review. British Journal of Dermatology. 2016; 175:678-686. doi.org/10.1111/bjd.14588

41.      Vakharia PP, Chopra R, Sacotte R, Patel KR, Singam V, Patel N, et al. Burden of skin pain in atopic dermatitis. Annals of Allergy, Asthma and Immunology. 2017; 119:548-552. doi.org/10.1016/j.anai.2017.09.076

42.      Brunner PM, Leung DYM, Guttman-Yassky E. Immunologic, microbial, and epithelial interactions in atopic dermatitis. Annals of Allergy, Asthma & Immunology. 2018; 120:34-41. doi.org/10.1016/j.anai.2017.09.055

43.      Kim JE, Kim HS. Microbiome of the skin and gut in atopic dermatitis (ad): understanding the pathophysiology and finding novel management strategies. Journal of Clinical Medicine. 2019; 8:444-467. doi.org/10.3390/jcm8040444

44.      Nakatsuji T, Chen TH, Narala S, Chun KA, Two AM, Yun T, et al. Antimicrobials from human skin commensal bacteria protect against Staphylococcus aureus and are deficient in atopic dermatitis. Science Translational Medicine. 2017; 9:eaah4680. doi.org/10.1126/scitranslmed.aah4680

45.      Musso P, Chiappini E, Bernardini R. Human microbiome and allergic diseases in children: pathogenetic role and therapeutic options. Current Pediatric Reviews. 2019; 16:89-94. doi.org/10.2174/1573396315666191025110849

46.      Pascal M, Perez-Gordo M, Caballero T, Escribese MM, Lopez Longo MN, Luengo O, et al. Microbiome and allergic diseases. Frontiers in Immunology. 2018; 9:1584. doi.org/10.3389/fimmu.2018.01584

47.      Geoghegan JA, Irvine AD, Foster TJ. Staphylococcus aureus and atopic dermatitis: a complex and evolving relationship. Trends in Microbiology. 2018; 26:484-497. doi.org/10.1016/ j.tim.2017.11.008

48.      Stalder JF, Fluhr JW, Foster T, Glatz M, Proksch E. The emerging role of skin microbiome in atopic dermatitis and its clinical implication. The Journal of Dermatological Treatment. 2019; 30:357-364. doi.org/10.1080/09546634.2018.1516030

49.      Thomas L, Fernández-Peñas P. The microbiome and atopic eczema: more than skin deep. Australasian Journal of Dermatology. 2017; 58:18-24. doi.org/10.1111/ajd.12435

50.      Wollina U. Microbiome in atopic dermatitis. Clinical, Cosmetic and Investigational Dermatology. 2017; 10:51-65. doi.org/10.2147/CCID.S130013

51.      Shi B, Leung D, Taylor PA, Li H. Methicillin-resistant staphylococcus aureus colonisation is associated with decreased skin commensal bacteria in atopic dermatitis. The Journal of Investigative Dermatology. 2018; 138:1668-1671. doi.org/10.1016/j.jid.2018.01.022

52.      Wang Z, MacLeod DT, Di Nardo A. Commensal bacteria lipoteichoic acid increases skin mast cell antimicrobial activity against vaccinia viruses. The Journal of Immunology. 2012; 189:1551-1558. doi.org/10.4049/jimmunol.1200471

53.      Blanchet-Réthoré S, Bourdès V, Mercenier A, Haddar CH, Verhoeven PO, Andres P. Effect of a lotion containing the heat-treated probiotic strain Lactobacillus johnsonii NCC 533 on Staphylococcus aureus colonisation in atopic dermatitis. Clinical, Cosmetic and Investigational Dermatology. 2017; 10:249-257. doi.org/10.2147/CCID.S135529

54.      Nodake Y, Matsumoto S, Miura R, Honda H, Ishibashi G, Matsumoto S, et al. Pilot study on novel skin care method by augmentation with Staphylococcus epidermidis, an autologous skin microbe–A blinded randomised clinical trial. The Journal of Dermatological Science. 2015; 79:119-126. doi.org/10.1016/j.jdermsci.2015.05.001

55.      Neroyev V, Saakian S, Miakoshina E, Iurovskaia N, Riabina M, Zaĭtseva O, Lysenko V. Differential diagnosis of early central choroidal melanoma and late stage age-related macula degeneration. Vestnik Oftalmologii. 2013;129(1):39-45

56.      Krichevskaya G, Slepova O, Sahakyan S, Myakoshina E, Denisova Y. On the role of infections in the pathogenesis of retinoblastoma. Russian Ophthalmological Journal. 2013; 6(2):37-40.

 

 

Received on 24.09.2021            Modified on 10.10.2021

Accepted on 29.10.2021           © RJPT All right reserved

Research J. Pharm. and Tech 2021; 14(11):6041-6048.

DOI: 10.52711/0974-360X.2021.01050