INTRODUCTION:

Damage to the mucous membrane, which leads to the destruction of surface tissue as well as the breakdown and necrosis of epithelial tissue, which results in irritation and a burning sensation from inflammation, is just what caused traumatic ulcers.¹Traumatic ulcer prevalence ranges from 3 to 24% around the world.²

The increasing lesions are ulcerative lesions that extend past the basal layer and may even reach the lamina propria in the epithelial layer. They have an oval shape, significant reddish borders, and a yellowish-white necrotic pseudomembrane that can be removed in the center.^3,4

Ulcer is a situation in which epithelial layers are lost and the lamina propria is affected. A traumatic ulcer has been triggered by thermal, chemical, or physical damage. When an ulcer does not fully heal, the possibility of complications including infection and wound rupture increases.^5,6Traumatic ulcers are treated with the topical and/or systemic therapy of antiseptics, antibiotics, anti-inflammatories, antihistamines, and corticosteroids.⁷Steroids and antibiotics are only used in certain illnesses, such as diabetes, and their prolonged usage can lead to side effects and resistance. They also do not promote recovery. Alternative treatments are required because these disorders exist.^2,8 Probiotics can be used both topically and internally like a wound healing agent that helps to control inflammation and prevent infection.⁹

Probiotics, according to the Food and Agriculture Organization of the United Nations (FAO) and the World Health Organization (WHO), are live microorganisms that, when given in great amounts, can have positive effects on health.¹⁰ The microorganisms from the species Lactobacillus, Bifidobacterium, and Saccharomyces that are most frequently used as probiotics are described here.¹¹ Local probiotics have been demonstrated to balance the skin's microbiota and modulate the immune system to prevent infection and control inflammation. Probiotics function systemically to out-compete pathogens, stimulate the production of cytokines by the immune system, and ultimately eliminate pathogens.^12–14

The balance between T helper 1 (Th1), which will create proinflammatory cytokines, and T helper 2 (Th2), that will produce antiinflammatory cytokines, will be regulated by probiotics, according to studies currently available.¹⁵ A strain of Lactobacillus sp. called Lactobacillus casei Shirota is typically consumed as a probiotic in the form of fermentation. Probiotics have the ability to strengthen the good flora in the intestines, eliminate harmful bacteria, and boost immunity (called immunomodulators).^12,16–18IL-10 is an anti-inflammatory cytokine that has the ability to preserve healthy tissue homeostasis and has an advantageous effect on airway remodeling.^19,20

Interleukin-10 (IL-10) is a regulatory cytokine that controls how the immune system and cells respond to inflammation. It also has anti-inflammatory properties that prevent pro-inflammatory cytokines, chemokines, and chemokine receptors from working, which reduces the inflammatory response. After a skin injury, IL-10 is crucial for restoring tissue integrity and expediting wound healing. Because of its capacity to stimulate macrophage or monocyte activity and decrease the production of pro-inflammatory cytokines, IL-10 functions as a factor suppressing cytokine synthesis. In addition to its potent anti-inflammatory effects, IL-10 has been demonstrated to regulate fibrogenic cytokines, such as Transforming Growth Factor (TGF), which are involved in the regulation of proliferation and tissue remodeling. Increased IL-10 contributes to the tissue's early response to injury, which reduces the formation of scar tissue and promotes regenerative healing.^15,21

Observations were made on the expression of IL-10 after 4 and 8 days of probiotic administration because, during the wound healing process, the 4th day was characterized by enhanced proliferation of fibroblasts and collagen cells, whose mechanisms were driven by IL-10. On day 8, tissue proliferation and remodeling are regulated by fibrogenic cytokine signaling, which is regulated by the expression of IL-10.^21–23

Probiotics can be administered topically and internally to promote wound healing, which helps to control inflammation and prevent infection⁹. When skin dysbiosis results from tissue injury, topical probiotics can work as immunomodulators to restore microbial equilibrium.¹¹ Bacterial metabolites or Microbial Associated Molecular Patterns (MAMP) may be responsible for mediating this impact. These molecules are identified by pattern recognition receptors on host cells, such as Toll-like Receptors (TLR). A decrease in pro-inflammatory signals that promote signaling pathway is a characteristic of the immune response that follows, which results in balanced immunity.²⁴ When provides a true, probiotics will modulate the immune system by interacting with the lamina propria's dendritic cells and intestinal epithelial cells (IECs), which can increase the release of the probiotic IL-10.²⁵ IL-10 secretion causes important signaling to maintain homeostasis by inhibiting excess inflammation and accelerating wound healing.²⁶

The goal of this study was to see if there were any differences between the effects of both topical and systemic management of Lactobacillus casei Shirota on increasing interleukin-10 (IL-10) expression in the tissue repair of traumatic ulcers in the Wistar rat. This was done for the reasons mentioned above as well as the fact that there is still little research on Lactobacillus casei Shirota and the nature of specific strain probiotics (Rattus norvegicus).

MATERIALS AND METHODS:

This research has received approval with ethical clearance from the Committee of Dental Medicine, Airlangga University, Indonesia (No.395/HRECC.FDOM/VII/2021). 36 male Wistar rats (Rattus norvegicus), acclimatized for a week, weighing 175-250 grams, 2-3 months old, healthy, with vigorous movements, the capacity to stand, shining eyes, and fur that is not dull, were used in a laboratory experiment. The investigation was divided into 6 groups, each with 6 samples (control days 3, control days 7, topical treatment days 3, topical treatment days 7, and systemic treatment days 3, systemic treatment days 7).

The fermented milk brand Y in 65ml packaging with the same manufacture date and expiration date contained the probiotics that were employed. They were bought right off the shelf and kept chilled for the research at a temperature below 10°C. Wistar rats that have been housed in a cage at a temperature of roughly 20–25°C for seven days to become acclimated. Five minutes prior to creating the ulcer, the operator gave intramuscular injections of ketamine to the test animals to make them unconscious. Then, after heating it for 15 seconds until the burnisher's tip lit up, it was pressed for 1 second into the lower incisive operating point regiolabile of the test animal, reaching a depth equal to the burnisher's round tip's (2 mm) diameter. Additionally, observations were conducted at 24, and 48 hours following the formation of the ulcer. At 24 hours, there was evident injury to the lip mucosa with a thin, 3 mm-diameter white base. Deep ulcers with a yellow base were visible on the lip mucosa 48 hours after the event.²⁷

RESULTS:

Research data:

This study compared the rise in IL-10 expression following topical and systemic treatment of Lactobacillus casei Shirota probiotics to make observations about the healing process of Wistar's ulcerative colitis. The mean and standard deviation (SD) estimations for each group were derived from this research and are shown in Table 1 as mean SD.

Table 1: Mean and Standard Deviation of IL-10 Amounts in Each Treatment Group

Group	Mean± SD
Control days 4	2.5 ± 0.54
Control days 8	3.67 ± 0.81
Topical Treatment days 4	6.14 ± 0.90
Systemic Treatment days 4	5.57 ± 0.97
Topical Treatment days 8	8.67 ± 0.51
Systemic Treatment days 8	6.57 ± 0.97

In Table 1, it can be seen that there were differences in the control group, the topical treatment group, and the systemic treatment group both on day 4 and day 8 of treatment.

Figure 1. Comparison of Mean IL-10 Expression in each treatment group

In Figure 1, It was found that the lowest average amount of IL-10 was in the control group for 4 days, and the largest increase in the amount of IL-10 between administration for 4 days and 8 days was in the topical group, which was 2.53.

The Shapiro-Wilk Test for Normality and the Homogeneity Test were used to conduct statistical tests on all the data (Levene Test). All treatment groups were determined to be normally distributed in the normality test with a 95% degree of truth (p-value>0.05) and a significance level of 0.054. So that the assumptions of normality and homogeneity of the data are satisfied, the analysis is completed with a homogeneity test that demonstrates homogeneous data fluctuations with a p-value of 0.501>0.05.

To ascertain whether groups differ significantly, it is crucial to conduct a separate test comparing treatment groups using the one-way ANOVA test. This test indicates that at least one pair of groups is significantly different from the other with a p value of 0.00 0.05. To determine the groups that have significantly different pairings, the Post-Hoc Scheffe Test must be run. This test found a significant difference in almost every group (p 0.05). This demonstrates the validity of the research hypothesis that probiotic treatment of traumatized ulcers increases the production of IL-10. The outcomes of this experiment also demonstrated that topical probiotic usage significantly increased the expression of IL-10 during the healing of traumatic ulcers. The difference between topical 4 days and topical 8 days is substantial.

Immunohistochemical Examination Results

Figure 2. Immunohistochemical result show IL-10 in the control group for 4 days (A), the systemic treatment group for 4 days (B), and the topical treatment group for 4 days (C) under the microscope with 400x magnification. Immunohistochemical result show IL-10 in the 8-day control group (D), the 8-day systemic treatment group (E), and the 8-day topical treatment group (F) under the microscope with 400x magnification

Figure 2 shows that the amount of IL-10 was found to be higher in the 4-day topical treatment group (C) when compared to the control group (A) and 4-day systemic treatment (B). Figure 2 shows that the amount of IL-10 was found to be higher in the 8-day topical treatment group (C) when compared to the control group (A) and the 8-day systemic treatment group (B).

DISCUSSION:

Probiotics are regarded as functional foods, which are described as living microorganisms that, when given in the proper dosage, will help the host's health.^28–30 Probiotics are frequently employed in clinical settings. An effective probiotic must meet the following requirements: To survive passage through the GI tract, it must: (1) be resistant to hydrochloric acid, bile, and pancreatic juice; (2) release antimicrobial compounds to fight pathogens; (3) adhere to the intestinal epithelium; (4) colonize the target organ (such as the GI tract, skin, urogenital system, etc.); (5) be safe; and (6) survive during storage under normal circumstances.^31,32

In the context of food, this concept might be modified by emphasizing that these beneficial benefits are derived from microbes "when consumed in appropriate amounts as part of food".^28,33 Probiotic cultures have historically been linked to cultured milks and dairy products, which have a strong link to improved human health and wellbeing in general. The gastrointestinal tract's transitory lactic acid bacteria are able to transfer enzymes and other compounds into the colon, which may help regulate intestinal flora. Additionally, lactic acid bacteria have been reported to have antioxidative activity.³⁴ Probiotics have anti-inflammatory effects as well. Studies have demonstrated the probiotic bacteria's anti-inflammatory effects on Salmonella-induced IL-8 production, which starts inflammatory responses to fight the pathogen. The advantages of probiotics are mediated through their suppression of IL-8 production.^35,36

Research by Utami et al. (2017), who treated traumatic ulcers in the control group with sterile aquadest and gave the treatment group Lactobacillus casei Shirota (LcS) at a dose of 10.9 x 107cells/kg body weight, served as the foundation for the treatment of experimental animals for probiotic administration. Previous research has demonstrated that at these concentrations, it will have a therapeutic effect and won't have any negative effects on test animals. While LcS administration has benefits for the body, including immune system immunomodulation, the decrease of inflammation by strengthening protective function, and positive effects on the digestive system, it was used in this investigation.^17,24 A research hypotheses by Lopes et al. (2017), which shown that Lactobacillus sp. can interact with mucosa to regulate inflammation and affect the immune system during wound healing, provided additional support for this.

Kusumaningsih et al. (2021) discovered that topi-cal probiotic treatment was more successful in raising the number of fibroblast cells and blood vessels in the wound healing process due to probiotic adhesion that occurred directly on the wound area. Probiotics may be more beneficial for the wound healing process when applied topically. This is in line with research by Cervin (2018), who found that topical probiotic administration is a more effective treatment than systemic probiotic administration. This is because topical probiotic administration uses a combination of mechanisms that promote healing, including the intervention of probiotic bacteria and immune system stimulation. Furthermore, probiotics applied topically will naturally enter the digestive system, enabling interactions between lymphoid tissue and probiotic bacteria there. Additional impacts on the wound healing process will be seen due to immune system modification.³⁷

According to the study's findings, there were notable differences between the 4-day topical treatment and 4-day control groups as well as the 4-day systemic treatment and 4-day control groups. These findings suggest that on days 4 and 8, there is an increase in IL-10 levels both topically and systemically. On day 4, there was a rise in IL-10, showing that there had been an anti-inflammatory reaction that supported decreased inflammation throughout the wound-healing process. This occurred as a result of monocyte chemoattractant protein 1, which was present on day 4 of the inflammatory phase, when monocytes transformed into macrophages and entered the area around the wound (MCP-1). In arrange for M2 polarization to become more predominate, M1 polarization, which is a producer of pro-inflammatory cytokines, will be encouraged to exchange for M2 polarization by macrophages, cells that are crucial in the wound healing process and have the purpose of phagocytosis of bacteria and dead tissue. Pro-inflammatory cytokines are decreasing, which suggests that T helper-2 lymphocytes are more prevalently expressed. T helper-2 cytokines (IL-4, IL-10, and IL-13) are involved in M2 polarization. In order to reduce the activity of neutrophils and macrophages, IL-10 release blocks the creation of pro-inflammatory cytokines (TNF-, IL-1, and IL-6).^2,38–42

Between the 8-day topical treatment group and the 8-day control group, as well as between the 8-day systemic treatment group and the 8-day control group, significant differences were also discovered. Platelets and macrophages dominate matrix turnover on the eighth day, which is the proliferative phase, and are eventually displaced by fibroblast cell migration and extracellular matrix production. Growth factors include vascular endothelial growth factor (VEGF), angiopoetin, fibroblast growth factor (FGF), and TGF- dominate this proliferative phase. By means of the processes of angiogenesis (the construction of new blood vessels), fibroblast production, and re-epithelialization, this proliferative phase seeks to achieve a balance between the formation of scar tissue and tissue regeneration.^41,43

A reduction in inflammation and the induction of Treg, which play a part in establishing homeostatic conditions, are brought about by the release of anti-inflammatory cytokine mediators like IL-10. In this instance, it demonstrates that IL-10 plays a little function during the proliferative phase but a major part during the anti-inflammatory and anti-fibrotic responses when inflammation is present or during the inflammatory phase. Although it has been suggested by numerous studies that IL-10 can prevent the development of fibrosis, particularly by controlling the inflammatory response that encourages fibroproliferation, the molecular mechanism behind this effect is still not entirely understood. As a forerunner in fibrotic or anti-fibrotic communication between the inflammatory phase and the proliferative phase throughout the healing process, IL-10 plays a more significant function.^40,44,45

In this study, it was discovered that IL-10 levels increased on day 8 of the proliferative phase in both the topical and systemic therapy groups when compared to the control group. This finding suggests that the wound did not experience homeostatic conditions, causing IL-10 production to rise. This can happen when there is physiologically active inflammation or hyper-inflammation, which triggers M2 to create a lot of IL-10 as an anti-inflammatory strategy. Excessive inflammatory reactions will result in lymphocyte death, impair tissue healing, and prolong the inflammation process. Chronic problems or severe scarring may arise when the tissue repair response turns aberrant (hypertrophic or keloid). Under these conditions, several studies have been conducted and show that there is a continuous competition between inflammatory and anti-inflammatory signals that leads to an unbalanced environment for wound healing that occurs.^46–48

There was no discernible difference between the systemic therapy group (4 days) and the systemic treatment group in the research's findings (8 days). After 4 and 8 days, there was a significant difference in the mean level of IL-10 in the group receiving topical therapy. As a result of probiotic adhesion occurring on the wound site when probiotics are supplied topically as opposed to systemically, the data indicated that topical treatment of probiotics was more successful in raising IL-10 production. According to studies by Sudiono et al. (2013) and Lopes et al. (2017), LcS given topically or systemically has been demonstrated to have anti-pathogenic effects on the immune system that are either direct or indirect. After being digested, LcS found in probiotics that is in M cells in Peyer's patches in the intestine will protect the intestinal mucosa by helping to prevent pathogen colonization, increase tissue repair, and increase phagocytosis as a cell defense in burn rats. Probiotics applied topically enter the body naturally and can interact with lymphoid tissue in the digestive tract, which will have an extra impact on wound healing by modifying the immune system.^49,50

Following the preceding explanation, it has been established that both topical and systemic treatment of the probiotic Lactobacillus casei Shirota can boost IL-10 expression in the healing of traumatic ulcers in Wistar rats, and topical administration of probiotics for 4 days is thought to be more effective in enhancing IL-10 expression than systemic administration of probiotics. Probiotics used topically for eight days and given systemically to treat traumatic ulcers This is in line with the earlier explanation, which demonstrates the function of IL-10 as an anti-inflammatory, making it more advantageous to utilize it during the inflammatory phase. Probiotics that are used topically in a more stable form, such gels and the like, will work best for curing traumatic ulcers, with a direct mechanism.

CONCLUSION:

The systemic delivery of the probiotic Lactobacillus casei Shirota promoted the healing of traumatic ulcers in Wistar rats, and there was an increase in IL-10 expression after the application of the probiotic Lactobacillus casei Shirota topically in the treatment group compared to the control group (Rattus norvegicus).

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Received on 13.04.2023 Modified on 23.10.2023

Research J. Pharm. and Tech 2024; 17(5):2103-2108.

DOI: 10.52711/0974-360X.2024.00333