INTRODUCTION:

Traumatic ulcers are one of the most prevalent mucosal disorders. Normal outcomes of soft tissue injury lesions in the oral cavity include the development of ulcerated surfaces that extend to the basalis membrane¹. Traumatic ulcers are caused by accidental damage.

Traumatic ulcers show clinical signs of discomfort, red and inflamed edges, and no induration. If caused by the sharp point of a broken tooth, it commonly occurs in the tongue or buccal mucosa^2,3.

Traumatic ulcers in the oral cavity have a prevalence of 15–30% and are more common in women aged 16-25 years^4,5.Patients with oral mucosal injuries, such as traumatic ulcers, are always given anti-inflammatory and antiseptic medications, such as mouthwash, to treat them. Drug resistance can prevent traumatic ulcers from fully healing in some circumstances; alternate therapies are needed for this disease. Topical anti-inflammatory drugs and growth factor stimulation are essential for ulcer healing. Immune cells create growth factors, which are proteins that help oral wounds begin to heal. To stimulate tissue regeneration, macrophages, fibroblasts, and endothelial cells release a multitude of growth factors, including fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), and collagen type 1 (COL-1)^6,7.

The immune-inflammatory response involves the pro-inflammatory cytokine IL-6⁸. Local IL-6 synthesis prolongs the pathogenic process, actively participates in the migration of inflammatory cells, and contributes to the pathogenic process through enhanced RANK ligand production. Serum amyloid A, fibrinogen, and C-reactive protein (CRP) are a few examples of acute-phase inflammatory mediators that are induced by IL-6⁹. When local inflammation occurs, several proinflammatory immune mediators, including IL-6, are ejected and removed from circulation systemically¹⁰.

Probiotics are live bacteria that can promote nutritional balance and modify mucosal and systemic immunity. When taken in sufficient proportions, the microbes found in probiotics can help the host by promoting the growth of advantageous microorganisms that can displace dangerous ones^11,12. Probiotics generally work in two ways: by fightingpathogenic bacteria and by snatching up nutrients to stop those bacteria from proliferating and growing. The second approach is that probiotics cause a drop in pH in the intestine as a result of metabolism and fermentation, which in turn creates an extreme environment for the growth of pathogenic bacteria like Salmonella and E. coli¹³.

Gut-associated lymphoid tissue (GALT) allows probiotics to interact with intestinal epithelial cells (IECs) and dendritic cells (DCs). Because these DCs can affect cytokine production, major histocompatibility complex molecules for antigen presentation, and co-stimulatory molecules that polarize T cells into T helper or CD4 + CD25 + regulatory T cells in mesenteric lymph nodes (MLNs) or domes of sub-epithelial GALT, it is crucial to comprehend how these DCs respond to probiotics. Additionally, it might change how interleukins and transforming growth factor (TGF)11 express themselves¹⁴.

In this study, Wistar rats with traumatic ulcers received topical LcS probiotics to see if there were any changes in interleukin-6 (IL-6) after probiotic delivery. Probiotics applied topically may function as a modulator to restore microbial homeostasis when tissue damage occurs. Because topical administration of probiotics will interact directly, it is anticipated to produce a faster healing effect. As LcS has been demonstrated to have antimicrobial activities against pathogenic bacteria generally, it was selected as the probiotic employed in this study¹⁵.

Probiotics were applied topically for 3 days during the inflammatory phase and 7 days during the proliferative phase in traumatic ulcers. The inflammatory phase of the healing process of traumatic ulcers begins on day 3, therefore probiotics provided on that day will affect high cytokine levels in that phase. The proliferative phase, or healing phase, of the traumatic ulcer, begins on day seven. During this phase, there is a lot of granulation tissue, which serves as a source of nutrients for the tissues, including vitamins, minerals, glucose, and amino acids. Growth factors are in charge of controlling this tissue stimulation. The administration of LcS probiotics has the potential to affect cytokine levels throughout the proliferative phase¹⁶.

According to this theory, there is still a lack of information on how the expression of interleukin-6 (IL-6) changes after administration of the probiotic L. casei Shirota in traumatic ulcers in Wistar rats, which is believed to be an alternative therapy in dealing with inflammation, this study was accomplished under the title Differences in IL-6 Expression Before and After Administration of Topical Lactobacillus casei Shirota Probiotics in Wistar Rats. The study focused on the topical administration of Lactobacillus Casei Shirota. The efficacy of other administration routes (e.g., oral or systemic) was not explored, which could provide additional insights into the therapeutic potential of probiotics for ulcer healing.

MATERIALS AND METHODS:

The Committee of Dental Medicine, Universitas Airlangga, Indonesia, has approved and given their ethical clearance for this research (No. 396/HRECC.FODM/VII/2021).

Although the study looked into the differences in IL-6 expression, it passed over the underlying molecular mechanisms that underlie the impacts that were seen. Following studies may examine the precise mechanisms by which Lactobacillus Casei Shirota impacts the expression of IL-6 and the healing of ulcers. Although IL-6 expression may have been assessed in the study, histological alterations in the ulcer healing process were not fully investigated.

This is an experimental laboratory study including 24 male Wistar rats (Rattus norvegicus) aged 2-3 months, weighing 175-250 grams, with lively movements, the capacity to stand, eyes that shine, fur that is not dull, and who have been acclimatized for a week. In this investigation, there were 4 groups: 3 days of control, 7 days of control, 3 days of topical, and 7 days of topical-each with 6 samples. The probiotics utilized were fermented milk brand Y in the 65-ml bottle with identical manufacture and expiration dates. They were bought right off the shelf and kept chilled for the research at a temperature below 10 °C. Wistar rats have spent seven days becoming used to being in a cage with a 20–25°C ambient temperature Five minutes before 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 touched for 1 second to the labial region of the experimental animal's inferior incisor fornix as deeply as the burnisher's round tip's (2 mm in diameter) diameter. Moreover, observations were conducted at 24, and 48 hours following the formation of the ulcer. At 24 hours, there was evident damage to the lip mucosa with a thin, 3 mm-diameter white base. A deep lesion with a yellow base was visible on the lip mucosa 48 hours after the trauma¹⁷^,¹⁸.

Following tissue retrieval in the labial region of the inferior incisive fornix (lower jaw labial mucosa) on the 4th and 8th days of application of sterile distilled water and probiotics, preparations were produced. The prepared preparations were then stained with IHC using an anti-rat IL-6 monoclonal antibody as the main antibody. Data were analyzed statistically using the SPSS application version 20 and displayed as the mean standard deviation (XSD).

RESULTS:

Research data:

In the current study, measurements of IL-6 expression were obtained throughout the healing of traumatic ulcers in Wistar rats, and IL-6 expression levels following topical Lactobacillus casei Shirota probiotic therapy were compared. The mean (x) and standard deviation (SD) calculations for each group are presented in the table as mean SD based on the research that has been done.

Immunohistochemical Examination Results:

The results of an immunohistochemical examination of IL-6 expression in immunohistochemical (IHC) staining preparations of traumatic ulcers of the labial tissue of the inferior incisive fornix of Wistar rats were observed using a microscope at 400 times magnification with 8 fields of view in the control group for 3 days and 7 days and in the group treated topically with probiotics Lactobacillus casei Shirota for 3 days and 7 days.

Figure 1. IL-6 expression in the 3-day control group (left) and IL-6 expression in the 3-day topical group (right) observed using a microscope at 400 times magnification

In figure 1, the arrows show macrophage cells expressing IL-6 in the control group 3 days and the topical treatment group 3 days after administration of the probiotic Lactobacillus casei Shirota. Observed with a microscope at 400 times magnification and 8 fields of view.

Figure 2. IL-6 expression in the 7-day control group (left) and IL-6 expression in the 7-day topical group (right) observed with a microscope at 400 times magnification

In figure 2, the arrows show macrophage cells expressing IL-6 in the control group 7 days and the topical treatment group 7 days after administration of the probiotic Lactobacillus casei Shirota. Observed with a microscope at 400 times magnification and 8 fields of view.

Table 1. Mean and Standard Deviation of IL-6 in each treatment group

Sample Group	Mean±Standar Deviation
3 days control	8.83±0.75
7 days control	7.83±0.75
3 days topical treatment	5.14±1.06
7 days topical treatment	4.83±0.75

In table 1, it can be seen that there were differences between the control group and the topical treatment group for both the 3 days treatment and the 7 days treatment.

Figure 3. Comparison of Mean IL-6 Expression in each treatment group

Figure 3 demonstrates that at 3 and 7 days, IL-6 expression was lower in the experimental group. In this study, it was discovered that the control group's average IL-6 expression was higher than that of the group receiving topical probiotics, and that the 3-day control group's average IL-6 expression was higher than that of the 7-day group.

The Shapiro-Wilk test was employed to determine the normality of all data, and it indicated that all groups had normal distributions with a 95% level of truth (p-value 0.05). In order to ascertain the general homogeneity of the IL-6 expression group, the Levene Test was employed. After the results of the data homogeneity test using the Levene test indicated that the overall data was homogeneous, a different test was carried out using the one-way ANOVA test. With a p-value of 0.00 or 0.05, the one-way ANOVA test demonstrates that there is at least one pair of groups that are substantially different from one another. Therefore, additional observations are made in the post-hoc Scheffe table to determine which groups are significantly different from one another.

The results of the post hoc Scheffe test significant test revealed that almost all groups had significant differences (p 0.05). Probiotic treatment of traumatized ulcers considerably changes the expression of IL-6; this supports the validity of the research. According to the test results, applying topical probiotics dramatically decreased IL-6 expression. This was shown by the fact that, at 3 and 7 days, the topical administration group was significantly different from the control group, whereas at 3 and 7 days, there was no significant difference in the topical administration group.

DISCUSSION:

This study analyzes the effects of topical Lactobacillus casei Shirota therapy on IL-6 expression during the healing of traumatic ulcers in Wistar rats. It is an experimental laboratory study to demonstrate the differences between the two. Wistar rats were chosen for this study because they have several benefits, including the fact that their oral mucosa and that of humans are similar—basically, both have epithelial tissue on the surface and connective tissue beneath it, known as the lamina basalis, which supports and nourishes epithelium¹⁹. The Wistar rats used in this study were 2-3 months old because the rats were sexually mature at that age, and the male rats were chosen to avoid hormonal influences on the female Wistar rats so that the research sample was homogeneous.

In this study, examinations were carried out on days 3 and 7 to determine IL-6 levels that occur in the acute inflammatory process. According to Shaikh (2011), inflammation is a response to wounds, where there is an accumulation of leukocytes, mediators of inflammation such as cytokines. Inflammation occurs in the acute stage and subacute/chronic. In the acute inflammation stage occurs release of pro-inflammatory cytokines including IL-6²⁰. Moreover, IL-6 and sIL-6Rα contribute to the change from acute to chronic inflammation by inducing a shift between the early, primarily neutrophilic stage of infection and the longer-lasting mononuclear cell infiltration²¹.

Ulcers were created on the labial inferior incisive fornix with a heated, 2 mm-diameter round burnisher tip¹⁷. The newly created traumatic ulcer loses the epithelial layer to transcend the basement membrane, according to the histological picture. As a result of the fact that they produce powerful growth factors in response to tissue injury and supply collagen to the new extracellular matrix., fibroblasts play a crucial part in wound healing. In wound tissue, probiotics can encourage fibroblast migration and growth. Probiotics can stimulate immune cells like macrophages and dendritic cells to induce the lymphoid tissue in the lamina propria to cause plasma cells to produce IgA, which has a purpose in the mucosal immune system²²^,²³.

The control group and the treatment group were the two groups used in the current study. Probiotic Lactobacillus casei Shirota was applied topically to the treatment group at a dose of 10.9 x 107 cells/kg body weight, whereas sterile aqua dest was applied topically to the control group at a dose of 20 L/20gr body weight. According to research by Utami et al. (2017), it has a therapeutic effect and is safe for the body at a dose of 10.9 x 107 cells/kg body weight, which justifies the usage of this dose¹⁸. The probiotic Lactobacillus casei Shirota was chosen for this study because it is the most commonly consumed by the general public and, when consumed in sufficient quantities, can provide benefits to the host²⁴.

The removal of the etiologic component, minimizing the pathogen or commensal microbe in the oral niche that might delay healing, and other factors all affect how well oral ulcer treatment works. A biocompatible biomaterial that supports cell, and the potential growth factor in biomaterial to support endogenous cell metabolic activities is necesary needed²⁵. Probiotics can boost innate immunity by modulating NF-B activation. Because of its interaction with IKB (IB, IB, and IB), NF-B is inactive and restricted to the cytoplasm under physiological conditions. They can be engaged to mediate the NF-B signaling pathway in response to stimulation with bacteria, in this case, gram-positive bacteria on probiotics, and diverse immunological receptors including TLRs. The degradation of IB serves as the primary mechanism for NF-B activation. IKK phosphorylates IB in this mechanism through ligase-dependent proteasome destruction. By binding to DNA and controlling the production of the proinflammatory cytokine IL-6 in macrophages, NF-B is consequently liberated from the cytoplasm and translocated to the nucleus^26,27.

A comparative test was performed in each group to evaluate if there was a difference in the effects of applying Lactobacillus casei Shirota probiotics topically on IL-6 expression between the control group for 3 days and 7 days and the topical group for 3 days and 7 days in this study. There was no statistically significant change in IL-6 expression between the groups receiving topical treatments for 7 days and those receiving treatments for 3 days (p=0.934). This demonstrates that topical application of the probiotic Lactobacillus casei Shirota for three days can successfully reduce IL-6 expression to the same level as the topical therapy group for seven days. The 3-day topical treatment group and the 3-day control group were not different significantly from the other, while the 7-day topical treatment group and the 7-day control group did (p=0.000). This supports the research hypothesis that there are changes in IL-6 expression following topical administration of Lactobacillus casei Shirota, which states that topical administration of the probiotic Lactobacillus casei Shirota efficiently lowers IL-6 expression. In this case, topical administration can reduce IL-6 expression, which is by the research by Azad et al. (2018) that the probiotic Lactobacillus sp. acting as an immunomodulator can significantly reduce the production of pro-inflammatory cytokines through interaction with immunocompetent cells¹⁵.The results of the study showed that there were no significant changes which could be caused by several factors, one of which was because the days studied were only days 3 and 7. However, the results obtained still explained the influence of differential expression of il-6 following topical administration of the probiotic lactobacillus caseiShirota in the healing of traumatic ulcers in Wistar rats. Therefore, further research is needed to determine the changes that occur on other days.

The immunomodulatory effects of probiotics are a result of their interactions with epithelial cells, dendritic cells, macrophages, and lymphocytes. Controlling the host's immunological reaction is one of the probiotics' modes of action. PAMP-binding Pattern Recognition Receptors (PRR) mediate the majority of immunological responses to infections. Many immune and nonimmune cells, such as B cells, dendritic cells, macrophages, fibroblast cells, epithelial cells, and endothelial cells, include TLRs, also known as transmembrane proteins²⁸. The probiotic Lactobacillus casei Shirota can inhibit inflammatory cytokines like IL-6²⁹.Because Lactobacillus casei Shirota can influence Treg cell activity, it can significantly reduce the pro-inflammatory cascade's overall activity by preventing T cell growth. T cells become active after antigen recognition, and finally, APCs migrate antigens to lymphoid follicles, lymphoid tissues, and mesenteric lymph nodes. In mucosal immune defense, IgA serves as the first line of defense³⁰.

Several other studies that support the benefits of probiotics in healing oral cavity lesion are according to Jacouton et al (2017) L. casei BL23 has an immunomodulatory effect by downregulating the proinflammatory cytokine IL22^31,32. According to Kusumaningsih et al. (2021) L. caseishirota increases the number of fibroblasts, thereby helping speed up the healing process of traumatic ulcers in rats. L. casei Shirota was applied topically or given orally to rats for 3 or 7 days after induction of traumatic ulcers/burns on the inferior incisor labial fornix (mandibular labial mucosa) to determine the stimulation and proliferation of fibroblast and blood cells. formation of blood vessels during the healing process. Hematoxylin-eosin staining showed significantly increased numbers of fibroblasts and blood vessels on day 8 compared with day 3, with higher numbers after 7 days of topical treatment compared with oral treatment, a finding that supports the choice of topical use and long-term application of the treatment probiotics^33,34.

The topical treatment group and the control group (3 days and 7 days) had a significant difference, according to the study's findings (3 days and 7 days). This substantial difference suggests that topical probiotic therapy is efficient in lowering the production of IL-6 cytokines. The proliferative process started on day 7 and IL-6 cytokine levels were still required for the proliferative phase, so there was no significant change when the 3-day and 7-day topical groups were compared. IL-6 in the proliferative phase plays a role in epithelial proliferation, and the presence of IL-6 on day 7 plays a role in ensuring that blood enters the wound area through the capillary walls, resulting in deposits of fibrin matrix as an early sign of the process of wound closure³⁵.Optimizing the healing process of wounds requires reducing inflammatory activity. According to earlier research, a prolonged inflammatory phase of wound healing could prevent the proliferative phase from occurring, which could result in the development of chronic wounds³⁶. Probiotics can be an alternative and supportive medication to accelerate the healing of wounds in the oral cavity. It is intended that more research will be conducted in order to determine the advantages of probiotics as a substitute wound-healing treatment in the oral cavity. Suggestions for further studies regarding the benefits of probiotics for healing wounds in the oral cavity using another marker. Despite efforts to control variables, there may be unaccounted factors or confounding variables that could influence the results. Future studies could implement more rigorous control measures to mitigate these potential sources of bias.

CONCLUSION:

IL-6 expression differs following topical administration of the probiotic Lactobacillus casei Shirota compared to controls, according to the research that has been done. Probiotics applied topically can slow the expression of IL-6 during the healing of traumatic ulcers in Wistar rats (Rattus novergicus).

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Received on 26.01.2024 Revised on 15.04.2024

Accepted on 22.06.2024 Published on 20.01.2025

Available online from January 27, 2025

Research J. Pharmacy and Technology. 2025;18(1):196-202.

DOI: 10.52711/0974-360X.2025.00030

This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Creative Commons License.