ABSTRACT

Lactobacillus sp. is considered an indispensable probiotic, and this probiotic has an effective role in maintaining the immune system. We evaluated the effect of the probiotic Lactobacillus sp. on modulating inflammation in several cases. In collecting the literature, we used databases from the Web of Science, the Cochrane Central Register of Controlled Trials, PubMed, and Embase. Studies that met the inclusion criteria were analyzed using Review Manager (version 5.4). A p-value of <0.05 of the total effect is considered statistically significant. Finally, 1895 references were retrieved and 20 were included in the meta-analysis. This meta-analysis suggested that most cases in this study were healthy elderly who received treatment with Lactobacillus sp. Lactobacillus sp. has a positive effect on B cells, eosinophils, IgE, NK cells, TNF-α, and IL-10. Lactobacillus could regulate the immune system by modulating inflammation in the healthy elderly.

Keywords:

Good health and well-being, inflammation response, immune system, Lactobacillus sp.

INTRODUCTION

Many studies have shown that probiotics, especially Lactobacillus sp., play an effective role in maintaining the immune system. This role is evidenced by the interaction between probiotics and commensal organisms in modulating mucosal immune cells or epithelial cells. The number of Lactobacillus sp. in the small intestine in adults is small, but this number can be increased through food fermentation assisted by short-chain fatty acids. The amount of microbiota found in feces is small, ranging from 0.01% to 0.6% of total counts¹. Some Lactobacilli, such as Ligilactobacillus salivarius, Lactobacillus rhamnosus, and Lacticaseibacillus paracasei, were also detected in infants with amounts ranging from 10⁵ to 10⁸ CFU/g².

Lactobacillus is a genus of rod-shaped, Gram-positive, non-spore forming, facultatively anaerobic bacteria from the phylum Firmicutes³. In March 2020, 261 Lactobacillus species had been identified and reclassified into 25 genera (including 23 new genera); this was due to their high genotypic, phenotypic, and ecological diversity⁴.

Inflammation occurs not only in diseased conditions but also in aging and obesity. Consuming probiotics can modulate inflammation to balance it. Today, the use of probiotics is becoming popular because many studies have proven the benefits of probiotics in modulating human health. Lactobacillus has been widely used in both children and the elderly, and probiotics are not only used as a treatment for disease but also as a prevention. One of the probiotics that is often used in research is Lactobacillus sp. and Bifidobacterium however this study limits the effectiveness of Lactobacillus sp. on the immune system, and the mechanism of Lactobacillus sp. in modulating the immune system through the gut microbiome is still unknown.

There have been many studies on Lactobacillus probiotics with different strains, proving that Lactobacillus has great potential for use in human and murine models. While some clinical studies have been negative or inconclusive⁵, other studies have shown positive results^6-8. Lactobacillus has shown significant and promising results in treating acute infectious diarrhea and in the prevention of antibiotic-associated diarrhea in human clinical trials⁶. Recent research has examined the use of the probiotic Lactobacillus in the treatment and prevention of allergic diseases and allergic rhinitis/asthma. There have been many studies proving the role of L. rhamnosus GG in the prevention of atopic eczema or dermatitis⁹.

Lactobacillus sp. maintains intestinal homeostasis by stimulating regulatory T-cells to produce interleukin (IL)-10 and increasing the expression in a TLR2-dependent manner, thereby inducing B cell production. In some cases of inflammation, Lactobacillus sp. has been shown to significantly influence dendritic cells, thereby activating NK cells. Lactobacillus sp. plays a dual role, one of which is inhibiting IkB phosphorylation and degradation, thereby preventing NF-κb translocation which results in decreasing tumor necrosis factor alpha (TNF-α) expression. In allergic cases, Lactobacillus sp. inhibits Th2 cytokine production, thereby reducing eosinophil infiltration.

The aim of this meta-analysis study was to analyze whether probiotic Lactobacillus sp. affects the modulation of the immune system, especially on B cells, eosinophils, immunoglobulin (Ig)E, NK cells , TNF-α, and IL-10, under inflammatory conditions. This study provides more reliable evidence for clinical decisions.

MATERIALS and METHODS

Study Strategy

Four databases serve as reference sources for this analysis: Cochrane Library , Web of Science, Embase, and PubMed. All basic research from this source takes Lactobacillus sp. probiotic intervention against the immune system taken from 1992 to 2022. The keywords used for the literature search are “Lactobacillus”, “Probiotic”, “Immune System”, and “Immunity”.

Inclusion criteria: (1) clinical study of Lactobacillus sp. administered to humans; (2) research using immunological parameters; (3) the data have a mean, standard deviation, and total of samples. Exclusion criteria: (1) meta-analysis studies, reports, reviews, and meeting conclusions; (2) tests on experimental animals, in vitro tests, and research other than clinical trials; (3) research without original data; (4) research using prebiotics or other ingredients; (5) non-randomized controlled trials; (6) no measure of immune outcome; (7) not relevant to Lactobacillus sp. probiotics and immune system.

Publication bias uses the value from Egger’s test; if p>0.05, then there is no publication bias. The determination of publication bias fulfills the following requirements: (1) Random sequence generation; (2) allocation concealment; (3) blinding of participants and personnel; (4) blinding of outcome assessments; (5) incomplete outcome data; (6) selective reporting.

Data Collection

The supporting PRISMA 2019 checklist for this study is available as supporting information¹⁰. Data extracted from journals filtered based on inclusion and exclusion criteria. Some authors independently extracted data, made decisions, and compared their conclusions with those of other studies. If there is a disagreement between studies, a third person (a member of the writing team) is needed to solve the problem through discussion and consultation. During the extraction process of the original data, authentication and reliability are required to avoid bias. Bias caused by the subject will be evaluated as soon as possible. To ensure the reliability of data extraction and minimize bias and error, the authors conducted systematic training of the experts. The information data obtained from this study were as follows: the type of Lactobacillus sp. obtained, the type of disease, and the dose used Lactobacillus sp. effect on B cells, NK cells, eosinophils, IgE, IL-10, and TNF-α.

Data Organization and Analysis

Before conducting the meta-analysis, several indicators were standardized. The meta-analysis used Review Manager 5.4 (Cochrane Collaboration Network, London, UK). This study used the Cohen’s method, and the effect measure was std. Mean difference. Forest plots were used to detect heterogeneity from the collection of journals obtained. Funnel plots are used for possible publication bias. Sample size, mean difference, and 95% confidence interval (CI) were calculated to analyze the results of the acquired immunological parameters. A p-value <0.05 of the total effect was assumed to be statistically significant. I² is an indicator that measures the degree of heterogeneity of the total data obtained. If I² <50%, the heterogeneity of the total data obtained is low, so the fixed-effects model is used. Conversely I²>50%, then the heterogeneity of the total data obtained is high so that it uses a random-effects model.

RESULTS

A total of 1895 references were obtained from the four databases shown in Figure 1. A total of 604 references were excluded because they were not relevant =325, duplications =96, and journal reviews =870. Furthermore, several exclusion criteria from references obtained animal trial results =237, no measure immune outcome =160, not randomized clinical trials =187. This meta-analysis study originally used 20 references; however, 10 references have the same authors and title but different parameters of the immune system in Tables 1, 2. Review Manager 5.4 (Cochrane Collaboration Network, London, UK) was used to perform statistical analysis on six indicators: Eosinophils (five studies), B cells (four studies), IgE (seven studies), NK cells (four studies) TNF-α (six studies), and IL-10 (four studies). The mean difference and 95% CI of these indicators are shown in Figures 2-4.

Effect of the Disease

This meta-analysis pooled studies examining several inflammatory diseases and conditions such as atopic dermatitis^11-13, allergic rhinitis^14-16, Japanese cedar pollinosis^{17, 18}, human immunodeficiency virus (HIV)¹⁹, healthy elderly^20-25, inflammatory bowel disease (IBD)²⁶, and hypercholesterolaemic adults. Our study shows that the most popular reaction to inflammation was in the healthy elderly.

Effect of Probiotic Species

Lactobacillus probiotics have many strains, the most commonly used of which is Lactobacillus casei Shirota (LcS)^{16, 25, 27}. In addition, the type of strain used to test the effectiveness of Lactobacillus probiotics on the immune system was Lactobacillus plantarum CJLP133¹¹, L. plantarum YIT 0132¹⁴, Lactobacillus acidophilus strain L-92¹⁵, Lactobacillus GG and Lactobacillus gasseri TMC0356¹⁷, L. rhamnosus GR-1¹⁹, L. casei DNl14001^20-28, L. paracasei NCC 2461²¹, L. gasseri TMC0356²², Lactobacillus reuteri DSM 17938²³, L. salivarius LS01¹³, L. plantarum HSK201¹⁸, L. plantarum L-137²⁴, L. plantarum ECGC 13110402²⁹, Lactobacillus pentosus¹², L. rhamnosus GR-1 and L. reuteri RC-14²⁶, and L. acidophilus³⁰.

Effects of Age

The majority of the population in this study was >50 years old and found in healthy elderly cases^20-25,30. Meanwhile, in other studies, the population was 1-13 years old^{11, 12} and 18-45 years old^{13, 15, 16, 18, 27}.

Effect of Treatment Length Probiotic was Administered

This study shows that the length treatment of Lactobacillus probiotic on the immune system was administered 8 weeks, because it considered effective to modulate eosinophil¹⁴, B cell^{20, 23}, IgE,^{15, 18, 27}, NK cell²⁰, IL-10²³, and TNF-α²³.

Effect of the Probiotic Form

The most popular forms of Lactobacillus probiotic was yogurt^{11, 16, 19, 20, 26, 28}, and milk^{15, 17, 18, 25, 27} than other supplement forms such as juice¹⁴, powder^{13, 21, 30}, tablet^{12, 22, 23}, and capsule²⁴.

Effect by Country

The results of the meta-analysis of data collection showed that most countries that intervened with the probiotic Lactobacillus are Japan^{14, 15, 17, 18, 22, 24, 27}.

Effect of the Immune System

After an intervention, the 95% CI of eosinophils was -0.50 (the lower limit was <0 and the upper limit was >0). The significant p=0.05 means that Lactobacillus has an effect on eosinophils. The mean difference of the total effect was -0.50/mm³, and its 95% CI was -0.99 to -0.01/mm³(Figure 2a), indicating that Lactobacillus could effectively decrease the level of eosinophils and regulate host immunity.

For IgE, the 95% CI of IgE was -0.10 (the lower limit was <0 and the upper limit was >0). A significant p=0.56 means that Lactobacillus has no significant effect on IgE. The mean difference of the total effect was -0.10/mm³, and its 95% CI was -0.42 to 0.23 pg/mL (Figure 2b), indicating that Lactobacillus could effectively decrease the level of IgE but not significance.

The forest plot of B cells showed that the significant p=0.02 suggests that Lactobacillus has an effect on B cells. The mean difference of the total effect was -0,37/uL, its 95% CI was -0.69 to -0.05/uL in Figure 3a, indicating that Lactobacillus could effectively decrease the level of B cells in the treatment group.

The forest plot of NK cells showed that the significant p=0.77 mean that Lactobacillus had no significant effect on NK cells, the mean difference of the total effect was -0.04/mm³, its 95% CI was -0.30 to 0.22/mm³ in Figure 3b, indicating that Lactobacillus could effectively decrease the level of NK cells in the treatment group but not significant.

IL-10, the 95% CI was -0.25 (the lower limit was <0 and the upper limit was >0). The significant p=0.10 indicates that Lactobacillus has no significant effect on IL-10. The mean difference of the total effect was -0.25 pg/mL, and its 95% CI was -0.55 to 0.05 pg/mL (Figure 4a), indicating that Lactobacillus could effectively increase the level of IL-10 in the treatment group, but the difference was not significant.

After the intervention, the 95% CI of TNF-α -0.12 were -0.50 (the lower limit was <0 and the upper limit was >0). The significant p=0.39 means that Lactobacillus has no significant effect on TNF-α. The mean difference of the total effect was -0.12 pg/mL, and its 95% CI was 0.40 to 0.16 pg/mL (Figure 4b), indicating that Lactobacillus could effectively decrease the level of TNF-α and regulate host immunity. Only 20 studies met the requirements of Egger’s test. Overall, these studies have a low risk of bias due to the incomplete outcome requirements in Figure 5.

DISCUSSION

In recent years, probiotics have attracted extensive attention for treatment because of their low cost and minimal adverse reactions. However, previous studies regarding probiotics have shown limitations such as a small sample size, lack of medical evidence, and incomplete evaluation indicators. Our meta-analysis study mainly focused on the systematic evaluation of the efficacy of Lactobacillus on the immune system. This study gathered 20 studies, 10 of which have the same references but different immune cells that have proven the effect of Lactobacillus on the immune system, such as B cells, eosinophils, IgE, NK cells, TNF-α, and IL-10. Currently, research proves the immunomodulatory effect of Lactobacillus on several diseases such as allergies, IBD, and atopic dermatitis.

Lactobacillus probiotic strains improve the integrity of intestinal defenses, thereby maintaining immune cell tolerance, reducing translocation of bacteria across the intestinal mucosa, and causing disease-coding phenotypes such as gastrointestinal infections, IBD, and irritable bowel syndrome³¹. Probiotics have a significant influence on the intestinal microbiota, which has been proven in experimental animal studies and clinical trials in humans. Lactobacillus also plays a significant role in the modulation and production of B cells, eosinophils, IgE, NK cells, TNF-α, and IL-10.

Many studies have proven that consumption of Lactobacillus has a good effect on the body. The probiotic effect is commonly accepted with daily consumption of a minimum of 10⁶ CFU/mL or gram of probiotics³². Consumption of probiotics has different effects on each individual. The effect was based on immunological reactions and symptomatic parameters caused by the amount of Lactobacillus probiotic consumption. Probiotics can be administered orally in the form of capsules^{33, 34}, yoghurt^{35, 36}, dairy drinks or milk^{15, 16, 37, 38}, and tablets^{39, 40}. Our data suggest that the majority of Lactobacillus probiotics are administered in the form of milk. Factors that influence the effectiveness of probiotic consumption are the duration and timing of intake. Moreover, the duration of Lactobacillus consumption in human trials differed from 2 to 12 weeks, and 8 weeks is the most popular time for Lactobacillus treatment. LcS is the most popular strain used for Lactobacillus treatment.

Our data show that age is the inflammatory reaction that triggers the activation of immunological cells. The majority of them are >50 years old. In several studies, aged >50 years, there has been an inflammatory reaction such as activation of TNF-α and IL-6^41-43. This study proves the effect of Lactobacillus probiotics can modulate inflammatory reactions in healthy 50-year-olds. It showed that Lactobacillus probiotics could modulate the activity of B cells, eosinophils, IgE, NK cells, TNF-α, and IL-10.

B cells play a role in eliminating incoming bacteria. On the other hand, B cells can also cause autoimmune and allergic diseases⁴⁴. This study proves that Lactobacillus impacts reducing the number of B cells. This decrease in B cells is necessary because antibodies can damage the intestinal mucosa. In some cases, such as allergies and autoimmune diseases, B cell activation is very high and can attack other immune cells. The results of our meta-analysis prove that a decrease in Lactobacillus plays a role in reducing the activation of B cells.

Several studies using probiotics have proven effective in increasing NK cell activity. Studies have shown that the administration of L. rhamnosus HN001 supplements for 3 weeks shows the activity of NK cells in middle-aged and elderly populations⁴⁵. Our analysis proves that Lactobacillus positivity increases NK cell activation, which means that NK cells are effective for the treatment group. One probiotic that is often used in research trials is the lactic acid bacteria strain, LcS, which is currently manufactured in Japan as a commercial beverage. Many studies have shown the immunomodulatory effects of LcS on the gut immune system, particularly NK cell activity within the innate immune system⁴⁶.

Our analysis also showed that Lactobacillus had a positive result on TNF-α which means that Lactobacillus acts as an immunomodulator to decrease TNF-α cells. Probiotics such as Lactobacillus can inhibit TNF-α expression, generating an immunosuppressant and anti-inflammatory effect as a response; this statement has been widely reported by other studies. A study showed that the probiotic Lactobacillus can reduce TNF-α expression, and treat colitis symptoms⁴⁷.

Like TNF-α, we proved that Lactobacillus downregulates IgE. This effect is essential in patients with food allergies because it avoids clinical manifestations with vital consequences for allergic patients. IgE is an amply recognized antibody (immunoglobulin) associated with allergic responses. In different cases, IgE antibodies can bind to allergens and increase host resistance against parasites (helminths and protozoans). Mechanism of IgE as a defense through binding to allergen products and FcεRI on basophils and mast cells, antigen and IgE-induced aggregation of FcεRI can trigger the release of histamine, proteases, prostaglandins, leukotrienes, chemokines and cytokines⁴⁸.

IL-10 plays a central role in downregulating inflammatory cascades by suppressing the secretion of proinflammatory cytokines. Lactobacillus was positive for IL-10 expression. Some studies have revealed the positive effect of Lactobacillus sp. in stimulating IL-10. Current research has demonstrated that administering L. casei can modify intestinal microbiota composition and TLR expression and increase IL-10 levels in the colonic mucosa of patients with mild ulcerative colitis⁴⁹.

The strength of this study was that the probiotic Lactobacillus sp. is highly effective in the elderly who are >50 years old through modulation of eosinophils and B cells. The limitations of this study: (1) Many studies have examined the effects of Lactobacillus sp. probiotics but did not include the mean, standard deviation, and the number of samples, so that studies were excluded from this study; (2) There is little evidence of the effect of probiotic Lactobacillus sp. on anti-inflammatory parameters; (3) Only collects a few cases (atopic dermatitis, allergic rhinitis, Japanese cedar pollinosis, HIV, healthy eldery, hypercholestrolaemic, and IBD), so the role of probiotic Lactobacillus sp. in other cases is not known.

CONCLUSION

In conclusion, our meta-analysis demonstrated that most cases in this study were healthy elderly patients who received treatment with Lactobacillus sp. Lactobacillus sp. positively affects B cells, eosinophils, IgE, NK cells, TNF-α, and IL-10. This means that Lactobacillus could regulate the immune system by modulating inflammation in the healthy elderly.

Acknowledgements: Thank you to the Center of Women Empowerment in Law Enforcement Research Found for funding this study.

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A Meta-analysis of the Effect of Probiotic Lactobacillus sp. as Immunomodulating Inflammatory Responses