**4. Probiotics stimulate humoral immune system**

Probiotics are used to sensitize the host's immune system to potentially dangerous pathogens. Oral administration of B. bifidum increased humoral immune response to egg albumin, whereas *B. breve* increased IgA exposure to cholera toxin [32]. Oral administration of *L. rhamnosus* triggered antibody IgA secreted B-cells in children with rotavirus infection in control studies [33]. Lactobacilli were given orally to suckling rats that had been sensitized with cow milk, and the number of cells secreting antibodies β-lactoglobulin increased. Human babies develop atopic dermatitis after consuming cow milk. Probiotic therapy, on the other hand, has been scientifically proven to minimize atopic dermatitis infection in humans. Food antigens are processed in the intestine with the aid of the gut microbiota. Low-molecular-weight peptides produced by bacteria collected from of the gastric microbiota can stimulate the immune reaction [34].

Probiotic derived proteases have been shown to digest cow milk casein and produce peptides that inhibit inflammatory cytokines in healthy people. A study was conducted to see whether caseins digested by probiotic bacteria producing proteases might induce the production of cytokine and anti-CD3 immunoglobulin mononuclear cells in atopic dermatitis in infants with cow milk allergies. Casein from cow's milk stimulates the synthesis of IL-4, which causes hypersensitivity [35]. Oral administration of *L. rhamnosus* GG, on the other hand, breaks down casein and inhibits IL-4 synthesis. These results indicate that probiotics in diet change the composition of potentially toxic pathogens, thus altering their immunogenicity function [36].

The ability of probiotics to increase the number of T-regulated lymphocytic cells contributes for their anti-inflammatory and anti-colitis properties. *B. longum* has helped in the treatment of colorectal colitis in mice by upregulating T-regulated lymphocytic cells. As a result, IL-10 and IL-12 levels in the blood have risen, while inflammatory cytokines including IL-23, IL-12, and IL-27 have decreased [37]. In healthy people, *B. infantis* induces Foxp3 T-cells to become activated, which decreases the levels of inflammatory cytokines in psoriasis patients [38].

Probiotics strain produced short chain fatty acids molecules such as propionate, isobutyrate, acetate, butyrate etc., which directly or indirectly regulate the homeostasis of T-cells. Butyrate activates Foxp3+ cells and Treg cell production outside of the hypothalamus. Propionate regulated the production of T-cell by inhibiting histone deacetylase. Probiotics e.g. *L. acidophilu, B. breve*, *L. gasseri, B. longum*, *B. longum subsp. infantis* prevented the development of Th17 inflammatory cells, which are responsible for the pathogenesis and progression of different inflammatory diseases such as irritable bowel syndrome [39]. Further to that, *L. rhamnosus* GG and *B. breve* inhibit IL-17 and IL-23, which are necessary for Th17 growth, stability, and stimulation. INFγ and TNF-α was produced by various Lactobacillus and Bifidobacterium species, which inhibited the expansion of Th17 inflammatory cells. *B. longum* (JCM) increased IL-27 development, which has been linked to a reduction in the amount of IL-17 stimulating Th-17 cells [40].

Probiotics have the ability to shift the immune response from Th2 to Th1. L. casei can stimulate IL-12 development, polarizing the Th1 response and mitigating Th2 linked illnesses. *L. rhamnosus* curtails Th2 as well as Th17 cells and improves clinical symptoms of seasonal allergies, atopic dermatitis and psoriatic arthritis. Probiotic fermented dairy milk modified the allergic process triggered by ovoalbumin in rats, polarizing a Th1 instead of a Th2 pattern reaction and leading throughout the production of IgG rather than IgE, with increased concentration of IFN-γ and IL- 10 accountable immunomodulation [41].

Probiotics have a direct effect on the cells of the lamina propria and payers patches, resulting in an increase in IgA production cells. IgA plays an important function in the prevention of mucosal pathogens. Toxins are neutralized by IgA, which prevents pathogens bacteria from binding to intestinal epithelial cells. *L. gasseri* (SBT2055) has been shown in mice to activate the TLR2 signal pathway, which triggers IgA generating cells in the mucosa and payers patches of the small intestine. While B lymphocytes are responsible for production of specific immunoglobulin and are the primary players in the adaptive immune response, they can also deprecating antibodies by manufacturing IL-10 through inflammatory and chronic diseases. The use of probiotics during combination with influenza vaccine increased an individual's total number of IgG and memory B-cells [42].

#### **5. Role of probiotics as antibacterial**

The oral cavity is a highly complex structure containing over 700 different types of bacteria. When there is a disturbance in this environment, abnormalities such as periodontal disease may occur, resulting in a reduction of indigenous microbial populations to the advantage of infectious agents. The causative agents of oral cavity disease are *S. mutans, A. viscosus, F. nucleatum* and *P. gingivalis*. Microbial resistance tends to be a safe way to battle against the establishing of bacterial pathogens with in oral ecosystem, and this fight might well be enabled by probiotic strains [43].

Anti-bacterial substances formed by probiotic strains included defensin, acetaldehydes, hydrogen peroxide, bacteriocins, organic acids, ethanol, and peptides. Peptides and bacteriocins, in general, are essential in increasing the vascular permeability of target cells that contributes to activation of the membrane permeability and, eventually, cell damage [44].

Probiotics have antibacterial effect, which is an essential feature. Bacteriocin synthesis may be one way to accomplish this antibacterial activity. Bacteriocins are produced by the industrial probiotic strains *L. casei* YIT 9029 and *L. johnsonii* LA1. The antimicrobial compound's existence can be deduced from its behavior, which includes a limited inhibiting range, lack of function if administered with proteinases, and relatively tiny molecular weights [45]. *L. amylovorus* (DCE 471), *L. johnsonii* (LA1), and *L. casei* (YIT 9029) all developed bacteriocins that prevented helicobacter pylori infection in humans. Regrettably, H. pylorus was not inhibited by a fourth bacteriocin induced by *L. acidophilus* (IBB 801). This suggests that certain bacteriocins formed by unique probiotic strains may help to inhibit this specific bacterium [46].

The most commonly used probiotic strains are from the Lactobacillus genus, which is recognized as safe. Some researchers have explained the function of probiotics in the buccal mucosa during the last few decades. Intake of lactic acid bacteria containing items has been shown to mitigate dental caries of mutant streptococci, but the studied species were ATCC strains rather than standard probiotic species such as *L. rhamnosus* GG. It has been demonstrated that probiotic strains with good antibacterial activity are needed to eliminate or stop harmful bacteria [47]. Lactobacilli have long been considered to be able to produce antimicrobial compounds. Lactobacilli may produce organic acid compounds as a result of carbohydrate fermentation, which can intervene with the function of neighboring microbes via depressing the pH of the environment. Some probiotic strains produce bacteriocins, which are well-known types of microbial animosity. *L. gasseri* was abundant in healthier people's oral mucosa and developed bacteriocin against pathogenic microbes. *L. reuteri* appears to be able to produce reuterin, a powerful antibacterial substance derived from glycerol fermentation [48].
