The Immunomodulatory Role of Probiotics

*Faisal Siddique, Kashif Akram, Etab Saleh Alghamdi, Qandeel Arshad and Ayesha Siddique*

#### **Abstract**

Probiotics are particularly beneficial living microorganisms that help improve human health. Although probiotics have long been used as nutritional supplements in various cultures around the world, new research has investigated their antimicrobial and immune boosting effects in individuals. Lactobacillus and Bifidobacterium are popular probiotics used worldwide that benefit human health by acting as antibacterial, antiviral, and antifungal agents, reducing pathogen binding to the host receptor and thus capturing pathogenic microorganisms. Probiotics have been shown to be beneficial in a variety of bacterial and viral diseases worldwide. The regulation of the host's immune response is one of the most important mechanisms of probiotic action. Immunomodulatory effects of probiotic-derived compounds have been characterized using genomic and proteomic analysis. These compounds have the ability to regulate and initiate mucosal immunity against various diseases. Probiotics produce many bactericidal compounds, which inhibit the growth of pathogenic microorganisms and their toxins, promoting the sustainability and structural integrity of enterocytes. This chapter focused on recent scientific research findings that help us better understand how probiotics regulate the host immune response and how they can be used to prevent and treat disease and there beneficial role to improve the health status of individuals.

**Keywords:** Immunomodulatory, Antibacterial, Antiviral, Probiotics, Lactobacillus

#### **1. Introduction**

The human body is prone to many virulent microbes and their oxidative metabolic substances. The human body is shielded from potentially pathogenic microbes by the immune system [1]. The gastrointestinal tract, which is approximately 7.5 meters long, is the largest area of the immune system. Furthermore, trillions of bacteria reside in the gut, particularly in the colon, which served as the main reservoir for these mutualistic species. Most of the time, it is said that the number of human cells in the body is ten times less than that of bacterial cells, while this proportion has been revamped to about 1:1 [2]. Normal vaginal and fecal microorganisms were injected at birth to study the host microbe's relationship with the newborn. This inoculum contains aerobic, anaerobic, gram-positive, and gram-negative bacteria belonging to dominant species such as Sneathia spp., Lactobacillus spp., and Prevotella spp. [3]. It has been studied that how gestational stage, environment, type of delivery, attitude, and breastfeeding habits influenced the proliferation and stability of the infant's microbiome [4].

The host-microbe relationship is critical for the growth of the gastrointestinal immunity within the first weeks after giving birth. The proliferation and growth of gut microorganisms continues until about the age of two years, at which point the intestinal immune system is said to be mature [5]. The intestinal environment of gut microorganisms is generally stable, particularly at the species and genus levels. Besides that, irrational antibiotic use, pathogenic parasites, malnutrition, or cold and hot stress all have an impact on the structural composition of gut microbiota [6].

Antimicrobial drugs, as well as human-targeted medicines, have been attributed to changes in gut microbial composition. More than a thousand antimicrobial drugs have been evaluated against forty different intestinal bacteria around the world. They discover 24 drugs that inhibit the growth of one or even more bacterial strains in vitro [7]. The defensive mechanism is triggered by innate immunity when an individual's body is exposed to a foreign particle or sustains tissue damage. Innate immunity protects cells physiology by signaling adaptive immune responses to persistent threats and stimulating inflammatory response. Inconsistent innate and adaptive responses, on the other hand, result in highly inflammatory reactions, tissue damage, and disease. The host mucosal immune response induced by gut microbiota is important for maintaining intestinal homeostasis and developing a systemic defense response. Manipulation of the intestinal microbiota can thus be a viable alternative route to improving health and to prevent and/or cure illness [8].

Probiotics were described as 'live microorganisms that impart benefits to the host health when taken in sufficient quantities as component of food". Saccharomyces, Lactobacillus, and Bifidobacterium are three important probiotic Genus that have been extensively researched and used in animal and human feed [9]. Recent research indicates that probiotics have a number of beneficial effects on the host's gastrointestinal tract protection mechanism. They produce bactericidal substances by which they counteract pathogenic microorganisms' consequences and bind to the intestinal epithelium by interacting with pathogenic microorganisms and their toxins. Probiotics facilitate the longevity of epithelial cells, improve the immune barrier, and improve the immune response to intestinal epithelium, all of which lead to gastric mucosal homeostasis [10]. Most notably, immune system regulation is among the most potential factors behind probiotics' beneficial health effects. Probiotics strengthen innate and adaptive immunity and suppress bacterial infection through toll-like receptor-regulated signal transduction pathways. Probiotic bacteria have been seen to enhance intrinsic host immune mechanisms. The use of probiotic microbes has significant effects on people's immune systems, such as stabilizing the non-immunological or innate immune response triggered by gut microbes, improving adaptive intestinal immune response, and regulating non-specific inflammatory and hypersensitivity reactions [11].

#### **2. Historical background of probiotics**

The concept of probiotics therapy emerged after the discovery of gut microbiome that is an inherent part of the intestinal epithelial cells. A probiotic is represented as a live microorganism's dietary supplement that benefits the individual by boosting the intestinal microbiome in the gastrointestinal tract. The probiotic definition is incomplete for the aim of human health and nutrition. In response, the European Commission and the International Institute of Life Sciences collaborated to reframe the concept of probiotics as a live microbial food item which is beneficial to human health [12].

#### *The Immunomodulatory Role of Probiotics DOI: http://dx.doi.org/10.5772/intechopen.98839*

In 1953, German researcher Werner Kollath coined the term probiotic, which is comes from the Latin terms pro, which means for, and biotic, which means "bios" or "life." Probiotics were defined by Lilly and Stillwell in 1965 as substances produced naturally by one microorganism that promotes the growth of another. In 1992, Fuller described probiotics as "live microorganisms added as a supplement in feed that benefits the host by improving its intestinal microbial balance" Probiotics have a modern history dating back to the early 1900s, when future Nobel laureate Elie Metchnikoff, a Russian scientist working at the Pasteur Institute in Paris, performed groundbreaking research [13].

Louis Pasteur established the microbes required for the fermentation process, while Metchnikoff first sought to determine the potential impact of the microbiota on public health. He attributed Bulgarian village peoples' long life spans to their regular consumption of yoghurt, which are fermented dairy products. He related this to Stamen Grigorov, a physician who found the Bulgarian bacillus, and further proposed that lactobacilli could mitigate the decaying impact of digestive fermentation, that led to illness and aging. Furthermore, Socrates said over two thousand years ago that "death lies in the guts" and that "poor absorption is the root of all evil." Metchnikoff also reported that toxins generated by microbial decomposition in the gastrointestinal tract and then discharged into to the bloodstream trigger aging [14]. Such microbes were originally referred to as decomposing microbes, but they are now known as proteolytic clostridia. Metchnikoff also noted that "the gastrointestinal microbiota' reliance on food allows us to take steps to change the microbiome in our gastrointestinal tract and exchange pathogenic microorganisms with good bacteria." Metchnikoff scientific theory of probiotics was the foundation for the first dairy industry in France [15].

Modern techniques have selected probiotics strains that manufacture fortified milk with strong nutritional and organoleptic features more than anyone else. Yoghurt was the first functional fermented food based to historical evidence [16]. However, since probiotics are usually associated to the consumption of fermented foods, they have a long and distinguished history. In ancient Indian Vedic literature, milk and milk products are associated to a reliable and comfortable life. According to legend, the first kefir grain was distributed by Prophet Muhammad (SAW) to the descendants of Caucasian mountaineers as a reward. Kefir is a fermented milk drink that contains a lot of lactic acid bacteria and probiotics. Cheese and yoghurt have been used by Hippocrates, Marco Polo, Galeno, and Chinese people throughout history [17].

#### **3. Probiotics stimulate innate immune system**

The most distinguished cells of natural immunity in probiotic research are the dendritic and epithelial cells. These are the first cells to interact with the gut microbiota and its toxic metabolites. Gut associated lymphoid tissue (GALT) and intestinal mucosa is the reservoir of intestinal dendritic cells. Dendritic cells are also known as detector cells because they have unique receptors that attach to specific sites on pathogen surfaces. Dendritic cells also act as a catalyst for various forms of signaling pathways that modify phenotypes and secreted cytokines such as Toll-like receptors and c-type lectin receptors [18].

*Bifidobacterium infantis* 35624 is a probiotic strain that can regulate dendritic cells activity, leading to a rise in cDC1 (CD103+ DC) in the basal lamina. It has many advantages for human health because it decreases the incidence of Dextran sulphate sodium-induced colitis, which is caused by a retinoid acid-dependent process [19]. Furthermore, oral administration of B. infantis 14.518 to Albino

BALB/C mice stimulates the growth, development, and maturation of dendritic cells in GALT, which is responsible for the regulation of T cells and the inhibition of Th2-biased responses through a process known as differentiation [20]. Additionally, other *B. longum*, *B. infantis*, *L. rhamnosus*, and *L. casei* enhance CCR7, CD40, and CD80 production in both juvenile and old Dendritic cells donors, whereas only old donors can boost IFN-γ and TGF- expression. The oral administration of *B. longum bv. infantis* CCUG increased IL-10 output [21].

The use of probiotic strain *L. rhamnosus* JB-1 has many advantages to regulate the dendritic cells by production of haemoxygense, stimulation of DC-SIGN and TLR-2 pattern recognition receptors (PRRs). *L. rhamnosus* JB-1 helps reduce inflammation via inhibiting the expression of co-stimulatory molecules, production and maturation of cytokines and TH1/TH17 through stimulations of the human monocyte derived dendritic cells. The immunomodulatory activity of *L. rhamnosus* JB-1, which expresses Foxp3 and induces IL-10 development, has been documented. Probiotic bacterial strain cell wall components also regulate the immunomodulation of DCs. When capsular polysaccharide binds with TLR-2 receptors on dendritic cells, it stimulates the development of IL-10 from T helper cells, which reduces the inflammatory response caused by colitis [22]. Similarly, exo-polysaccharides derived from *Bacillus subtilis* are useful in the treatment of intestinal infections because they protect against *Citrobacter rodentiumin* toxicity. Probiotics, on the other hand, control the microbial populations in the intestine after modifying dendritic cells activation [23].

The absorptive role of intestinal epithelium is well described. Epithelial cells produce a mucosal barrier to safeguard the individual from harmful microbes and toxicants. The intestinal mucosa barrier has a powerful connection with the intrinsic immune system of the Peyer's patches and lamina propria [24]. Probiotics are well-known for preserving the integrity of the intestinal barrier through a variety of mechanisms, including starvation of infectious agents as they compete for nutrients, detachment of bacteria from intestinal epithelium, which prevents pathogen invasion, immune response regulation, and aiding in regulatory T cell responses. Most of these are probiotics' positive effects on the host's internal health [25]. The use of *B. infantis* prevents Salmonella infection by reducing the induction of Peyer's patch macrophage inflammatory protein-1 (MIP)-1 and MIP-1 through a Treg-dependent pathway [26]. Human-defensin-2 is a probiotic-produced antimicrobial peptide that strengthens the mucosal barrier against pathogenic microbes. Defensins are wide ranging anti-microbial peptides released by macrophages, epithelial cells, neutrophils and, Paneth cells as part of a natural immune reaction [27]. *Shirota strain (L. casei)* increases defensin mRNA transcription in Caco-2 colonic intestinal cells by increasing hBD-2 [28].

Multiple probiotic strains of the genus Bifidobacterium, such as *B. infantis, B. adolescentis, B. bifidum, and B. longum*, could be modulate the apoptosis process in intestinal epithelial cells. They can also enhance mucin secretion, which serves as the first line of protection against infectious agents in the intestine [29]. *L. rhamnosus* GG3 induces mucin production in intestinal epithelial cells by activating the Muc2 and p40 genes expression. When an antigen attaches to enterocytes, pro-inflammatory neurotransmitters, chemokine's, and some tumor necrosis factor are secreted, triggering an efficient immune response [30]. *L. casei* and *L. rhamnosus* reduce the production of proinflammatory cytokines in enterocytes after infection with *Clostridium difficile*. *B. polyfermenticus*, *Bifidobacterium lactus*, *B. animalis ssp. lactis Lactobacillus casei, L. paracasei* ssp. *paracase*i, and *L. plantarum* stimulate the production of natural killer cells after infection [31].
