In the intricate world of human health, the immune system stands as a vigilant guardian, ever-ready to combat pathogens and maintain the body's delicate balance. Among the most fascinating allies in this battle are probiotics—live microorganisms that, when administered in adequate amounts, offer a plethora of health benefits (Figure-1). These microscopic warriors, traditionally harnessed from fermented foods and dairy products, have long been celebrated for their ability to enhance gut health and boost immunity . However, as science progresses, so too does our understanding and utilization of these beneficial bacteria. Enter the Next Generation of Probiotics (NGPs): genetically engineered strains and novel species meticulously designed to provide targeted and potent health benefits.

Figure 1: Diverse Applications of Probiotics in Health Modulation

The history of probiotics dates back to ancient times when fermented foods were first consumed for their health benefits. Early records from 3600 BC indicate that the Mesopotamians were among the first to use fermentation, primarily for making beer and bread. Ancient Egyptians (around 3000 BC) also consumed fermented foods such as sour milk and cheese, which were believed to have medicinal properties. The Greek physician Hippocrates, known as the "Father of Medicine," around 400 BC, emphasized the importance of diet, which likely included fermented products. In ancient India, Ayurveda, the traditional system of medicine, recommended fermented dairy products like yogurt for their health benefits.

The scientific exploration of probiotics began in the early 20th century. Nobel Prize-winning Russian scientist Élie Metchnikoff, in 1907, proposed that the longevity of Bulgarian peasants was due to their consumption of fermented milk products containing Lactobacilli. This hypothesis spurred interest in the potential health benefits of beneficial bacteria. The term "probiotics," meaning "for life," was introduced in 1965 by Lilly and Stillwell, referring to substances produced by microorganisms that promote the growth of other microorganisms. In the 1980s, research on probiotics expanded, with studies demonstrating their benefits for gastrointestinal health. Notable products included Yakult, introduced in Japan in 1935 but gaining global popularity in the late 20th century (Figure-2).

Figure 2 :  Probiotics: A timeline of discovery and development

The 21st century marked a significant advancement in probiotics research and application. Studies revealed that probiotics could help manage conditions such as irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), and even mental health issues through the gut-brain axis. The Human Microbiome Project, launched in 2008, further highlighted the critical role of gut microbiota in overall health, fueling interest in probiotics. Today, probiotics are a mainstream component of health and wellness, available in various forms such as capsules, powders, and fortified foods. Their applications extend beyond gut health to immune modulation, metabolic health, and even skincare. The evolution of probiotics from ancient dietary practices to modern therapeutic applications underscores their enduring significance in human health (Table-1).

Table 1: Comprehensive Overview of Probiotic Strains

The study of probiotics began in the late 19th century, when Henry Tissier isolated Bifidobacteria from infants’ stools, emphasizing their role in human intestinal flora. Coined in 1953 by Kollath and refined by Fuller in 1989, the term “probiotic” describes live microbial supplements that improve the host’s intestinal microbial balance. Ilya Metchnikoff’s research on Lactobacillus-rich yogurt among Bulgarian peasants laid foundational principles linking probiotics to health and longevity. Defined by the FAO/WHO in 2001, probiotics are live microorganisms that, when consumed in adequate amounts, confer health benefits (Gogineni et al., 2013; Kechagia et al., 2013; Vitetta et al., 2018; Rajkumar et al., 2020). In the 21st century, advancements in microbiology and biotechnology have enabled the identification and characterization of probiotic strains with documented health benefits. This has led to a surge in probiotic products, including supplements and functional foods, driven by growing consumer awareness of gut health (Dong et al., 2024; Prakash et al.,2020).

Concept of Probiotics

Taxonomic Significance of Probiotics

Taxonomy is essential for understanding the classification and evolutionary relationships of probiotic microorganisms, particularly lactic acid bacteria. Traditionally, classification was based on phenotypic traits like morphology and lactic acid production. However, 16S ribosomal RNA sequence analysis has revealed discrepancies between phenotypic and phylogenetic classifications, highlighting the need for more accurate methods. Phylogenetic analysis using conserved molecules like ribosomal RNA helps delineate evolutionary relationships. Molecular techniques such as pulsed-field gel electrophoresis and polymerase chain reaction are vital for identifying and characterizing probiotic strains (Holzapfel, 2001). Accurate taxonomic identification is crucial for understanding the specific benefits of probiotics, ensuring their safety and effectiveness. Each probiotic strain may have unique properties that contribute to health benefits. Precise identification allows researchers and regulators to monitor the impact of probiotics on individuals and populations over time, which is critical for postmarketing surveillance and epidemiological studies. Proper identification is also essential for regulatory compliance, ensuring probiotic products meet quality and safety standards. By identifying probiotic strains at a taxonomic level, researchers can better evaluate their efficacy in promoting health (Morelli, 2013).

General Mechanism of Probiotic Action in the Immune System

Probiotics offer health benefits primarily by modulating the immune system. They enhance epithelial barrier function, produce antimicrobial substances, and stimulate immune cells (Plaza-Diaz, 2019; Dhundale et al., 2018). By promoting the production of mucins and tight junction proteins, probiotics improve the epithelial barrier, preventing pathogen invasion. Additionally, they produce bacteriocins and short-chain fatty acids that inhibit pathogens. Probiotics interact with the gut-associated lymphoid tissue (GALT), stimulating immune cells such as dendritic cells (DCs), macrophages, and T cells (Plaza-Diaz, 2019). This interaction leads to the production of cytokines, including anti-inflammatory cytokines (e.g., IL-10) and reduced levels of pro-inflammatory cytokines (e.g., TNF-α), thereby balancing immune responses. Probiotics also enhance natural killer (NK) cell activity, which is crucial for defence against viral infections and tumors. Furthermore, probiotics stimulate the production of secretory immunoglobulin A (sIgA), an antibody that neutralizes pathogens and prevents their adherence to the intestinal mucosa. The interaction with toll-like receptors (TLRs) on immune cells triggers signaling pathways that activate nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), which regulates the expression of genes involved in immune responses. Examples of probiotics and their effects include Lactobacillus rhamnosus GG, which enhances sIgA production and reduces respiratory infections in children, while increasing NK cell activity and anti-inflammatory cytokines (Gill & Rutherfurd, 2001).

Bifidobacterium longum reduces inflammation in patients with inflammatory bowel disease by modulating the cytokine profiles. Saccharomyces boulardii prevents antibiotic-associated diarrhea by inhibiting pathogenic bacteria such as Clostridium difficile (Boge et al., 2009). Probiotic bacteria stimulate both innate as well as adaptive immune responses in the intestine by activating various immune cells and enhancing IgA producing cells and secretion . Specific strains like Lactobacillus helveticus IMAU70129, Lactobacillus rhamnosus GG and Lactobacillus casei IMAU60214 increase the phagocytic and bactericidal activities of macrophages and reactive oxygen species levels. They also enhance NF-κB nuclear translocation and TLR2-dependent signalling. Lactobacillus johnsonii NBRC 13952 pre-treatment increases macrophage phagocytic activity and IL-1β and CD80 expression (Mazziotta et al., 2023).

Traditional and NGPs and its impact on the immune system

Traditional probiotics play an important role in maintaining gut health by enhancing beneficial bacteria and competing against harmful pathogens. By enhancing the gut barrier, probiotics can help stop harmful substances from entering the bloodstream. Furthermore, traditional probiotics can modulate the immune system, reduce inflammation and enhance the body’s defense mechanisms (Abouelela & Helmy, 2024). The term “probiotic” has expanded beyond lactic acid bacteria and Bifidobacteria to include NGPs like Roseburia intestinalis, Akkermansia muciniphila, Faecalibacterium prausnitzii, and others, which show promising effects in managing inflammatory diseases, cancer and metabolic disorders (Al-Fakhrany & Elekhnawy, 2024). Efforts to address metabolic and inflammatory disorders increasingly highlight probiotics as both prophylactic and therapeutic solutions. Beneficial bacteria play pivotal roles in human physiology, contributing to metabolic, barrier, and immunomodulatory functions, thereby reducing disease risk.

The Bifidobacterium and Lactobacillus genera host the most commercialized probiotic strains, with NGPs such as Faecalibacterium prausnitzii, Akkermansia muciniphila, and Eubacterium hallii identified for their potential in managing inflammatory and diet-related disorders (Almeida et al., 2020). NGPs exert multifaceted effects on the immune system by modulating the immune cells like T-cells and B-cells, producing bioactive compounds like short-chain fatty acids and antimicrobial peptides, crucial for gut health. NGPs like Faecalibacterium prausnitzii induce anti-inflammatory cytokines, suggesting roles in immune regulation (Abouelela & Helmy, 2024). These probiotics are tailored for specific health conditions, involving complex biological processes including targeted delivery of therapeutic agents (Abouelela & Helmy, 2024; O’Toole et al., 2017). NGPs extend beyond gut health to impact metabolic disorders, cancer and inflammatory diseases. For example, Faecalibacterium prausnitzii demonstrates anti-inflammatory properties beneficial in managing Crohn’s disease (O’Toole et al., 2017).

NGPs are crucial in addressing conditions related to leaky gut syndromes through enhancements in intestinal integrity, IgA production, bile acid modulation, and antimicrobial peptide synthesis. Identification of NGP candidates employs next-generation sequencing and bioinformatics, highlighting Bifidobacterium spp. for their potential in anticancer therapies and immune modulation. NGPs hold promise in personalized health strategies, such as the role of Prevotella copri in improving glucose tolerance and hepatic glycogen storage through dietary fiber metabolism. Akkermansia muciniphila, thriving on mucin, correlates with improved metabolic disorders when promoted by prebiotics like inulin-type fructans. Traditional probiotics like Bifidobacterium spp. show efficacy in anticancer therapies and immune modulation. Specific strains such as Christensenella minuta and Parabacteroides goldsteinii link to insulin resistance and obesity reversal, respectively. Faecalibacterium prausnitzii and Bacteroides fragilis exhibit protective and anti-inflammatory properties in intestinal health and cancer. These diverse functions and mechanisms of NGPs underscore their potential therapeutic applications across various health conditions, necessitating ongoing research for their full exploration (Chang et al., 2019).

Immunomodulatory Mechanisms of Probiotic Bacteria

Probiotics exert profound effects on innate and adaptive immune responses by interacting with key immune cells within the intestinal mucosa, including DCs macrophages, and B and T lymphocytes. These interactions primarily occur at the intestinal epithelium and lamina propria interface. Upon ingestion, probiotic bacteria adhere to intestinal epithelial cells and activate them through pattern recognition receptors (PRRs), initiating a cascade of immune responses (Figure-3). This activation leads to the secretion of cytokines that promote the differentiation and activation of T regulatory (Treg) cells, pivotal for maintaining immune balance within the intestinal mucosa. Additionally, probiotics facilitate antigen uptake by DCs located in the lamina propria, which in turn stimulate naïve T cells and direct helper T cell responses towards various immune profiles such as Th1, Th2, Th17 or regulatory T cell patterns. These immune responses are characterized by the production of specific cytokines like IFN-γ, IL-4, IL-5, IL-17, IL-10, and TGF-β, depending on the type of immune challenge (Mazziotta et al., 2023). Furthermore, probiotics induce the maturation of B cells into immunoglobulin (Ig)A producing plasma cells. These IgA antibodies play a crucial role in mucosal immunity by controlling bacterial adherence to host tissues and contributing to immune defense within the intestinal tract.

Figure 3: Interaction Between Host Intestinal Immune Cells and Probiotics (Mazziotta et al., 2023)

Immunomodulatory Mechanism of Lactobacilli and Bifidobacterium

Lactobacillus species play a significant role in immunomodulation by interacting with various components of the immune system. They stimulate Treg cells to produce anti-inflammatory cytokines (TGF-β, IL-10, and IL-8), which help maintain immune tolerance and reduce inflammation. Additionally, Lactobacillus increases IL-6 secretion in a TLR-2-dependent manner, promoting the clonal expansion of IgA-producing B cells and enhancing the expression of the macrophage mannose receptor CD206. This enhances the phagocytic capability of macrophages. Lactobacillus also inhibits the expression of inflammatory genes, specifically JAK and NF-κB, and increases the release of cytokines like IL-12p70 and IL-4, which are important for immune responses. Furthermore, it modulates receptor expression by reducing TLRs and increasing co-stimulatory molecules CD40 and CD80, critical for T cell activation. Lactobacillus degrades the proinflammatory chemokine IP-10 and enhances the expression of TLR-9 and components of the inflammasome pathway, such as NLRP3, Caspase-1, and IL-18, contributing to a balanced immune response.

In contrast, Bifidobacterium species exert immunomodulatory effects by inhibiting inflammatory pathways and promoting anti-inflammatory responses. They inhibit the expression of JAK and NF-κB genes, thus reducing inflammation. Bifidobacterium also promotes the over expression of anti-inflammatory cytokines IL-10 and TGF-β while stimulating the production of IgAs, which are essential for mucosal immunity. Furthermore, they favor the differentiation of Treg cells, which help maintain immune tolerance, and increase the number of total helper (CD4+) and activated (CD25+) T lymphocytes, as well as NK cells. The expression of CD19 on B cells is reduced, affecting B cell activation and antibody production. Bifidobacterium induces the production of MCP-1 and TNF-α through TLR-9 stimulation and increases the number of Foxp3(+) T regulatory cells. Additionally, they enhance the release of chemokines such as CCL20, CCL22, CXCL10, and CXCL11, contributing to a comprehensive immune response that supports gut health and systemic immunity.

Immunomodulatory Mechanism in Akkermansia muciniphila

Akkermansia muciniphila degrades the colonic mucus produced by goblet cells leading to the production of bioactive molecules such as acetate and butyrate. These molecules are linked to distinct beneficial effects on the host, improving the intestinal barrier integrity that prevents metabolic endotoxemia, a key characteristic of metabolic disorders such as, type 2 diabetes and insulin resistance; Butyrate also exerts immunoregulatory properties promoting an anti-inflammatory phenotype. Akkermansia muciniphila mediates glucose tolerance through the control of the negative effects of Interferon gamma and, also through the increase of gut hormone production such as Glucagon-like peptide-1 (GLP-1) via production of 2-Oleoylglycerol (Figure-4a).

Figure 4: Typical immuno-mechanisms of Akkermansia muciniphila (a) and Faecalibacterium pruasnitzii (b) in host gut epithelium (Almieda et al., 2020)

Immunomodulatory Mechanism in Faecalibacterium pruasnitzii

Faecalibacterium pruasnitzii acetate metabolism leads to the production of bioactive molecules like butyrate, Microbial Anti-inflammatory Molecule (MAM) and Extracellular Polymeric Matrix (EPM). These biomolecules exert immunoregulatory properties promoting an anti-inflammatory phenotype. MAM peptide effects NF-kB (Nuclear Factor kB) signal transduction pathway ultimately blocking the production of pro-inflammatory cytokines. A particular Faecalibacterium pruasnitzii strain HTF-F is able to produce EPM leading to an increase of anti-inflammatory cytokines production like IL-10 and IL-2 (Figure-4b).

Significance of NGPs

Globally, conditions such as diabetes, obesity and inflammatory bowel diseases pose significant public health challenges, often linked to changes in the gut microbiota diversity. The gut microbiota, along with the gut barrier, regulates host inflammatory and metabolic profiles, promoting cellular homeostasis and overall health (Almeida et al., 2020).

NGPs offer personalized treatment potential by modulating gut microbiota to target specific diseases. They are developed either by identifying strains associated with health benefits or by engineering effective molecules into probiotics (Singh & Natraj, 2021). Unlike traditional probiotics, NGPs provide targeted therapies with broader therapeutic properties, including the production of beneficial metabolites like short-chain fatty acids, serotonin and gamma-aminobutyric acid (GABA) (Abouelela & Helmy, 2024; O’Toole et al., 2017).

NGPs face challenges in industrial transformation due to their complex culture requirements, requiring expensive and anaerobic conditions (Al-Fakhrany & Elekhnawy, 2024). However, they promise enhanced therapeutic efficacy over traditional probiotics in personalized and combination therapies for conditions like liver disease, mood disorders, hypercholesterolemia and metabolic disorders (Al-Fakhrany & Elekhnawy, 2024).

NGPs in Malignancies

Cancer affects over 19.3 million people globally and is the second leading cause of death. Common treatments, such as chemotherapy and radiotherapy, often have unpleasant side effects. Innovative strategies like probiotics are being used to manage these complications (Rodriguez-Arrastia et al., 2021). The role of NGPs in immunomodulation and the treatment of malignancies represents a burgeoning field of research with promising implications for cancer therapy. NGPs, which include genetically engineered probiotics and strains isolated from the human microbiome with enhanced therapeutic potential, are being explored for their ability to modulate the immune system and improve cancer treatment outcomes. These advanced probiotics can influence the gut microbiota composition, leading to enhanced mucosal immunity and systemic immune responses. Recent research studies have focused on the potential of NGPs in cancer treatment, revealing promising results. Probiotics have been explored for their anti-cancer properties (Abouelela, M. E., & Helmy, Y. A., 2024). They are effective against colorectal, gastric, hepatocellular carcinoma, and cervical cancer. They work by promoting epithelial repair, inhibiting tumour growth, inducing apoptosis, producing immunomodulatory metabolites, inhibiting biofilm production, and excluding harmful microorganisms. Studies have shown that certain NGPs can enhance the efficacy of immune checkpoint inhibitors, a class of drugs that has revolutionized cancer therapy by enabling the immune system to better recognize and attack tumor cells (Pei, Bo, et al., 2024). NGPs, including genetically modified strains and novel species, show enhanced therapeutic potential. Studies have demonstrated that these probiotics can modulate the gut microbiota, influence immune responses, and produce metabolites that inhibit tumor growth (Hussein, L. A., 2022). NGPs produce metabolites such as short-chain fatty acids (SCFAs), that can inhibit tumor growth and promote apoptosis in cancer cells. For instance, Lactobacillus rhamnosus GG has been found to enhance the efficacy of chemotherapy by modulating the gut microbiota and reducing inflammation (Rahimpour, M., 2022). Bifidobacterium longum has shown potential in enhancing the anti-tumor effects of immune checkpoint inhibitors by promoting a favorable immune microenvironment (Sivan et al., 2015).

NGP strains, such as Lactobacillus reuteri, Lactobacillus acidophilus, Bifidobacterium infantis, and Streptococcus thermophilus, have shown promising results in animal models. These findings suggest NGPs' potential in cancer therapy, though further research is needed to confirm their clinical efficacy Lactobacillus rhamnosus GG has also demonstrated inhibitory effects on human gastric and colonic cancer cells.

Gut microbiota impacts anti-cancer treatment efficacy and patient’s quality of life. They can also serve as predictive biomarkers for early cancer detection. Modifying gut microbiota through prebiotics, probiotics, synbiotics, postbiotics, and fecal microbiota transplantation can enhance anti-cancer treatments (Kaźmierczak-Siedlecka et al., 2022). Faecalibacterium prausnitzii, Akkermansia muciniphila, and Bacteroides fragilis are NGPs that can benefit cancer patients. They enhance the immune system, reduce LPS-related signaling, improve gut microbiota activity and maintain intestinal barrier integrity. F. prausnitzii can reduce gastrointestinal complications from chemotherapy/radiotherapy, while A. muciniphila may improve immunotherapy efficiency. The safety of these NGPs in human cancer patients remains unclear. Although generally considered non-toxic, A. muciniphila and enterotoxigenic B. fragilis have been linked to colitis and colorectal cancer in animal studies.

One of the mechanisms by which NGPs exert their effects is through the modulation of dendritic cells and T cells, which are critical components of the adaptive immune system. For example, Lactobacillus rhamnosus GG has been demonstrated to enhance the maturation of dendritic cells, thereby promoting the activation of T cells and subsequent anti-tumor immunity (Gopalakrishnan et al., 2018). Moreover, specific strains of Bifidobacterium have been shown to improve the infiltration of CD8+ T cells into tumors, which is associated with better clinical outcomes in cancer patients (Vétizou et al., 2015). The ability of NGPs to modulate the tumor microenvironment is another key aspect of their therapeutic potential. By altering the local immune landscape, NGPs can reduce immunosuppressive factors within the tumor, thus enhancing the efficacy of conventional therapies such as chemotherapy and radiation (Yi et al., 2019).

Furthermore, the safety profile of NGPs makes them attractive candidates for adjunctive cancer therapy. Unlike traditional chemotherapeutic agents, probiotics are generally well-tolerated and associated with fewer adverse effects. This favorable safety profile allows for the potential long-term use of NGPs in cancer prevention and treatment. Clinical trials are currently underway to evaluate the efficacy of various NGP strains in combination with standard cancer therapies. Early results are promising, suggesting that NGPs can enhance the overall response rates and survival outcomes in patients with certain types of cancer, such as melanoma and colorectal cancer (Matson et al., 2018). Genetic engineering has allowed the development of probiotics that can deliver therapeutic molecules directly to tumors, improving targeting and reducing side effects (Ho et al., 2020). These engineered probiotics can produce cytokines or other anti-cancer agents in situ, offering a novel approach to cancer therapy. Moreover, NGPs can impact cancer through epigenetic modulation, altering gene expression to suppress tumorigenesis (Kumar, M, et al., 2013). Clinical trials are underway to evaluate the safety and efficacy of these probiotics in cancer patients, with initial results indicating a favourable safety profile and promising therapeutic outcomes (Chang, C. J. et al., 2019). NGPs hold significant promise in the field of oncology, offering a novel approach to immunomodulation and cancer treatment. By harnessing the power of the microbiome, these advanced probiotics can enhance the immune response against tumors, improve the efficacy of existing therapies, and potentially reduce the side effects associated with conventional cancer treatments. However, challenges remain in the standardization of probiotic formulations and ensuring consistent clinical benefits. The variability in individual microbiomes poses another challenge, necessitating personalized approaches to probiotic therapy. Despite these hurdles, the integration of NGPs into cancer treatment regimens holds significant potential for improving patient outcomes and advancing the field of oncology.

As research in this area progresses, NGPs may become an integral part of the therapeutic arsenal against malignancies, paving the way for more effective and personalized cancer treatments.

Traditional Probiotics and NGPs as Personalized Medicine

Advancements in genomics and microbiome research are paving the way for personalized probiotic therapies. The concept of personalized medicine aims to tailor healthcare to individual patient characteristics, including genetic, microbiome, and lifestyle factors. Probiotics are increasingly being explored within this framework. Traditional probiotics exert beneficial effects by restoring gut microbiota balance, enhancing gut barrier function, and producing antimicrobial substances (Liu et al., 2022; Monika et al., 2021). Their therapeutic applications span a range of conditions, including gastrointestinal disorders, allergic diseases, and metabolic disorders (Dargenio et al., 2022; Michail, 2009;Aggarwal et al., 2013). However, the efficacy of traditional probiotics can be highly variable and strain-specific, making it difficult to generalize their benefits across diverse populations (McFarland., 2021). Individual differences in gut microbiota composition further complicate their clinical outcomes, underscoring the need for a personalized approach (Quin et al., 2018). Additionally, regulatory and quality control challenges persist in the probiotic industry, impacting the standardization and consistency of probiotic products (Mills, 2019). NGPs, including genetically engineered microorganisms and commensal bacteria with enhanced functionalities, offer promising advancements in personalized medicine. NGPs such as Bacteroides, Akkermansia, and Faecalibacterium species can be engineered to produce therapeutic molecules, modulate specific metabolic pathways, and interact with the host genome to influence gene expression (Al-Fakhrany & Elekhnawy, 2024; Kumari et al., 2021;Suez et al., 2020; Zhang et al., 2022). These capabilities enable NGPs to provide more targeted and effective therapeutic actions compared to traditional probiotics. NGPs hold significant potential in various medical fields, including oncology, autoimmune diseases, and neurological disorders. For instance, NGPs can enhance the efficacy of conventional cancer treatments, modulate the tumor microenvironment, and improve outcomes in autoimmune and neurological conditions through gut-brain axis modulation (Lu et al., 2021;Yousefi et al, 2019; Sharma et al., 2021; Bi et al., 2023). However, the development and application of NGPs face challenges such as safety concerns, ethical considerations, and evolving regulatory frameworks (Mazhar et al., 2020 ;Koirala et al., 2022). The integration of traditional probiotics and NGPs into personalized medicine represents a promising avenue for optimizing patient care (Table-2). By tailoring probiotic treatments to individual microbiome profiles and health needs, personalized probiotic therapy can enhance therapeutic efficacy and safety (Singh & Natraj, 2021). Ongoing research and advancements in microbiome science are essential to fully realise the potential of probiotics in personalized medicine.

Table 2: Probiotic Strains in Cancer Therapy: Origins, Mechanisms, and Market Products

Current Trends in Research on Immunomodulatory Probiotics

The field of probiotics as biotherapeutic agents shows promise for enhancing human health. Current establishment in scientific validity of probiotic effects through rigorous studies that explore interactions between probiotic strains and host microbiota, using multidisciplinary approaches are attracting considerable global attention (Mercenier, 2003). Probiotics and NGPs are increasingly recognized for their potential in addressing global health challenges, such as antimicrobial resistance and infectious diseases. NGPs have shown efficacy in decolonizing antimicrobial-resistant microbes and modulating the microbiome and immune system. Amidst COVID-19, probiotics and NGPs have been proposed for preventative and acute care due to their immunomodulatory properties, with clinical studies showing reduced morbidity and mortality in COVID-19 patients (Al-Fakhrany & Elekhnawy, 2024).

There is ongoing exploration into using NGPs for conditions like cancer, though further clinical validation is needed (Kaźmierczak-Siedlecka et al., 2022). Advances in molecular technologies are aiding in understanding probiotic mechanisms, and well-designed clinical studies are crucial for substantiating health claims. Consumer demand for natural health maintenance methods such as probiotics is growing, driving market expansion and highlighting the need for clear regulations and robust scientific evidence.

Developing probiotics as immunomodulators faces several challenges, including understanding their complex interactions with the immune system. Probiotics, such as strains of Lactobacillus and Bifidobacterium, interact with various components of the immune system, including GALT, mucosa-associated lymphoid tissue (MALT), and systemic immune cells, influencing immune responses through mechanisms like cytokine production and DCs modulation (Lim et al., 2020; Wells et al., 2011). Identifying and characterizing probiotic strains with consistent immunomodulatory properties is essential (Medina et al., 2007). Issues related to formulation and delivery, such as probiotic viability affected by gastric acidity and bile salts, require novel encapsulation techniques (Koh et al., 2022). Translating preclinical findings into clinical applications involves rigorous trials to establish safety, efficacy, and optimal dosing regimens (Patel & Shah, 2014).

Ethical considerations, including informed consent and equitable access, are crucial for integrating probiotics into clinical practice (Hill & Artis, 2009). Despite challenges like variability in effects due to individual differences in gut microbiota and regulatory hurdles, future research should focus on elucidating probiotic mechanisms, improving strain-specific efficacy, and integrating probiotics into personalized medicine frameworks. Advances in understanding probiotic-host interactions, formulation technologies, clinical validation, and ethical considerations are essential for realizing the full therapeutic potential of probiotics in modulating immune function and improving human health.

Traditional and NGPs represent promising avenues for immunomodulation, leveraging their ability to interact with the gut microbiota and influence immune responses through diverse mechanisms. Traditional probiotics, such as strains of Lactobacillus and Bifidobacterium, have shown potential in modulating immune functions, though their effects can vary significantly based on strain specificity and host factors. The evolution towards NGPs, involves overcoming challenges in formulation, delivery, and clinical translation to enhance efficacy and ensure reproducible outcomes. Advances in understanding the intricate interactions between probiotics and the immune system, coupled with innovative approaches in strain selection, formulation technologies, and personalized medicine frameworks, offer opportunities to optimize therapeutic interventions. Moving forward, rigorous clinical validation through well-designed trials and addressing ethical considerations will be pivotal in realizing the full therapeutic potential of probiotics as immunomodulators, thereby advancing their integration into mainstream healthcare for personalized immune support and disease management. The role of probiotics in cancer therapy is gaining attention. Probiotics have shown potential in enhancing the efficacy of cancer treatments by modulating the gut microbiota, which can influence the metabolism of chemotherapeutic agents and the body's immune response to tumors. Some probiotic strains have been found to produce metabolites that possess anti-carcinogenic properties, adding another layer to their therapeutic potential. In the context of malignancies, probiotics are being explored as adjunct therapies to improve patient outcomes. For example, certain probiotic strains can mitigate the side effects of chemotherapy and radiation, improve nutritional status, and reduce the risk of infections in immunocompromised patients. Moreover, the gut microbiota's influence on the immune system can be leveraged to enhance the body's natural defenses against cancer cells. The integration of probiotics with personalized medicine approaches is another emerging trend. By analyzing an individual's microbiome, it is possible to tailor probiotic therapies to their specific needs, leading to more precise and effective treatments. This personalized approach can optimize the benefits of probiotics and minimize potential adverse effects. Despite the promising prospects, several challenges remain. Ensuring the stability and viability of probiotic formulations, understanding the complex interactions between probiotics and the host microbiome, and establishing standardized protocols for clinical applications are critical areas that require further research. Regulatory frameworks also need to evolve to keep pace with the rapid advancements in probiotic technologies.the field of probiotics is witnessing a paradigm shift, with next-generation probiotics offering novel biotherapeutic and immunomodulatory prospects. The integration of advanced probiotics into healthcare has the potential to revolutionize the management of health and malignancies, providing a holistic and personalized approach to disease prevention and treatment. As research continues to unravel the complexities of the microbiome and its interactions with human health, probiotics are poised to become a cornerstone of modern medicine.

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