The role of the gut microbiome in immune modulation: implications for autoimmune diseases and cancer therapy

* Corresponding author: Fagbemi Oluwaseyi Ajibola; Email: Copyright © 2025 Author(s) retain the copyright of this article. This article is published under the terms of the Creative Commons Attribution Liscense 4.0. The role of the gut microbiome in immune modulation: implications for autoimmune diseases and cancer therapy Fagbemi Oluwaseyi Ajibola 1, *, Esther Chigbaziru Nwojiji 2, Mustapha Lawal 3, Suara Temilola Barakat 4, Iyiola Aanuoluwa Temitayo 5, Victor Ekoche Ali 6 and Taiwo Bakare-Abidola 7 1 Department of Human Anatomy, College of Medicine, Federal University Lokoja, Kogi State, Nigeria. 2 Department of Microbiology and Parasitology, David Umahi Federal University of Health Sciences, Uburu, Nigeria. 3 Department of Microbiology, Kebbi State University of Science and Technology Aleiro, Nigeria. 4 Department of Pharmaceutical Chemistry, University of Ibadan, Nigeria. 5 Department of Biochemistry, African Centre of excellence of Mycotoxins and Food safety Research, Federal university of Technology, Minna, Nigeria. 6 Department of Medical Laboratory Sciences, University of Nigeria Nsukka. 7 Department of Environmental Science, Georgia Southern University, Georgia, USA. World Journal of Biology Pharmacy and Health Sciences, 2025, 22(01), 564-590 Publication history: Received on 07 March 2025; revised on 23 April 2025; accepted on 25 April 2025 Article DOI: https://doi.org/10.30574/wjbphs.2025.22.1.0434 Abstract The gut microbiome has emerged as a powerful regulator of immune function, profoundly influencing both autoimmune diseases and cancer therapies. Recent advances in microbiome research have unveiled the dynamic interplay between microbial communities and host immunity, revealing how microbial metabolites, bacterial surface molecules, and hostmicrobe interactions shape immune responses. This review explores the intricate mechanisms by which gut microbiota modulate immune tolerance, inflammation, and cancer immunosurveillance, highlighting the potential of microbiometargeted interventions. Emerging therapeutic strategies, including fecal microbiota transplantation, engineered probiotics, and microbiome-derived metabolites, offer novel avenues for modulating immune dysfunction and enhancing treatment efficacy. Furthermore, artificial intelligence-driven microbiome profiling and CRISPR-based microbiome engineering hold promise for precision medicine, allowing personalized modulation of microbial ecosystems. Despite these breakthroughs, challenges such as interindividual microbiome variability, mechanistic gaps, and regulatory hurdles continue to impede clinical translation. Addressing these barriers will be crucial to unlocking the full potential of microbiome-based therapies in immune modulation, autoimmunity, and oncology. By integrating multi-omics approaches and advancing microbial therapeutics, the gut microbiome may soon transition from an adjunct to a cornerstone of precision medicine. Keywords: Gut Microbiome; Immune Modulation; Autoimmune Diseases; Cancer Immunotherapy; Microbiota-Based Therapeutics; Precision Medicine; Fecal Microbiota Transplantation; Engineered Probiotics 1. Introduction A vast and ever-changing population of bacteria known as the gut microbiome inhabits the human gastrointestinal system, which is increasingly acknowledged as a key factor influencing host physiology and general health. This highly diverse microbial ecosystem includes not only bacteria, which have been the primary focus of most early microbiome studies, but also a vast array of fungi (mycobiome), viruses (primarily bacteriophages), and archaea, many of which are yet to be fully characterized [1,2]. These microorganisms form a complex and symbiotic network that exists in a finely tuned balance with the host, engaging in both mutualistic and commensal interactions that influence virtually every World Journal of Biology Pharmacy and Health Sciences, 2025, 22(01), 564-590 565 aspect of gastrointestinal function and systemic biology. Far from being passive passengers, the members of the gut microbiota actively engage in digestion, vitamin synthesis, neurotransmitter production, and regulation of host immunity, among other vital roles [2]. Recent developments in the technique of high-throughput sequencing has greatly improved our comprehension of the richness, composition, and functional capacities of these microbial communities, especially in the areas of metagenomics, shotgun whole-genome sequencing and 16S rRNA gene sequencing [3]. These technologies have demonstrated the gut microbiome's taxonomic diversity as well as its potential applications in both health and illness. According to Lloyd-Price et al. [4], the intestinal barrier's integrity, host metabolic pathways, and the regulation of the immunological response are all impacted by the gut microbiota. Numerous clinical problems, including obesity, type 2 diabetes, neurological disorders, and inflammatory bowel disease, and even some types of cancer, have been linked to dysbiosis, or the dysregulation of this microbial community. As a result, there is a growing perception that the gut microbiota resembles an organ with the potential to have major systemic effects and to be a therapeutic aim in the management and prevention of several illnesses [4]. 1.1. Overview of the Gut Microbiome The gut microbiome is made up of trillions of bacteria that live in the human digestive system. The majority of these organisms are bacteria; the most prevalent phyla are Bacteroidetes and Firmicutes, which are followed by Verrucomicrobia, Proteobacteria, and Actinobacteria. According to the findings of Qin et al. [5], the microbiome of the human intestine has more than 3.3 million distinctive microbial genes significantly outnumbering the host's genetic material. In addition to bacteria, fungi (the mycobiome) such as Candida albicans, Malassezia, and Saccharomyces boulardii are integral to gut ecology, influencing immune responses and contributing to homeostasis or dysbiosis depending on their abundance and balance [6]. Viruses—especially bacteriophages—play crucial regulatory roles by modulating bacterial population dynamics through predation and horizontal gene transfer. The archaea in the human gut, although less abundant, are important in metabolic processes such as methanogenesis. Methanogenic archaea, particularly Methanobrevibacter smithii, are involved in breaking down complex carbohydrates and reducing hydrogen accumulation, thus influencing energy harvest and potentially contributing to obesity when dysregulated [7]. The gut microbiome exerts profound effects not only on local gut immunity but also on systemic physiological processes, including those of the central nervous system. As illustrated in Figure 1, the microbiota communicates with both the gut and the brain through a complex network of pathways involving the immune system, the vagus nerve, the neuroendocrine axis, the circulatory system, and the enteric nervous system [8,9]. The gut microbiome functions as a virtual organ as well, providing metabolic and immunological functions vital to host health. It participates in digesting dietary fibers, synthesizing vitamins like K and B12, regulating bile acids, and training the immune system during early life. Moreover, it forms a critical barrier against pathogen colonization by outcompeting invaders for nutrients and adhering to epithelial cells, a condition referred to as colonisation resistance [8]. Any alteration in its makeup, known as dysbiosis, has been connected to several diseases, including type-II-diabetes and obesity, autism spectrum disorder, inflammatory bowel disease (IBD), as well as diverse autoimmune diseases [9,10]. To better appreciate the diversity and immunological roles of gut microorganisms, Table 1 presents a summary of the major microbial taxa within the human gastrointestinal tract. It highlights representative species, their associated immune-modulatory metabolites, and the implications of their activity for health and disease. Table 1 Major Microbial Taxa in the Human Gut and Their Immune Functions Microbial Group Representative Species Immune Functions Key Metabolites Health Implications Firmicutes Clostridium spp. (clusters IV & XIVa), Faecalibacterium prausnitzii Promote Treg differentiation, antiinflammatory cytokine production Butyrate, acetate Enhances immune tolerance, reduces inflammation; decreased in IBD, RA Bacteroidetes Bacteroides fragilis Induces Tregs, modulates dendritic cells and cytokine balance Polysaccharide A (PSA) Critical for immune balance; alteration linked to colitis and MS World Journal of Biology Pharmacy and Health Sciences, 2025, 22(01), 564-590 566 Actinobacteria Bifidobacterium longum, B. adolescentis Enhance gut barrier integrity, stimulate IgA production Lactic acid, acetate Support mucosal immunity and tolerance; reduced in autoimmune diseases Proteobacteria Escherichia coli (AIEC strains), Klebsiella spp. Activate proinflammatory pathways via TLRs LPS (lipopolysaccharide) Promote inflammation; enriched in IBD, RA, and CRC Verrucomicrobia Akkermansia muciniphila Enhances epithelial integrity, modulates T cell responses Mucin degradation products Linked to improved response to immunotherapy (PD1 blockade) Archaea Methanobrevibacter smithii Supports SCFAproducing bacteria by reducing H2 accumulation Methane Associated with energy harvest and gut homeostasis; altered in obesity Fungi (Mycobiome) Candida albicans, Saccharomyces boulardii Interact with immune cells, promote IL-17 production β-glucans Can support or exacerbate inflammation depending on balance Viruses (Virome) Bacteriophages (crAssphage, Siphoviridae) Regulate bacterial populations, horizontal gene transfer N/A Influence microbiota stability and immune surveillance Figure 1 Bidirectional communication pathways in the Microbiota–Gut–Brain axis. Reproduced with permission from Ref. [10] 1.2. Gut Microbiota and the Immune System Together with the human host, the gut microbiota has developed into a two-way regulatory axis with the immune system. An essential equilibrium between immunological tolerance and activation is established by the interaction, which starts at birth and lasts throughout life. The microbiota influences immunological responses that are both innate World Journal of Biology Pharmacy and Health Sciences, 2025, 22(01), 564-590 567 and adaptive through various molecular and cellular mechanisms [11,12]. When commensal bacteria digest dietary fibres, short-chain fatty acids (SCFAs) such acetate, propionate, and butyrate are produced, which are among the gut microbiota's primary immune-modulatory products. From the findings of Furusawa et al. [13], SCFAs control the Foxp3 gene's epigenetic modification, this, in turn, controls the activity of regulatory T cells (Tregs), promoting tolerance and lowering inflammation. Additionally, it has been demonstrated that butyrate inhibits histone deacetylases (HDACs), which impact dendritic cells' and macrophages' cytokine expression [14]. Two pattern recognition receptors (PRRs) expressed on immune cells and gut lining epithelial cells are Toll-like receptors (TLRs) and NOD-like receptors (NLRs), which make up another crucial interface. These receptors can recognise MAMPs, which include lipopolysaccharide (LPS), flagellin, and peptidoglycan. Nuclear factor-κB (NF-κB) and interferon regulatory factors (IRFs) are activated by TLR contact, which coordinate proor anti-inflammatory signalling pathways, according to Kusiak and Brady [15]. Immune homeostasis depends on the exact regulation of this signalling; unchecked activation can result in autoimmunity and chronic inflammation [15]. Furthermore, the gut microbiota influences antigen presentation, an essential part of the immune system's adaptation. Depending on the situation, the gut-associated lymphoid tissue's (GALT) dendritic cells send dendrites into the lumen to collect microbial antigens and transport them to CD4+ T cells using molecules of the major histocompatibility complex (MHC) class II, which directs their differentiation into Tregs or T-helper subsets [16,17]. It has been shown that certain bacterial taxa like Clostridium clusters IV and XIVa enhance Treg induction, which significantly affects the equilibrium between regulatory and effector T cells [18]. 1.3. Objective and Scope of the Review This review's main goal is to analyse the gut microbiota's immune-modulatory functions and clarify how It has an effect on the host immunological system to affect the course of cancer immunotherapy as well as autoimmune pathogenesis. Although homeostasis depends on the symbiotic relationship between immunity and microbiota, changes in microbial composition and metabolite production can lead to immune dysregulation, which is the root cause of autoimmune diseases such as systemic lupus, erythematosus rheumatoid arthritis, and multiple sclerosis. According to Zhang et al. [19], it has been possible to identify specific microbial signatures in patients with autoimmune diseases, suggesting a causative or exacerbating role of dysbiosis. The gut microbiota's effects on cancer immunology will also be examined in this review, specifically as it relates to the efficacy of immunological checkpoint blockade treatments. Recent findings by Routy et al. [20] demonstrate that by promoting dendritic cell activity and T cell activation, some commensals, such as Akkermansia muciniphila, enhance the anti-PD-1 immunotherapy response in non-small cell lung cancer patients. Additionally, we will go over new treatment techniques that aim to change the microbiome to enhance immunological control and clinical results. These consist of dietary changes, faecal microbiota transplantation (FMT), probiotics, prebiotics, and postbiotics. Microbiota-targeted immunomodulation has enormous potential as a new paradigm in disease prevention and therapy, especially as microbiome characterisation and personalised medicine become more widely available. With an emphasis on its translational potential for autoimmune and cancer treatment, This review attempts to provide a comprehensive and critical assessment of the gut microbiota – immune system interaction by synthesising existing evidence and outlining future prospects. 2. Gut Microbiota and Immune System Regulation The immune system and gut microbiome have a link that is deeply intertwined, reflecting a long history of co-evolution between host and microbes. From early life, the gut's microbial colonization is essential in forming immune development, helping the body distinguish between harmless antigens and harmful pathogens. This intricate dialogue continues throughout life, with microbial signals continuously influencing immune homeostasis, tolerance, and activation. Disruptions in this balance have been increasingly associated with immune-related disorders, underscoring the importance of microbial communities in maintaining immune resilience. As research deepens, it becomes clear that understanding the gut microbiota's capacity to modulate the immune system is essential for understanding the fundamental mechanisms of health and disease [21,22]. 2.1. Microbiota-Immune System Cross-Talk Through complex mechanisms involving pattern recognition receptors, microbial metabolites, and cytokine signalling pathways, the gut microbiota is essential for controlling the immune system of the host. Short-chain fatty acids (SCFAs) are created when dietary fibre is fermented by proteobacteria. These SCFAs include butyrate, propionate and acetate. World Journal of Biology Pharmacy and Health Sciences, 2025, 22(01), 564-590 568 Apart from supplying energy to colonocytes, these SCFAs have immunomodulatory effects via interacting with certain G-protein-coupled receptors (GPCRs) on immune cells. Regulatory T cell (Treg) development, which is essential for maintaining immunological tolerance and preventing excessive inflammatory reactions, might result from activation of these receptors [23]. Apart from SCFAs, the immune system is also impacted by the gut microbiota through the activation of toll-like receptors (TLRs), which are pattern recognition receptors that detect microbial-associated molecular patterns that aid the immune system in distinguishing between commensal and pathogenic microbes. Engagement of TLRs by microbial ligands triggers signalling cascades that produce cytokines and other mediators, which in turn shapes the immune response. For instance, TLR5 recognizes bacterial flagellin, and its activation has been connected to the control of gut microbial composition and intestinal homeostasis [24]. The dynamic relationship between gut microorganisms and the immune system is further demonstrated by cytokine signalling. The synthesis and operation of many cytokines, which are essential for immune cell communication and response regulation, can be influenced by microbial metabolites. This complex network of interactions underscores the importance of a balanced gut microbiota in sustaining immune equilibrium and highlights potential therapeutic avenues for managing immune-related disorders through microbiome modulation [24,25]. The gut’s immune system maintains a delicate balance between tolerance and activation to ensure homeostasis. As shown in Figure 2, microbial metabolites and antigens interface with specialized intestinal cells, such as goblet cells and M cells, which in turn mediate immune responses via dendritic cell activation, cytokine secretion, and B and T cell modulation. This intricate dialogue contributes to the education of immune cells in structures like Peyer's patches and mesenteric lymph nodes, ultimately influencing systemic immunity and maintaining mucosal integrity. To clarify how gut microorganisms influence immune responses, Table 2 outlines key microbiota-derived metabolites, their microbial origins, mechanisms of immune modulation, and implications for health and disease. These compounds represent promising targets for novel immunotherapies. Figure 2 Schematic representation of gut microbiota-immune system interactions in the intestinal mucosa. Reproduced with permission from Ref. [25] World Journal of Biology Pharmacy and Health Sciences, 2025, 22(01), 564-590 569 Table 2 Gut Microbiota-Derived Metabolites and Their Effects on the Immune System Metabolite Microbial Source(s) Target Immune Pathways/Cells Mechanism of Action Health/Disease Relevance Therapeutic Potential Butyrate Clostridium spp., Faecalibacterium prausnitzii Regulatory T cells (Tregs), Dendritic cells HDAC inhibition, Foxp3 gene epigenetic modulation Anti-inflammatory, supports gut barrier; reduced in IBD, MS Promotes Treg induction and mucosal healing Acetate Bifidobacterium spp., Akkermansia muciniphila Neutrophils, Tregs GPCR43 activation, mucin production Maintains epithelial barrier, enhances Treg activity Supports barrier integrity, modulates inflammation Propionate Bacteroides spp., Veillonella spp. Tregs, Eosinophils Histone acetylation, cytokine modulation Regulates allergic responses and colonic inflammation Modulates immune tolerance in allergic disease Indole-3lactate (ILA) Lactobacillus spp. Microglia, Tregs AhR receptor activation Reduces neuroinflammation, supports immune quiescence Promotes remyelination in MS models Polysaccharide A (PSA) Bacteroides fragilis Tregs, Dendritic cells TLR2 engagement, IL-10 induction Promotes immune tolerance, suppresses autoimmunity Used in probiotic immunotherapy studies Secondary Bile Acids Clostridium spp., Bacteroides spp. Macrophages, Dendritic cells FXR and TGR5 signaling Anti-inflammatory, controls NLRP3 inflammasome Explored in IBD and metabolic disorders Tryptophan Metabolites (e.g. Kynurenine, Indoles) Bacteroides, Clostridium, Lactobacillus Th17/Treg balance, Innate lymphoid cells AhR and IDO pathway modulation Influences mood, autoimmunity, gutbrain axis Candidate for neuroimmune disorder modulation 2.2. Key Immune Cells Influenced by the Microbiome The gut microbiota has a major impact on the development and function of many immune cells, forming a complex network of interactions that are necessary for preserving immunological homeostasis and combating infections. Among these immune cells, dendritic cells (DCs), T helper 17 cells (Th17), regulatory T cells (Tregs), and macrophages are particularly affected by microbial signals, which modulate their roles in antigen presentation, immune tolerance, inflammation, and innate immunity [27]. 2.2.1. Dendritic Cells and Antigen Presentation As the primary antigen-presenting cells that connect innate and adaptive immunity, dendritic cells are quite essential. They continuously sample the intestinal environment, capturing antigens from both commensal and pathogenic microorganisms. The gut microbiota significantly influences DC maturation and function through various microbial products. Toll-like receptors (TLRs) and other pattern recognition receptors on DCs are bound by peptidoglycans from bacterial cell walls and lipopolysaccharides (LPS) from Gram-negative bacteria, which causes these cells to mature and become active. Co-stimulatory molecules rise as a result of this activation, and cytokines that regulate T cell growth are released. On the other hand, DCs can have an anti-inflammatory phenotype due to microbial metabolites such as shortchain fatty acids (SCFAs), which encourage the conversion of naïve T cells into Tregs and support immunological tolerance in the gut environment [27,28]. World Journal of Biology Pharmacy and Health Sciences, 2025, 22(01), 564-590 570 2.2.2. Immune Tolerance and Regulatory T Cells (Tregs) The production and function of regulatory T cells (Tregs) are significantly influenced by the gut microbiota. These Tregs which are necessary for immunological tolerance and limiting excessive inflammation. Certain commensal bacteria, particularly those belonging to the Clostridia class, have been demonstrated to encourage colonic Treg accumulation. This action is mostly mediated by SCFAs such as butyrate, which are formed during the fermentation of dietary fibre. By encouraging histone acetylation at the Foxp3 gene locus, which is necessary for Treg development, butyrate aids in the differentiation of naïve T cells into Tregs. Additionally, butyrate can activate G-protein-coupled receptors like GPR109a on DCs, leading to increased production of retinoic acid and further promoting Treg differentiation. These interactions underscore the importance of microbial metabolites in fostering intestinal environment with antiinflammatory properties [29]. 2.2.3. Th17 Cells and Inflammation Balance One subset of CD4+ T cells that generates pro-inflammatory cytokines are T helper 17 cells. They are crucial for maintaining mucosal barriers and defending against extracellular infections. Th17 cell growth and activity are significantly regulated by the gut microbiome. Microbial-derived adenosine triphosphate (ATP) has been found to be a crucial element in encouraging Th17 cell differentiation. ATP released by commensal bacteria can activate lamina propria DCs via purinergic receptors, resulting in the generation of cytokines including IL-6 and IL-23, which are necessary for Th17 differentiation. However, an imbalance favoring Th17 cells over Tregs can contribute to inflammatory diseases, highlighting the necessity of a balanced microbial environment for immune homeostasis [30,31]. 2.2.4. Macrophages and Innate Immune Activation Macrophages are versatile innate immune cells involved in pathogen clearance, tissue remodeling, and the activation of inflammatory reactions. The gut microbiota influences macrophage polarization and activity through various microbial components and metabolites. LPS from Gram-negative bacteria can induce a pro-inflammatory M1 macrophage phenotype via TLR4 signaling, marked by the generation of cytokines such as IL-6 and TNF-α. In contrast, SCFAs, including propionate and butyrate, induce an anti-inflammatory M2 phenotype that is linked to tissue repair and inflammation resolution. The gut microbiota modulates macrophage activity, which is necessary to keep gut homeostasis stable and avoid chronic inflammatory diseases [27,32]. In general, by affecting the development and operation of vital immune cells, the gut microbiota significantly affects the immune system. Gut microorganisms contribute to the delicate balance of immunological activation and tolerance, which is critical for health and disease prevention, by producing different metabolites and interacting with immune receptors. 2.3. Impact of Dysbiosis on Immunity Immunological equilibrium depends on the gut microbiota, a dynamic and diverse community of microorganisms found in the human gastrointestinal tract. A normal microbial ecology promotes optimal immune function, but changes to this balance—known as dysbiosis—can result in immunological malfunction, chronic inflammation, and increased vulnerability to numerous illnesses. The immunological consequences of dysbiosis also extend beyond local gut inflammation to systemic immune dysregulation. To better elucidate the link between dysbiotic states, immune mechanisms, and disease phenotypes, Table 3 presents a categorized overview of different types of dysbiosis, their mechanistic contributions to immune dysfunction, and the diseases with which they are commonly associated. Table 3 Impact of Dysbiosis on Disease Pathogenesis Type of Dysbiosis Mechanism of Immune Disruption Associated Disease(s) Key Microbial Players Relevant Metabolites / Molecules Reduced microbial diversity Loss of regulatory T cell induction, decreased SCFA production leading to impaired immune tolerance Inflammatory Bowel Disease (IBD), Type 1 Diabetes, Multiple Sclerosis Faecalibacterium prausnitzii, Bifidobacterium spp., Clostridium clusters IV/XIVa Butyrate, acetate, propionate World Journal of Biology Pharmacy and Health Sciences, 2025, 22(01), 564-590 571 Overgrowth of pathobionts TLR overstimulation triggering excessive cytokine production and chronic inflammation Rheumatoid Arthritis, Systemic Lupus Erythematosus, IBD Escherichia coli (AIEC), Ruminococcus gnavus, Klebsiella spp. LPS (lipopolysaccharide), flagellin Loss of keystone commensals Impaired gut barrier integrity, antigen leakage, systemic immune activation Autoimmune diseases (MS, RA), Allergies Akkermansia muciniphila, Bacteroides fragilis Mucin-derived peptides, Polysaccharide A Increased fungal and viral load Activation of innate immunity via TLRs and inflammasomes, skewed Th17 responses Ulcerative Colitis, SLE, Atopic Dermatitis Candida albicans, Saccharomyces spp., crAssphage β-glucans, dsDNA, TLR ligands Early-life dysbiosis Disrupted immune programming, reduced Treg formation, increased allergy risk Asthma, Atopic Dermatitis, Type 1 Diabetes Low Bifidobacterium spp., high Enterobacteriaceae Imbalanced SCFAs, low indole derivatives 2.3.1. Dysbiosis and Immune Dysfunction According to Sun et al. [33], dybiosis is defined by an imbalance in the microbial population, which frequently includes a decrease in helpful bacteria and an increase in harmful species. The intestinal barrier may be weakened by this imbalance, leading to increased permeability and what is frequently referred to as "leaky gut." Microbial substances like lipopolysaccharides (LPS) can enter the systemic circulation through the hole, causing an immunological response. Weiss and Hennet [34] found that this immune activation causes pro-inflammatory cytokines to be produced, contributing to systemic inflammation and immune dysregulation. 2.3.2. Chronic Inflammation and Disease Susceptibility The pathophysiology of many illnesses has been linked to the chronic inflammation caused by dysbiosis. According to Shin et al. [35], abnormalities in the gut microbiota have been linked to gastrointestinal disorders including Crohn's disease and ulcerative colitis. IBD patients frequently have more pathogenic Proteobacteria and less commensal bacterial diversity. This microbial imbalance contributes to the chronic intestinal inflammation characteristic of these diseases. Beyond the gut, dysbiosis has systemic implications. Atherly et al. [36] reported that changes in the makeup of the gut microbiota have been linked to metabolic diseases such as type 2 diabetes and obesity. Further connecting gut microbial composition to metabolic health, the inflammatory environment produced by dysbiosis might worsen insulin resistance and encourage inflammation of adipose tissue [36]. 2.3.3. Microbiota and Mucosal Immunity The mucosal immune system is largely educated and controlled by microbes in the stomach. As stated by Sun et al. [33], commensal bacteria engage in interactions with intestinal epithelial cells and immune cells to encourage the formation of regulatory mechanisms that stop unwarranted immune reactions. Dysbiosis can disrupt these interactions, resulting in a decline in immunological tolerance and a higher chance of developing autoimmune and allergy disorders. The relevance of microbial balance in immunological development is shown by the fact that, for example, a higher frequency of allergy disorders has been associated with less diversity in the gut microbiota throughout early life. 2.3.4. Therapeutic Consequences Understanding how dysbiosis affects immunity has prompted research into microbiome-targeted treatments meant to improve immune-mediated illnesses and restore microbial balance. Weiss and Hennet [34] discussed that the promise of dietary interventions, probiotics, and prebiotics to modify the composition and activity of the gut microbiota is being investigated. Faecal microbiota transplantation (FMT) has been studied as a therapy option for recurrent Clostridium difficile infections, but research into its potential as a treatment for other dysbiosis-related disorders is currently ongoing. World Journal of Biology Pharmacy and Health Sciences, 2025, 22(01), 564-590 572 Figure 3 Gut Dysbiosis-Induced Immune Disruption and Systemic Inflammation. Reproduced with permission from Ref. [39] 3. Gut Microbiome and Autoimmune Diseases The gut microbiome, a varied community of bacteria that inhabit the gastrointestinal system, is essential to immune homeostasis. Changes in this microbial ecology have been connected to a number of autoimmune illnesses, when the body's immune system mistakenly attacks its own tissues. Recent research has highlighted the intricate connections between gut microbes and the host's immune system, suggesting that modifications in the microbe composition may influence the onset and progression of conditions such as type 1 diabetes, systemic lupus erythematosus, and rheumatoid arthritis. Knowing these connections opens up exciting possibilities for new treatment approaches that modify the microbiota to re-establish immunological equilibrium [37]. 3.1. The Role of Dysbiosis in Autoimmunity Immune homeostasis and self-tolerance depend on the gut microbiota, a dynamic and diverse population of bacteria present in the human gastrointestinal tract. Numerous autoimmune illnesses have been related to dysbiosis, or abnormalities in the makeup and function of the gut microbiota. According to research by Christovich and Luo [38], dysbiosis can cause immune hyperactivation and a breakdown of self-tolerance, which may have a role in the development of autoimmune disorders. 3.1.1. Altered Gut Microbiota Composition and Immune Hyperactivation According to Christovich and Luo [38], the immune system's proper development and function rely on a balanced gut flora. Commensal bacteria engage in interactions with immunological and intestinal epithelial cells, protecting selftolerance and preventing autoimmune responses by promoting the growth of regulatory T cells (Tregs). Loss of selftolerance and the onset of autoimmunity can result from disturbances in the gut microbiota that affect Treg differentiation and function. Furthermore, pathogenic bacteria that create pro-inflammatory chemicals like lipopolysaccharides (LPS) can proliferate as a result of dysbiosis [39]. These compounds can activate the toll-like receptors (TLRs) on immune cells, which causes pro-inflammatory cytokines to be released and inflammatory pathways associated with autoimmune illnesses to be stimulated. Christovich and Luo [38] reported that it has been discovered that autoimmune disease patients have higher amounts of LPS, suggesting a link between dysbiosis, endotoxemia, and immune hyperactivation. World Journal of Biology Pharmacy and Health Sciences, 2025, 22(01), 564-590 579 Faecalibacterium prausnitzii Melanoma PD-1 Enhancement Produces SCFAs that enhance anti-inflammatory signaling and cytotoxic T cell responses Bacteroides fragilis Melanoma, Colorectal Cancer CTLA-4 Enhancement Stimulates Th1 responses and promotes dendritic cell maturation Bifidobacterium longum Melanoma (preclinical evidence) PD-1 Enhancement Boosts dendritic cell activity and supports CD8+ T cell priming Enterococcus hirae Lung, Kidney, Melanoma PD-1 Enhancement Enhances IL-12 production and cross-presentation of antigens via dendritic cells Ruminococcus obeum Melanoma PD-1 Resistance Linked with suppression of T cell function and promotion of immune escape pathways Escherichia coli (pathogenic strains) Pan-cancer PD-1, CTLA-4 Resistance Induces myeloid-derived suppressor cell expansion and systemic inflammation 4.2.1. Checkpoint Inhibitors (PD-1/PD-L1, CTLA-4) Immunocheckpoint inhibitors that target programmed death-ligand 1 (PD-L1), programmed death-1 (PD-1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) have revolutionized cancer treatment. However, the variability in patient responses has prompted investigations into underlying factors, including the gut microbiome's function [88]. Studies Linking Gut Microbiota Composition to Success or Failure of Checkpoint Blockade Therapies According to Gopalakrishnan et al.'s research [89], melanoma patients who reacted to anti-PD-1 treatment had more diverse gut flora than those who did not. Specifically, responders had an increased abundance of Faecalibacterium and Ruminococcaceae species, which correlated with enhanced systemic and antitumor immune responses. In contrast, nonresponders showed a predominance of Bacteroidales, associated with limited immune activation. These findings imply that positive reactions to checkpoint blockade treatments may depend on a varied and particular makeup of the gut microbiota [89]. Moreover, from the findings of Routy et al. [90] individuals undergoing anti-PD-L1 and anti-PD-1 therapy had better results when their gut microbiome contained specific bacterial species. Notably, improved clinical responses were linked to higher levels of Akkermansia muciniphila. There may be a way for the gut microbiome to increase checkpoint inhibitor efficacy, as patients with greater concentrations of this bacteria showed enhanced infiltration of CD4+ T cells into tumour beds. Key Bacterial Species Enhancing Anti-PD-1 Efficacy The ability of Akkermansia muciniphila to regulate immunological responses has drawn interest. According to Matson et al.'s research [91], individuals with melanoma who had A. muciniphila showed better responses to anti-PD-1 therapy. Mechanistically, this bacterium appears to enhance CD8+ T cell recruitment and activation in the tumour microenvironment, thereby potentiating antitumor immunity [91,92]. Although Bifidobacterium species have been linked to improving immune responses in preclinical models, it is unclear how they function in human research. Baruch et al. [93] state that the use of a multi-strain Bifidobacterium probiotic did not significantly alter outcomes in patients receiving checkpoint inhibitors. This suggests that the impact of Bifidobacterium on immunotherapy efficacy may be context-dependent and warrants further investigation. These investigations highlight the intricate connection between gut bacteria and cancer treatment outcomes. It may be possible to increase the effectiveness of checkpoint blockade treatments by modifying the gut microbiota to encourage the development of beneficial bacterial species such as Akkermansia muciniphila. However, a more thorough comprehension of microbial interactions and how the immune system is affected by them is necessary to translate these results into therapeutic practice. World Journal of Biology Pharmacy and Health Sciences, 2025, 22(01), 564-590 580 4.2.2. CAR-T Cell Therapy Numerous host and environmental factors affect the effectiveness of chimeric antigen receptor T cell (CAR-T) therapy; in particular, the gut microbiota has recently attracted a lot of attention because of its ability to control systemic immunological preparedness [94]. Although CAR-T cell therapy is very effective in treating some haematologic cancers, faces challenges in solid tumors and in cases marked by treatment resistance or toxicity. There is increasing evidence that the gut microbiome influences toxicity, growth, and persistence of CAR-T cells in a controllable way. According to the findings of McPhedran et al. [95], germ-free or antibiotic-treated mice displayed diminished CAR-T cell efficacy, underscoring the importance of microbial-derived cues in sustaining T cell activation and memory. The study highlighted that microbial metabolites, particularly SCFAs like butyrate, promote CAR-T cell metabolism and enhance effector function by increasing histone acetylation at genes involved in cytotoxicity. Furthermore, from the findings of Stein-Thoeringer et al. [96], patients with a higher baseline abundance of Ruminococcaceae and Lachnospiraceae taxa exhibited improved outcomes following CD19-targeted CAR-T therapy. These bacterial groups appeared to regulate systemic inflammation and modulate cytokine release syndrome, a common and potentially fatal CAR-T-related toxicity. Diet-based modulation and prebiotic supplementation are under exploration as strategies to prime the microbiome prior to CAR-T cell infusion. According to Mojgani et al. [97], patients receiving fiber-enriched diets before therapy demonstrated lower rates of cytokine storm and more favorable immune reconstitution post-treatment. This emerging connection between dietary intervention, microbial composition, and CAR-T outcomes emphasizes the microbiome as a key target in improving both safety and efficacy of next-generation immunotherapies [97]. 4.2.3. Chemotherapy and Radiotherapy Chemotherapy and radiation therapy, which are two therapies in the category of cytotoxic cancer therapies, have a major effect on healthy tissues, including the gut mucosa and its residing microbiota, as well as tumour cells. The host's reaction to these therapies can then be influenced by the integrity and makeup of the gut microbial population, especially through its effects on mucosal healing, systemic inflammation, and immunological reconstitution. According to the findings of Viaud et al. [98], certain commensal bacteria, such as Barnesiella intestinihominis and Enterococcus hirae, enhanced the efficacy of cyclophosphamide by stimulating Th17 and Th1 polarization. The depletion of these microbes in antibiotic-treated mice correlated with reduced therapeutic outcomes, highlighting the microbiome’s role in supporting immunogenic cell death. Similarly, Iida et al. [99] demonstrated that antibiotic-induced dysbiosis impaired the recruitment of myeloid cells to tumors following platinum-based chemotherapy, ultimately diminishing anti-tumor immunity. These outcomes imply that maintaining microbiota diversity during chemotherapy is crucial to preserving immune priming. In the context of radiotherapy, according to Gerassy-Vainberg et al. [100], radiation-induced intestinal injury was significantly exacerbated in mice with depleted commensals. Microbial loss led to increased intestinal permeability, bacterial translocation, and inflammatory cytokine release, compounding tissue damage. Moreover, the application of FMT (fecal microbiota transplantation) in irradiated mice accelerated mucosal repair and enhanced hematopoietic recovery, pointing to microbiota-based interventions as viable adjuncts to standard cancer therapies [100]. Altogether, these findings establish the microbiome not merely as a collateral target of cancer therapy but as a critical mediator of treatment efficacy and toxicity, with growing implications for patient-specific microbial profiling and supportive care strategies. 4.3. Microbiome-Based Strategies in Cancer Treatment The complex connection between cancer treatment and the gut microbiota has led to research into microbiome-based approaches to improve patient outcomes and treatment effectiveness [101]. In order to increase anticancer immune responses and enhance treatment effectiveness, these strategies concentrate on modifying the gut microbiome. 4.3.1. Fecal Microbiota Transplantation (FMT) to Enhance Immunotherapy Response In order to re-establish a balanced gut microbiome, patients undergoing faecal microbiota transplantation (FMT) receive faecal material from healthy donors. The potential of FMT to enhance responses to immune checkpoint inhibitors (ICIs) in cancer therapy has been examined in recent research. According to a National Cancer Institute study, patients with advanced melanoma who had not responded to ICIs showed excellent results after getting FMT from donors who had responded favourably to them. Specifically, six out of 15 patients exhibited either tumor reduction or disease stabilization post-FMT, suggesting that modifying the gut microbiome can influence immunotherapy outcomes [102]. World Journal of Biology Pharmacy and Health Sciences, 2025, 22(01), 564-590 581 Further supporting this, research by Liu et al. [103] indicates that FMT, when combined with immunotherapy, has shown promise across various cancer types. Larger clinical research is needed to confirm these findings and improve FMT techniques for cancer patients, the report highlights [103]. 4.3.2. Probiotics and Engineered Bacteria to Boost Anticancer Immune Responses The potential of probiotics—beneficial living microorganisms—to strengthen anticancer immunity has been investigated. According to a review by Marinelli et al. [104], specific probiotic strains can modulate the immune system, potentially improving responses to anticancer therapies [104]. Additionally, engineered bacteria are being developed to deliver therapeutic agents directly to tumors. Columbia University researchers have created probiotics that may safely deliver immunotherapies, such as nanobodies against CTLA-4 and PD-L1, into tumours. These engineered bacteria continuously release therapeutic agents, facilitating an immune response that results in tumor eradication [105]. Moreover, a study published in Cell Reports Medicine describes the development of an oncolytic and immunotherapeutic protein co-expressed by a multipurpose leaky probiotic. This engineered probiotic demonstrated enhanced anticancer immune responses and tumor eradication in preclinical models [103]. 4.3.3. Dietary Modifications and Their Role in Therapy Outcomes Dietary practices have a significant effect on the gut microbiome's function and composition, which in turn affects the results of cancer treatment. High-fiber diets have been associated with improved responses to immunotherapy. According to research funded by the National Institutes of Health, melanoma patients having a high-fiber diet intake had enhanced responses to ICIs in contrast to people who consume less fibre [106]. According to the study, dietary fibre may improve antitumor immunity by encouraging the development of beneficial gut flora. Furthermore, research has shown that diets rich in polyphenols, such fruits and vegetables, positively alter the microbiome of the gut. An evaluation by Nguyen et al. [107] discusses how dietary components, including polyphenols, may affect the makeup of the gut microbiota and function, potentially impacting immune responses and cancer therapy outcomes. All of these research highlight how microbiome-based strategies, including FMT, probiotics, engineered bacteria, and dietary changes, might boost anticancer immune responses can enhance the outcomes of cancer therapy. To create standardised procedures and completely clarify the mechanics behind these therapies, more study is necessary. 5. Emerging Microbiome-Based Therapeutics for Immune Disorders and Cancer The therapeutic potential of the gut microbiome is no longer confined to theoretical frameworks; it is steadily shaping the contours of next-generation treatments for immune-mediated diseases and cancer. As mechanistic insights deepen, microbiome-targeted interventions are transitioning from experimental stages to clinical application [108]. This section explores the forefront of these innovations—ranging from precision microbial consortia and metabolite-based drugs to synthetic biology platforms—each offering a new dimension to immune modulation and oncologic therapy. Advancements in microbiome research have paved the way for innovative therapeutic strategies targeting immune disorders and cancer. This section delves into emerging approaches, including next-generation probiotics, microbiomederived metabolite therapy, CRISPR-based microbiome engineering, and personalized microbiome medicine, highlighting their potential in disease modulation and treatment optimization [108]. 5.1. Next-Generation Probiotics and Live Biotherapeutics Traditional probiotics have been recognized for their health benefits; however, recent developments focus on engineering microbial strains to enhance their therapeutic potential. These engineered probiotics, termed live biotherapeutics are intended to cure, prevent, or diagnose diseases by adjusting the host's defences [109]. Meng et al. [110] claim that because engineered probiotics have been genetically altered to target particular illnesses, treatments for inflammation, cancer, infections, and metabolic disorders have been created. To decrease systemic side effects and increase treatment effectiveness, several bacterial strains have been modified to carry anticancer drugs directly into tumour microenvironments [110–112]. Additionally, a review by Charbonneau et al. (2024) addresses how modified probiotics may be used to treat autoimmune illnesses, cancer, obesity, and inflammatory bowel disease. The authors point out that these living World Journal of Biology Pharmacy and Health Sciences, 2025, 22(01), 564-590 582 biotherapeutics may be modified to generate certain proteins or metabolites that alter immune responses, providing a customised method of treating illness [109]. 5.2. Microbiome-Derived Metabolite Therapy The gut microbiota produces a variety of compounds that significantly affect host physiology and immunological function. Among them, tryptophan metabolites and SCFAs, or short-chain fatty acids, have garnered interest due to their potential to modulate illness [114]. According to research by Agus et al. [114], gut bacteria digest dietary fibres to produce SCFAs, including acetate, propionate, and butyrate. These metabolites may be used as treatment for illnesses such as colorectal cancer and inflammatory bowel disease because of their shown ability to control immunological responses, have anti-inflammatory properties and maintain the intestinal barrier's integrity. Furthermore, the effects of tryptophan metabolites produced from the microbiome on health and illness are explained by Miyamoto et al. [115]. Serotonin and kynurenine, which are involved in immunological and mood control, are produced as a result of tryptophan metabolism. Numerous illnesses have been connected to disturbances in this metabolic system, suggesting that targeting tryptophan metabolites could offer novel therapeutic avenues [114,115]. 5.3. CRISPR-Based Microbiome Engineering The advent of CRISPR-Cas technology has revolutionised the field of genetic engineering by expanding its uses to the gut microbiota. This approach allows for precise editing of microbial genomes, enabling the modification of bacterial functions to influence host immunological reactions [116]. A thorough review by Abavisani et al. [116] claims that, utilizing the CRISPR-Cas system for microbiome editing holds promise for therapeutic interventions. The authors discuss how targeted gene editing can be employed to eliminate pathogenic bacteria or enhance the beneficial properties of commensal microbes, thereby modulating immune responses and potentially treating various diseases [116]. Moreover, research highlighted by Nath et al. [117] shows how phage-delivered CRISPR systems may be used to fight off infections that are resistant to drugs. This strategy involves using bacteriophages to deliver CRISPR-Cas components to specific bacterial populations, achieving targeted bacterial depletion without disrupting the overall microbiome balance. 5.4. Personalized Microbiome Medicine The integration of artificial intelligence (AI) with microbiome research has opened new avenues for personalized medicine. AI-driven microbiome sequencing enables the development of customized treatment strategies tailored to individual microbial compositions. From the findings of researchers at Rutgers University, AI models have been employed to redefine the core microbiome, facilitating the detection of microbial fingerprints linked to certain illnesses. This approach allows for the design of personalized therapeutic interventions that target dysbiosis and restore microbial balance. Additionally, a research by Novielli et al. [119] highlights the function of explainable AI in the processing of microbiome data. The authors highlight how AI can enhance the interpretability of complex microbiome data, supporting the development of customised treatment strategies and the forecasting of illness outcomes. Collectively, these new microbiome-based therapies offer tailored and targeted strategies that capitalise on the intricate relationship between the microbiota and the host, thereby revolutionising the treatment of cancer and immune disorders. 6. Challenges and Future Directions The integration of microbiome science into immunology and oncology is reshaping therapeutic innovation, but this progress is tempered by conceptual, technical, and translational challenges. While mounting evidence links gut microbial communities to immune regulation and disease outcomes, translating these insights into safe, reproducible, and clinically effective therapies remains complex. Individual variability in microbiome composition, combined with the dynamic nature of host-microbe interactions, complicates the identification of universal biomarkers and consistent treatment protocols. Moreover, the development of scalable manufacturing practices, harmonized analytical methodologies, and robust regulatory frameworks is essential for advancing live biotherapeutics and microbiomederived products. As interdisciplinary research deepens mechanistic understanding and refines intervention strategies, World Journal of Biology Pharmacy and Health Sciences, 2025, 22(01), 564-590 583 this evolving field holds the ability to completely rethink how immune-mediated and oncologic illnesses are being managed—though with a trajectory that must remain both transformative and rigorously cautious. 6.1. Challenges in Translating Microbiome Research to Clinical Practice Efforts to incorporate microbiome-based therapies into mainstream medicine have been complicated by considerable variability across individuals, both in terms of microbial composition and host responses. According to Zhernakova et al. [121], even among healthy populations, microbial profiles vary substantially depending on age, diet, geography, host genetics, and prior exposure to antibiotics, all of which influence disease susceptibility and therapeutic outcomes. Such inter-individual variability poses a major hurdle in designing broadly effective microbiome-based treatments. Compounding this challenge is the absence of standardized procedures for the study of microbiomes, including inconsistencies in sample collection, sequencing depth, and bioinformatics pipelines. As noted by Marchesi et al. [122], reproducibility across studies is often compromised, impeding the establishment of robust microbial biomarkers and therapeutic targets. Additionally, the dynamic nature of the microbiome—subject to rapid shifts in response to diet, medications, or illness—further complicates clinical translation. Regulatory frameworks governing microbiome interventions remain underdeveloped, particularly regarding live biotherapeutics and fecal microbiota transplantation (FMT). According to a regulatory review by El Hage et al. [123], inconsistencies in defining microbiota-based products, classifying them under existing pharmaceutical guidelines, and validating safety standards hinder their pathway to approval. The absence of universally accepted manufacturing and quality control standards for microbial therapeutics also limits scalability and clinical reproducibility. Moreover, ethical considerations regarding donor selection, long-term risks, and potential off-target effects are still being actively debated. These factors collectively delay the transition of microbiome science from academic research to bedside application, despite promising early results in specific therapeutic areas. 6.2. Future Research Directions Future directions in microbiome research increasingly point toward the incorporation of high-throughput multi-omics technologies capable of providing a more thorough understanding of interactions between microbes and their hosts. From the findings of Lloyd-Price et al. [124], the incorporation of metagenomics, metabolomics, and proteomics not only enhances taxonomic resolution but also allows researchers to track functional pathways linked to immune regulation and disease progression. These multi-layered datasets are instrumental in identifying causal relationships rather than mere associations. The use of machine learning algorithms and AI-based models to integrate multi-omic profiles with clinical phenotypes is poised to accelerate biomarker discovery and therapeutic prediction. According to Franzosa et al. [125], such integrative approaches have already shown promise in distinguishing microbiome signatures predictive of response to immune checkpoint inhibitors and autoimmune flare-ups. These models are expected to support the creation of more personalised and dynamic treatment regimens. Additionally, expanding the clinical scope of microbiome interventions beyond autoimmune disorders and cancer represents a promising frontier. Research by Rooks and Garrett [126] indicates that modulating the gut microbiome may enhance graft survival in organ transplantation through the reduction of alloimmune responses. Similarly, according to Boehme et al. [127], specific microbial taxa and their metabolites have shown neuroprotective effects in preclinical models of neurodegenerative disorders such as Parkinson's and Alzheimer's, suggesting a potential therapeutic function in neurology. Age-related immune decline—immunosenescence—has also been linked to dysbiosis, as seen in Thevaranjan et al.'s work [128], indicating that specific microbiome modification may promote more healthful ageing. As the field matures, addressing these challenges through collaborative, interdisciplinary research will be essential to move microbiome science from theory to tangible clinical solutions. 7. Conclusion Advances in microbiome science are rapidly reshaping our understanding of immune regulation and cancer therapy, demonstrating the gut microbiota's dual roles as a therapeutic ally and dynamic regulator in complex disease landscapes. It is now known that a major element influencing the onset, course, and resolution of autoimmune illnesses and cancers is the intricate relationship between microbial populations and the human immune system. From the findings of various authors cited throughout this review, it is clear that microbial signals—including metabolites, bacterial surface molecules, and secreted proteins—can influence not only local immune environments but also World Journal of Biology Pharmacy and Health Sciences, 2025, 22(01), 564-590 584 systemic immunological homeostasis. This interdependence has laid the groundwork for novel interventions that harness the microbiome to enhance therapeutic responses, reduce treatment toxicity, and restore immune balance. Yet, the full therapeutic promise of microbiome-based strategies rests on our capacity to accurately decipher the intricate relationships between microbes and hosts. Clinical translation continues to face hurdles related to interindividual microbiome variability, incomplete mechanistic understanding, and a lack of regulatory consensus on live microbial interventions. However, emerging tools such as multi-omics integration, AI-guided microbial profiling, and gene-editing approaches are poised to overcome these limitations. Future research will need to move beyond correlation and toward causation, refining our capacity to manipulate specific microbial pathways in a targeted and personalized manner. Ultimately, the gut microbiome stands at the threshold of redefining immune and cancer therapies—not as a supplementary consideration, but as a foundational component of precision medicine. The integration of microbiome science into clinical practice will require sustained interdisciplinary collaboration, rigorous standardization, and a commitment to ethically and scientifically grounded innovation. As this field matures, its impact on patient care may well transform how immune and oncological disorders are understood and treated in the decades to come. Compliance with ethical standards Acknowledgments The authors wish to acknowledge the collaborative effort of all contributing scholars and colleagues who jointly authored and edited this review paper. This work was conducted entirely through the intellectual and academic contributions of the authoring team, without external funding or assistance from any individual, institution, or organization. Disclosure of conflict of interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. References [1] Gomaa, E. Z. (2020). Human gut microbiota/microbiome in health and diseases: a review. Antonie Van Leeuwenhoek, 113(12), 2019-2040. [2] Vemuri, R., Shankar, E. M., Chieppa, M., Eri, R., & Kavanagh, K. (2020). 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