Therapeutic targeting of the host-microbiota-immune axis: implications for precision health

Pattern recognition receptors (PRRs) are a crucial component of the immune system that enables the host to detect and respond to microbial invaders and danger signals. These receptors are found on various immune cells and are responsible for recognizing conserved molecular structures called pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). The recognition of these patterns initiates immune responses that are essential for maintaining immune homeostasis and protecting the host from infections, tissue damage, and diseases such as cancer. PRRs are classified into several types, each specialized for recognizing different microbial or host-derived patterns. The main categories of PRRs include Toll-like receptors (TLRs), NOD-like receptors (NLRs), C-type lectin receptors (CLRs), and the various PAMPs and DAMPs recognized by these receptors (33, 34).

The gut microbiota’s production of SCFAs, including acetate, propionate, and butyrate, plays a fundamental role in maintaining immune tolerance, gut health, and host metabolism (49, 50). Figure 2 illustrates how gut microbiota ferments dietary fibers to produce SCFAs, including acetate, butyrate, and propionate. These SCFAs play a crucial role in epithelial cell growth, immune response, and metabolic regulation. These microbial metabolites are primarily produced in the colon through distinct bacterial pathways. Acetate is synthesized via the pyruvate pathway by Akkermansia muciniphila, Bacteroides spp., Bifidobacterium spp., and Ruminococcus spp. (51, 52). Propionate is generated through the succinate, acrylate, and propanediol pathways by species such as Bacteroides spp., Veillonella spp., and Roseburia inulinivorans (53). Butyrate a key immunomodulatory SCFA, is predominantly via the phosphotransbutyrylase/butyrate kinase and butyryl-CoA:acetate CoA-transferase pathwaysinvolving Coprococcus catus, Faecalibacterium prausnitzii, and Eubacterium rectale (54, 55).

Among butyrate-producing bacteria, Faecalibacterium prausnitzii plays a crucial role due to its ability to modulate gut immune responses and reinforce epithelial integrity (55). This bacterium exerts anti-inflammatory effects by inhibiting NF-κB activation and stimulating IL-10 production, thereby reducing gut inflammation and maintaining homeostasis (56). Additionally, butyrate enhances the expression of tight junction proteins such as ZO-1 and occludin, essential for maintaining gut barrier function (57). Disruptions in F. prausnitzii abundance have been linked to inflammatory bowel disease (IBD) and colorectal cancer, emphasizing its potential as a probiotic candidate for microbiota-targeted therapies (58).

SCFAs exert systemic effects by modulating immune function and metabolism. Acetate, the most abundant SCFA in circulation, can cross the blood-brain barrier to regulate appetite via central homeostatic mechanisms (59). Propionate, predominantly metabolized in the liver, contributes to lipid and glucose metabolism but remains at low peripheral concentrations (50). Butyrate plays a key role in reinforcing gut barrier integrity, reducing inflammation, and promoting regulatory T cell (Treg) differentiation, which is crucial for immune tolerance and the suppression of excessive inflammation (60–62). It also directly modulates dendritic cells and macrophages, enhancing their ability to recognize pathogen-associated molecular patterns (PAMPs) and regulating pro-inflammatory cytokine secretion (63).

A significant mechanism underlying butyrate’s immunomodulatory effects is its inhibition of histone deacetylases (HDACs), leading to epigenetic modifications that regulate gene expression associated with immune homeostasis (64–66). This process fosters anti-inflammatory signaling, supports tissue repair, and balances immune responses in conditions such as infections and cancer. Mammals rely on gut bacteria to break down indigestible dietary components, such as fiber, generating SCFAs as metabolic byproducts that contribute to host health and disease prevention (11). The dynamic interplay between diet, microbial metabolism, and immune regulation highlights the potential of SCFAs as therapeutic targets for inflammatory and metabolic disorders.

Cytokine signaling pathways are fundamental to immune regulation, with the microbiome playing a key role in modulating both pro-inflammatory and anti-inflammatory responses. Pro-inflammatory cytokines, such as TNF-α, IL-1β, IL-6, and IFN-γ, are critical in initiating inflammatory reactions and serve as primary mediators of immune responses during infection or injury (67). Microbial components, including lipopolysaccharides (LPS), activate signaling pathways such as the nuclear factor NF-κB pathway through Toll-like receptors, particularly TLR4, TLR3 and TLR5. The recognition of LPS by TLR4 triggers NF-κB activation, activator protein-1 (AP-1), and mitogen-activated protein kinase (MAPK) (68). These pathways stimulate the release of proinflammatory cytokines and chemokines, including interleukin (IL)-1, tumor necrosis factor (TNF)-α, and IL-6 (44, 69, 70). Cytokines are versatile proteins that play a key role in regulating osteoclast development and bone resorption, altering vascular endothelial permeability, and attracting immune cells to sites of inflammation (44, 71). The recognition of viral components by TLR3 triggers the TRIF-mediated signaling pathway, leading to the activation of Interferon Regulatory Factor 3 (IRF3) and the subsequent production of Interferon Beta (IFN-β), which plays a crucial role in inhibiting viral replication (72). Additionally, TLR3 stimulation activates the MAP kinase and NF-κB signaling pathways, promoting the production of pro-inflammatory cytokines (73).

This cytokine signaling process involves a highly regulated molecular cascade that is crucial for maintaining immunological homeostasis. Immune cells, such as dendritic cells and macrophages, recognize PAMPs from microbes or host-derived signals, such as SCFAs produced by microbiota. Upon recognition, these cells release cytokines, which can either promote or suppress inflammation, depending on the signals received (66). Cytokines bind to specific receptors on target cells, initiating intracellular signaling pathways involving kinases and transcription factors like NF-κB or STAT proteins. Once activated, these transcription factors translocate to the nucleus and regulate the expression of genes critical for immune responses, thereby enhancing T and B cell functions to combat infections and malignancies (74).

For instance, in inflammatory bowel disease (IBD), an overactive cytokine response leads to chronic inflammation in the gut, driven by excessive production of TNF-α, IL-1β, and IL-6, which contribute to tissue damage and immune dysregulation (75). Similarly, in rheumatoid arthritis, dysregulated cytokine signaling—particularly involving TNF-α and IL-6—results in persistent joint inflammation and autoimmunity (76). In contrast, in cancer, certain cytokines such as IL-10 and TGF-β suppress immune responses, allowing tumor cells to evade immune detection and promote tumor progression (77). These disease models illustrate the dual role of cytokines in either driving or suppressing immune responses, emphasizing the necessity of maintaining a precise balance between pro-inflammatory and anti-inflammatory signals.

To prevent excessive immune activation and inflammation, the immune system carefully balances pro-inflammatory and anti-inflammatory signals, ensuring a controlled response that maintains systemic homeostasis while addressing challenges such as infections, cancer, and interactions with the microbiota (34).

Pathogenic interactions occur when microorganisms invade the host, triggering an immune response that aims to eliminate the threat but can also lead to inflammation and tissue damage. Pro-inflammatory cytokines like IL-6, TNF-α, and IFN-γ are released to recruit immune cells and amplify the response (78). Pathogens are detected by pattern recognition receptors (PRRs) such as TLRs and NLRs, which recognize microbial-associated molecular patterns and initiate immune signaling (79). The adaptive immune system further engages by activating effector T cells and stimulating antibody production (2). However, excessive immune activation can lead to collateral damage and worsen disease outcomes (80). For example, Salmonella enterica triggers IL-6-mediated gut inflammation (81), Mycobacterium tuberculosis evades immune detection while inducing chronic inflammation (82), and SARS-CoV-2 provokes a severe cytokine storm, causing lung injury and systemic complications (83).

Symbiotic microbes establish stable, non-harmful relationships with the host, offering benefits. These interactions can be mutualistic, where both the host and microbe benefit or commensal, where the microbe benefits without harming the host (84). In mutualistic interactions, microbes regulate immune responses, enhance barrier protection, and support immune homeostasis. For instance, Bacteroides fragilis produces polysaccharide A (PSA), which promotes regulatory T cells and prevents colitis (85). Lactobacillus reuteri secretes antimicrobial peptides that help protect the mucosal lining and prevent pathogen colonization (86). Additionally, mutualistic microbes stimulate anti-inflammatory cytokines like IL-10 and TGF-β, promoting immune tolerance and preventing excessive inflammation (87). They also strengthen epithelial integrity, as seen with Lactobacillus and Bifidobacterium, and foster immune balance through regulatory T cell activity (2).

In contrast, commensal relationships, where microbes coexist with the host without causing harm, are typically associated with a more regulated immune response. The immune system often promotes the production of anti-inflammatory cytokines, such as IL-10, and enhances processes supporting immune tolerance, including the activity of regulatory T cells (Tregs). For example, Staphylococcus epidermidis on the skin produces antimicrobial molecules that protect against Staphylococcus aureus infections, preventing harmful overgrowth (88). Similarly, the gut microbiome maintains a balance between beneficial and opportunistic bacteria, reducing the risk of infections like Clostridioides difficile (89). These mechanisms work to prevent unnecessary immune activation and inflammation, allowing commensals to persist in a balanced state without triggering excessive inflammatory responses (87). This delicate equilibrium between immune activation and regulation is crucial for maintaining host homeostasis while permitting the coexistence of beneficial microorganisms without compromising immune system integrity (90, 91).

Immunological interventions aimed at promoting health encompass enhancing immune function, preventing infections, and managing chronic diseases. Targeting cytokines such as TNF-α and IL-6 has been effective in reducing inflammation in autoimmune disorders like rheumatoid arthritis. Likewise, immune checkpoint inhibitors targeting PD-1, PD-L1, and CTLA-4 have revolutionized cancer therapy by reactivating T cells to combat malignant cells. Another significant target is regulatory T cells (Tregs), which can be modulated to restore immune tolerance in autoimmune diseases or to enhance anti-tumor immunity (93). The gut microbiota plays a crucial role in immune modulation, with probiotics (94), prebiotics, and dietary interventions demonstrating therapeutic potential for conditions such as inflammatory bowel disease and obesity (95). Nutritional strategies (96), including supplementation with vitamin D, zinc, and omega-3 fatty acids, are also critical for maintaining optimal immune function (97). Additionally, targeting inflammasomes which are the key components responsible for the production of pro-inflammatory cytokines like IL-1β and IL-18—holds promise for treating diseases such as gout and autoimmune conditions (98). Vaccination remains a cornerstone of public health, offering cost-effective protection against infectious diseases and enhancing immunological memory. Technological advances, particularly mRNA vaccine platforms (99), have significantly improved immunity against pathogens such as influenza, HPV, and COVID-19 (100, 101). Toll-like receptors essential in pathogen recognition, are also being explored for their potential to boost immune responses against infections and cancers while mitigating excessive inflammation in autoimmune diseases (102, 103). Monoclonal antibodies and Janus kinase (JAK) inhibitors represent advanced therapeutic modalities for treating autoimmune disorders, cancers, and chronic inflammatory diseases by specifically targeting immune components. Furthermore, enhancing immune processes like antibody-dependent cellular cytotoxicity (ADCC) is being investigated for its potential to treat cancer and infections (104). By strategically modulating these immunological targets, it is possible to enhance immune function, improve disease management, and promote overall health (105). By strategically modulating these immunological targets, it is possible to enhance immune function, improve disease management, and promote overall health (106). Notably, microbiota-driven interventions hold immense promise in shaping immune responses by influencing T cell differentiation, mucosal immunity, and systemic inflammation. Harnessing microbial-derived metabolites, such as SCFAs, and engineered probiotics provides novel avenues for immunotherapy and personalized medicine (23). Advancing research in microbiota-immune interactions could lead to breakthroughs in disease prevention and therapeutic strategies, reinforcing the pivotal role of the gut microbiome in sustaining immune balance and health (107).

Monoclonal antibodies are sophisticated biological therapeutics that target specific antigens, thereby inducing their destruction or facilitating their elimination through mechanisms such as antibody-dependent cellular cytotoxicity (ADCC) and complement activation. These agents have demonstrated efficacy in reducing inflammation and joint damage in rheumatoid arthritis by neutralizing TNF-α and alleviating the inflammatory symptoms of psoriasis by targeting IL-17 and IL-23 (105). In oncology, monoclonal antibodies that block the PD-1/PD-L1 interaction restore T-cell functionality in non-small cell lung cancer, enhancing the immune system’s capacity to target and eliminate tumors. Similarly, anti-CD20 monoclonal antibodies in hematological malignancies promote B cell depletion through ADCC and complement activation. In the context of inflammatory bowel disease integrin α4β7 inhibitors limit the migration of lymphocytes to the gut mucosa, thereby reducing intestinal inflammation (108). In parallel, JAK inhibitors, which are small molecule agents, interfere with the JAK-STAT signaling pathway which is a central regulator of pro-inflammatory cytokines and cellular growth factors. By inhibiting specific JAK isoforms such as JAK1, JAK2, and JAK3, these inhibitors reduce cytokine signaling and inflammation (109). For instance, JAK1 and JAK3 inhibitors are effective in managing cytokine-driven inflammatory responses in conditions like rheumatoid arthritis and ulcerative colitis. Targeting JAK2 specifically addresses abnormal cytokine signaling and mitigates tissue fibrosis in myelofibrosis. Additionally, JAK inhibitors have been shown to reduce skin inflammation in atopic dermatitis by modulating dysregulated cytokine pathways. In the context of graft-versus-host disease (GVHD), these inhibitors play a critical role in limiting immune-mediated tissue damage, thus providing essential immunological control following transplantation (Table 3) (115). Collectively, these therapeutic agents, both monoclonal antibodies and JAK inhibitors, represent significant advances in the treatment of a variety of inflammatory and immune-mediated disorders, leveraging distinct but complementary mechanisms of action to modulate immune system activity and reduce pathological inflammation.

Probiotics are live microorganisms that confer a health benefit on the host when administered in adequate amounts (Table 4). They are primarily found in fermented foods and supplements, and their therapeutic potential is linked to their ability to modulate immune responses, particularly in the gut (124). A prominent example is Lactobacillus rhamnosus GG, a probiotic strain that has been used in clinical trials for treating inflammatory bowel diseases (IBD), such as ulcerative colitis (116). L. rhamnosus GG has been shown to enhance gut mucosal immunity by promoting anti-inflammatory cytokines like IL-10 and reducing pro-inflammatory cytokines such as TNF-α. Other probiotic strains, including Lactobacillus and Bifidobacterium species, are known for their immunomodulatory effects, promoting a balanced immune response by stimulating the production of regulatory T cells (Tregs) and strengthening mucosal immunity (117, 125). These probiotics also improve gut barrier function and reduce intestinal inflammation, helping prevent infections and alleviating the severity of autoimmune diseases and allergies (94). The beneficial effects of probiotics on immune regulation are also supported by their ability to increase gut microbiota diversity, which has been shown to help restore immune tolerance and mitigate disease pathology (118).

In addition to probiotics, prebiotics have gained significant attention as a tool for modulating immune responses (119). Prebiotics are non-digestible fibers that selectively stimulate the growth of beneficial gut bacteria (Table 5). These fibers influence immune function by fostering a gut microbiota composition that promotes immune tolerance, particularly in preventing and treating allergic diseases (126). One key case study involves the supplementation of inulin, a prebiotic, in infants at high risk for allergies. The intervention resulted in a reduced incidence of atopic dermatitis, along with an increase in beneficial bacteria like Bifidobacterium and Lactobacillus, which support immune regulation (49). Similarly, oligofructose supplementation in children with allergic rhinitis demonstrated a reduction in allergen-specific IgE production, which is linked to allergic responses, and improved the balance between pro-inflammatory Th2 cells and Tregs (122). This suggests that prebiotics can help alleviate allergic symptoms by modulating the immune system and fostering a more balanced, less inflammatory immune response.

A key mediator of both probiotic and prebiotic effects on immune regulation is SCFAs, particularly butyrate (128). Butyrate plays a crucial role in maintaining intestinal barrier integrity, enhancing the regeneration of epithelial cells, and reducing intestinal permeability, which is often implicated in inflammatory diseases (129). Butyrate also activates Tregs, which are essential for immune tolerance, and inhibits the production of pro-inflammatory cytokines such as TNF-α, further promoting a balanced immune response (122). The production of SCFAs, including butyrate, is influenced by the gut microbiota’s fermentation of dietary fibers, underscoring the importance of a balanced microbiome in producing these metabolites (127). Beyond their gut health benefits, SCFAs like butyrate exert systemic effects, modulating immune responses and potentially protecting against chronic diseases, including obesity, type 2 diabetes, and autoimmune disorders (130, 131). Figure 3. illustrates the contrasting effects of symbiotic and pathogenic microbial interactions on the immune response

Together, probiotics and prebiotics work synergistically to enhance immune health by improving gut microbiota diversity, promoting the production of anti-inflammatory cytokines, and regulating immune responses through metabolites like butyrate. These effects are essential for reducing inflammation, preventing infections, and mitigating the risks associated with autoimmune diseases and allergies (94, 120).

Fecal microbiota transplantation (FMT) has emerged as a revolutionary immunological strategy for modulating the host-microbe axis, particularly in cases of diseases where the gut microbiota is disrupted. FMT involves transferring fecal material from a healthy donor into the gastrointestinal tract of a recipient, thereby restoring microbial diversity and balance (132). One of the most well-documented and successful applications of FMT is in the treatment of recurrent Clostridium difficile (C. difficile) infection, which often arises after antibiotic treatments disrupt the natural gut microbiota. A landmark case study demonstrated that FMT achieved a 90% success rate in curing recurrent C. difficile infections (133). Patients who underwent FMT experienced significant restoration of gut microbiota diversity, which helped re-establish immune homeostasis. Safety and efficacy of fecal microbiota transplantation (FMT) as a modern adjuvant therapy in various diseases and disorders (134). The restored microbiota was able to suppress the overgrowth of C. difficile and reduced intestinal inflammation, offering a direct example of how microbiota modulation can enhance immune function and control infection (135). Beyond infectious diseases, FMT has shown promise in autoimmune and inflammatory disorders. For instance, in patients with ulcerative colitis (UC), a form of inflammatory bowel disease (IBD), FMT has been explored as a means of reducing inflammation and modulating the immune system (136). A study involving UC patients who received FMT showed improvements in clinical symptoms, including reduced disease activity and inflammation. This therapeutic effect was attributed to changes in the gut microbiota that promoted a shift from pro-inflammatory to anti-inflammatory immune responses, including an increase in regulatory T cells (Tregs) that are crucial for immune tolerance (137). Additionally, FMT has been investigated in the context of multiple sclerosis (MS), an autoimmune disease where the immune system attacks the central nervous system (138). Preliminary clinical studies in MS patients receiving FMT have shown promising results, with some patients experiencing reduced disease progression and fewer relapses, potentially due to changes in gut microbiota composition that impact the peripheral immune system (134). These case studies highlight FMT’s potential not only for treating infections but also for modulating the immune system in autoimmune and inflammatory diseases by restoring microbial diversity and re-establishing immune balance, suggesting a new frontier for therapeutic interventions in immunology.

Dietary components provide not only essential nutrients for the body’s physiological processes but also substrates that nourish the microbiota within the gastrointestinal tract, collectively known as the gut microbiome (139). This symbiotic relationship between the host and the microbiome is critical for maintaining health Table 5. Key dietary elements such as dietary fibers (140), polyphenols, and fatty acids play significant roles in modulating the gut microbiota and supporting immune function. Their combined effects are essential in maintaining a balanced immune system and improving overall health, as demonstrated in (Figure 4) (141). Gut bacteria metabolize dietary fibers into SCFAs, including butyrate, which contribute to the reinforcement of the intestinal epithelial barrier, reduce inflammatory responses, and promote the differentiation and activity of regulatory T cells (142). These SCFAs are essential for maintaining gut health and preventing dysregulated immune responses. Some of the compounds such as polyphenols, found abundantly in fruits, vegetables, and beverages such as tea, act as prebiotics. These compounds possess potent antioxidant and anti-inflammatory properties and facilitate the growth of beneficial gut bacteria, including Lactobacillus and Bifidobacterium (143). These bacteria, in turn, help maintain a balanced microbial ecosystem and modulate immune responses, thereby supporting systemic health. Additionally, omega-3 fatty acids, which are present in fatty fish and certain plant oils, exert anti-inflammatory effects and modulate immune cell activity, further contributing to the resolution of chronic inflammation and the maintenance of immune homeostasis (144).

Dietary interventions are crucial in managing various inflammatory diseases, including neuroinflammatory, gastrointestinal, autoimmune, and cardiovascular diseases. In neuroinflammatory conditions, dietary fibers, polyphenols, and omega-3 fatty acids help modulate the gut microbiota, reduce inflammation, and improve immune function, with clinical evidence suggesting benefits in conditions like Alzheimer’s and multiple sclerosis (145). For gastrointestinal diseases like Crohn’s and ulcerative colitis, high-fiber diets and polyphenols enhance gut barrier integrity and reduce inflammation, showing promise in clinical trials (146). In autoimmune diseases such as rheumatoid arthritis and lupus, omega-3 fatty acids and polyphenols have demonstrated significant anti-inflammatory effects, improving symptoms and immune regulation (147). Furthermore, in cardiovascular diseases, diets rich in omega-3s and antioxidants have been shown to reduce oxidative stress.

By supporting both the gut microbiota and immune function, these nutrients provide a holistic approach to managing inflammation and immune dysregulation. In animal models, the ketogenic diet led to reduced systemic inflammation, improved brain function, and decreased levels of pro-inflammatory cytokines in the central nervous system. Furthermore, the diet modulated immune cell populations, particularly by reducing the activation of microglia, the resident immune cells in the brain. These findings suggest that dietary interventions can modulate the gut-brain immune axis and provide therapeutic benefits in conditions that involve neuro-inflammation (21). Tryptophan, an essential amino acid, plays a critical role in maintaining normal growth, health, and metabolic functions in both humans and animals. Beyond its fundamental physiological functions, tryptophan has a significant impact on modulating the gut-brain axis (GBA) through the metabolites produced during its metabolism by gut microbiota. Microbial communities in the gut can convert tryptophan into a range of bioactive compounds, most notably indole and its derivatives. These metabolites have profound effects on immune regulation and the maintenance of gut homeostasis (148). Indole derivatives, in particular, interact with the aryl hydrocarbon receptor a ligand-activated transcription factor present on immune and epithelial cells. Activation of AhR by these metabolites influences various immune cell functions, including the differentiation and expansion of regulatory T cells (Tregs), which are critical for maintaining immune tolerance and controlling inflammatory responses (149). This interaction not only influences immune cell activity but also modulates cytokine production, promoting an anti-inflammatory profile. By facilitating the differentiation of Tregs, indole derivatives help regulate local gut immunity and systemic immune responses, thus balancing the production of pro-inflammatory and anti-inflammatory signals. Additionally, these metabolites play a crucial role in gut barrier function, enhancing epithelial cell integrity and strengthening the intestinal mucosal barrier. This contributes to preventing the translocation of pathogens and reducing intestinal permeability, further supporting immune function and gut health (149). The metabolic products of tryptophan metabolism thus serve as a key link between gut microbiota activity and immune system regulation. Through their interaction with AhR, indole derivatives connect microbiome function with immune responses, ultimately enhancing both gut health and systemic immunity. This integration underscores the importance of the gut microbiota in modulating immune processes and highlights the therapeutic potential of tryptophan-derived metabolites in managing gastrointestinal (150) and systemic inflammatory conditions (117).

A growing area of research is the use of microbiome-derived metabolites to modulate the immune system in the context of cancer therapy (Table 6).

Recent evidence suggests that the gut microbiome plays a crucial role in influencing responses to immune checkpoint inhibitors (ICIs), such as anti-PD-1 and anti-CTLA-4 therapies, which are widely used in cancer treatment. Among the microbial taxa associated with enhanced ICI efficacy, Firmicutes, particularly Faecalibacterium prausnitzii, Ruminococcus spp., and Clostridium cluster XIVa, have been identified as key contributors to a favorable immunological landscape (154).

Mechanistically, Firmicutes influence ICI efficacy through several pathways. Faecalibacterium prausnitzii produces butyrate, a short-chain fatty acid that plays a crucial role in regulatory T cell (Treg) differentiation while simultaneously supporting CD8+ T cell activation in the tumor microenvironment. This dual effect reduces chronic inflammation while enhancing anti-tumor immunity (23). Additionally, certain Firmicutes species promote dendritic cell maturation and MHC class I expression, which in turn enhances tumor antigen presentation and activation of cytotoxic T cells (155). Higher levels of Firmicutes have been correlated with increased infiltration of cytotoxic CD8+ T cells, which improves the effectiveness of PD-1 blockade therapies (156). Furthermore, Firmicutes reinforce gut barrier integrity by upregulating tight junction proteins such as occludin and ZO-1, thereby preventing microbial translocation and systemic inflammation, both of which are known to suppress anti-tumor responses (22, 157, 158).

Clinical studies have provided compelling evidence supporting the association between Firmicutes and ICI response. A landmark study by Routy et al. (8) demonstrated that cancer patients with a higher abundance of Firmicutes in their gut microbiome had improved progression-free survival and overall response rates to anti-PD-1 therapy. Similarly, Gopalakrishnan et al. (159) found that melanoma patients who responded well to ICIs had increased levels of Firmicutes, particularly Ruminococcus and Faecalibacterium, compared to non-responders. Fecal microbiota transplantation (FMT) studies further validated this association, as transplanting microbiota from ICI responders into germ-free mice restored anti-tumor immunity and enhanced PD-1 blockade efficacy (8).

These findings underscore the potential for modulating the gut microbiota through probiotics, dietary interventions, or FMT as a strategy to optimize ICI therapy outcomes. Future research should focus on identifying specific microbial signatures that could serve as predictive biomarkers for immunotherapy response and exploring the potential of microbiome-targeted interventions in cancer treatment (160).