Human microbiome refers to the microbial communities residing in various parts of the human body, including bacteria, fungi, viruses, and archaea. A wide range of anatomical sites, including the skin, mucous membranes, respiratory tract, uterus, vagina, and digestive tract, harbor complex microbial ecosystems that are specifically adapted to the unique characteristics of each niche (1, 2). These microorganisms engage in dynamic interaction with the human host, forming a highly complex ecosystem that profoundly influences health and disease states (3). The skin, being the largest human organ with a surface area of approximately 2 m², exhibits higher microbial community composition in areas rich in sebum and moisture (4–6). Compared with the lower gastrointestinal tract and skin, the respiratory tract demonstrates a lower microbial density. Furthermore, microbial density varies along the respiratory tract, with the upper respiratory tract exhibiting greater density and diversity compared to the lower respiratory tract (7, 8). The microbial ecosystem within the digestive tract is the most complex, diverse, and abundant across the entire body (9). The majority of these microorganisms are found in the oral mucosa and gastrointestinal tract, where the gut microbiota plays an important role in nutrition metabolism, immune regulation, and disease prevention (10). The gut microbiota contains approximately 10^9 to 10^11 microorganisms per gram of luminal content, with species diversity ranging from 1,000 and 3,000 (2, 3, 11). One gram of human feces can harbor 10^10 to 10^11 bacteria. The human gut microbiota is primarily composed of Firmicutes, Bacteroidetes, Actinobacteria, and Proteobacteria (12, 13). More than 1,000 bacteria species reside in the intestines, and their metabolites can generally be categorized into the following categories: SCFAs (such as acetate, propionate, butyrate), long-chain fatty acids (LCFAs), bile acids (primary bile acids and secondary bile acids), amino acid metabolites (e.g., ammonia, amine, indole and its derivatives),vitamins, and other metabolites such as trimethy lamine and its oxidants form (TMAO), hydrogen, methane, and carbon dioxide (14, 15) (Table 1). In certain studies, the gut microbiota has been redefined as an “important organ,” and the gut microbiota along with its metabolome have been demonstrated to influence the regulation, maturation, and function of the immune system, playing a crucial role in the differentiation of immune cells (16, 17). Many animal model studies have demonstrated that alterations in intestinal bacterial communities can influence the onset of diseases in distant organs, thereby giving rise to the concepts of the lung-gut axis and the skin-gut axis (18–20). SCFAs, such as propionic acid, butyric acid, and acetate, are the end products of dietary fiber fermentation by the gut microbiota. These metabolites can reach distant organs and exert beneficial effects on the immune system. For instance, acetate, produced by members of the Lachnospiraceae family within the gut, has been shown to activate the innate immune system in the lungs and subsequently modulate the skin's immune defense mechanism (21, 22).

Allergic diseases, also referred to as hypersensitivity disorders, can manifest at various stages of life, from infancy to old age. These conditions involve an abnormal immune response of the body to typically harmless substances, known as allergens (23). The pathogenesis of allergic diseases primarily involves an exaggerated immune reaction, particularly IgE-mediated responses (Figure 1). Globally, allergic diseases affect approximately 15% of the population and have shown a significant increase in incidence in recent years, with industrialized countries experiencing a marked rise (24). According to the latest report by the World Health Organization's (WHO), asthma is currently one of the most prevalent chronic diseases worldwide, affecting approximately 339 million individuals. Since the 1980s, the incidence rate of asthma has significantly increased, especially among children and in urban areas (25). Additionally, the prevalence of allergic rhinitis (AR) has risen by 50% over the past three decades, while food allergies has doubled globally. The high incidence of these diseases not only severely impacts patients’ quality of life but also imposes a substantial economic burden on public health system. Studies indicate that the treatment costs for allergic diseases account for more than 2% of global healthcare expenditures (26). With the continued rise in incidence rate, it is anticipated that the proportion of allergic diseases treatment costs in global healthcare expenditure may further increase in the coming years.

Research demonstrates that patients with allergic diseases often exhibit dysbiosis of their microbiota. In patients with skin bacteria, the diversity of skin bacteria is significantly reduced, accompanied by an increase in Staphylococcus aureus, and a decrease in beneficial bacteria such as Staphylococcus epidermidis (20, 27–29). Similarly, individuals with allergic diseases exhibit significantly lower gut bacterial diversity compared to healthy controls, characterized by a reduction in beneficial bacteria like Lactobacillus and an overgrowth of potentially harmful bacteria such as Escherichia coli. This dysbiosis of the microbiota is closely linked to the pathogenesis and progression of allergic diseases (30, 31). Beneficial bacteria play a crucial role in regulating the development and function of the immune system, promoting the differentiation of regulatory T cells (Tregs), inhibiting T helper 2 cell (Th2)-type immune responses, and thereby reducing IgE production and allergic reactions (32, 33). This microbial imbalance may lead to excessive immune responses and elevate the risk of allergic diseases (34). Metabolites produced by the gut microbiota influence immune responses by modulating the activity of immune cells. Acting as signaling molecules, these microbiota metabolites activate or inhibit intracellular signaling pathways, regulate gene expression, and modulate cell functions (35). Furthermore, by enhancing the barrier function of intestinal epithelial cells, these metabolites prevent allergens from entering the bloodstream, thereby mitigating systemic allergic reactions (Table 2).

The alterations in the composition and function of the gut microbiota can influence the development and function of the immune system, thereby contributing to the onset of allergic diseases. Metabolomics not only serves as a valuable tool for identifying biological markers but also plays a critical role in disease diagnosis and treatment monitoring. By integrating data on intestinal microbial communities with metabolomics analysis, we can gain deeper insights into the overall functional impact of the gut microbiota on host health, as well as the effects of host-derived metabolomics changes on resident bacterial populations (36). This approach facilitates the development of more effective prevention and treatment strategies for allergic diseases.

SCFAs are defined as fatty acids with a carbon chain length of 1–6 carbon atoms, including acetate, propionate, and butyrate. In the intestine, SCFAs are primarily produced through the fermentation of dietary fiber and resistant starch by the gut microbiota, particularly involving bacterial genera such as Bacteroides and Akkermansia (37, 38). Changes in the quantity, species, or proportions of these bacterial populations within the gut can lead to corresponding alterations in the production and composition of SCFAs (12). Among these, butyrate is considered one of the most important SCFAs due to its critical physiological roles (12, 39).

As an essential energy source for colonocytes, SCFAs play a critical role in maintaining intestinal health. Butyrate, specially, generates ATP in cellular mitochondria via the β-oxidation pathway, supplying approximately 70% of the energy requirements for colonocytes. During the development of AR, the population of beneficial bacteria such as Lactobacillus and Bifidobacterium decrease, potentially leading to reduced production of SCFAs, particularly acetate. Simultaneously, certain harmful bacteria of the Clostridium genus may over proliferate, altering the levels and ratios of SCFAs, including butyrate. The reduction in butyrate can disrupt intestinal cell energy metabolism, inducing apoptosis and impairing intestinal barrier function. This dysfunction allows inflammatory factors to enter the bloodstream, triggering systemic allergic reactions (40).

SFCAs not only serves as an essential energy source for intestinal cells but also play a pivotal role in regulating immune cells function (41) (Figure 2). In allergic diseases, SCFAs function as naturally occurring immune modulators, contributing significantly to regulating the activity of immune cells, and acting as signaling molecules involved in various physiological processes. In Food allergies, propionate inhibits the NF-κB pathway, thereby reducing the expression of pro-inflammatory cytokines such as TNF-α and IL-6 (42). Additionally, SCFAs can promote the differentiation of Tregs and enhance their secretion of IL-10, an important anti-inflammatory cytokine that suppresses the activation and proliferation of various immune cells, exerting potent anti-inflammatory effects (43). The hallmark of AR is a Th2-mediated immune response, characterized by elevated IgE levels and mast cells degranulation, which elicits allergic symptoms (44, 45). Tregs suppress the activation and proliferation of Th2 by secreting transforming growth factor-beta (TGF-β), thereby reducing the production of Th2 proinflammatory cytokines and inhibiting mast cells degranulation and the release of inflammatory mediators, thus alleviating the AR symptoms (46). Additionally, there exists a dynamic balance between Th17 and Treg. Th17 cells promote inflammatory cells infiltration and may induce changes in mucosal barrier function (40). A decrease in butyrate affects the proliferation and function of Tregs, increases the differentiation of Th17, disrupts immune homeostasis, and further exacerbates nasal inflammation and allergic reactions. Group 2 innate lymphoid cells (ILC2s) are increasingly recognized as key regulators of type 2 inflammation and are markedly elevated in human airway disease characterized by type 2 inflammatory, including AR and asthma (47). Gavin Lewis and his team demonstrated that propionate salts can significantly inhibit the production of type 2 cytokines by ILC2s in vitro and alleviate ILC2-dependent allergic inflammation, such as asthma, in vivo. Succinate salt have been shown to downregulate the expression of the critical transcription factor GATA-3, which governs ILC2 development and function (48). This reduction in GATA-3 expression decreases cellular metabolism, thereby regulating immune cell activity and inhibiting lung ILC2 function in asthma, as well as the subsequent development of airway hyperresponsiveness (AHR) (49). In allergic asthma, SCFAs enhances systematic delivery by upregulating intestinal monocarboxylic acid transporters (MCTs), thereby attenuating Th2/ILC2-mediated inflammatory responses and inhibiting eosinophil infiltration and lung mucin production (50–53). Furthermore, dendritic cells (DCs) serves as a central bridge between the innate and adaptive immune systems. In allergic diseases such as AR and allergic asthma, succinate and propionate salts can suppress T cell activation by inhibiting DC maturation, thus dampening the intensity of the immune response (54).

SCFAs function as agonists for several G protein-coupled receptors (GPCRs), thereby regulating immune modulation and intestinal barrier function (12, 38). GPCRs, including free fatty acid receptor 2 (FFAR2, or GPR43) and 3 (FFAR3 or GPR41), as well as hydroxycarboxylic acid receptor 2 (HCAR2 or GPR109A), are expressed in various cell types, such as intestinal epithelial cells and immune cells. SCFAs stimulate these GPCRs to activate mitogen-activated protein kinases (MAPKs) and extracellular signal-regulated kinases (ERK1/2), exerting immunoregulatory effects. Butyrate promotes cellular energy metabolism and maintains intestinal barrier integrity by activating GPCRs such as GPR43 and GPR109A (55). In AR, the activation of GPR43 and GPR41 by butyrate can inhibit the NF-κB pathway, reduce pro-inflammatory cytokines production, and alleviate nasal mucosa inflammation.

SCFAs can also influence the occurrence and progression of allergic diseases by modulating the gut-lung axis. The gut-lung axis refers to the bidirectional communication pathway between the gut microbiota and the lungs (56). In an in vivo study, the Chinese herbal formula (Gu-Ben-Fang-Xiao Decoration, GBFXD), used for asthma treatment, was shown to alleviate lung inflammation while increasing the abundance of SCFAs-producing bacteria and SCFAs levels, especially acetate. SCFAs through binding to receptors such as GPR43, inhibit inflammation, regulate the differentiation and function of immune cells. SCFAs, particularly acetate, can enhance the differentiation and function of Tregs, thereby suppressing allergic airway inflammation. After treating mice with antibiotics, the protective effect of bone-resisting anti-soup on the lungs was weakened (57). These findings indicate that SCFAs derived from gut microbiota are important immunoregulators and contributors to the gut-lung axis. SCFAs derived from the gut microbiotaserve as critical immunoregulatory agents and play a pivotal role in the gut-lung axis.

Overall, multiple studies have demonstrated that the gut microbiotaproduce diverse SCFAs via fermentation, thereby exerting distinct anti-allergic effects. Additionally, the consumption of dietary fiber has been shown to modulate the composition of gut microbiota. Specifically, it reduces the abundance of the Firmicutes phylum while increasing that of Bacteroidetes at the phylum level, and enhances Lactobacillaceae at the family level. Therefore, supplementing the diet with foods rich in dietary fiber or directly administering SCFAs may serve as effective strategies for the treatment of allergic diseases. Future research should focus on elucidating the specific mechanisms by which SCFAs influence allergic diseases, developing personalized treatment regimens, and enhancing therapeutic efficacy.

LCFAs in the gut generally refer to fatty acids with a carbon chain length of 12–20 carbon atoms, including saturated fatty acids, monounsaturated fatty acids, and polyunsaturated fatty acids (PUFAs). Among these, the PUFAs linoleic acid (n-6) and alpha-linolenic acid (n-3) play critical roles in human energy metabolism, cell membrane structure, and signal transduction (58). The n-6 long-chain polyunsaturated fatty acids (n-6 LCPUFA) primarily include arachidonic acid (AA), while the n-3 LCPUFA mainly consist of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Dietary intake is the primarily source of LCFAs, although the human body can also synthesize certain LCFAs in the liver and other tissues from carbohydrates and proteins. Essential fatty acids, such as n-3 and n-6 PUFAs, must be obtained through diet.

LCFAs decrease the body's sensitivity to allergens by influencing the early development of the immune system (17). A prospective cohort study conducted in Sweden demonstrated that children who consumed higher levels of very long chain n-3 polyunsaturated fatty acids (n-3 VLCPUFAs) at the age of 8 exhibited a reduced risk of AR from ages 8 to 16. In this study, AA was identified as a mediator of inflammation due to its role as the precursor of pro-inflammatory eicosanoids, such as prostaglandin D2, which contribute to the establishment of an immune-allergic predisposition toward asthma. AA-derived prostaglandin E2 can suppress Th1 response while promoting Th2 responses, thereby influencing the balance of the body's immune response (59). A study by the University of Southampton in the UK indicated that during the early life development, breastfeeding promotes immune maturation, prevents infections, and may reduce the risk of allergies (26). AA and DHA are the primarily LCPUFAs found in human breast milk. The immune system of newborns undergoes development over several months to years, establishing balances between Th1 and Th2 responses, as well as a balance between effector T cells and Tregs (60–62). Impairments in immune development can lead to inadequate cellular responses or sustained immune imbalance (e.g., imbalance between Th1 and Th2 systems), increasing infants' susceptibility to allergens or predisposing them to immune-mediated diseases such as food allergies. Furthermore, studies have shown that supplementing pregnant women with n-3 LCPUFAs can modulate immune cell function and their responses in umbilical cord blood, typically characterized by inhibition of Th2-type responses, promotion of Th1 and Th2 balance, and enhancement of immune maturation (60, 63). Supplementation of pregnant women with n-3 LCPUFAs has been associated with reduced infants sensitivity to common food allergens, decreased risk and severity of atopic dermatitis during the first year of life, and reduced risk of persistent wheezing and asthma between the age of 3 and 5. Therefore, LCPUFAs play a critical role in the early prevention and management of allergic diseases.

LCFAs play a significant role in modulating the degree of inflammatory response in the body. In healthy individuals, the Firmicutes/Bacteroidetes (F/B) ratio is typically maintained within a relatively stable range. Studies have demonstrated that the F/B ratio is often decreased in patients with allergic diseases, reflecting an increased relative abundance of Bacteroidetes and a decreased relative abundance of Firmicutes (64–66). This alteration is closely associated with excessive immune response and inflammation. David Johane Machate reported that a high-fat diet enriched in LCFAs can increase the proportion of Firmicutes and Proteobacteria while decreasing the proportion of Bacteroidetes. Conversely, a diet rich in n-3-PUFAs can elevate the ratio of Bacteroidetes and Actinobacteria while reducing the ratio of Firmicutes and Proteobacteria, thereby mitigating inflammation. On the other hand, a diet abundant in n-6-PUFAs is linked to metabolic disorders such as obesity and inflammatory bowel disease (15).

The dietary intake of LCFAs may also influence the progression of allergic diseases. Research indicates that in the pathogenesis of allergic asthma, fatty acid binding protein 5 (FABP5) is regulated under IL-4/IL-13 stimulation, modulating the metabolism of LCPUFAs, particularly the accumulation of oleic acid. This process activates the PPARγ signaling pathway, promoting M2 macrophage polarization and exacerbating disease progression. Excessive intake of oleic acid may similarly worsen disease progression through this mechanism, suggesting a potential link between dietary fatty acids intake and the progression of asthma (67, 68).

LCFAs influence the balance of gut microbiotaand the progression of allergic diseases in the human body. Further investigation is required to elucidate the specific roles of LCFAs in allergic diseases and to explore their potential application in mitigating allergic reactions. Additionally, the significance of LCFAs in early immune system development and homeostasis, particularly regarding allergen sensitivity and allergic manifestations such as wheezing and asthma for LCPUFAs, warrants greater attention. Research suggests that LCPUFAs (typically a combination of EPA and DHA) confer immunomodulatory benefits during pregnancy, lactation, and infancy. However, the duration of these effects remains unclear. Therefore, clarifying the immunological and clinical impacts of LCPUFAs in infants and children, as well as the persistence of these effects, will provide valuable insights for future research directions.

The human body requires a diverse of vitamins to maintain normal physiological functions and overall health. Vitamins are organic compounds, including water-soluble vitamins (the B complex and vitamin C) and fat-soluble vitamins (vitamins A, D, E, and K). Some vitamins cannot be synthesized by the human body or are produced in insufficient quantities, necessitating their acquistion through dietary intake. Notably, vitamins K and certain B vitamins (e.g., vitamin B12) must be synthesized by specific bacteria, such as Lactobacillus, which participate in the biosynthesis of vitamins B and K.

Vitamins modulate immune responses by altering the balance of the gut microbiota and its environment. Studies have demonstrated that certain vitamins can promote the growth and proliferation of beneficial bacteria, such as Bifidobacteria and Akkermansia. For instance, vitamin C exhibits antioxidant properties, reducing oxidative stress in the intestines and creating a more favorable environment for the growth of beneficial bacteria. Components of the B-vitamin group, such as vitamin B1 (thiamine) and vitamin B6 (pyridoxine), function as coenzyme in bacterial metabolic processes, thereby promoting bacterial growth. Furthermore, certain vitamins can inhibit harmful bacteria, such as Escherichia coli. For example, the active form of vitamin D (1,25-dihydroxyvitamin D) possesses antibacterial effects, suppressing the growth of Escherichia coli (69), while the antioxidant properties of vitamin E reduce the survival capacity of harmful bacteria under oxidative stress. By influencing the balance of the gut microbiota, vitamin D indirectly regulates the immune system, thereby decreasing the risk of allergic diseases, including allergic airway diseases (69, 70).

The gut microbiota can also influence the absorption and utilization of vitamins. By modulating the intestinal micro-environment, such as pH levels and redox states, the gut microbiota can affect the efficiency of vitamin absorption. For instance, SCFAs produced by certain bacteria can reduce the pH of the intestines, thereby enhancing the solubility and absorption rate of specific vitamins. Additionally, the gut microbiota can promote vitamin production and utilization by metabolizing vitamin precursors. For example, certain bacteria species can convert dietary plant sterols into vitamin D precursors, thus facilitating vitamin D synthesis. The interaction between vitamins and the gut microbiota plays a crucial role in maintaining gut health and overall health. During allergic inflammation, the antibacterial properties of vitamin D and the regulatory effects of the gut microbiota can synergistically alleviate inflammatory symptoms. Adjusting vitamin intake and modulating the composition of the gut microbiota can serve as a strategy for preventing and treating allergic diseases. For example, supplementing with vitamin D and probiotics can optimize the structure of the gut microbiota, enhance the function of the intestinal mucosal barrier, prevent allergens from entering the bloodstream, and mitigate systemic allergic reactions.

In addition to influencing the gut microbiota, vitamin metabolism plays a critical role in the body's immune system and the synthesis of specific substances. Vitamin deficiency may lead to various diseases. The vitamin D receptor (VDR) and 1α-hydroxylase are expressed in various immune cells, including T lymphocytes, B lymphocytes, DCs, neutrophils, and monocytes. This enables these cells to produce calcitriol, the active form of vitamin D3 (71). Vitamin D can suppress the production of IgE, which is associated with allergic diseases, by inhibiting the Th2 response (72). Th2 cells play a crucial role in allergic reactions, as they promote IgE generation through the secretion of IL-4 and IL-13. These processes can be inhibited by vitamin D, thereby alleviating allergic reactions (73, 74). If vitamin D reduces IgE levels against specific allergens (e.g., dust mites), it can mitigate the intensity of asthma- related allergic reactions. Vitamin D can regulate the production of various cytokines, including reducing the secretion of pro-inflammatory cytokines such as IL-5, which play an important role in allergic reactions. By inhibiting the production of these cytokines, vitamin D helps reduce allergic inflammation (75). Multiple studies have shown that IL-5 levels are positively correlated with eosinophil counts and the degree of airway inflammation in asthma patients (76). Anti-IL-5 monoclonal antibodies (such as mepolizumab) have been used to treat severe eosinophilic asthma with significant efficacy (77). Vitamin D can reduce the cytotoxic release of eosinophils, such as the release of peroxidase and necrotic factors, which can cause tissue damage during allergic inflammation (78). Overall, vitamin D is considered to have anti-inflammatory effects. Research at Chang Gung University College of Medicine in Taiwan found a significant correlation between vitamin D-related metabolites (such as 3-hydroxyisobutyrate and glutamine) and metabolites related to allergic diseases (such as succinic acid and proline) (79). This correlation is not only highly significant statistically, but also has important biological implications. For example, glutamine plays a key role in regulating immune responses and maintaining intestinal mucosal integrity (80), while succinic acid directly promotes inflammation by regulating the signaling transduction and metabolism of immune cells; meanwhile, alanine indirectly regulates inflammation by affecting the function and metabolic state of T cells. This indicates that vitamin D may affect childhood allergic airway diseases by influencing gut microbiota and immune allergic reactions (81). Studies from the Fourth Military Medical University have demonstrated that obesity-related asthma, a special phenotype of asthma, is associated with vitamin D deficiency. Obesity may result in increased storage of vitamin D in adipose tissue, thereby reducing its circulating concentrations (82, 83). The risk of asthma is significantly elevated in obese individuals, and obesity-related asthma often exhibits poor responsiveness to conventional treatments, frequently accompanied by metabolic disturbance. Rapid weight gain during childhood represents the strongest predictor for the development of asthma. Multiple clinical studies have revealed that the serum vitamin D levels in obese asthmatic patients are inversely correlated with asthma symptom severity, with lower vitamin D levels being linked to more severe symptoms. Additionally, studies have indicated that obese asthmatic patients with lower vitamin D levels also tend to exhibit reduced lung function parameters, such as forced expiratory volume in one second (FEV1) and forced vital capacity (FVC), suggesting that vitamin D may play a role in modulating lung function (82, 84, 85). Research indicates that vitamin D levels are negatively correlated with the severity of symptoms of AR (86). Vitamin D supplementation may help alleviate symptoms of these allergic diseases and improve patients' quality of life (87). Other studies suggest that supplementing vitamin D during pregnancy may reduce the risk of children developing asthma and allergic diseases (88, 89). Although existing research indicates a link between vitamin D deficiency and an increased risk of allergic diseases, the correlation is not consistent across different populations. More research is needed in populations of varying ages, genders, races, and geographic regions to clarify the relationship between vitamin D deficiency and allergic diseases in the future.

Gut microbiota are capable of synthesizing and metabolizing a diverse array of amino acids, generating various biologically active metabolites. These metabolites play critical roles in the physiological and pathological processes of the host, including certain essential amino acids that the host is unable to synthesize autonomously (90).These amino acids are crucial for the host's energy metabolism. During amino acid metabolism, gut microbiota produce a range of metabolic products, such as SCFAs, ammonia, hydrogen sulfide, and others. These amino acids and their metabolites not only influence the survival and functionality of the gut microbiota themselves but also exert significant effects on the host's intestinal health, immune regulation, and metabolic homeostasis.

Metabolites derived from amino acid produced by the gut microbiota contribute to maintaining the balance of gut microbiota and the integrity of the intestinal mucosa. For example, fructooligosaccharides in the human intestinal tract cannot be degraded by digestive enzymes but can be fermented and utilized by the gut microbiota. Fructooligosaccharides promotes the growth of beneficial bacteria, such as Bifidobacteria and Lactobacilli, inhibits the proliferation of harmful bacteria, and enhances nutrients absorption in the intestines, thereby preserving the equilibrium of the gut microbiota (91, 92). Additionally, amino acid metabolites produced by the gut microbiota help sustain immune tolerance in the intestinal mucosa, preventing excessive immune responses. These metabolites strengthen tight connections between intestinal epithelial cells, improve the integrity of the intestinal barrier, and prevent the invasion of pathogens and harmful substances (93).

Bacteria-derived amino acids and their metabolic products can modulate the activity and function of immune cells. For instance, D-Tryptophan has been shown to decrease the production of Th2 cytokines and chemokines in both human peripheral immune cells and murine immune cells, thereby inhibiting the progression of allergic airway disease in mice (94). Additionally, tryptophan metabolities influence the balance between Th17 and Treg cells by activating AhR. Activation of AhR promotes Treg differentiation while suppressing Th17 differentiation, thus regulating immune responses and preventing allergic airway diseases such as asthma (91, 95). Furthermore, bacterial amino acids and their metabolites exhibit anti-inflammatory properties by inhibiting the production and release of pro-inflammatory factors, such as bacterial tryptophan metabolites (e.g., indole-3-propionic acid) inhibit NF-κB and reduce the release of pro-inflammatory factors through activation of the PXR/TLR4 pathway, which promotes the subsidence of inflammation and accelerates the repair and regeneration of tissues (96).

The gut microbiota are capable of metabolizing amino acids and generating a variety of metabolites, among which tryptophan metabolites play a particularly critical role. Given their importance in regulating immune responses and maintaining gut microbiota, tryptophan metabolites may serve as potential therapeutic for allergic diseases. Modulating the levels of tryptophan metabolites or their metabolic pathways could potentially alleviate the symptoms and improve the prognosis of allergic diseases.

Bile acids are primarily categorized into two types: primary bile acids and secondary bile acids. These amphiphilic molecules are derived from cholesterol, mainly synthesized in the liver, and secreted into the intestine via bile. In terms of immune regulation, bile acids modulte various physiological functions, including immune responses and the composition of the gut microbiota, by binding to specific receptors (97, 98).

Bile acids suppress allergic reactions by regulating immune cells through the activation of specific receptors. The Farnesoid X receptor (FXR) and G protein-coupled bile acid receptor (TGR5) are the primary receptors involved in this process (97). In food allergies, bile acids inhibit NF-κB activation by activating FXR, thereby reducing the production of pro-inflammatory cytokines such as TNF-α, IL-6, and IL-1β. Additionally, bile acids promote the secretion of anti-inflammatory cytokines, such as IL-10, by activating TGR5, exerting anti-inflammatory effects (95, 97, 99, 100). This mechanism promotes the differentiation of Tregs, inhibites the differentiation of Th2 cells, and consequently reduces allergic reactions. Research indicates that bile acids inhibit the maturation and activation of DCs by modulating retinoic acid signaling pathways within DCs, diminishing their antigen-presenting capacity and suppressing T cells activation. This process affects the sensitization process of food allergens. Changes in the bile acid profile induced by antibiotics can enhance retinoic acid signaling in mucosal DCs, thereby promoting the production of food allergen-specific IgE and IgG1 (101). The production of allergen-specific IgG1 and IgE is a hallmark of allergic responses.

Bile acids influence the intestinal environment through interactions with the gut microbiota. They promote the growth of beneficial bacteria, such as Bifidobacterium and Lactobacillus, while inhibiting the proliferation of harmful bacteria, including Escherichia coli. This modulation of the gut microbiota composition helps maintain microbial balance, reduce intestinal inflammation, and further prevent systemic allergic reactions (97). Additionally, bile acids enhance the expression of tight junction proteins, such as ZO-1 and claudin, on intestinal epithelial cells by activating the FXR. This process reduces intestinal permeability and prevents the occurrence of systemic allergic inflammation symptoms (51).

Bile acids play a clinically significance role in regulating immune responses and allergic diseases. By modulating diet or administering bile acid supplements, FXR and TGR5 can be activated, thereby suppressing inflammatory responses, alleviating symptoms of allergic diseases, and providing novel therapeutics strategies and targets for the management of these conditions (99).

In recent years, with the rapid advancement of urbanization and changes in lifestyle, there has been a significant increase in the incidence of allergic diseases. The WHO predicts that allergic diseases associated with industrialization and Western lifestyles will double in the future, potentially due to gut microbiota imbalance. In contemporary medicine and life sciences, research into gut microbiota imbalance and its role in the prevention of allergic diseases has gained increasing attention. Investigation the interactions between the microbiome, metabolome, and host, as well as their collaborative mechanisms in maintaining intestinal homeostasis, has become a critical factor in developing more convenient and efficient treatment methods, as well as enabling early disease prevention. With the advent of high-throughput sequencing technology, we have achieved a deeper understanding of the composition and diversity of gut microbiota. The extensive application of multi-omics technologies, including metagenomics, metatranscriptomics, metaproteomics, and metabolomics, enables us to study the interactions between gut microbiota and hosts at multiple levels. These studies provide a theoretical foundation for the development of diagnostic markers and therapeutic strategies based on gut microbiota.

In the context of personalized treatment, a randomized controlled trial (N = 1,591 participants) demonstrated that eight out of nine probiotics could alleviate at least one clinical symptom of allergic rhinitis. Furthermore, lactate, ornithine, and six additional metabolites were identified as potential predictors of the efficacy of sublingual immunotherapy for allergic rhinitis. These metabolites regulate metabolic pathways, modulate immune system function, and mitigate symptoms of allergic rhinitis. Conversely, another double-blind randomized controlled study revealed that a probiotic mixture did not exhibit significant therapeutic effects on moderate to severe atopic dermatitis in children. Regarding the overall treatment process for allergic diseases, probiotics can alleviate allergy symptoms, reduce medication usage, and lower medical expenses. However, prolonged use may increase costs. Metabolite supplementation can enhance treatment effectiveness, decrease disease recurrence, and reduce long-term medical expenses. Nevertheless, the high cost of metabolite supplements may also lead to increased treatment expenses.

Notwithstanding these findings, there are notable limitations in the gut microbiota research. Significant inter-individual variability in gut microbiota communities limits the generalizability of research findings. Therefore, mother-infant cohort studies and cross-regional, multi-center collaborations are essential for addressing these generalizability issues. Individual genetic background, dietary habits, lifestyle, and environmental factors all influence the composition and function of the gut microbiota, adding complexity and challenges to the research. Currently, most studies can only establish correlations between gut microbiota and disease, making it difficult to determine causation. Although some intervention studies (e.g., probiotics, prebiotics, fecal microbiota transplantation) offer insights into causal relationships, these studies often suffer from small sample sizes and lack of long-term follow-up, hindering definitive conclusions. The interaction between gut microbiota and the host is a complex process influenced by multiple factors, involving systems such as the immune, metabolic, and nervous systems. Current research often focuses on single factor or pathway, which makes it challenging to comprehensively elucidate the intricate interactive mechanisms between gut microbiota and the host.

Therefore, future research should place greater emphasis on individual differences and actively pursue personalized investigations based on individual characteristics. By integrating multiple-omics datasets, incorporating individual genetic, dietary, lifestyle information, and constructing personalized gut microbiota models, a foundation for precision diagnosis and treatment can be established. Through the application of advanced experimental designs and analysis methods, such as randomized controlled trials and causal inference analyses, further exploration of the causal relationship between gut microbiota and diseases can be achieved. Simultaneously, combining animal models with clinical studies will help validate the reliability and reproducibility of these causal relationships. Based on findings regarding the relationship between gut microbiota and diseases, novel intervention strategies have been developed, including personalized probiotics formulations, prebiotics, fecal microbiota transplantation, and microbiota-derived metabolic products. Their safety and efficacy can be confirmed through rigorous clinical trials, providing new avenues for diseases prevention and treatment. Long-term follow-up studies should be conducted to monitor the dynamic changes in gut microbiotacommunities and their impact on host health and diseases progression. Through continuous monitoring and data analysis, the long-term associations between gut microbiota communities and disease development can be elucidated, offering a basis for early warning and intervention strategies. In conclusion, while significant advancements have been made in the study of gut microbiota and metabolites, numerous challenges remain. Future research should aim to uncover the specific mechanisms underlying the roles of gut microbiota and metabolomics in allergic diseases, develop personalized treatment plans, and enhance the effectiveness of disease management.