The wide range of small molecules that bacteria make due to their metabolic processes are called bacterial metabolites. These molecules are essential to many different biological interactions and activities. Although they are not directly involved in core metabolic pathways, secondary metabolites frequently support the competitiveness, adaptation, and survival of bacteria. Secondary metabolites are typically generated during particular stages of growth or in response to stress. It has been discovered that secondary metabolites contain antibacterial, anti-inflammatory, and anti-aging properties (Demain and Vaishnav, 2011). Antitumor, cholesterol-lowering, immunosuppressive, antiprotozoal, antihelminth, antiviral, and anti-ageing properties are some of these alternative uses. Bacterial-derived metabolites have the potential to be immunoactive agents, but there are several challenges associated with their use (Arun et al., 2022). The complex interactions between immune cells and microbial metabolites must be better understood to harness their immunomodulatory effects completely (Uchimura et al., 2018).

The potential for systemic side effects and the need to modulate the local microbiota further complicate using bacterial-derived metabolites as immune active agents (Garrett, 2020). The human gut harbors a vast population of microbes that produce secondary metabolites, which have been shown to influence human health by modulating metabolism, immune function, and the nervous system. The human gut microbiota and humans have a symbiotic relationship, which indicates that the metabolites these microorganisms produce, as well as their presence are essential to the host’s health (Afzaal et al., 2022). Gut dysbiosis directly and negatively affects host homeostasis because certain gut microorganisms are responsible for the bioavailability of certain metabolites (Krishnamurthy et al., 2023). Particularly, a few metabolites derived from the microbiota regulate populations of adaptive immune cells like Th17 and Treg cells. This influences immune regulation and plays a role in immune-related or immune-mediated diseases. Scaling up production for commercial use demands optimization of fermentation processes and improvements in yields, making it imperative to address these knowledge gaps and technical intricacies to successfully apply microbial metabolites across various industries (O’Brien and Wright, 2011). Moreover, the chemical complexity of microbial secondary metabolism presents challenges in studying and manipulating these metabolites effectively, requiring a deeper understanding of synthesis pathways and regulation. While bacterial derived metabolites hold promise as immunoreactive agents, further research is needed to overcome these challenges and fully exploit their therapeutic potential.

Common commensal microorganisms that can synthesize natural substances with anti-inflammatory and immunomodulatory effects include Lactobacilli, Bifidobacteria, Bacteroides fragilis, E. coli, and Bacillus sp. Pro-inflammatory cytokines like IL-1β, IL-6, and TNF-α are involved in pathological pain processes. Natural compounds from microorganisms have the potential to modulate cytokines and inhibit inflammation. These natural compounds including omega-3 fatty acids, cyclic peptides, and antimicrobial peptides offer anti-inflammatory effects that can be easily incorporated into diets without adverse effects ( Table 1 ).

Examples such as exopolysaccharides, peptide bacteriocin, polycyclic peptide bacteriocin (nisin), and short-chain fatty acids (SCFAs) are proposed for treating conditions like atherosclerosis, orthopedic postoperative infections, and mycobacterium tuberculosis infection (Jenab et al., 2020). Bacterial compounds are crucial in inducing immunomodulation and boosting the immune system. Lipoamino glycosides can improve immunotherapies by promoting antitumor immune cell activity (Colombani et al., 2019). Notable examples of immunomodulatory compounds include lipopolysaccharide and lipid A (Le Garrec, 1986; O’Brien and Wright, 2011). These compounds, particularly Lipid A and its analogs, exhibit immunomodulatory effects such as adjuvant activity, enhancing immune responses, and immunostimulation. Bacterial derived lipopolysaccharide and Lipid A are well-studied immunomodulatory substances; research is being done on synthetic versions. Additionally, synthetic derivatives of gram-negative bacterial cell walls activate immune responses, serving as immunoadjuvants to enhance vaccine effects. Furthermore, meta-MAMP (Microbe-Associated Molecular Patterns) like rapamycin and soraphen A can modulate T cell fate and function by targeting key metabolic pathways triggered during T cell activation. Recent research indicates that microbial products such as short-chain fatty acids and metabolites like retinoic acid may also play a significant role in controlling the functional specialization of Tregs (Hoeppli et al., 2015).

Cyclosporin A was initially found as a fungus-produced substance with antifungal properties. However, its discovery as an immunosuppressant led to its use in organ transplants. Although successful, newer and more potent immunosuppressants, FK-506 and rapamycin, were developed, offering better results with fewer side effects. These drugs interact with a specific protein inside cells, disrupting the signals that activate immune responses. Another immunosuppressant, mycophenolic acid, derived from an old antibiotic, has been developed for use after being initially discovered in 1896. It was found effective for treating psoriasis before being approved as an immunosuppressant (Demain, 1999). Microbial metabolites bidirectionally promote tolerance and immunity to effectively fight infection without developing inflammatory diseases. Numerous metabolites produced by bacteria that have immunomodulatory properties have been found. The actinobacteria Streptomyces calvus, are prolific sources of secondary metabolites with immunomodulatory effects on cytokine gene expression (Mahmoudi et al., 2016). Monophosphoryl lipid A, a safe lipidic derivative from bacteria, has been accepted as an adjuvant in humans and has demonstrated potential in enhancing immunotherapies (Colombani et al., 2019). Similar immunomodulatory agents are released by Staphylococcus aureus biofilm and planktonic cultures, encouraging leukocytes to generate cytokines and other immune responses (Sadowska et al., 2013). It has also been discovered that certain antibiotics, including spergualin, neothramycin, mazethramycin, aclacinomycin, and oxanosine, have immunomodulatory properties (Ishizuka et al., 1995). The polysaccharides, exopolysaccharides, capsular polysaccharides, selenium-exopolysaccharide, mannosyl‐oligosaccharides, glucooligosaccharides, oligosaccharides, and fructooligosaccharides offer immunomodulatory effects were summarized in Table 2 .

Since its discovery, numerous studies have highlighted the role of microbiota in health and diseases. Microbiota can be divided into four categories: gut, oral, respiratory, and skin microbiota, depending on the specific areas (Hou and Majumder, 2021). The microbiota significantly shapes the host immune system, affecting how it is trained, activated, and functions. As a result, the immune system has developed to coexist harmoniously with these various microorganisms. This partnership makes it possible to mount defences against infections and to regulate tolerance to harmless antigens (Belkaid and Hand, 2014). Major groups of microbial metabolites include carbohydrate metabolites, amino acid and related metabolites, and lipid and bile acid metabolites ( Figure 2 ). Bacteria in our digestive tract convert carbohydrates into SCFAs, such as butyrate, propionate, and acetate. The non-digestive carbohydrates such as non-starch polysaccharides (NSPs), resistant oligosaccharides, and starch are used as substrates by colonic microbes, transforming them into various metabolites including SCFAs (Cronin et al., 2021). The insoluble NSPs, such as cellulose and hemicellulose, are effective laxatives. In contrast, soluble NSPs, such as mixed-link beta-glucans, reduce plasma cholesterol levels and help normalize blood glucose and insulin levels. Polysaccharides such as these can be incorporated into dietary plans to treat cardiovascular disease and type 2 diabetes (Kumar et al., 2012). In particular, short-chain fatty acids promote effective large bowel function and promoting health.

Soluble fibers and resistant starches are fermented to produce these (butyrate, propionate, and acetate) advantageous fatty acids. The capacity of different gut bacteria to produce SCFAs varies. After being created, SCFAs are taken up by gut cells and other cells, where they interact with particular surface receptors. These receptors, like GPR43 and GPR41, are responsible for the various effects SCFAs have on our bodies (Henrissat, 1991). They are important energy sources for colonocytes, affect the function of the epithelial barrier, and control both innate and adaptive immune cells (Parada Venegas et al., 2019). As tumor suppressors, SCFAs promote intestinal epithelial cell growth, impede histone deacetylase (HDACs) activity, and cause the differentiation and apoptosis of cancer cells. SCFAs can encourage the hyperproliferation of some colon epithelial cells, which may contribute to the development of tumors, so caution is advised. Mucin production, barrier integrity, and epithelial cytokine production are all positively impacted by SCFAs. They control the functional activities of dendritic cells (DCs), macrophages, and neutrophils. Additionally, SCFAs enhance the populations of regulatory and effector T-cells by promoting B-cell production of antibodies and modulating T-cell differentiation. However, depending on concentration, organ, and host state, SCFAs can also elicit inflammatory responses despite their positive effects. SCFAs are essential for immune regulation and inflammation (Sakata and Von Engelhardt, 1983). Gut bacteria break down leftover proteins from our diet, producing various metabolites. These include branched-chain SCFAs, ammonia, and biogenic amines. Particularly, the metabolism of tryptophan produces indole, which can activate cellular pathways such as AhR and PXR (Macfarlane et al., 1988).

Aryl hydrocarbon receptor (AhR) activation is a major function of major indole derivatives derived from tryptophan or plant-derived glucobrassicin in the immune regulatory functions of amino acid and indole-related metabolites. AhR reacts to a variety of natural and artificial substances, affecting immune responses that are modulated by environmental pollutants as well as those that are controlled by dietary factors. AhR translocate to the nucleus upon ligand binding and forms a complex with AhR nuclear translocator. The xenobiotic responsive element in genes that code for immune-regulatory molecules or toxicant-modifying enzymes is bound by this complex. Many genes, such as those for CYP450 1A1, IDO, IL-10, Aiolos, FoxP3, IL-21, and CD39, are regulated by AhR. The way that AhR ligands affect T-cell responses is complex, depends on different cell types and factors, and isn’t always the same as how AhR functions in immune responses as a whole (Apetoh et al., 2010). Polyamines have anti-inflammatory properties and control transcription, translation of proteins, responses of stress proteins, and cellular metabolism. They help to repair tissue damage while suppressing inflammatory T-cells, cytokine production, and nitric oxide (NO). It is still unknown, though, how gut microbiota-derived polyamines cross the gut barrier to control immune cells at the molecular level (Keough et al., 2011).

Through enzymatic processes, gut bacteria modify bile acids and dietary lipids. New molecules are produced by these reactions, such as secondary bile acids and hydroxy fatty acids. It’s interesting to note that these bacterial metabolites are more than just waste materials; they can also interact with particular cell receptors like FXR, VDR, PXR, and TGR5. These receptor interactions play a crucial role in regulating various cellular processes within our body (Polan et al., 1964; Kishino et al., 2013). Although bile acids have anti-inflammatory properties and are important in cholestatic and metabolically driven inflammatory diseases, long-term exposure to high levels of bile acids can cause cancer and inflammation. Secondary bile acids control the immune system through receptors like TGR5, FXR, and PXR, such as lithocholic acid and deoxycholic acid. Animals with more severe colitis exhibit deficiencies in these receptors, indicating a potential function for these receptors in immune tolerance promotion. TGR5 ligands inhibit nuclear factor kappa B (NF-κB) by inducing cAMP synthesis, suppressing TNF-α production, and phosphorylating c-Fos. The NF-κB is a transcription factor that plays a role in many biological processes, including immune response and inflammation. Additionally, DCs produced by TGR5 ligands produce less IL-12 (Gerard, 2013; Kishino et al., 2013).

Metagenomics is a new player in this field, which combines mass spectrometry-based metabolomics research with genome sequencing and automated gene cluster annotation. The discovery of previously unidentified physiologically active compounds resulted from research focusing on the relationship between genes and metabolites or metabolites and genes. Identifying new secondary metabolites and concurrent redesign of established biosynthetic pathways to improve the synthesis of novel compounds will be aided by integrating genes to secondary metabolites and secondary metabolites to genes employing a forward or retro-biosynthetic approach. The immune regulatory roles of specific metabolites in health and disease need to be further investigated. More importantly, it is still unclear how the combination of these microbial metabolites affects the host immune system. In addition, research on the relationship between altered gut microbial metabolite composition and immune responses and particular diseases is necessary to find pathological condition biomarkers. In conclusion, despite the potential that bacterial metabolites have as immunomodulators and for the treatment of immune-related illnesses, several obstacles and restrictions prevent their broad application. These include the intricacy and diversity of bacterial metabolites, our incomplete knowledge of their mechanisms of action, problems with their stability, production, and purification, as well as safety, immune tolerance, and off-target effects concerns. To overcome these challenges and fully realize the therapeutic potential of bacterial metabolites in precision medicine approaches for immune-related disorders, collaborative interdisciplinary research efforts are essential.