Prebiotics, probiotics and synbiotics in human health

Introduction

Since the beginning of the 21st century, the composition and functionality of the intestinal microbiota have gained significant attention within the scientific community. In comparison to microbial populations inhabiting other regions of the human body, the gut microbiota is markedly more abundant and exhibits greater diversity and complexity. In adults, the colon harbors an estimated 3.9 × 10¹³ microbial cells, a quantity that slightly exceeds the total number of human somatic and germ cells. This dense and diverse microbial ecosystem plays a critical role in maintaining host physiological homeostasis [36] . The intestinal microbiota plays a vital role in the digestion and metabolism of dietary components and contributes to a wide range of systemic physiological processes in the host, thereby exerting a significant influence on overall human health. Based on their functional effects on the host, gut microorganisms can be broadly classified into three groups: beneficial microorganisms (probiotics), commensal or neutral bacteria, and pathogenic microorganisms [16] . In healthy individuals, these microbial populations coexist in a state of dynamic equilibrium, where mutual competition and regulatory interactions contribute to the maintenance of intestinal homeostasis. The gastrointestinal tract, often referred to as the "second brain" due to its extensive neural network and regulatory functions, plays a pivotal role in overall health. The intestinal microbiota engages in complex interactions with the host, facilitating the digestion and absorption of nutrients, biotransformation and detoxification of intestinal metabolites, and the synthesis of essential bioactive compounds. These include amino acids, vitamins, and short-chain fatty acids (SCFAs), which are critical for maintaining physiological functions and metabolic balance [8] .

Disruption of the intestinal microbiota, commonly referred to as dysbiosis, can adversely impact host health and is associated with the development of various disorders, including obesity, diabetes mellitus, irritable bowel syndrome, and colorectal cancer [48] . Therefore, the maintenance of microbial homeostasis within the gut is essential for preserving normal physiological function and preventing disease. Therefore, to maintain a balanced and functionally stable intestinal microbiota, it is essential to employ external interventions aimed at modulating microbial composition, particularly by enhancing the abundance of beneficial microorganisms while suppressing the proliferation of pathogenic species. Probiotics are defined as viable microorganisms that confer health benefits to the host when administered in adequate amounts. These beneficial microbes contribute to the modulation of the intestinal microbial community by promoting a favorable microbial balance and inhibiting the establishment and proliferation of pathogenic organisms within the gut. Furthermore, probiotics play a significant role in maintaining intestinal integrity by supporting the formation of a protective mucosal barrier, enhancing epithelial barrier function, and modulating immune responses, thereby improving overall host immunity [45] . Based on the functional attributes of probiotics, it is essential to elucidate their mechanisms of action within the host and to develop strategies that facilitate their survival, proliferation, and metabolic activity in the gastrointestinal environment (Fig 1). The proliferation and metabolic activity of probiotic microorganisms are significantly influenced by the presence of prebiotics. Prebiotics are selectively fermentable dietary components, predominantly non-digestible polysaccharides, that resist digestion in the upper gastrointestinal tract and are subsequently utilized by beneficial gut microbiota. Through this selective utilization, prebiotics stimulate the growth and activity of advantageous microorganisms within the host [23] . Prebiotics play a significant role in modulating immune function, enhancing resistance against pathogenic microorganisms, and influencing host metabolic processes. Additionally, they facilitate the absorption of essential minerals and contribute to the overall improvement of host health and physiological well-being [29] . Prebiotics generally encompass a diverse group of bioactive substrates, including polysaccharides, oligosaccharides, microalgal derivatives, and compounds derived from natural plant sources. These substances are widely distributed across various biological materials. In recent years, novel prebiotic candidates have been increasingly identified in sources such as algae, fruit juices, fruit peels, seeds, traditional medicinal plants, and microbial systems. These emerging prebiotics predominantly comprise complex biomolecules, including polysaccharides, polyphenolic compounds, and polypeptidebased polymers, which contribute to their functional properties Most earlier research has focused on elucidating the healthpromoting effects of prebiotics and probiotics [25] . However, comprehensive, systematic investigations addressing the diversity of prebiotics and probiotics, their mechanisms of action, and their interactions remain limited. Accordingly, this study presents an extensive overview of commonly recognized prebiotics, along with emerging sources and their functional roles within the intestinal environment. It further examines the classification, functional attributes, and practical applications of probiotics, with particular emphasis on elucidating their mechanisms of action in the host.

Mechanisms of action of prebiotics

Prebiotics serve as fermentable substrates for beneficial gut microorganisms, leading to the generation of metabolites such as short-chain fatty acids (SCFAs). These bioactive compounds play a crucial role in maintaining intestinal homeostasis and exert systemic physiological effects beyond the gastrointestinal tract [26] . Elucidating the precise mechanisms through which prebiotics improve gastrointestinal health and mitigate the risk of various digestive disorders and associated comorbidities is essential for fully harnessing their therapeutic potential. Prebiotics, including inulin, fructo-oligosaccharides (FOS), and galacto-oligosaccharides (GOS), are non-digestible dietary fibers that resist enzymatic digestion in the upper gastrointestinal tract and are delivered intact to the colon, where they undergo selective fermentation by the resident microbiota [21] . These non-digestible fibers function as selective substrates for beneficial gut microorganisms, including probiotic genera such as Lactobacillus and Bifidobacterium. Through this targeted utilization, prebiotics facilitate the growth, colonization, and metabolic activity of these advantageous microbes, thereby contributing to the maintenance of a balanced intestinal microbiota [24] . Short-chain fatty acids (SCFAs) generated through the microbial fermentation of prebiotics contribute to a reduction in intestinal pH, typically from approximately 6.5 to around 5.5. This acidification of the gut environment inhibits the proliferation of pathogenic microorganisms while favoring the growth and metabolic activity of beneficial bacteria that are well adapted to such conditions. Consequently, this shift in the intestinal milieu supports the maintenance of microbial balance and overall gut health [34] . In a study conducted by [47] , substrates including inulin, lactose, galacto-oligosaccharides (GOS), and fructooligosaccharides (FOS) were evaluated using an in vitro colon model to investigate the influence of pH gradients, representative of physiological colonic conditions, on gut microbiota composition and metabolite production. The findings demonstrated that lower pH conditions significantly altered microbial composition, characterized by an increased relative abundance of Bifidobacterium spp. and a reduction in Bacteroides spp. Furthermore, short-chain fatty acid (SCFA) production was modulated by higher simulated colonic pH in a manner dependent on both the microbial donor and substrate type. Elevated pH conditions enhanced butyrate production from inulin fermentation, accompanied by an increased abundance of butyrate-producing bacteria such as Butyricimonas. Additionally, higher colonic pH levels were associated with increased relative abundances of Phascolarctobacterium, Bacteroides, and members of the Rikenellaceae family, along with enhanced propionate production when GOS and FOS were utilized as substrates. The gut-associated lymphoid tissue (GALT) constitutes a critical component of the host immune system. Prebiotics promote the proliferation of beneficial gut microbiota, which interact with GALT and contribute to the modulation and regulation of immune responses [38] . This interaction facilitates the maintenance of immune homeostasis and attenuates inflammatory responses through the regulation of immune activity within the intestinal environment [50] . Within the intestinal environment, short-chain fatty acids (SCFAs) play a significant role in modulating immune responses. They promote immune tolerance and regulate the activity of immune cells, particularly regulatory T cells (Tregs). Through these immunomodulatory effects, SCFAs contribute to the maintenance of gut homeostasis and support overall immune function [28] . Prebiotics contribute to the preservation of intestinal barrier integrity by promoting the proliferation of beneficial microbiota, which stimulate the production of key structural components such as tight junction proteins and mucins [29] . Tight junction proteins play a critical role in maintaining epithelial integrity by sealing intercellular spaces, thereby preventing the translocation of pathogens and harmful substances into the systemic circulation. Mucins, on the other hand, form a protective mucus layer over the intestinal epithelium, providing an additional barrier against luminal insults. Colonocytes, the epithelial cells of the colon, primarily derive their energy from short-chain fatty acids (SCFAs), particularly butyrate. By serving as an energy source, SCFAs support epithelial cell metabolism, promote mucosal regeneration, and contribute to the maintenance of intestinal barrier integrity [12] . Prebiotics have been shown to enhance the functional activity of key immune cells, including phagocytes and lymphocytes, which play essential roles in the recognition and elimination of pathogenic microorganisms [27] . Prebiotics facilitate the functional activity of immune cells by promoting the proliferation of beneficial microbiota and modulating host immune responses. Through these mechanisms, they enhance the host's defense against infections and contribute to the maintenance of intestinal health [2] . Short-chain fatty acids (SCFAs), generated through the microbial degradation of prebiotics in the intestine, also play a significant role in supporting and modulating the host immune defense system [39] , reported that prebiotic interventions exert differential effects in individuals with non-alcoholic fatty liver disease (NAFLD) and in obese patients who have undergone gastric bypass surgery, proposing several mechanistic hypotheses based on molecular and biochemical pathways. Specifically, the partial fermentation of non-digestible carbohydrates into short-chain fatty acids (SCFAs), along with a reduction in endogenous intestinal alcohol production, may contribute to a decreased risk of NAFLD progression, primarily through improvements in insulin sensitivity.Prebiotics indirectly suppress the proliferation of pathogenic microorganisms by promoting the growth and metabolic activity of beneficial gut microbiota, thereby contributing to a competitive and inhibitory intestinal environment [35] . Within the intestinal environment, beneficial microorganisms compete with pathogenic bacteria for available nutrients and occupy adhesion sites on the epithelial surface. This competitive exclusion limits the attachment, colonization, and subsequent proliferation of pathogenic organisms [33] .

Health benefits of Prebiotic

Prebiotics are beneficial microorganisms that help maintain a balanced intestinal microbiota by inhibiting the growth of harmful pathogens. Prebiotics, such as inulin, Lactulose galactooligosaccharides, arabinoxylan, resistance starch, pectin and betaglucans (Fig 2 ), serve as selective substrates that promote the growth of these beneficial microbes (Fig 2 ). They play a crucial role in improving digestive health, enhancing nutrient absorption, and strengthening the intestinal barrier. Additionally, probiotics support immune function by modulating immune responses, thereby contributing to overall health and reducing the risk of various gastrointestinal and metabolic disorders, as shown in Table 1. Helps relieve constipation while promoting better gut health [7] Soy Oligosaccharides

Promotes the growth of Lactobacilli and Clostridia while inhibiting Bifidobacterium and Bacteroides

Enhances the production of acetate, lactate, propionate, butyrate, and branchedchain fatty acids (BCFAs) Promotes better lipid metabolism and strengthens immune function. [11] Type 3 Resistant Starch Specifically promotes the proliferation of Bifidobacteria.

Elevates acetate and butyrate production

Supports colonocyte health, reduces inflammation, and may lower the risk of colorectal cancer.

Synbiotics

The concept of prebiotics was first introduced by [14] , also proposed the potential for combining prebiotics and probiotics to form synbiotics [14] . Subsequently, synbiotics were classified into two major categories based on their functional interactions: complementary and synergistic synbiotics, as described [19] . Complementary synbiotics consist of probiotics and prebiotics selected independently,

where each component exerts distinct physiological effects or health benefits. In such systems, the prebiotic is not necessarily selectively utilized by the probiotic strain and may instead be metabolized by other members of the gastrointestinal microbiota. Consequently, the probiotic organism may not gain a competitive ecological advantage and, in some cases, may not be capable of fermenting the substrate. Therefore, the overall effect of complementary synbiotics is typically additive, reflecting the independent contributions of each component [19] . In contrast, synergistic synbiotics are specifically formulated so that the prebiotic substrate selectively enhances the growth and metabolic activity of the coadministered probiotic strain [19] . This targeted interaction promotes improved survival, colonization, and functional efficacy of the probiotic within the gut environment. Unlike complementary synbiotics, these formulations do not depend on the presence of other microbial populations capable of fermenting the prebiotic substrate. Furthermore, considering the well-established inter-individual variability in gut microbiota composition and response to dietary interventions [37] , synergistic synbiotics provide a significant advantage by reducing non-responder outcomes. By delivering both the probiotic strain and its specific growth substrate simultaneously, they enhance the consistency and effectiveness of microbiota modulation.

Health benefits releated to synbiotics

Synbiotics, a combination of probiotics and prebiotics, provide enhanced health benefits by synergistically improving the growth and activity of beneficial gut microorganisms. They help restore microbial balance, promote the production of short-chain fatty acids, and improve digestive health. Additionally, synbiotics strengthen the intestinal barrier, support immune function, and reduce inflammation, thereby contributing to overall gut health and lowering the risk of various metabolic and gastrointestinal disorders (Table 2). Short-chain fatty acid production Enhanced fermentation producing acetate, propionate, butyrate Improved colon health and energy metabolism [42] Digestive health Improved gut motility and microbial activity Relief from constipation and better digestion [10] Immune system support Modulation of gut-associated lymphoid tissue (GALT) Enhanced immune response and reduced infections [4] Gut barrier function Strengthening of intestinal epithelial integrity Reduced intestinal permeability [18] Anti-inflammatory effects Reduction in pro-inflammatory cytokines Lower inflammation and improved gut health [31] Lipid metabolism Regulation of cholesterol metabolism Reduced serum cholesterol levels [1] Glycemic control Modulation of glucose metabolism and insulin sensitivity Improved blood glucose regulation [46] Colon health Increased butyrate production and colonocyte nourishment Reduced risk of colorectal disorders [13] Pathogen inhibition Competitive exclusion and antimicrobial compound production Reduced growth of harmful bacteria [30] Commercial Synbiotics: Challenges, Limitations, and Future Perspectives By 2018, the global probiotic market was projected to surpass USD 40 billion, while the prebiotic sector was expected to approach USD 5 billion, reflecting substantial commercial growth and consumer interest [5] Despite this expansion, significant scientific and industrial challenges persist, particularly in establishing robust clinical evidence to substantiate health benefits [40] . A major limitation identified is the difficulty in demonstrating consistent clinical efficacy, further complicated by variations in regulatory requirements for health claims across different regions [41] . At present, neither the European Food Safety Authority (EFSA) nor the United States Food and Drug Administration (FDA) has approved specific health claims for probiotic or synbiotic formulations. Regulatory classification also presents a challenge, as such products may be categorized either as foods or pharmaceutical agents depending on their intended use [15] . According to FDA guidelines, any substance, including probiotics, intended for the prevention, treatment, or diagnosis of disease is regulated as a drug and must comply with stringent pharmaceutical approval processes. Similarly, European Union regulations mandate that health claims must be scientifically substantiated, clear, and not misleading to consumers [41] . Consequently, well-designed human intervention studies are essential to validate the efficacy of these products. Synbiotic formulations are commonly incorporated into food matrices, particularly fermented dairy and non-dairy products. While prebiotics are generally stable and compatible with a wide range of food applications, the viability of probiotics is often compromised by environmental factors such as temperature, oxygen, and processing conditions, thereby limiting their use in nonrefrigerated products (Saulnier, 2008). Advances in microencapsulation technologies, however, have shown promise in enhancing the stability and survival of probiotic microorganisms during processing and storage. These innovations may facilitate the development of novel synbiotic products, including confectionery, beverages, dairy products, and chocolate-based systems [20] . It is noteworthy that many commercially available prebiotic and synbiotic products contain relatively low concentrations of prebiotic components, which may be insufficient to elicit significant physiological effects. Such low inclusion levels are often employed to minimize gastrointestinal discomfort and reduce production costs [9] . The formulation of clinically effective synbiotic combinations remains complex and requires careful consideration of several factors. Determination of the minimum effective dose for both probiotic and prebiotic components is essential. Additionally, the design of clinical trials should incorporate appropriate controls, including placebo, probiotic-only, and prebiotic-only groups, to accurately assess additive or synergistic effects. Clear justification for the selection and pairing of probiotic strains with specific prebiotic substrates is also necessary. Furthermore, establishing causality requires precise detection, quantification, and monitoring of the administered probiotic strain within the gastrointestinal tract.

Comprehensive evaluation of changes in gut microbiota composition is equally important to understand underlying ecological interactions, such as cross-feeding, niche competition, niche partitioning, and exclusion phenomena within the resident microbial community.

Future Perspectives on Sustainable Prebiotics, Probiotics, and Synbiotics

The future development of prebiotics, probiotics, and synbiotics is increasingly driven by the need for sustainability, innovation, and personalized nutrition. These functional components are gaining attention as eco-friendly and health-promoting alternatives to synthetic additives and antibiotics, aligning with global efforts to promote sustainable food systems and improve public health. Their integration into dietary and therapeutic strategies offers significant potential to enhance gut health while minimizing environmental impact.One of the most promising areas is the utilization of sustainable and low-cost sources for prebiotic production. Agricultural by-products, food processing residues, fruit peels, and algal biomass are being explored as novel substrates for extracting prebiotic compounds. This approach not only reduces food waste but also supports the development of a circular bioeconomy by converting underutilized resources into valuable functional ingredients. Such innovations are expected to improve the economic feasibility and large-scale production of prebiotics.In the field of probiotics, future research is focused on the development of next-generation probiotics (NGPs), which include newly identified microbial strains with specific health benefits. Advances in omics technologies, such as genomics and metagenomics, are enabling the identification of targeted probiotic strains with enhanced functional properties. These developments will facilitate the design of precision probiotics tailored to individual gut microbiota profiles, thereby improving their efficacy and consistency in different populations.Synbiotics are expected to play a central role in future microbiomebased interventions due to their synergistic effects. The rational design of synbiotic formulations, where specific prebiotics are paired with compatible probiotic strains, will enhance microbial survival, colonization, and metabolic activity. This targeted approach can help overcome interindividual variability in gut microbiota composition and improve therapeutic outcomes.Technological advancements, such as microencapsulation and controlled-release delivery systems, will further support the stability and viability of probiotics during processing and storage. These innovations will enable the incorporation of synbiotics into a wider range of food products, including plant-based and nonrefrigerated systems.Additionally, the application of prebiotics, probiotics, and synbiotics in sustainable agriculture and animal nutrition is gaining importance. Their use as alternatives to antibiotics in livestock can improve animal health, reduce antimicrobial resistance, and contribute to environmentally sustainable farming practices.

Conclusion

The intestinal microbiota is a complex and essential component of human health, playing a key role in metabolism, immune regulation, and maintenance of gut integrity. An imbalance in this microbial ecosystem (dysbiosis) is associated with various chronic diseases, highlighting the need for effective strategies to maintain microbial homeostasis.Probiotics and prebiotics serve as important tools for modulating gut microbiota. Probiotics enhance microbial balance and immune function, while prebiotics selectively stimulate the growth of beneficial bacteria and promote the production of short-chain fatty acids (SCFAs), which support gut health and metabolic functions.Synbiotics, combining both probiotics and prebiotics, offer a more effective approach by improving probiotic survival and activity. However, challenges such as limited clinical evidence, regulatory issues, and stability of formulations still exist.Future research should focus on welldesigned clinical studies and advanced technologies to optimize synbiotic formulations. Overall, prebiotics, probiotics, and synbiotics hold significant potential for improving gut health and preventing disease

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