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Full Terms & Conditions of access and use can be found at https://www.tandfonline.com/action/journalInformation?journalCode=ijds20 Journal of Dietary Supplements ISSN: (Print) (Online) Journal homepage: www.tandfonline.com/journals/ijds20 Prebiotics, Probiotics and Postbiotics: The Changing Paradigm of Functional Foods Naveen Kango & Suresh Nath To cite this article: Naveen Kango & Suresh Nath (16 Jun 2024): Prebiotics, Probiotics and Postbiotics: The Changing Paradigm of Functional Foods, Journal of Dietary Supplements, DOI: 10.1080/19390211.2024.2363199 To link to this article: https://doi.org/10.1080/19390211.2024.2363199 Published online: 16 Jun 2024. 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However, while the new probiotics are being added to the list, more recently, the nature and role of their counterparts, viz. prebiotics, postbiotics and parabiotics have also drawn considerable attention. As such, intricate relationships among these gut-biotics vis-à-vis their role in imparting health benefits is to be delineated in a holistic manner. Prebiotic dietary fibers are selectively fermented by probiotics and promote their colonization in the gut. the proliferation of probiotics leads to production of fermentation by-products (postbi- otics) which affect the growth of enteropathogens by lowering the pH and producing inhibitory bacteriocins. After completing life-cycle, their dead remnants (parabiotics e.g. exopolysaccharides and cell wall glycoproteins) also inhibit adhesion and biofilm formation of patho- gens on the gut epithelium. these beneficial effects are not just endemic to gut but a systemic response is witnessed at different gut-organ axes. thus, to decipher the role of probiotics, it is impera- tive to unravel the interdependence between these components. this review elaborates on the recent advancements on various aspects of these gut-biotics and the mechanism of potential attributes like anti-oxidant, anti-inflammatory, anti-neoplastic, anti-lipidemic and anti-hyperglycemic benefits. Introduction The indiscriminate use of antibiotics, once hailed as life-saving drugs, as an immediate relief measure has resulted into evolution of multi-drug resistance (MDR) and extreme drug resistance (EDR) among pathogens. In view of the gut microbiome, antibiotics bring Tsunami of change in the gut microflora as they do not distinguish among the good and pathogenic microorganisms. Consumption of antibiotics is a major cause of dysbiosis and gut related disturbances in convalescent patients. The microbiota of the gut is an ever-changing milieu whose constitution is governed by multiple factors including genetic, nutritional and environmental influences (Gomaa 2020). Any © 2024 taylor & francis Group, llC CONTACT naveen Kango nkango@gmail.com Department of microbiology, Dr. Harisingh Gour Vishwavidyalaya (a Central university), Sagar, madhya pradesh 470003, india https://doi.org/10.1080/19390211.2024.2363199 KEYWORDS Parabiotics; postbiotics; prebiotics; probiotics; synbiotics mailto:nkango@gmail.com https://doi.org/10.1080/19390211.2024.2363199 http://crossmark.crossref.org/dialog/?doi=10.1080/19390211.2024.2363199&domain=pdf&date_stamp=2024-6-13 http://www.tandfonline.com 2 N. KANGO AND S. NAtH alteration in the gut microbiota may trigger a series of changes in digestion, immunity, gut permeability, and host behavior. To overcome the harmful impact of regular usage of antibiotics, by humans, in poultry and various other domains, there is an immediate need to revisit this paradigm. Prebiotic dietary fibers (oligosaccharides) are selectively fermented by probiotics which help their colonization in the gut lumen, thus inhibiting the growth of entero- pathogens by competition. Liu et al. (2023) explained various mechanisms by which these non-digestible oligosaccharides deliver antimicrobial properties against MDRs. Prebiotic oligosaccharides also directly hinder pathogen growth in the lumen by impart- ing anti-adhesion effect upon pathogen and by acting as a barrier around the pathogen and its toxins (Monteagudo-Mera et al. 2019). Numerous other applications of prebi- otics, besides acting as a selective food for probiotics, have been explored in this article. Clinical trials and in vivo experiments have extended our current understanding of the important roles that probiotics play in human gut microbiome-associated dis- eases. It has been documented through many clinical trials that probiotics (live-biotherapy) could shape the intestinal microbiota leading to potential control of multiple bowel diseases and promotion of overall wellness (Kim et al. 2019). Probiotics along with prebiotics (synbiotics) modulate immune system, treat infections, manage inflammatory bowel disease and recently are being explored in cancer therapy (Yadav et al. 2022). Synbiotics deliver antimicrobial effects by two mechanisms (i) by producing fer- mentation by-products (postbiotics) which indirectly limit the growth of enteropatho- gens by lowering the pH of the lumen (short-chained fatty acids) and secreting bacteriocins that interfere with the synthesis of various necessary biomolecules required for the growth and development of pathogens; (ii) the remnants of probiotics or para- biotics (biosurfactants and glycoproteins of cell wall) which directly inhibit the adhesion and biofilm formation of pathogens on the gut epithelium (Figure 1). Postbiotics feature constituents produced by or released through the metabolic action of the probiotics and exert a valuable impact on the host, directly or indirectly. As postbiotics do not contain live microorganisms, the risks associated with their intake are minimized (Żółkiewicz et al. 2020). Salva et al. (2021) have described the cross talk between postbiotics and immune cell populations of the respiratory mucosa and its effects on the maintenance of normal proliferation of immune cells which is crucial for the establishment of protective innate and adaptive immune responses. The inactivated or dead cells of probiotics and their residues are called parabiotics. The inactivation of live bacteria can be achieved by various methods viz. heat treatment, chemicals (e.g. formalin), gamma or ultraviolet irradiation, and sonication, however, most commonly, heat treatment remains the method of choice for inactivation (Nataraj et al. 2020). Parabiotics when present in the gut lumen also deliver a variety of antimicrobial effects against enteropathogens. From the preceding discussion, it is pertinent that there is a multitude of factors related to probiotics that entails their significant10.12688/ f1000research.13958.1. 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Nutrients. 12(8):2189. doi: 10.3390/nu12082189. https://doi.org/10.1016/j.carbpol.2020.115977 https://doi.org/10.1016/j.carbpol.2020.115977 https://doi.org/10.1016/j.ijbiomac.2020.05.027 https://doi.org/10.1039/d1fo01576a https://doi.org/10.3390/nu16030380 https://doi.org/10.3390/antibiotics12081281 https://doi.org/10.1007/s00284-020-02258-y https://doi.org/10.1371/journal.ppat.1009774 https://doi.org/10.7150/thno.43189 https://doi.org/10.1038/s41467-022-35130-7 https://doi.org/10.3390/nu12082189 Prebiotics, Probiotics and Postbiotics: The Changing Paradigm of Functional Foods ABSTRACT Introduction Gut microbiota: a dynamic ecosystem Prebiotics: selective food for probiotics Probiotic intervention: a way out for avoidance of drug resistance Postbiotics: fermentation end-products and dead-remnants Market size and regulatory aspects Side effects, contraindications and long-term safety Clinical trials and personalized dietary recommendations Conclusion About the authors Disclosure statement Funding Referencesrole in the promotion of well-being. For long, probiotics and more recently, prebiotics, have been assessed for their impact, however, an understanding of their synergistic effect is of paramount importance for delineating a comprehensive picture. This review explores various aspects of these gutbiotics and their interdependence. The interplay among these components can JOuRNAl Of DietARy SuPPlemeNtS 3 provide a valuable understanding of their functions and various health promoting immunomodulatory, anti-hyperglycemic, anti-lipidemic, antioxidant effects. Gut microbiota: a dynamic ecosystem The total number of microorganisms that inhabit the human body (39 trillion microbial cells) exceeds the sum of the number of cells of the host (30 trillion human cells). However, being very small in size, these microorganisms make up only 1–3% of the body mass (Sender et al. 2016). The diversity and number of the microbiota associated with human body, thus has 500 times more genes. In 2012, NIH mentioned that the human body performs its functions through 20,000 genes, while the gut microbiome is believed to execute 3.3 × 106 prokaryotic genes. Various parts of the human body make diverse kinds of niches and small ecosystems for microorganisms. Our skin exudates provide nourishment to the microorganisms hooked to both dry (face, hands) and moist surfaces (armpits, mouth, eyes, ears, sex organs). Moreover, the major chunk of microorganisms thrive in the intestine, where there is constant input (through consumed water and food) concomitant with the growth and efflux (excretion) of the microorganisms. The gut microbiota is dominated by the anaerobic bacteria colonizing the colon or the large intestine (Figure 2). Beginning with 10–102 CFU/ml in the Figure 1. the interplay among pre, pro, post and parabiotics: prebiotics are selectively utilized by living probiotics which then lead to production of postbiotics and parabiotics. the control of intestinal pathogens is achieved either (i) direct competition for adhesion, biofilm formation and biosurfactant production and (ii) by lowering down the pH of the lumen due to production of short chain fatty acids (SCfa) by the enriched population of probiotics. the presence of probiotics also elicits anti-inflammatory, anti-neoplastic and anti-oxidant response. 4 N. KANGO AND S. NAtH upper gastrointestinal tract, their number reaches to 1010–1012 CFU/ml in the colon (Cresci and Bawden 2015). The microbiota of the intestine plays a very significant part in maintenance of the host’s health. Microbes assist the host body in numerous ways, where they compete and outnumber harmful microorganisms, digest and ferment complex carbohydrates and proteins, produce vitamins and bacteriocins and activate immune system. The effect of the gut microbiome is systemic and affects various organ systems of the body and these paradigms are now being understood as gut-brain, gut-lung, gut-skin axes. The composition of the gut microbiota is hugely dependent upon those acquired after the birth (perinatal) and subsequent exposure due to neonatal exposure and feeding, food habits, medications (antibiotics) and lifestyle. More recently, the dysbiosis or chronic disturbance in the intestinal microflora has been more prominently related to disorders such as irregular bowl syndrome (IBS), skin diseases, auto-immune dis- eases, stress and other psychiatric diseases etc. The four main phyla which are reported to contribute majorly to the human gut microbiome include Firmicutes, Bacteroidetes, Actinobacteria, and Proteobacteria (Belizário and Napolitano 2015). It is pertinent to mention that the probiotics are not stand-alone effectors, but their ability to confer health benefits is also dependent upon mobilization of prebiotics and elaboration of postbiotics. Prebiotics: selective food for probiotics Prebiotics are oligosaccharides that are not digested and absorbed by human small intestine and are selectively utilized by the probiotics in the gut. Gibson and Roberfroid Figure 2. the nature and health promoting effects of prebiotics, probiotics, postbiotics and parabiot- ics with prominent examples. JOuRNAl Of DietARy SuPPlemeNtS 5 (1995) introduced the concept of prebiotics as non-digestible oligosaccharides and described fructo-oligosaccharides (FOS), in particular, to be the only available prebiotic. Since then, a lot of work has been done and a variety of non-digestible oligosaccharides are being explored for human benefit and well-being (Jana et al. 2021a). Gibson et al. (2017) revised the definition of prebiotics as ‘substrates selectively utilized by pro- biotics to confer health benefits’ to justify the concept of prebiotics with the upcoming scientific advancements. However, now prebiotics are no longer known only to just support the proliferation of probiotic bacteria in the gut, but are also known to support various metabolic and physiological functions such as antioxidant activity, enhanced mineral absorption and hypolipidemic activity (Roberfroid 2000). Date seed hetero- polysaccharide, primarily consisting of xylan, showed free radical scavenging activity, antioxidant potential and antimicrobial activity against food borne pathogens along with prebiotic potential (Jayasree Subhash et al. 2024). Also, the prebiotics functions are not just limited to the gut, but have also expanded to other parts with the gut remaining just a gateway to most such effects (Table 1). Prebiotic oligosaccharides show the antimicrobial action either through direct or indirect mechanism. Oligosaccharides directly affect the cell membrane secretory system and increase membrane permeability in entero-pathogens and moreover, prebiotic oligosaccharides can act as structural analogs to bacterial surface proteins and thus, hinder the biofilm formation of pathogenic bacteria on the host surface. Vo et al. (2012) reported that chito-oligosaccharides imparted anti-inflammatory activities by blocking degradation of inhibitor of kappa B-alpha (IκB-α), translocation of nuclear factor (NF)-κB, and phosphorylation of mitogen-activated protein kinases (MAPKs) in a dose-dependent manner and reduced the level of nitric oxide (NO) and prosta- glandine 2 (PGE 2) production by suppressing the expression of NO synthase (iNOS) and cyclooxygenase (COX-2) without significant cytotoxicity. Silva et al. (2021) showed the antimicrobial activity of chitosan-oligosaccharides against various pathogenic bac- teria as well as Candida albicans. Wang et al. (2020) demonstrated the increased permeability in Staphylococcus aureus and decreased expression of transcriptional genes related to biofilm formation using xanthan-oligosaccharides. Antimicrobial oligosac- charides have also been found to inhibit harmful toxins secreted by pathogens. Cai et al. (2021) showed that galacto-oligosaccharides administration reduced the population of Mannheimia haemolytica in calves with lung infection and repressed leukotoxin-induced ATP production in primary bronchial epithelial cells. Prebiotics also inhibit the growth of pathogenic bacteria indirectly by selectively enriching the population of probiotics, which in turn, leads to the production of SCFA and many antimicrobial peptides. Fooks and Gibson (2002) showed the inhibitory effect of prebiotics and probiotics on the growth of selected human entero-pathogens and suggested that the acetate and lactate produced after fermentation of prebiotic oligosaccharides conferred antagonistic effects. Kido et al. (2016) reported that cello-oligosaccharides increased population of fibrinolytic bacteria and methanogenic archaea in weaned calves on pasture diet. Recently, exopolysaccharides (EPS) procured from probiotics (Lactobacillus delbrueckii and Lacticaseibacillus rhamnosus) showed prebiotic potential with other probiotics Faecalibacterium prausnitzii and Ruminococcus bromii and promoted SCFA production alongwith antioxidant and antiproliferative 6 N. KANGO AND S. NAtH effects on cancer cell lines (Tarique et al. 2023). More recently, Tarique et al. (2024) used EPS derived from Enterococcus faecium and Streptococcus thermophilus and showed growth promotion of F. prausnitzii and R. bromii along with antioxidant potential, ACE-inhibition and antiproliferative effects on cancer cell lines. Parametrically opti- mized production of EPS from L. fermentum Lf2 enhanced the amount of heteroglycan rather than β-glucan (Ale et al. 2020). Numerous other functions associated with prebiotic oligosaccharides are also being explored. Khat-Udomkiri et al. (2019) showed the anti-hyperglycemic effect of xylo-oligosaccharides (XOS) derived from rice husk in high-fat diet and low-dose streptozotocin-induced type 2 diabetic rat model. Hoshino-Takao et al. (2008) stated that manno-oligosaccharides (MOS) from coffee mannan showed antihypertensive effect and significantly suppressed the blood pressure in Dahl salt-sensitive rats. Schaafsma et al. (2021) reported that galacto-oligosaccharides (GOS) derived from dairy products reduced salivary cortisol, which is perceived to be important for sleep improvement. FOS reduced total serum uremic toxins of non-dialysis-dependent chronic kidney Table 1. Health promoting activites of the prebiotic oligosaccharides. S. no. prebiotics applications reference 1. Cellooligosaccharides (CoS) increase in fibrolytic bacteria and methanogenic archaea in weaned calves on pasture, but longer-term Cellooligosaccharide supplementation may be required to exhibit the effect Kido et al. 2016 2. Xylooligosaccharides (XoS) antihyperglycemic effect of rice husk derived xylooligosaccharides in high-fat diet and low-dose streptozotocin-induced type 2 diabetic rat model Khat-udomkiri et al. 2019 3. mannooligosaccharides (moS) mannooligosaccharides from coffee mannan showed antihypertensive effect and significantly suppresses the blood pressure in Dahl salt-sensitive rats Hoshino-takao et al. 2008 4. Galactooligosaccharides (GoS) Galactooligosaccharides derived from dairy products reduced salivary cortisol and stimulated Bifidobacterium, which possibly is important for sleep improvement Schaafsma et al. 2021 5. fructooligosaccharides (foS) reduced serum total uremic toxins of non-dialysis-dependent chronic kidney disease patients. ramos et al. 2019 6. pectinoligosaccharides (poS) remarkable antioxidant properties, especially scavenging activity against DppH radicals up to 94.07%. yu et al. 2021 7. Chitooligosaccharides (ChoS) reduced the level of nitric oxide (no) and prostaglandin e2 (pGe2) production by suppressing the expression of no synthase (inoS) and cyclooxygenase (CoX)-2 without significant cytotoxicity and exerted anti-inflammatory activities via blocking degradation of inhibitor of kappaB-alpha (iκB-α), translocation of nuclear factor (nf)-κB, and phosphorylation of mitogen-activated protein kinases (mapKs) in a dose-dependent manner. Vo et al. 2012 8. alginate-oligosaccharides improve germ cell development and testicular microenvironment to salvage busulfan disrupted spermatogenesis Zhao et al. 2020 JOuRNAl Of DietARy SuPPlemeNtS 7 disease patients (Ramos et al. 2019). Remarkable antioxidant properties of pectino-oligosaccharides, especially scavenging of DPPH radicals up to 94.07% has been reported (Yu et al. 2021). Zhao Y et al. (2020) demonstrated that the intake of alginate-oligosaccharides improved germ cell development and testicular microenvi- ronment to salvage busulfan disrupted spermatogenesis. Probiotic intervention: a way out for avoidance of drug resistance It is pertinent to mention that in 1908, Elie Metchnikoff, for the first time, mentioned the use sour milk in gaining health in his book ‘The Prolongation of Life: Optimistic Studies’ and thus highlighted the importance of sour milk, lactic acid bacteria and lactic acid in maintenance of gut health and in controlling dyspepsia, enteritis, colitis, diabetes and tuberculosis. Lilly and Stillwell (1965) coined the term probiotics to describe substances secreted by one microorganism which supported the growth of the other. However, as of now, probiotics are defined as ‘live microorganisms which upon ingestion impart health promotion effects which is not limited to the nutri- tional effects’ (Hill et al. 2014). Probiotics are live nonpathogenic microorganisms administered to improve microbial balance, particularly in the gastrointestinal tract. Mainly, these consist of members of the genera Lactobacillus and Bifidobacterium, while several novel strains such as Saccharomyces boulardii, Bacillus clausii, Bacillus coagulans, Streptococcus thermophilus, Enterococcus faecalis, Clostridium butyricum etc., have also been added (Sniffen et al. 2018). Pimentel et al. (2022) suggested the use of probiotics in frozen food products like ice-cream and yogurt for maintaining the overall gut and oral microbiome. Tarique et al. (2022) observed postbiotic properties and the probiotic potential of several lactic acid bacteria (LAB) that were isolated from conventional high-acid, low-moisture yogurt-like products (Labaneh). Similarly, Alameri et al. (2022) have reported the potential probiotic traits of selected lactic acid bacteria (LAB) iso- lated from vegetable products, such as bile salt hydrolysis, cholesterol removal, lysozyme and vancomycin resistance, EPS production, auto-aggregation and hydrophobicity. The microbiota organizes itself as an ecosystem and changes from one organ to another, especially when comparing microbes living in mucus or attached to the intes- tinal wall (parietal microbiota), with microbes living in conjunction with food in transit and stools (luminal microbiota) (Wieërs et al. 2019). In case of opportunistic invasion, the abundant bacterial population inside intestinal tissues may face potential health problems such as inflammation and infections. Therefore, the immune system has evolved to sustain the host-microbiota symbiotic relationship. Feng et al. (2022) reported that Bifidobacterium spp. and Bacteroides spp. activate immune response with the help of stimuli (anti-CD3 and anti-CD28 antibodies). Leuconostoc mesenteroides, Latilactobacillus curvatus and Lactiplantibacillus plantarum were found to increase the production of nitric oxide (NO) and TNF-α and IL-6 (Kim SH et al. 2022). As the concept of probiotics evolved over the past decades, the assumption was that their effects would be mediated through direct interaction with commensal micro- biota. According to some early definitions, probiotics function ‘by contributing to the host’s intestinal microbial balance’ or ‘by improving the properties of the indigenous microflora’. However, in the current consensus definition of probiotics, the effects of probiotics are not considered to be only microbiota mediated, and other types of 8 N. KANGO AND S. NAtH mechanisms are also known (Plaza-Diaz et al. 2019). This idea that probiotics function in ways that might act beyond affecting the colonizing microbiota opens the door to a wider range of probiotic possibilities, encouraging innovation in the field. Probiotics exert beneficial effects through various mechanisms, including lowering intestinal pH, decreasing colonization and invasion by pathogenic microorganisms, and by modifying the host immune response. A summary of the recent work on probiotics delivering immunomodulatory effect is presented in Table 2. The strongest evidence for the clinical effectiveness of probiotics has been in the treatment of acute diarrhea, most commonly due to rotavirus infection and pouchitis. More research is needed to clarify the role of probiotics for preventing antibiotic-associated diarrhea, Clostridium difficile infection, traveler’s diarrhea, irritable bowel syndrome (IBS), ulcerative colitis, Crohn’s disease, and vulvovaginal candidiasis(Goldenberg et al. 2017). There is no consensus about the minimum number of microorganisms that must be ingested to obtain a beneficial effect, however, a probiotic formulation, to be effective, should typically contain several billion colony forming units (CFU) to increase the chances of adequate gut colonization. On the other hand, to maintain host immune homeostasis, the intestinal microflora often exerts an immunoregulatory function that cannot be ignored. An area of great interest is the association of either microbiota or probiotics with the immune system with prospective clinical uses. You et al. (2020) reported production of exopolysac- charides from Lactobacillus pentosus LZ-R-17 which enhanced the proliferation, phago- cytosis, nitric oxide and cytokines production in macrophage cell line RAW264.7. Probiotic microbial community regulates some of the host’s metabolic and physiological functions and drives early-life immune system maturation, contributing to immune homeostasis throughout life. Changes in gut microbiota can occur through modification in function, composition (dysbiosis), or microbiota-host interplays. Studies on animals and humans showed that probiotics can have a pivotal effect on the modulation of immune and inflammatory mechanisms; however, the precise mechanisms have not yet been well defined. Licona-Jain et al. (2020) reported an enhancement in the immune parameters in shrimp fed on yeast (Yarrowia lipolytica) diet. Diet, age, body mass index (BMI), medications, and stress may affect the benefits of probiotic intake. In addition to host gut functions (permeability and physiology), all these factors have profound implications on the gut microbiome composition. Wang et al. (2020) reported that a composite preparation consisting of 14 probiotic species, i.e. Lactococcus (1), Lactobacillus (10), Candida ethanolica, Kluyveromyces marxianus and Pichia membranifaciens significantly improved blood glucose metabolism by pro- moting glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) secretion. Zhao et al. (2021) reported activation of aryl hydrocarbon receptor by Lactobacillus reuteri tryp- tophan metabolism and alleviated Escherichia coli-induced mastitis in mice. Bifidobacterium bifidum H3-R2 induced expression of inflammatory cytokines, enhanced the production of secretory IgA, splenic lymphocyte, natural killer (NK) cell activity and phagocytosis in immunosuppressed mice (Shang et al. 2020). Recently, Angulo et al. (2023) have reported that the intake of Debaryomyces hansenii CBS 8339 impacted total serum IgG and IgA titers and were higher at day 7 and day 15. The use of probiotics could improve the gut microbial population, increase mucus-secretion, and prevent the destruction of tight junction proteins by decreasing the number of JOuRNAl Of DietARy SuPPlemeNtS 9 lipopolysaccharides (LPS). When LPS binds endothelial cells to toll-like receptors (TLR 2 & 4), dendritic cells and macrophage cells are activated, and inflammatory markers are increased. Genomic DNA of Bifidobacterium longum subsp. infantis is a potent Table 2. Health promoting immunomodulatory effects of probiotics. S. no. probiotic immunostimulatory effect references 1. Heat-killed Lactiplantibacillus plantarum CKDB008 increased the production of no and pro-inflammatory cytokines, including tnf-α, il-6, and il-1β noh et al. 2022 2. Bifidobacterium spp. and Bacteroides spp. activates immune response with the help of stimuli (anti-CD3 and anti-CD28 antibodies) feng et al. 2022 3. probiotic consortium (Bacillus licheniformis tSK71, Bacillus amyloliquefaciens SK27, Bacillus subtilis SK07, Pseudomonas sp. aBSK55) Significantly increased shrimp immunity i.e. total hemocyte count, phagocytosis, total plasma protein, respiratory burst and bactericidal activity. fernandes et al. 2021 4. Heat-treated Lactiplantibacillus plantarum lm1004 increased release of no, tumor necrosis factor-α and interleukin-6 and upregulated the inducible no synthase in raW 264.7 macrophage cells. Bae et al. 2022 5. Synbiotic of Lactococcus lactis SG-030 and glucooligosaccharides. increased no production in raW 264.7 cells alongwith, increased expression of tnf-α, il-1β, il-6, and inducible no synthase genes. Kwon and park 2021 6. Bifidobacterium- and lactobacillus-derived extracellular vesicles Generation of proinflammatory cytokines (tnf-α and il-6) in tlr2-expressing mouse macrophage-like raW264.7 cells and mouse dendritic DC2.4 cells. morishita et al. 2022 7. Lactococcus lactis based vaccine expressing a fusion protein of fms-like tyrosine kinase 3 ligand and co-stimulator oX40 ligand activation of natural killer cells, cytotoxic t lymphocytes, and conventional-type-1-dendritic cells in the tumors and tumor-draining lymph nodes. Zhu et al. 2022 8. Leuconostoc mesenteroides, Latilactobacillus curvatus and Lactiplantibacillus plantarum increased the production of no, tnf-α and il-6 Kim SH et al. 2022 9. Lactobacillus helveticus lZ-r-5 producing exopolysaccharide increased proliferation of raW264.7 macrophages and enhancing phagocytosis, acid phosphatase activity, nitric oxide production and cytokines production in macrophages. you et al. 2020 10. Bifidobacterium BB-12, Lactobacillus acidophilus la-5, Lactobacillus delbrueckii lBy-27, Lactobacillus paracasei lC-01, and Streptococcus thermophilus Sty-31 it was not sufficiently immunostimulatory in trypanosomosis. okolo et al. 2020 11. Lactobacillus delbrueckii subsp. lactis CiDCa 133 immunostimulatory properties capable of upregulating anti-inflammatory cytokines il-10 and tgfb1 gene expression through inhibition of nfkb1 gene expression de Jesus et al. 2021 12. B. longum subsp. infantis Genomic Dna of B. longum subsp. infantis is a potent CD25+ forkhead box p3-positive regulatory t cells (treg) inducer. li et al. 2020 13. Lactobacillus pentosus lZ-r-17 produced exopolysaccharides enhanced the proliferation, phagocytosis, nitric oxide and cytokines production of raW264.7 cells you et al. 2020 14. Bifidobacterium bifidum H3-r2 induced expression of inflammatory cytokines, enhanced the production of secretory immunoglobulin a (Siga), and promoted splenic lymphocyte proliferation, natural killer (nK) cell activity and phagocytosis of macrophages in immunosuppressed mice. Shang et al. 2020 15. Debaryomyces hansenii CBS 8339 total serum igG and iga titers were higher at days 7 and 15. angulo et al. 2023 15. Yarrowia lipolytica increase in the immune parameters was observed in shrimp fed yeast diet licona-Jain et al. 2020 10 N. KANGO AND S. NAtH inducer of regulatory T cells (Treg) (Li et al. 2020). de Jesus et al. (2021) reported that Lactobacillus delbrueckii subsp. lactis CIDCA 133 improved immunostimulatory properties and was capable of upregulating anti-inflammatory cytokines IL-10 and Tgfb1 gene expression through the inhibition of Nfkb1 gene expression. Furthermore, a decrease in gut dysbiosis and intestinal leakage after probiotic therapy may minimize the development of inflammatory biomarkers and unnecessary stimulation of the immune system (Cristofori et al. 2021). Synbiotics are combined preparations of probiotics and prebiotics which can show a synergistic beneficial effect on the host health. Thus, a combination of prebiotics and probiotic can also be used for antimicrobial activity against pathogens in a more effective manner. Synbiotic prepared using Lactococcus lactis SG-030 and gluco-oligosaccharides increased nitric oxide (NO) production in RAW 264.7 macro- phage cells along with increased expression of TNF-α, IL-1β, IL-6, and inducible NO synthase genes (Kwon and Park 2021). Skrzydło-Radomanska et al. (2020) reported significant improvement in the symptoms of adult patients with diarrhea-dominant IBS (IBS-D) after the consumption of a synbiotic preparation containing probiotic Lactobacillusrhamnosus, L. acidophilus, Bifidobacterium lactis, B. longum, B. bifidum and fructo-oligosaccharides (FOS). Yang et al. (2021) observed that use of synbiotics ameliorated constipation and elevated levels of fecal propionate and butyrate. Wu et al. (2022) explored the role of probiotics (Lactobacillus acidophilus LA-5, L. rhamnosus GG, and Bifdobacterium animalis subsp. lactis BB-12 and prebiotics (FOS and galacto-oligosaccharides) in regulating acute airway inflammation induced by pneumonia and observed decreased perivascular inflammation, mucus secretion, peribranchial and goblet cell hyperplasia, thus modulating immune responses to prevent allergic disorders. Postbiotics: fermentation end-products and dead-remnants Postbiotics, sometimes also referred as metabiotics, are defined as metabolites/cell-free supernatants (CFS) and soluble factors (products or metabolic byproducts) secreted by probiotics (Salminen et al. 2021). The prebiotics, after being selectively utilized by the probiotics, result in the enrichment of probiotic population concomitant with the production of a variety of metabolites. Some of these substances such as bacteriocins, defensins, short chain fatty acids, branched chain amino acids etc. are known to impart health promoting benefits (Jana et al. 2021b). This clearly highlights that the actual health benefits are imparted by such metabolites produced by the growth and metab- olism of the probiotics. In recent times, the idea of postbiotics has been promulgated to refer to such substances (Thorakkattu et al. 2022). Comprehensive details of various postbiotics and the associated health benefits are provided in Table 3. Over the time, the term ‘postbiotics’ has been defined in a variety of ways. Initially, these were referred as metabolic products or non-viable metabolic by-products of probiotics which on behalf of their functionality confer health benefits. Recently, the postbiotics have been given a consensus definition by the International Scientific Association for Probiotics and Prebiotics (ISAPP) as ‘a preparation of inanimate microorganisms and/or their components that confers a health benefit on the host’ (Salminen et al. 2021). Thus, it clarifies that it will be either a dead microorganism or some of its parts (cell wall, cell membrane, enzymes, peptides, metabolites etc.) JOuRNAl Of DietARy SuPPlemeNtS 11 Table 3. Sources and health promoting benefits of postbiotics. S. no. postbiotics probiotic Health benefits reference 1. Cell-free supernatants Lactobacillus gasseri 1a-tV, Lactobaccilus fermentum 18a-tV, and Lactobacillus crispatus 35a-tV antimicrobial activity mediated by CfSs were assessed against multidrug urogenital pathogens Scillato et al. 2021 L. gasseri Bnr17 anti-melanogenesis and reducing oxidative stress in B16-f10 murine melanoma cells and HaCat human keratinocytes. lee et al. 2022 2. Vitamins L. fermentum mtCC 8711 produced riboflavin vitamin B2 which is the basic component for cellular metabolism Jayashree et al. 2010 3. organic acids (Benzoic acid, fumaric acid, phosphoric acid, and formic acid) Bacillus subtilis and Clostridium butyricum improved daily feed intake, egg production rate, and body weight of ducks Cao et al. 2022 4. Short-chain fatty acid Bifidobacterium animalis subsp. lactis BB-12 the fecal acetate levels in the probiotic group increased over the remainder of the study and returned to the baseline levels on day 30 merenstein et al. 2021 C. butyricum Butyrate treatment reduces the levels of CD11b and CoX-2 and suppresses phosphorylation of nf-κB p65 in the aβ-induced BV2 microglia. Sun et al. 2020 Butyrate, inhibited high-fat diet (HfD)-induced intestinal tumor development in apcmin/+ mice Chen et al. 2020 C. butyricum (butyric acid-producing bacteria) was better than that of Bifidobacterium pseudolongum on cardiac fibrosis. Wang et al. 2022 5. Bacteriocins Pediococcus acidilactici and Lactococcus garvieae antimicrobial activity is related to heat-stable proteins/peptides that presumably belong to the class iia bacteriocins Desiderato et al. 2021 Lactobacillus curvatus et06, et30 and et31, Lactobacillus fermentum et35, Lactobacillus delbrueckii et32, Pediococcus acidilactici et34 and Enterococcus faecium et05 produced bacteriocins active against several strains of listeria monocytogenes todorov et al. 2011 probiotic bacteria consisted of five isolates from tiger shrimps and five isolates from freshwater prawns Bacteriocin activity was determined using a diffusion method against pathogenic bacteria Vibrio alginolyticus, Aeromonas hydrophilla and Pseudomonas stutzeri. feliatra et al. 2018 6. neurotransmitters novel synbiotic (SBt) attenuated diphenoxylate-induced constipation, recuperated colonic epithelial integrity and increased serum levels of gastrointestinal excitatory neurotransmitters (p substance, vasoactive intestinal peptide, motilin, gastrin and serotonin) yang et al. 2021 L. acidophilus eG004 produce butyrate and therefore modulate neurotransmitters and neurotrophic factors Jeon et al. 2022 (Continued) 12 N. KANGO AND S. NAtH which will impart a beneficial effect to the host health. The concept of postbiotics is rather in contrast to that of the probiotics, which entails the benefit conferred by live microorganisms. Recently, the physical, chemical, and sensory qualities of the butter were enhanced when it was fortified with a postbiotic metabolite derived from L. plantarum subsp. plantarum and a spray-dried encapsulated Ferulago angulata extract nano-emulsion (Anvar et al. 2023). However, the source of the postbiotic has to be a well identified microorganism or a defined consortia and the generation of postbiotic should be well demarcated. The major deviation from the last definition is that it does not restrict itself to the products of probiotic (Salminen et al. 2021). The most important postbiotics are organic acids, short chain fatty acids (SCFA) and bacteriocins (Martyniak et al. 2021). Production of organic acids such as, benzoic acid, fumaric acid, phosphoric acid, and formic acid from probiotic Bacillus subtilis and Clostridium butyricum given to ducks has been reported to improve their feed intake, egg production rate, and body weight (Cao et al. 2022). SCFAs are involved in many aspects of gut health maintenance including luminal pH regulation and the creation of an environment that inhibits pathogen growth while promoting the growth of beneficial microorganisms. Moreover, lower pH improves mucosal function and absorption by increasing the solubility of mineral salts. This increases the host’s ability to absorb vital minerals like magnesium and calcium, which is important in preventing osteoporosis. Among SCFAs, butyrate is noteworthy for being the main energy source for colonic cells, supporting a healthy gut barrier and having anti-inflammatory qual- ities (Ji et al. 2023). The benefit of using postbiotics, depending upon their own type may be imparted directly or indirectly. Direct benefits to the host result from the action of postbiotics on the host cells like anti-adhesion and anti-biofilm formation of pathogens. L. acidophilus produced a biosurfactant that significantly reduced expres- sion of genes involved in Proteus mirabilis biofilm formation (Shokouhfard et al. 2022). Indirect benefits include growth promotion of probiotics and the inhibition of the development of enteropathogens by SCFA and bacteriocins as fermentation by-products. Scillato et al. (2021) have demonstrated the antimicrobial activity of cell-free super- natants derived from Lactobacillus gasseri 1 A-TV, L. fermentum 18 A-TV and L. crispatus 35 A-TV against multidrug urogenital pathogens. Lee et al. (2022) reported S. no. postbiotics probiotic Health benefits reference 7. Biosurfactants L. acidophilus Biosurfactant significantly reduced rsma expressionwhereas, increased flhDC expression in P. mirabilis isolates. Shokouhfard et al. 2022 Lactobacillus plantarum subsp. plantarum ptCC 1896 Dynamic surface tension measurement for the screening of biosurfactants produced to check its anti-adhesive activity Bakhshi et al. 2017 8. flavonoids L. casei Shirota Soy isoflavones and fermented soy beverage produced using probiotics takagi et al. 2015 Bifidobacterium ftDC 8943, B. Longum ftDC8643, Lactobacillus sp. ftDC2113, and L. casei atCC393 increased concentrations of bioactive aglycones in synbiotic-soymilk yeo and liong 2011 Table 3. Continued. JOuRNAl Of DietARy SuPPlemeNtS 13 anti-melanogenesis and reduced oxidative stress in B16-F10 murine melanoma cells and HaCaT human keratinocytes by the cell-free supernatant of L. gasseri BNR17. The important benefits of postbiotics include their anti-inflammatory and antioxidant effects. In a recent study, Wang et al. (2022) reported that Clostridium butyricum (butyric acid-producing bacteria) was better than Bifidobacterium pseudolongum in alleviation of cardiac fibrosis in mice. Administration of Bifidobacterium animalis subsp. lactis BB-12 resulted in increased fecal acetate levels and helped in overcoming antibiotic induced functional and compositional changes in human fecal microbiome (Merenstein et al. 2021). Sun et al. (2020) demonstrated that C. butyricum induced butyrate levels suppressed microglia mediated neuro-inflammation in Alzheimer’s disease. Chen et al. (2020) reported that butyrate inhibited high-fat diet (HFD) induced intestinal tumor development in mice. More recently, Jeon et al. (2022) reported that L. acidophilus EG004 produced butyrate and modulated neurotransmitters and neurotrophic factors favorably. The antimicrobial activity of potential probiotics, Pediococcus acidilactici and Lactococcus garvieae against Listeria monocytogenes was due to Class IIa bacteriocins (Desiderato et al. 2021). Probiotics impart several health benefits by modulating gut microbiome; however, limitations such as viability and associated side effects, have hampered their full potential applications in the food and pharmaceutical sectors. Para-probiotics of L. plantarum L67 are a safer and more reliable choice for preventing the etiology of chronic colitis in comparison to the probiotics alone (Song et al. 2023). Therefore, the focus is gradually shifting from viable probiotic bacteria toward probiotics derived biomolecules. In this regard, postbiotics are the emerging candidates among the func- tional foods because they impart an array of health-promoting properties (Nataraj et al. 2020). Parabiotics are the inactivated microbial cells of probiotics (intact or ruptured cells containing peptidoglycans, teichoic acids, surface proteins, etc.) or crude cell extracts (i.e. with complex chemical composition). A yoghurt preparation containing killed strains, L. acidophilus ATCC SD5221 and B. animalis subsp. lactis BB-12, had better rheological and sensory properties (Molaee Parvarei et al. 2021). Postbiotics is a broader term including all the metabolites, cell-free supernatants and the components of the probiotics, thus, all parabiotics are postbiotics but, all postbiotics are not para- biotics (Nataraj et al. 2020). Some noteworthy parabiotics and their immunomodulatory effects are listed in Table 4. Postbiotics overcome some limitations of the probiotics and have several advantages over probiotics like (i) availability in isolated form (ii) ease of production, easy transport and storage (iii) feasible industrial scale-up (iv) specific mechanism of action (v) better accessibility of Microbes Associated Molecular Pattern (MAMP) during recognition and interaction with Pattern Recognition Receptors (PRR) and (vi) more specific targeted responses due to specific ligand-receptor inter- actions. Kim et al. (2021) reported improved anti-inflammatory responses in porcine peripheral blood mononuclear cells due to lipoteichoic acid derived from L. plantarum, L. casei, and L. rhamnosus. Peptidoglycan derived from L. rhamnosus MLGA up-regulated the expression of chicken β-defensin-9 without triggering deleterious risks of an inflam- matory response (Huang et al. 2020). Recently, Morishita et al. (2022) harvested pep- tidoglycan of Bifidobacterium and Lactobacillus and showed pro-inflammatory cytokine tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in TLR2-expressing mouse macrophage-like RAW264.7 cells and mouse dendritic DC 2.4 cells. The extracellular 14 N. KANGO AND S. NAtH Table 4. Sources and health promoting effects parabiotics. S. no. parabiotics probiotics Health benefits reference 1. lipoteichoic acids L. plantarum, L. casei, and L. rhamnosus improved anti-inflammatory responses of porcine peripheral blood mononuclear cells Kim et al. 2021 L. plantarum it significantly inhibited adhesion of Vibrio anguillarum to the silvery pomfret (Pampus argenteus) gut epithelial cells and also showed anti-inflammatory and inhibition of apoptosis effects. Gao et al. 2016 2. peptidoglycan Lactobacillus rhamnosus mlGa up-regulates the expression of chicken β-defensin 9 without triggering deleterious risks of an inflammatory response Huang et al. 2020 Bifidobacterium and Lactobacillus extracellular vesicles generated proinflammatory cytokines (tumor necrosis factor-α (tnf-α) and interleukin-6 (il-6) in tlr2-expressing mouse macrophage-like raW264.7 cells and mouse dendritic DC2.4 cells morishita et al. 2022 3. peptidoglycan-derived muropeptide Lactobacillus salivarius ls33 protected mice from colitis in a noD2-dependent macho fernandez et al. 2011 4. extracellular polymer substances L. rhamnosus (CiCC 22825), Lactobacillus sake (atCC 15521), L. casei (CiCC 20296), L. paracasei (CGmCC 20241), and L. plantarum (CmGB-l8) inhibition of biofilm formation in Klebsiella pneumoniae was mainly due to the reduced expression of yfin and mrkJ genes, and the decreased concentration of c-di-Gmp in cells and thus, reduced the expression of the mrkaBCDf gene and prevented the synthesis of the type 3 fimbriae. Zhang et al. 2021 Lacticaseibacillus rhamnosus GG SpaCBa pili have been shown to contribute to adherence, biofilm formation and host signaling tytgat et al. 2021 5. exopolysaccharides L. delbrueckii subsp. bulgaricus oll1073r-1 induced CCr6+ CD8+ t cells of mice and humans and antitumor adjuvant effect of exopoly-saccharides was also observed in germ-free mice Kawanabe-matsuda et al. 2022 Lacticaseibacillus paracasei aS20 (1) inhibitory effects on the growth of Listeria, Yersinia enterocolitica and Bacillus cereus. amini et al. 2022 Levilactobacillus brevis Sp48 high molecular weight compounds secreted by L. brevis Sp48 can contrast H. pylori and reduce inflammation related to intestinal bowel disease Cimini et al. 2022 6. Biosurfactants L. acidophilus Biosurfactant reduces the adhesion of strains to microtiter plate and glass slide surfaces due to the reduction of surface tension and reduced rsma expression whereas increased flhDC expression in P. mirabilis atCC 7002 Shokouhfard et al. 2022 L. acidophilus atCC 4356 interfere with the adhesion and biofilm formation of the Serratia marcescens Shokouhfard et al. 2015 L. fermentum anti-biofouling activity was seen because it reduced the process of attachment and biofilm production and also showed a reduction in gtfB/C gene expression in Streptococcus mutans tahmourespour et al. 2011 JOuRNAl Of DietARy SuPPlemeNtS 15 polymeric substances derived from Lactobacillus sake (ATCC 15521), L. rhamnosus (CICC 22825), L. casei (CICC 20296), L. paracasei (CGMCC 20241), and L. plantarum (CMGB-L8) inhibited biofilm formation in Klebsiella pneumoniae and decreased the concentration of c-di-GMP in cells and thus prevented the synthesis of the type 3 fimbriae (Zhang et al. 2021).Similarly, pili of L. rhamnosus GG have been shown to contribute to adherence, biofilm formation and host signaling (Tytgat et al. 2021). EPS of L. delbrueckii subsp. bulgaricus OLL1073R-1 induced CCR6+, CD8+ and T cells of mice and humans and also the antitumor adjuvant effect was observed in germ-free mice (Kawanabe-Matsuda et al. 2022). The above examples clearly state that the post- biotics may deliver the desired health promoting effect while circumventing the lim- itations of the live probiotic microorganisms. However, owing to the availability of choices and limited number of conclusive studies on postbiotics, a more systematic and elaborate approach to delineate their specific effect and underlying applications is required. Market size and regulatory aspects The ability of gut-biotics to provide positive health outcomes has increased consumer interest in dietary supplements, which has led to scientific and commercial interest in their administration as a health-promoting strategy. The global prebiotics market was estimated to be worth USD 6.05 billion in 2021, and between 2022 and 2030, the industry is projected to expand at a compound annual growth rate (CAGR) of 14.9% (Kumar et al. 2024). The worth of global probiotics market is estimated to be at USD 15 billion per annum and is projected to grow at a CAGR of 7% (Day et al. 2019). The postbiotic supplement market is also gaining considerable attention, for example, the global market of vitamin B9 sourced from a yeast, Scheffersomyces stipites, is anticipated to grow at a CAGR of 5.3%, reaching USD 1.02 billion in 2024 (Mastella et al. 2022). Growing relevance and consumer awareness of such nutraceuticals has led to their frequent labeling for regulatory purposes world over. With the passage of the Foods for Specified Health Use (FOSHU) act in Japan during the 1980s, the reg- ulation of additional functional foods, including prebiotics, was first noted (Scott et al. 2020). Later on, functional food regulations were implemented in Sweden, Netherlands, and the United Kingdom before coming together to establish the Joint Health Initiative (JHCI) in Europe. The European Food Safety Authority (EFSA) was founded in 2002 with the purpose of regulating food safety and direct and indirect effects (Bamigbade et al. 2022). The Nutrition Labeling and Education Act (NLEA) of 1990 of FDA (USA) allows for the evaluation of scientifically supported nutritional claims on food labels, especially dietary supplements (Thakkar et al. 2020). However, since the supposed health benefits of prebiotics in microbiota alterations have not yet been acknowledged as confirmed, these are considered under the category of complementary and alternative medicine (CAM) (Bamigbade et al. 2022). In 1991, Japan was the first country to establish a regulatory framework for nutraceuticals and functional foods (Arora and Baldi 2015). Probiotic standards and their present global classification are quite broad, which leads to complexity and legal uncertainty. Since different regulatory bodies across different nations are classifying and defining probiotics in different ways, there is currently a great deal of ambiguity surrounding the status of probiotic-based products. 16 N. KANGO AND S. NAtH As a result, producers, consumers, and regulatory bodies are uncertain of the claims made in relation to probiotic products (Arora and Baldi 2015). A consistent nomen- clature for probiotic consumables must also be introduced in order to ensure effective regulatory control over issues linked to probiotics (Chugh et al. 2023). FDA has sug- gested regulations that would guarantee the safety of probiotic product manufacturing, labeling, distribution, and marketing on a global scale (Chieffi et al. 2022). Generally marketed as dietary supplements, probiotics do not need FDA approval unless they include health claims. ISAPP (2013) suggested that the traditional fermented foods, rather than being referred to as probiotics, are better characterized as ‘containing live and active cultures’ (Hill et al. 2014). The postbiotics have a promising future ahead and a sizable section of the populace will profit from their use in the food sector. Also, those afflicted with particular illnesses or ailments may utilize postbiotics as therapeutic agents (Thorakkattu et al. 2022). Postbiotics, for which Mitsuoka coined the term ‘biogenics’ have been around for more than a century in Japan (Mitsuoka 1992). A variety of food products, such as juices, ice creams, popcorn, potato chips, natto (fermented soybeans), instant-style miso soup (traditional Japanese soup), sup- plements, tablets, pancake powder, and many more, use LAB or bifidobacteria. Some of these products display health claims based on a regulation of Foods with Function Claims (FFC) (Kamioka et al. 2019). ISAPP, in the year 2019, documented the regu- lation of postbiotics for adults and infants (Salminen et al. 2021). The FDA is yet to acknowledge the postbiotics in any particular way and as such does not recognizes the term ‘postbiotic’ (Rafique et al. 2023). Pogačar et al. (2022) documented the present regulatory landscape for usage of probiotics in a variety of medical situations, however, postbiotics are still not specifically regulated in the European Union, but as its con- sensus definition calls for proven health benefits, the current understanding is that using the term postbiotic on a food or nutritional supplement would require EFSA to approve the health claim (Vinderola et al. 2022). Zang et al. (2024) classified the 2215 patents awarded for pre-, pro- and postbiotics between 2001 and 2020 according to their functionality, allowing for the prediction of their future development trajectories. Side effects, contraindications and long-term safety Though prebiotics oligosaccharides are generally thought to be safe, if consumed at high levels, can lead to flatulence, cramps, bloating, or vomit (Marteau and Seksik 2004). Thus, standardized methods for determining dosage, dietary schedule and clinical correlations are necessary for making the preparations more efficacious. The develop- ment of adverse effects is significantly influenced by the length of prebiotic chains (Guarino et al. 2020). In most cases, consuming inulin as a liquid or solid meal does not have detrimental side effects (Ramirez-Farias et al. 2009). Furthermore, its safety profile may be impacted by the prebiotic dosage, e.g. low doses (2–10 g daily) can result in bloating, but high doses (40–50 g/day) may cause abdominal cramps (Clark et al. 2012). Lactulose has laxative effects due to its osmotic properties, however, it can cause uncomfortable symptoms like flatulence or bloating at high doses (10–20 g/ day) (Sakai et al. 2019). Upcoming prebiotics oligosaccharides of medium chain length like XOS, MOS, etc. are reported to have less side-effects. At daily dose of 1.4 and JOuRNAl Of DietARy SuPPlemeNtS 17 2.8 g, XOS were well tolerated for an 8-week intervention with no adverse gastroin- testinal symptoms (Finegold et al. 2014). MOS dosage (4 g/kg) administered to the fish, European seabass (Dicentrarchus labrax), had no adverse effect on the gut health after 8 wk (Torrecillas et al. 2015). The composition of any individual’s microbiota varies widely, and different gastrointestinal illnesses are characterized by different degrees of bacterial imbalance. Introducing new probiotic strains may cause initial discomfort and gastritis but, these adverse effects typically go away in a few days or weeks (Marteau and Seksik 2004). Probiotics should not be taken by those who have intravenous catheters, recent surgery, severe pancreatitis, weakened immune system, or extended hospitalization. There are probiotics that cause the digestive system to produce histamine and such bacteria may be avoided by those who are histamine intolerant. Amines are naturally present in fermentedmeals high in probiotics. After consuming these foods, some people may get headaches; in such cases, probiotic pills are a better option (Guarino et al. 2020). The number of probiotics propagules in currently used formulations varies widely, from 107 to 1011 CFU/g, which suggests that the number of live cells in these products is highly variable (Dore et al. 2019). Therefore, elaborate studies are needed to determine the best suitable probiotic strains and dosages that are helpful, while minimizing any negative effects. To overcome the side-effects of prebiotics and probiotics, postbiotics are being explored and have been shown to have no harmful effects like bloating, abdominal cramps, gastritis, vomiting, etc. Being a purified end-product resulting from fermentation of prebiotic oligosac- charides by a probiotic strain, postbiotic is generally regarded as safe (Bourebaba et al. 2022). However, the safety concerns of postbiotic therapy have not been fully inves- tigated yet and comprehensive trials are needed to determine the side effects and safety of different postbiotics (Ma et al. 2023). Thus, to further our understanding of the postbiotic safety issues, a great deal of study in animal models is required in addition to clinical studies. In addition, experimental investigations, randomized clinical trials, and metabolomic assessments are necessary to determine the appropriate dosage and optimal frequency of consuming postbiotics. Clinical trials and personalized dietary recommendations Probiotics, prebiotics, and postbiotics have been reported in an increasing number of clinical studies and the data shows them to be effective in the treatment of a wide range of diseases. However, at present, these are only approved for use as dietary sup- plements and not as medications, which limits their usage in the healthcare settings (Ji et al. 2023). This is due to inaccurate characterization, lack of supporting documen- tation and their mode of action. The prebiotics are ineffective if the target probiotic is not present in the gut (Pandey et al. 2015). However, issues relating to probiotic usage, such as antimicrobial resistance in probiotic Lactobacilli, prompts for stipulations to minimize any risk (Zavišić et al. 2023). Thus, using postbiotics may be a safer option but their large-scale production remains to be a distant goal. Accordingly, more concrete clinical evidence is necessary to substantiate the use of postbiotic supplements as med- icines. In a study, the prebiotic intervention on Parkinson’s disease patients resulted in favorable modulation of the gut microbiota (Hall et al. 2023). Under double-blind circumstances, thirty-three professional rugby union players were given a prebiotic 18 N. KANGO AND S. NAtH (2.8 g/day galacto-oligosaccharides) or a placebo (2.8 g/day maltodextrin) per day for 168 days. The prebiotic was found to shorten the duration of upper respiratory problems and lessen the frequency and intensity of gastrointestinal symptoms (Parker et al. 2023). Adult patients (n = 40; 22–64 years with average age 40) having discomfort during their defecation and facing sleep deprivation were fed either yeast MOS (YM) prebiotic (1.1 g/ day) or placebo diet for 1-month. Comparing the YM group to the placebo group, there was a substantial increase in both the frequency and amount of stool excretion. Following the therapy, the YM group’s total time in bed (TIB) duration was noticeably longer than the placebo groups (Tanihiro et al. 2023). Synbiotic formulated using Carob MOS as prebiotics (30 g/day) and probiotics (one pill per day that containing B. longum, L. helveticus, L. lactis and S. thermophilus) was administered as a part of diet of 45 obese patients (average age 48) for 1-month. After consumption of the personalized recommended diet, a notable reduction of body fat (p = 0.001) and enhancement in endurance and muscle strength (p = 0.008 and 0.004) along with a drop in fasting blood sugar (p = 0.02) was noticed (Ben Othman et al. 2023). Patients having S. aureus infection, were given either 250 mg of probiotic B. subtilis MB40 (n = 55) or a placebo (n = 60) for 30 days. Over 95% of S. aureus colonization was eradicated by the probiotic intervention without impacting the gut microbiota (Piewngam et al. 2023). Patients (n = 32) with cirrhosis and cognitive impairment were randomly assigned to either a multi-strain probiotic or a placebo. In cirrhosis patients, the multi-strain probiotic enhanced the serum glutamine/glutamate ratio, while improving their ability to detoxify ammonia (Laghi et al. 2023). In mildly malnourished pre-schoolers, dietary supplementation with edible film-coated multi-strain probiotic (Lacticaseibacilli) substantially improved the activity of multiple colonic indi- cators (Gad et al. 2024). In patients suffering from bacterial vaginitis (n = 55), following postbiotic gel application, the vaginal Lactobacilli’s relative abundance rose beyond baseline, which in turn, hindered the growth of vaginal pathogens such as Gardnerella, Prevotella, and Atopobium (Shen et al. 2023). In a recent study involving 100 healthy adults, consumption of heat-killed L. paracasei MCC1849 (5 × 1010) resulted in a significant increase in the expression of CD86 and stimulated gene expression levels of IFN-α, -β, and -γ, without causing any adverse effects. This is the first study demonstrating the beneficial effects of parabiotics on immunological cells in humans (Kato et al. 2024). In future, more such studies are required to be conducted for assessing their true potential. Conclusion The mannerisms of the gut microbiota have been elusive and we are yet to solve the jig-saw puzzle of the interrelationship and interplay of various factors affecting it. Lactobacillus and Bifidobacterium are the most enterprising probiotics as evidenced by their frequent use in various commercial pharmaceutical formulations. However, the desire for more efficacy in the probiotic preparations has led to their amalgamation with their ‘preferred substrates’ or prebiotic oligosaccharides. More recently, it has been realized that it is very important to configure the actual active components that directly take part in mitigating the gut dysbiosis. Over the years, short chain fatty acids, branched chain amino acids, exopolysaccharides, defensins, bacteriocins etc., produced by probiotics have been found to be the actual effector molecules in imparting health JOuRNAl Of DietARy SuPPlemeNtS 19 benefits. This narrative is now being pursued at large and it is very important to note that a number of studies are exploring the pre, pro and postbiotics synergy in order to figure out a more holistic, comprehensive and rational approach. Conclusive evi- dences for the role of postbiotics may pave the way for novel approaches of their usage based on direct applications and quicker responses. About the authors Prof. Naveen Kango is Chair, Department of Microbiology and Director, Academic Affairs, Dr. Harisingh Gour Vishwavidyalaya (A Central University), Sagar, MP, India. His research interest includes Probiotics, Prebiotics, Synbiotics, Food nutrition, Diabetology and Microbial Enzymes (mannanases, keratinases). Suresh Nath is ICMR-Fellow and final year Ph.D. student in the Department of Microbiology, School of Biological Sciences, Dr. Harisingh Gour Vishwavidyalaya (A Central University), Sagar, M.P., India. His research interest are Microbial enzymes, Prebiotics, Probiotics, Postbiotics and food science and nutrition. Disclosure statement Authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Funding Authors (NK-principal investigator; SN-research fellow) are thankful to Indian Council of Medical Research (ICMR), New Delhi for the financial support received under extramural project 2021-14350.References Alameri F, Tarique M, Osaili T, Obaid R, Abdalla A, Masad R, Al-Sbiei A, Fernandez-Cabezudo M, Liu SQ, Al-Ramadi B, et al. 2022. 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