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A Narrative Review on the Advance of Probiotics to Metabiotics
Department of Food Science and Biotechnology of Animal Resources, Konkuk University, Seoul 05029, Republic of Korea
Correspondence to:J. Microbiol. Biotechnol. 2024; 34(3): 487-494
Published March 28, 2024 https://doi.org/10.4014/jmb.2311.11023
Copyright © The Korean Society for Microbiology and Biotechnology.
Abstract
Keywords
Graphical Abstract
Introduction
According to the World Health Organization (WHO) and Food Agriculture Organization (FAO), probiotics are defined as live microorganisms administered in adequate amounts for health benefits on the host [1]. Generally, probiotics have been associated with many health benefits, such as regulating intestinal flora, immune functions, as well as antimicrobial, anticancer, and anti-inflammatory effects [2, 3]. However, various concerns including viability control, gastrointestinal side effects, fungemia, and endocarditis exist [4-6]. Therefore, next-generation probiotics are being investigated to overcome these concerns [5].
Metabiotics are defined as bioactive compounds generated through the metabolic process of probiotic microorganisms, exerting a positive influence on various physiological process [7]. Metabiotics collectively refers to constituents of probiotic microorganisms, their metabolic by–products, and signaling molecules with well-defined chemical compositions [8]. These components are characterized by their ability to enhance specific physiological functions tailored to the host, including regulatory, metabolic, and behavioral responses. These interactions are closely associated with host microbiota activity [9]. The representative components of metabiotics are short-chain fatty acids (SCFAs), polyunsaturated fatty acids (PUFAs), bacteriocins, polysaccharides, and peptides [10].
Thus, this review aims to provide an overview of the metabiotics. We outline the current status of probiotics advancements to metabiotics and their health benefits. We also summarized the functionalities of metabiotics and provide an outlook on their future potential.
An Advance from Probiotics to Metabiotics
Lactic acid bacteria (LAB), especially those with positive effects on health, are commonly known as probiotics, a term introduced by Nobel Prize winner, Elie Metchnikoff [11].
Prebiotics is defined as non-digestible dietary fibers or compounds that serve as food for beneficial microorganisms, particularly probiotics, in the gastrointestinal tract [24, 25]. In 2016, a panel of experts in the field of microbiology, nutrition, and clinical research was convened by the International Scientific Association for Probiotics and Prebiotics (ISAPP) to assess and redefine the scope of prebiotics [26]. Typical substances included in prebiotics are polysaccharides (resistant starch, dextrin, and pectin) and oligosaccharides such as fructooligosaccharides (FOS) and galactooligosaccharide (GOS), xylooligosacharides (XOS), isomaltooligosaccharides (IMO), mannanoligosaccharides (MOS), raffinoseoligosaccharides (RFOs), arabinoxylanoligosaccharides (AXOS), and lactulose [27-29]. Prebiotics has been reported to inhibit pathogenic bacteria and cancer, reduce cardiovascular disease and cholesterol levels, and prevent constipation and obesity [29]. In addition, prebiotics are fermented by microorganisms in the intestines to produce SCFAs, including propionate, butyrate, and acetate, showing various health benefits, such as prevention of gastrointestinal conditions and reduction of cancer [28, 30, 31]. Recently, the significance of gut microbiotas has become increasingly important for health. Consequently, there is an emerging strategy to control microbiotas and their relationship with host [28]. Owing to their characteristics, prebiotics have been used as functional ingredients in various food industries [30]. Significant research on prebiotics has indicated their utilization in functional food applications, which involve providing benefits beyond their inherent nutrient compound to enhance overall well-being [32].
Synbiotics are a combination of probiotics and prebiotics that synergistically improve overall health and well-being [33]. Notably, the beneficial effects of synbiotics are greater than those of probiotics or prebiotics [34]. Recently, the ISAPP has defined synbiotics as follows: “a mixture of viable microorganisms and substrate(s) that are selectively utilized by host microorganisms and confer a health benefit on the host” [35]. Representative functional health effects include the re-modulation of gut bacterial dysbiosis, improvement of immunomodulation, and prevention of obesity. A principal example of synbiotics containing
Postbiotics are bioactive compounds produced by probiotics during metabolic processes. Unlike probiotics, which are live microorganisms, and prebiotics, which are the substrate that promote the growth of beneficial microorganisms, postbiotics are microbial cell components and actual metabolic products that emerge from probiotic activity, such as secreted enzymes, proteins, vitamins, SCFAs, and phenols [5, 38]. The terms ‘post’, indicating ‘after’, and ‘biotic’, which refers to originate from living organisms’, resulted in ‘postbiotic’. These components together imply ‘after life’, indicating materials that are produced by living microorganisms [39]. In general, postbiotics possess the advantages of stability and convenient transportability, which improve shelf life and simplify packaging. Thus, the active ingredient can be transferred to the desired location in the intestine [40]. Furthermore, postbiotics have a wide range of beneficial effects, including immunomodulatory, anticancer, and antimicrobial effects [41]. As virus-related diseases have increased significantly over the pasts few years, studies of postbiotics, which are effective in immune-modulation, antimicrobial, and antiviral, have been reported [42]. However, the precise of mechanism of postbiotics action is yet to be determined and limited experimental studies have been conducted. It has been reported that viral diseases could be minimized by adjusting immune system through interaction with molecules such as peptidoglycans [43]. Additionally, postbiotics have been used as functional materials in various products such as dairy foods, vegetables, bread, meat, fish products, and food ingredients [38].
Over the years, studies to identify microorganisms that benefit the host have been increasing. The functional efficacy of microorganisms is transmitted by living and non-living cells, and their metabolites. Thus, terms referred to in these studies have also been developed, including probiotics, synbiotics, postbiotics, and metabiotics [44]. Recently, a new concept for the probiotic term, metabiotics, has emerged. This has emerged as a new trend in biotechnology to improve the side effects of living probiotics and apply them in human treatments and health functional foods [45]. Metabiotics are characterized as bioactive substances produced through the metabolic activities of probiotic microorganism, contributing positively to a range of physiological process [7]. The term metabiotics is derived from the Greek prefix
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Fig. 1. Composition and types of metabiotics.
Neurological Disorders Functionality by the Gut-Brain Axis
Recently, researchers have explored the health benefits associated with the composition of intestinal microorganisms. The gut microbiome plays a pivotal role in enhancing digestion and absorption of nutrients to generate energy [48]. Studies on the gut microbiome have highlighted the involvement of probiotics in various aspects of health, including the nervous system, inflammation, oncology, gastrointestinal tract, and endocrine system. Notably, probiotics plays a crucial role in supporting the immune system and brain health [49].
Furthermore, researchers have demonstrated a bidirectional association between the central nervous system (CNS) and gut microbiome [50]. Research indicates that microorganisms residing in the intestine release chemical messengers that affect cell responses along the vagus nerves, sending signals to the brain through these nerves [49]. Their main role is to regulate communication between the intestinal system and the CNS, now recognized as “gut-brain axis” [51].
Disruptions of the gut-brain axis can lead to neurological disorders such as depression, Alzheimer’s disease, and anxiety [51]. Intestinal bacteria are known to have the ability to produce numerous neuroactive molecules such as serotonin, gamma amino butyric acid (GABA) and SCFAs [52]. Recently, metabiotics, which is probiotic metabolites have recently been reported to possess neuroregulatory activity. Consequently, neurological disorders can be reduced through the delivery of substances produced by intestinal microbial communities, such as GABA, histamine, SCFAs, and serotonin [45, 51, 53, 54]. Table 1 shows metabiotics and associated microorganisms that control neurological disorders.
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Table 1 . Metabiotics related with microorganisms and their neurological properties.
Components Microorganism Health functional properties References Dopamine Lactobacillus reuteri ATG-F4Increase of cytokine IL-10 and serum dopamine level (AD) [66] Dopamine Lactobacillus plantarum PS128Reduction of motor dyskinesia and neurol apoptosis (PD) [69] Dopamine Bifidobacterium bifidum ,Bifidobacterium longum ,Lactobacillus rhamnosus ,Lactobacillus rhamnosus GG,Lactococcus lactis subsp.lactis ,Lactobacillus plantarum LP28Protection of dopamine-releasing neurons
Decrease of motor dysfunctions[71] GABA Lactobacillus sp.,Bifidobacterium sp.Reduction of anxiety and depression (anxiety and depression) [53] GABA Lactobacillus rhamnosus JB-1Alleviation of anxiety and depression by decreasing corticosterone (anxiety and depression) [8] GABA Lactobacillus rhamnosus YS9Control nerve [57] Histamine Lactobacillus sp.,Lactococcus sp.,Enterococcus sp.,Streptococcus sp.,Escherichia sp.Regulation of emotions Regulation of sleep and cognitive function (cognition) [53] Metabolites Bacteroides fragilis NCTC 9343Reduction of autistic behavior (AD) [49] Metabolites Bifidobacterium breve A1Reduction of neuroinflammation (AD) [67] SCFA Lactobacillus rhamnosus ,Lactobacillus reuteri ,Bacterioides fragilis Regulation of anti-inflammatory pathways (AD) [53] Serotonin Lactobacillus sp.Lactococcus sp.,Enterococcus sp.,Streptococcus sp.,Escherichia sp.Regulation of emotions, sleep, and cognitive function (anxiety and depression, cognition) [53] GABA, gamma-amino butyric acid; SCFAs, short-chain fatty acids; AD, Alzheimer's disease; PD, Parkinson’s disease.
Autism Spectrum Disorder
Autism spectrum disorder (ASD) is a brain development disorder characterized by difficulties in social interactions, language, and repetitive behavioral patterns [55]. The cause of ASD has not yet been indicated. However, the interaction between ASD and the gut-brain axis has received considerable attention [56]. As the association between gut microbiome and ASD has been reported, ASD research on the microbiota-gut-brain axis has been actively conducted [55]. In the autistic mouse model,
Anxiety and Depression
Increasing interest on the potential impact of the gut-brain axis on anxiety and depression, which are associated with mood or mental health disorders, has been observed. In particular, depression rates are expected to increase owing to coronavirus pandemic and post-pandemic conditions [58]. Recent studies suggests that the gut-brain axis, which involves bidirectional communication between the gut and the CNS, might play a pivotal role in the development and management of anxiety and depression [59]. Probiotics metabolites or metabiotics, are thought to influence this axis by modulating the production of neuroactive molecules, such as serotonin and GABA, both of which are involved in mental regulation [58]. In addition, the SCFAs produced by probiotics may have anti-inflammatory properties that can mitigate neuroinflammation, a factor implicated in mood and mental disorders. In addition, GABA, which is produced by
Alzheimer’s and Parkinson’s Diseases
Alzheimer’s (AD) and Parkinson’s (PD) disease are neurodegenerative disorders that profoundly affect the nervous system and lead to progressive and debilitating symptoms. Primary neuropathological characteristics of AD are the accumulation of protein fragments, known as beta-amyloid (beta-amyloid plaques) outside neurons and aggregation of abnormally structured tau protein (tau tangles) inside neurons [61]. AD is primarily characterized by cognitive decline, memory impairment, and behavioral changes. In addition, AD has been reported as a major cause of dementia; however, the exact reason for remains unknown [62]. Recent studies have emphasized the role of the gut microbiome as a significant conditional factor influencing this disease. This has been demonstrated by extensive studies linking gut microbiota communities to neurodegenerative diseases, such as AD [63]. One study reported that SCFAs such as butyrate and propionate produced by
PD is reported as one of the fastest growing neurological disorders globally due to various social and environmental factors and is the second most common neurodegenerative disorder [62, 66]. PD symptoms include motor, non-motor, emotional, and cognitive disorders, as well as inflammatory bowel syndrome [67]. This disease is idiopathic; however, the accumulation of alpha-synuclein and subsequent agitation of gastrointestinal function due to mucosal inflammation have been suggested as the main cause of PD development [51]. In addition, chronic gut inflammation results in systemic intestinal inflammation, neuroinflammation, and neurodegeneration, either through gut-vagus brain signaling or affecting the permeability of the blood-brain barrier [68]. Previous studies have shown that the ingestion of
Immunomodulation and Anticancer Properties
Inflammation and cancer complement each other and are interrelated. Cancer is a serious diseases caused by chronic inflammation. Chronic and uncontrolled inflammation can promote cancer development owing to epigenetic changes, genomic instability, proliferation increase, and apoptosis resistance [71]. Metabiotics substances related to inflammation and cancer prevention and their functionality are shown in Table 2.
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Table 2 . Metabiotics related with microorganism and their immunomodulation and anticancer properties.
Components Microorganism Health functional properties References Immunomodulation Capsular polysaccharides Bacillus fragilis Help innate and adaptive immunomodulation [53] Folate, acetate, propionate, and butyrate Lactobacillus plantarum ,Lactobacillus casei ,Bifidobacterium bifidum ,Bifidobacterium infantis ,Bifidobacterium longum Regulation of immunity through inhibition of histone deacetylases and histone acetylation [49] Lipoteichoic acid Lactobacillus paracasei D3-5Anti-inflammatory effect by regulation the nuclear factor-kB (NF-κB) signaling [8] Polysaccharide-peptidoglycan complex Lactobacillus casei Inhibition of IL-6 synthesis by inhibiting NF-κB [74] Anticancer Bacteriocin Enterococcus faecium ,Bacillus subtilis ,Bifidobacterium Inhibition of Helicobacter pylori growth (gastric cancer)[53] Butyrate Lactobacillus plantarum Anti-proliferative and apoptosis (colorectal cancer) [76] Cell-free supernatant Lactobacillus acidophilus 36YLCytotoxic effects in HT-29 and HeLa cell lines (colorectal cancer and cervical cancer) [78] Bacillus adolescentis SPM0212Inhibition of cancer cell growth (colorectal cancer) [53] Lipoteichoic acid (LTA) Lactobacillus rhamnosus GGPreventing of skin cancer development [49] Peptide Saccharomyces cerevisiae CNCM I 3856Modification of pro-inflammatory cytokine production (colorectal cancer) [77] SCFAs Propionibacterium freudenreichii ,Apoptosis or necrosis against gastric cancer [53] Lactobacillus rhamnosus MD14Preventing of colorectal cancer by targeting on the Wnt/β-Catenin pathway (colorectal cancer) [9] SCFAs, short-chain fatty acids.
Studies reported that immunomodulatory mechanisms can alleviate, prevent, and treat autoimmune diseases and inflammation, and eliminate malignant host cells [45]. Metabiotics have been reported to exert several immunomodulatory effects. One research has reported that SCFAs maintain balance by reducing inflammatory cytokines such as IL-6 and TNF-α, stimulating the anti-inflammatory cytokine, IL-10 [71]. In addition, exopolysaccharides (EPS), monolayer proteins, peptidoglycans, lipoteichoic acid (LTA), conjugated linoleic acid, and peptides derived from probiotics have been reported to modulate the immune system [71]. Another research has reported polysaccharide-peptidoglycan complex by
Gut microbiota or their metabolites are known to prevent various cancers. Among metabolic byproducts, SCFAs are widely acknowledged as potent anticancer components. Their primary focus was on histone deacetylases, which induce epigenetic alterations through posttranslational modifications of histone proteins [45]. Metabiotics
Conclusion and Prospects
Probiotics have progressively developed in various form such as prebiotics, synbiotics, postbiotics, and metabiotics. General outlook on metabiotics, which are considered the next-generation probiotics, is highly promising and has significant potential in the realm of health and well-being.
As research on the connection between the gut and brain neurological health increases, research on the gut-brain axis is expected to be particularly interesting. Research has shown that metabiotics can play a pivotal role in brain function, neuroinflammation, and even the management of conditions such as ASD. In addition, new substances derived from probiotics and metabiotics are need for further material demonstration and human clinical studies of anticancer effects caused by chronic inflammation.
In the future, prevention and therapy using metabiotics is expected. Metabiotics related to intestinal microflora will not only improve the well-being of society but also demonstrate potential efficacy in the treatment and prevention of neurological disorders, as well as immunomodulatory and anticancer effects.
Author Contributions
H.J.J.: Conceptualization, Investigation, Writing – original draft, Writing – review & editing; N.K.L.: Conceptualization, Investigation, Writing – review & editing; H.D.P.: Conceptualization, Writing – review & editing.
Acknowledgments
This research was supported by the Korea Institute of Planning and Evaluation for Technology in Food, Agriculture, and Forestry (IPET) through the High Value-added Food Technology Development Program, funded by the Ministry of Agriculture, Food, and Rural Affairs (MAFRA) (#321035-5).
Conflict of Interest
The authors have no financial conflicts of interest to declare.
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J. Microbiol. Biotechnol. 2024; 34(3): 487-494
Published online March 28, 2024 https://doi.org/10.4014/jmb.2311.11023
Copyright © The Korean Society for Microbiology and Biotechnology.
A Narrative Review on the Advance of Probiotics to Metabiotics
Hye Ji Jang, Na-Kyoung Lee, and Hyun-Dong Paik*
Department of Food Science and Biotechnology of Animal Resources, Konkuk University, Seoul 05029, Republic of Korea
Correspondence to:Hyun-Dong Paik, hdpaik@konkuk.ac.kr
Abstract
Recently, the term metabiotics has emerged as a new concept of probiotics. This concept entails combining existing probiotic components with metabolic by-products improve specific physiological functionalities. Representative ingredients of these metabiotics include short-chain fatty acids (SCFAs), bacteriocins, polysaccharides, and peptides. The new concept is highly regarded as it complements the side effects of existing probiotics and is safe and easy to administer. Known health functions of metabiotics are mainly immune regulation, anti-inflammatory, anticancer, and brain-neurological health. Research has been actively conducted on the health benefits related to the composition of intestinal microorganisms. Among them, the focus has been on brain neurological health, which requires extensive research. This study showed that neurological disorders, such as depression, anxiety, autism spectrum disorder, Alzheimer's disease, and Parkinson's disease, can be treated and prevented according to the gut-brain axis theory by changing the intestinal microflora. In addition, various studies are being conducted on the immunomodulatory and anticancer effects of substances related to metabiotics of the microbiome. In particular, its efficacy is expected to be confirmed through human studies on various cancers. Therefore, developing various health functional effects of the next-generation probiotics such as metabiotics to prevent or treatment of various diseases is anticipated.
Keywords: Metabiotics, gut-brain axis, neurological disorder, immunomodulation, anticancer
Introduction
According to the World Health Organization (WHO) and Food Agriculture Organization (FAO), probiotics are defined as live microorganisms administered in adequate amounts for health benefits on the host [1]. Generally, probiotics have been associated with many health benefits, such as regulating intestinal flora, immune functions, as well as antimicrobial, anticancer, and anti-inflammatory effects [2, 3]. However, various concerns including viability control, gastrointestinal side effects, fungemia, and endocarditis exist [4-6]. Therefore, next-generation probiotics are being investigated to overcome these concerns [5].
Metabiotics are defined as bioactive compounds generated through the metabolic process of probiotic microorganisms, exerting a positive influence on various physiological process [7]. Metabiotics collectively refers to constituents of probiotic microorganisms, their metabolic by–products, and signaling molecules with well-defined chemical compositions [8]. These components are characterized by their ability to enhance specific physiological functions tailored to the host, including regulatory, metabolic, and behavioral responses. These interactions are closely associated with host microbiota activity [9]. The representative components of metabiotics are short-chain fatty acids (SCFAs), polyunsaturated fatty acids (PUFAs), bacteriocins, polysaccharides, and peptides [10].
Thus, this review aims to provide an overview of the metabiotics. We outline the current status of probiotics advancements to metabiotics and their health benefits. We also summarized the functionalities of metabiotics and provide an outlook on their future potential.
An Advance from Probiotics to Metabiotics
Lactic acid bacteria (LAB), especially those with positive effects on health, are commonly known as probiotics, a term introduced by Nobel Prize winner, Elie Metchnikoff [11].
Prebiotics is defined as non-digestible dietary fibers or compounds that serve as food for beneficial microorganisms, particularly probiotics, in the gastrointestinal tract [24, 25]. In 2016, a panel of experts in the field of microbiology, nutrition, and clinical research was convened by the International Scientific Association for Probiotics and Prebiotics (ISAPP) to assess and redefine the scope of prebiotics [26]. Typical substances included in prebiotics are polysaccharides (resistant starch, dextrin, and pectin) and oligosaccharides such as fructooligosaccharides (FOS) and galactooligosaccharide (GOS), xylooligosacharides (XOS), isomaltooligosaccharides (IMO), mannanoligosaccharides (MOS), raffinoseoligosaccharides (RFOs), arabinoxylanoligosaccharides (AXOS), and lactulose [27-29]. Prebiotics has been reported to inhibit pathogenic bacteria and cancer, reduce cardiovascular disease and cholesterol levels, and prevent constipation and obesity [29]. In addition, prebiotics are fermented by microorganisms in the intestines to produce SCFAs, including propionate, butyrate, and acetate, showing various health benefits, such as prevention of gastrointestinal conditions and reduction of cancer [28, 30, 31]. Recently, the significance of gut microbiotas has become increasingly important for health. Consequently, there is an emerging strategy to control microbiotas and their relationship with host [28]. Owing to their characteristics, prebiotics have been used as functional ingredients in various food industries [30]. Significant research on prebiotics has indicated their utilization in functional food applications, which involve providing benefits beyond their inherent nutrient compound to enhance overall well-being [32].
Synbiotics are a combination of probiotics and prebiotics that synergistically improve overall health and well-being [33]. Notably, the beneficial effects of synbiotics are greater than those of probiotics or prebiotics [34]. Recently, the ISAPP has defined synbiotics as follows: “a mixture of viable microorganisms and substrate(s) that are selectively utilized by host microorganisms and confer a health benefit on the host” [35]. Representative functional health effects include the re-modulation of gut bacterial dysbiosis, improvement of immunomodulation, and prevention of obesity. A principal example of synbiotics containing
Postbiotics are bioactive compounds produced by probiotics during metabolic processes. Unlike probiotics, which are live microorganisms, and prebiotics, which are the substrate that promote the growth of beneficial microorganisms, postbiotics are microbial cell components and actual metabolic products that emerge from probiotic activity, such as secreted enzymes, proteins, vitamins, SCFAs, and phenols [5, 38]. The terms ‘post’, indicating ‘after’, and ‘biotic’, which refers to originate from living organisms’, resulted in ‘postbiotic’. These components together imply ‘after life’, indicating materials that are produced by living microorganisms [39]. In general, postbiotics possess the advantages of stability and convenient transportability, which improve shelf life and simplify packaging. Thus, the active ingredient can be transferred to the desired location in the intestine [40]. Furthermore, postbiotics have a wide range of beneficial effects, including immunomodulatory, anticancer, and antimicrobial effects [41]. As virus-related diseases have increased significantly over the pasts few years, studies of postbiotics, which are effective in immune-modulation, antimicrobial, and antiviral, have been reported [42]. However, the precise of mechanism of postbiotics action is yet to be determined and limited experimental studies have been conducted. It has been reported that viral diseases could be minimized by adjusting immune system through interaction with molecules such as peptidoglycans [43]. Additionally, postbiotics have been used as functional materials in various products such as dairy foods, vegetables, bread, meat, fish products, and food ingredients [38].
Over the years, studies to identify microorganisms that benefit the host have been increasing. The functional efficacy of microorganisms is transmitted by living and non-living cells, and their metabolites. Thus, terms referred to in these studies have also been developed, including probiotics, synbiotics, postbiotics, and metabiotics [44]. Recently, a new concept for the probiotic term, metabiotics, has emerged. This has emerged as a new trend in biotechnology to improve the side effects of living probiotics and apply them in human treatments and health functional foods [45]. Metabiotics are characterized as bioactive substances produced through the metabolic activities of probiotic microorganism, contributing positively to a range of physiological process [7]. The term metabiotics is derived from the Greek prefix
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Figure 1. Composition and types of metabiotics.
Neurological Disorders Functionality by the Gut-Brain Axis
Recently, researchers have explored the health benefits associated with the composition of intestinal microorganisms. The gut microbiome plays a pivotal role in enhancing digestion and absorption of nutrients to generate energy [48]. Studies on the gut microbiome have highlighted the involvement of probiotics in various aspects of health, including the nervous system, inflammation, oncology, gastrointestinal tract, and endocrine system. Notably, probiotics plays a crucial role in supporting the immune system and brain health [49].
Furthermore, researchers have demonstrated a bidirectional association between the central nervous system (CNS) and gut microbiome [50]. Research indicates that microorganisms residing in the intestine release chemical messengers that affect cell responses along the vagus nerves, sending signals to the brain through these nerves [49]. Their main role is to regulate communication between the intestinal system and the CNS, now recognized as “gut-brain axis” [51].
Disruptions of the gut-brain axis can lead to neurological disorders such as depression, Alzheimer’s disease, and anxiety [51]. Intestinal bacteria are known to have the ability to produce numerous neuroactive molecules such as serotonin, gamma amino butyric acid (GABA) and SCFAs [52]. Recently, metabiotics, which is probiotic metabolites have recently been reported to possess neuroregulatory activity. Consequently, neurological disorders can be reduced through the delivery of substances produced by intestinal microbial communities, such as GABA, histamine, SCFAs, and serotonin [45, 51, 53, 54]. Table 1 shows metabiotics and associated microorganisms that control neurological disorders.
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Table 1 . Metabiotics related with microorganisms and their neurological properties..
Components Microorganism Health functional properties References Dopamine Lactobacillus reuteri ATG-F4Increase of cytokine IL-10 and serum dopamine level (AD) [66] Dopamine Lactobacillus plantarum PS128Reduction of motor dyskinesia and neurol apoptosis (PD) [69] Dopamine Bifidobacterium bifidum ,Bifidobacterium longum ,Lactobacillus rhamnosus ,Lactobacillus rhamnosus GG,Lactococcus lactis subsp.lactis ,Lactobacillus plantarum LP28Protection of dopamine-releasing neurons
Decrease of motor dysfunctions[71] GABA Lactobacillus sp.,Bifidobacterium sp.Reduction of anxiety and depression (anxiety and depression) [53] GABA Lactobacillus rhamnosus JB-1Alleviation of anxiety and depression by decreasing corticosterone (anxiety and depression) [8] GABA Lactobacillus rhamnosus YS9Control nerve [57] Histamine Lactobacillus sp.,Lactococcus sp.,Enterococcus sp.,Streptococcus sp.,Escherichia sp.Regulation of emotions Regulation of sleep and cognitive function (cognition) [53] Metabolites Bacteroides fragilis NCTC 9343Reduction of autistic behavior (AD) [49] Metabolites Bifidobacterium breve A1Reduction of neuroinflammation (AD) [67] SCFA Lactobacillus rhamnosus ,Lactobacillus reuteri ,Bacterioides fragilis Regulation of anti-inflammatory pathways (AD) [53] Serotonin Lactobacillus sp.Lactococcus sp.,Enterococcus sp.,Streptococcus sp.,Escherichia sp.Regulation of emotions, sleep, and cognitive function (anxiety and depression, cognition) [53] GABA, gamma-amino butyric acid; SCFAs, short-chain fatty acids; AD, Alzheimer's disease; PD, Parkinson’s disease..
Autism Spectrum Disorder
Autism spectrum disorder (ASD) is a brain development disorder characterized by difficulties in social interactions, language, and repetitive behavioral patterns [55]. The cause of ASD has not yet been indicated. However, the interaction between ASD and the gut-brain axis has received considerable attention [56]. As the association between gut microbiome and ASD has been reported, ASD research on the microbiota-gut-brain axis has been actively conducted [55]. In the autistic mouse model,
Anxiety and Depression
Increasing interest on the potential impact of the gut-brain axis on anxiety and depression, which are associated with mood or mental health disorders, has been observed. In particular, depression rates are expected to increase owing to coronavirus pandemic and post-pandemic conditions [58]. Recent studies suggests that the gut-brain axis, which involves bidirectional communication between the gut and the CNS, might play a pivotal role in the development and management of anxiety and depression [59]. Probiotics metabolites or metabiotics, are thought to influence this axis by modulating the production of neuroactive molecules, such as serotonin and GABA, both of which are involved in mental regulation [58]. In addition, the SCFAs produced by probiotics may have anti-inflammatory properties that can mitigate neuroinflammation, a factor implicated in mood and mental disorders. In addition, GABA, which is produced by
Alzheimer’s and Parkinson’s Diseases
Alzheimer’s (AD) and Parkinson’s (PD) disease are neurodegenerative disorders that profoundly affect the nervous system and lead to progressive and debilitating symptoms. Primary neuropathological characteristics of AD are the accumulation of protein fragments, known as beta-amyloid (beta-amyloid plaques) outside neurons and aggregation of abnormally structured tau protein (tau tangles) inside neurons [61]. AD is primarily characterized by cognitive decline, memory impairment, and behavioral changes. In addition, AD has been reported as a major cause of dementia; however, the exact reason for remains unknown [62]. Recent studies have emphasized the role of the gut microbiome as a significant conditional factor influencing this disease. This has been demonstrated by extensive studies linking gut microbiota communities to neurodegenerative diseases, such as AD [63]. One study reported that SCFAs such as butyrate and propionate produced by
PD is reported as one of the fastest growing neurological disorders globally due to various social and environmental factors and is the second most common neurodegenerative disorder [62, 66]. PD symptoms include motor, non-motor, emotional, and cognitive disorders, as well as inflammatory bowel syndrome [67]. This disease is idiopathic; however, the accumulation of alpha-synuclein and subsequent agitation of gastrointestinal function due to mucosal inflammation have been suggested as the main cause of PD development [51]. In addition, chronic gut inflammation results in systemic intestinal inflammation, neuroinflammation, and neurodegeneration, either through gut-vagus brain signaling or affecting the permeability of the blood-brain barrier [68]. Previous studies have shown that the ingestion of
Immunomodulation and Anticancer Properties
Inflammation and cancer complement each other and are interrelated. Cancer is a serious diseases caused by chronic inflammation. Chronic and uncontrolled inflammation can promote cancer development owing to epigenetic changes, genomic instability, proliferation increase, and apoptosis resistance [71]. Metabiotics substances related to inflammation and cancer prevention and their functionality are shown in Table 2.
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Table 2 . Metabiotics related with microorganism and their immunomodulation and anticancer properties..
Components Microorganism Health functional properties References Immunomodulation Capsular polysaccharides Bacillus fragilis Help innate and adaptive immunomodulation [53] Folate, acetate, propionate, and butyrate Lactobacillus plantarum ,Lactobacillus casei ,Bifidobacterium bifidum ,Bifidobacterium infantis ,Bifidobacterium longum Regulation of immunity through inhibition of histone deacetylases and histone acetylation [49] Lipoteichoic acid Lactobacillus paracasei D3-5Anti-inflammatory effect by regulation the nuclear factor-kB (NF-κB) signaling [8] Polysaccharide-peptidoglycan complex Lactobacillus casei Inhibition of IL-6 synthesis by inhibiting NF-κB [74] Anticancer Bacteriocin Enterococcus faecium ,Bacillus subtilis ,Bifidobacterium Inhibition of Helicobacter pylori growth (gastric cancer)[53] Butyrate Lactobacillus plantarum Anti-proliferative and apoptosis (colorectal cancer) [76] Cell-free supernatant Lactobacillus acidophilus 36YLCytotoxic effects in HT-29 and HeLa cell lines (colorectal cancer and cervical cancer) [78] Bacillus adolescentis SPM0212Inhibition of cancer cell growth (colorectal cancer) [53] Lipoteichoic acid (LTA) Lactobacillus rhamnosus GGPreventing of skin cancer development [49] Peptide Saccharomyces cerevisiae CNCM I 3856Modification of pro-inflammatory cytokine production (colorectal cancer) [77] SCFAs Propionibacterium freudenreichii ,Apoptosis or necrosis against gastric cancer [53] Lactobacillus rhamnosus MD14Preventing of colorectal cancer by targeting on the Wnt/β-Catenin pathway (colorectal cancer) [9] SCFAs, short-chain fatty acids..
Studies reported that immunomodulatory mechanisms can alleviate, prevent, and treat autoimmune diseases and inflammation, and eliminate malignant host cells [45]. Metabiotics have been reported to exert several immunomodulatory effects. One research has reported that SCFAs maintain balance by reducing inflammatory cytokines such as IL-6 and TNF-α, stimulating the anti-inflammatory cytokine, IL-10 [71]. In addition, exopolysaccharides (EPS), monolayer proteins, peptidoglycans, lipoteichoic acid (LTA), conjugated linoleic acid, and peptides derived from probiotics have been reported to modulate the immune system [71]. Another research has reported polysaccharide-peptidoglycan complex by
Gut microbiota or their metabolites are known to prevent various cancers. Among metabolic byproducts, SCFAs are widely acknowledged as potent anticancer components. Their primary focus was on histone deacetylases, which induce epigenetic alterations through posttranslational modifications of histone proteins [45]. Metabiotics
Conclusion and Prospects
Probiotics have progressively developed in various form such as prebiotics, synbiotics, postbiotics, and metabiotics. General outlook on metabiotics, which are considered the next-generation probiotics, is highly promising and has significant potential in the realm of health and well-being.
As research on the connection between the gut and brain neurological health increases, research on the gut-brain axis is expected to be particularly interesting. Research has shown that metabiotics can play a pivotal role in brain function, neuroinflammation, and even the management of conditions such as ASD. In addition, new substances derived from probiotics and metabiotics are need for further material demonstration and human clinical studies of anticancer effects caused by chronic inflammation.
In the future, prevention and therapy using metabiotics is expected. Metabiotics related to intestinal microflora will not only improve the well-being of society but also demonstrate potential efficacy in the treatment and prevention of neurological disorders, as well as immunomodulatory and anticancer effects.
Author Contributions
H.J.J.: Conceptualization, Investigation, Writing – original draft, Writing – review & editing; N.K.L.: Conceptualization, Investigation, Writing – review & editing; H.D.P.: Conceptualization, Writing – review & editing.
Acknowledgments
This research was supported by the Korea Institute of Planning and Evaluation for Technology in Food, Agriculture, and Forestry (IPET) through the High Value-added Food Technology Development Program, funded by the Ministry of Agriculture, Food, and Rural Affairs (MAFRA) (#321035-5).
Conflict of Interest
The authors have no financial conflicts of interest to declare.
Fig 1.
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Table 1 . Metabiotics related with microorganisms and their neurological properties..
Components Microorganism Health functional properties References Dopamine Lactobacillus reuteri ATG-F4Increase of cytokine IL-10 and serum dopamine level (AD) [66] Dopamine Lactobacillus plantarum PS128Reduction of motor dyskinesia and neurol apoptosis (PD) [69] Dopamine Bifidobacterium bifidum ,Bifidobacterium longum ,Lactobacillus rhamnosus ,Lactobacillus rhamnosus GG,Lactococcus lactis subsp.lactis ,Lactobacillus plantarum LP28Protection of dopamine-releasing neurons
Decrease of motor dysfunctions[71] GABA Lactobacillus sp.,Bifidobacterium sp.Reduction of anxiety and depression (anxiety and depression) [53] GABA Lactobacillus rhamnosus JB-1Alleviation of anxiety and depression by decreasing corticosterone (anxiety and depression) [8] GABA Lactobacillus rhamnosus YS9Control nerve [57] Histamine Lactobacillus sp.,Lactococcus sp.,Enterococcus sp.,Streptococcus sp.,Escherichia sp.Regulation of emotions Regulation of sleep and cognitive function (cognition) [53] Metabolites Bacteroides fragilis NCTC 9343Reduction of autistic behavior (AD) [49] Metabolites Bifidobacterium breve A1Reduction of neuroinflammation (AD) [67] SCFA Lactobacillus rhamnosus ,Lactobacillus reuteri ,Bacterioides fragilis Regulation of anti-inflammatory pathways (AD) [53] Serotonin Lactobacillus sp.Lactococcus sp.,Enterococcus sp.,Streptococcus sp.,Escherichia sp.Regulation of emotions, sleep, and cognitive function (anxiety and depression, cognition) [53] GABA, gamma-amino butyric acid; SCFAs, short-chain fatty acids; AD, Alzheimer's disease; PD, Parkinson’s disease..
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Table 2 . Metabiotics related with microorganism and their immunomodulation and anticancer properties..
Components Microorganism Health functional properties References Immunomodulation Capsular polysaccharides Bacillus fragilis Help innate and adaptive immunomodulation [53] Folate, acetate, propionate, and butyrate Lactobacillus plantarum ,Lactobacillus casei ,Bifidobacterium bifidum ,Bifidobacterium infantis ,Bifidobacterium longum Regulation of immunity through inhibition of histone deacetylases and histone acetylation [49] Lipoteichoic acid Lactobacillus paracasei D3-5Anti-inflammatory effect by regulation the nuclear factor-kB (NF-κB) signaling [8] Polysaccharide-peptidoglycan complex Lactobacillus casei Inhibition of IL-6 synthesis by inhibiting NF-κB [74] Anticancer Bacteriocin Enterococcus faecium ,Bacillus subtilis ,Bifidobacterium Inhibition of Helicobacter pylori growth (gastric cancer)[53] Butyrate Lactobacillus plantarum Anti-proliferative and apoptosis (colorectal cancer) [76] Cell-free supernatant Lactobacillus acidophilus 36YLCytotoxic effects in HT-29 and HeLa cell lines (colorectal cancer and cervical cancer) [78] Bacillus adolescentis SPM0212Inhibition of cancer cell growth (colorectal cancer) [53] Lipoteichoic acid (LTA) Lactobacillus rhamnosus GGPreventing of skin cancer development [49] Peptide Saccharomyces cerevisiae CNCM I 3856Modification of pro-inflammatory cytokine production (colorectal cancer) [77] SCFAs Propionibacterium freudenreichii ,Apoptosis or necrosis against gastric cancer [53] Lactobacillus rhamnosus MD14Preventing of colorectal cancer by targeting on the Wnt/β-Catenin pathway (colorectal cancer) [9] SCFAs, short-chain fatty acids..
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