Classification of Postbiotics: Comparison
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Please note this is a comparison between Version 2 by Jason Zhu and Version 1 by Pratheep Thangaraj.

Postbiotics are (i) “soluble factors secreted by live bacteria, or released after bacterial lysis, such as enzymes, peptides, teichoic acids, peptidoglycan-derived muropeptides, polysaccharides, cell-surface proteins and organic acids”; (ii) “non-viable metabolites produced by microorganisms that exert biological effects on the hosts”; and (iii) “compounds produced by microorganisms, released from food components or microbial constituents, including non-viable cells that, when administered in adequate amounts, promote health and wellbeing”. A probiotic- and prebiotic-rich diet ensures an adequate supply of these vital nutrients. During the anaerobic fermentation of organic nutrients, such as prebiotics, postbiotics act as a benevolent bioactive molecule matrix. Postbiotics can be used as functional components in the food industry by offering a number of advantages, such as being added to foods that are harmful to probiotic survival. Postbiotic supplements have grown in popularity in the food, cosmetic, and healthcare industries because of their numerous health advantages. Their classification depends on various factors, including the type of microorganism, structural composition, and physiological functions. 

  • postbiotics
  • prebiotics
  • probiotics
  • metabolites

1. Introduction

The classification of postbiotics depends on various factors, including the type of microorganism, structural composition, and physiological functions. Various postbiotic compounds produced by extracellular and intracellular probiotic bacteria have also been identified. For example, muropeptides are derived from peptidoglycans, exopolysaccharides (EPSs), teichoic acids, surface-protruding molecules such as fimbriae, pili, or flagella that make up cell wall components, secreted proteins/peptides, bacteriocins such as acidophilin, reuterin, and bifidin, cell-free supernatants, organic acids, neurotransmitters, and biosurfactants [64,103][1][2]. Owing to their unique physical, chemical, and functional properties, postbiotics are classified into different types, including inactivated and dead probiotics, peptidoglycans, teichoic acids, exopolysaccharides, cell-free supernatants, short-chain fatty acids, bacteriocins, enzymes, and vitamins.

2. Inactivated and Dead Probiotics

Although other techniques, such as gamma or UV radiation, tyndallization, sonication, and chemical treatment, are used for the preparation of postbiotics, heat is the most frequently used method for the production of inactivated or dead probiotics. This inactivation process causes differences in the cellular makeup and biological functions [25][3]. According to studies conducted on experimental models, the biological characteristics of their viable counterparts, such as the ability to scavenge oxygen radicals, reduce inflammatory indicators, and modify host physiology, are retained by nonviable cells [104][4]. Recent studies on eight different strains of Lactobacillus reuteri suggest that both live and heat-killed cells of these bacteria adhered to caco 2 cell cultures and prevented enteropathogens such as E. coli, Salmonella typhi, Listeria monocytogenes, and Enterococcus faecalis from adhering to them [105][5].

3. Cell-Free Supernatants/Suspensions

Cell-free supernatants (CFSs) are a broad category of biomolecular and active metabolites with low or high molecular weights, such as organic acids, diacetylene, carbon dioxide, and bacteriocin-like substances, which are typically secreted by lactic acid bacteria and yeasts and may help maintain homeostasis in the body [106,107][6][7]. The composition of a medium can influence CFS composition. Cell-free supernatants (CFSs) are fluids that include nutrients from the growth medium that are not absorbed by microbes as well as any metabolites left over from microbial development. CFS, which is produced when microbes are fermented, has antibacterial, antibiofilm, anti-inflammatory, antioxidant, and anticancer activities and is used to treat diarrhea [108][8]. Generally, CFS is obtained from safe bacteria, and the bioactive material can be used as an alternative to common antimicrobials. The metabolites can be isolated from microbial cells by centrifugation and are highly abundant in anti-inflammatory, anticancer, antioxidant, phenolic, and flavonoid chemicals. These metabolites potentially increase the expression of anti-inflammatory cytokines like IL-10 and suppress pro-inflammatory cytokines like TNF α and IL-1β. Owing to the presence of organic acids, proteinaceous compounds, and fatty acids, the CFS generated by LAB may have an antimicrobial effect. Lactic and acetic acids, together with other substances, are principally responsible for the antibacterial action of LAB [109][9]. The anti-proliferative effects of a cell-free culture filtrate from Lactobacillus fermentum were also reported by Lee [110][10], who examined the anticancer capabilities of this substance. They used 3D spheroid cultures of colorectal cancer (CRC) cells as a model for their research. According to another study, cell-free Lactobacillus reuterine supernatant, which is likely to contain carbohydrates and fatty acid metabolites, has the potential to be used for the prevention and treatment of dental caries and periodontal diseases.
Hamad reported the antibacterial ability of culture suspensions produced from four probiotic strains, including L. rhamnosus, L. fermentum, L. delbrueckii subsp. lactis, and Pediococcus acidilactici, against Clostridium perfringens [111][11]. The growth of Staphylococcus aureus, E. coli, Aspergillus niger, and Aspergillus flavus is significantly suppressed by lactic acid, hydrogen peroxide, protein, and diacetyl generated from Lactobacillus and Pediococcus species culture filtrate [112][12]. The mechanism of inhibition appears to involve the creation of pores in cell membranes and cell lysis caused by lactic acid bacteria-producing bacteriocins, followed by the actions of diacetyl and bacteriocins. Lantibiotics (class I) are among the pore-forming peptides that are produced by lactic acid bacteria. These peptides typically form unstable pores and exhibit a wide range of activity. The majority of bacteriocins have interactions with anionic lipids, which are widely found in Gram-positive bacteria membranes. “Docking molecules” have the potential to improve the conductivity and stability of lantibiotic pores; “wedge-like” pores may be formed by antibiotics; and “carpet” or “barrel stave” pores may be formed by class II bacteriocins, which may increase membrane permeability [113][13].Hydrogen peroxide, fatty acids, secreted proteins, and organic acids have been detected in the culture suspension of the dental health probiotic Weissella cibaria strain CMU. Organic acids, secreted proteins, and hydrogen peroxide have all been shown to exert antibacterial activities against periodontal pathogens by disrupting cell membranes, lowering the pH of the cytosol, producing hydroxyl radicals, and interfering with cellular metabolic functions [94][14]. As with several biomolecules, CFS seems to have superior biological effects on host health compared with pure biomolecules [114][15]. Pyrrolo [1,2-a] pyrazine-1,4-dione has been observed in the CSF of several examined species of lactobacilli using GC-MS analysis. Strain-specific substances such as butyric acid, benzoic acid, biosurfactants (laurostearic acid), different peptides, fatty acids, ethanol, phenol, cyclopentanes, esters, and aldehydes are also present in strain-specific ways. Many of these substances exhibited antioxidant, biofilm removal, and antagonistic activities against L. monocytogenes, indicating their potential application as food additives, particularly L. salivarius [15][16]. The CFS antibacterial activity of Enterococcus faecalis was found to be thermostable and peaked at a neutral pH of 7.0, supporting its use in food preservation [115][17]. CFS is produced in various cultures, and bacterial strains exhibit differential functions. CFS derived from L. acidophillus and L. casei has antioxidant and anti-inflammatory effects [86][18]. Lactobacillus and Bifidobacterium also exert antibacterial activities by inhibiting E. coli strains [116][19]. It has been postulated that the antioxidant capacity of diverse intracellular fractions formed from Lactobacillus strains mediates an increase in cellular glutathione concentration, which is a significant non-enzymatic antioxidant essential for maintaining the intracellular redox state. However, these non-enzymatic postbiotic antioxidant properties may also have scavenging effects on ROS and reactive nitrogen species [26,117,118][20][21][22].

4. Cell Wall Fragments

The cell wall contains various components, including teichoic and lipoteichoic acids. Among the immunogenic components of bacterial cell walls, teichoic acids, lipoteichoic acids, and other compounds can elicit an immune response [119][23]. The cell wall of Gram-positive bacteria is mostly composed of lipoteichoic and teichoic acids, which account for approximately 60% of the cell wall mass [120][24]. Different lipoteichoic acid structures among the four strains of Lactobacillus plantarum lead to various immunological reactions in immune cells, as evidenced by the lipoteichoic acid recovered from the K8, K88, K5-5, and K55-5 strains of L. plantarum [121][25]. Teichoic acids are essential for the pathophysiology and development of antibiotic resistance [122][26]. According to Lebeer et al. [123][27], teichoic and lipoteichoic acids exhibit various bioactivities, including anticancer, immunomodulatory, and antioxidant activities.

5. Exopolysaccharides

According to Caggianiello et al. [124][28], lactobacilli and other bacteria produce a variety of homo- and heteropolysaccharides, including kefricin, glucans, and uronic acid. These are collectively referred to as exopolysaccharides (EPSs) and can be released extracellularly, cling to the surface of the microbial cell as a slime layer, or remain firmly attached as a capsule. These macromolecules have the power to defend against phages, phagocytes, and toxic substances; however, they also affect the immune system, physiological processes, lipid metabolism, and pathogen colonization in hosts. According to a study by Dinic et al. [125][29], EPS from Lactobacillus paraplantarum BGCG11 decreased proinflammatory (IL-I, TNF, and iNOS) and concurrently elevated anti-inflammatory (IL-6 and IL-10) cytokines, thereby reducing inflammation in rats. According to Liu et al. and Wang et al. [74[30][31],126], EPSs generated from probiotic Lactobacillus fermentum and Paenibacillus polymyxa cultures show antioxidant activity and may thus have therapeutic effects in diseases such as diabetes, atherosclerosis, and rheumatoid arthritis. Additionally, EPSs extracted from pathogenic E. coli and S. aureus prevented the development of biofilms and suppressed tumor growth and inflammation [74][30]. The bioremediation, pharmaceutical, food, and textile industries have significant applications of EPSs derived from various bacteria [127][32]. Examples of food additives include xanthan, alginate, gellen, levans, and pullulan [128][33]. Centrifugation is the first stage in a multiphase method to extract EPSs, which also includes acid protein removal, cold ethanol precipitation, filtration to remove small molecules, dialysis, and lyophilization [129][34]. EPSs are essential for cell adhesion and defense, and the structural diversity of EPSs produced by lactic acid bacteria (LAB) enables polymers to have a range of bioactivities, including immunomodulatory, antitumor, antimutagenicity, antioxidant, anti-inflammatory, antihypertensive, antibacterial, antiviral, cholesterol-lowering, and anti-gastrointestinal activities [130][35]. Khalil et al. [131][36] reported that EPS generated from Lactobacillus strains showed antibacterial and antioxidant activities and improved lipid metabolism by inhibiting cholesterol absorption. By increasing the activities of antioxidant enzymes, such as catalase, glutathione peroxidase, and superoxide dismutase, and lowering the levels of lipid peroxidation in serum and mouse livers, EPSs generated from Lactococcus lactis subsp. lactis displayed antioxidant activity [132][37]. Currently, the food industry uses EPSs as emulsifiers, stabilizers, and water-binding agents.

6. Enzymes

Enzymes are proteins that catalyze biological reactions. Based on their activities or functions, enzymes can be classified into six primary groups: oxidoreductases, transferases, hydrolases, lyases, isomerases, and ligases [133,134][38][39]. A small number of bacterial strains, primarily Bacillus subtilis and Bacillus licheniformis, as well as a few fungal strains, notably, Aspergillus niger and Aspergillus oryzae, are the primary sources of enzymes that are used in a variety of physiological, metabolic, and regulatory processes. A significant amount of glutathione peroxidase was detected in two strains of Lactobacillus fermentum, which was later discovered to possess strong in vitro antioxidant capabilities. Under difficult conditions such as temperature, pH, organic solvents, oxidizing agents, and detergents, Bacillus spp.can produce proteolytic enzymes in large yields that are remarkably stable. Catalase from a genetically modified strain of L. lactis can protect mice from chemically induced colon cancer [135,136,137][40][41][42].

7. Short Chain Fatty Acids (SCFAs)

Short-chain fatty acids (SCFAs) are an important class of compounds produced by gut bacteria such as Bacteroides and Firmicutes, which ferment plant polysaccharides [138][43]. Inulin and fructooligosaccharides, two prebiotics, are fermented to produce SCFAs, primarily acetate, propionate, and butyrate, which are found in the colon and feces at an estimated 60:20:20 molar ratio and aid in the regeneration of the intestinal epithelium [139,140][44][45]. In addition, they suppress the production of pro-inflammatory cytokines, preventing the activation of nuclear factor-kappa B (NF-κB). A reduction in atherogenesis in a mouse model was demonstrated using an in vivo butyrate model [141][46]. Acetate and lactate are produced by bifidobacteria when too many carbon atoms are available for development. Inhibiting the growth of Klebsiella oxytoca, for instance, Lactobacillus acidophilus, Lactobacillus fermentum, Lactobacillus paracasei ATCC 335, and Lactobacillus brevis produced SCFAs by lysing the cell wall [142][47]. SCFs exert several beneficial effects on health. In addition to improving colonic function and lowering pH, they promote the proliferation of epithelial cells and blood flow in the colon [143][48]. Bird et al. [144][49] found that SCFAs significantly lowered the prevalence of colorectal diseases. When colonic bacteria ferment undigested carbohydrates, they produce mostly acetate, propionate, and butyrate in ratios that normally vary from 3:1:1 to 10:2:1. Acetate aids cholesterol regulation and is used as a growth factor by other bacteria. Propionate and butyrate play a role in gluconeogenesis, providing colonocytes and epithelial cells with their main source of energy and promoting apoptosis of colon cancer cells [145][50].

8. Bacteriocins

Lactic acid bacteria (LAB), as well as other eubacteria and archaebacteria, produce tiny ribosomally synthesized peptides or proteins known as bacteriocins that can either kill or impede the growth of other bacteria. According to Soltani et al. [146][51], the therapeutic utility of bacteriocins as next-generation antimicrobials for reducing the threat posed by drug-resistant pathogenic organisms is highlighted by their restricted broad-spectrum inhibitory effect against bacterial growth. Examples include nisin, subtilosin, lactococcin G&Q, enterocin, lactocyclicin, bovicin, plantaricin, and lacticin, among others [147][52]. Bacteriocins have demonstrated potential for use in food preservation. Nisin was the first bacteriocin to receive regulatory approval for commercial use as a food preservative from organizations such as the European Food Safety Authority (EFSA), Food and FDA, and Health Canada. Currently, it is used as a food additive in more than 80 countries. Bacteriocins prevent pathogen growth in the GI tract by creating pores in cell membranes, preventing the proper construction of cell walls, and inhibiting enzyme and protein functions. Multibacteriocinogenic strains of L. paracasei and L. taiwanensis show antibacterial activity against E. coli, Salmonella gallinarum, and enteropathogenic E. coli [148,149][53][54]. Because of their various qualities, bacteriocins have been widely used in various applications, including medicine, cancer therapy, food, cosmetics, and veterinary medicine.

9. Vitamins

Vitamins are thermosensitive chemical substances that are necessary for the body to perform a number of physiological processes, including DNA replication, repair, and methylation, and vitamins must be supplied exogenously.Vitamins play a crucial role in many physiological processes such as bone health, brain function, and blood clotting, and riboflavin acts as a hydrogen carrier in redox reactions. Vitamin K also plays a role as a cofactor of gamma carboxylase activity in blood clotting, and various other critical vitamins, such as vitamin K, and various B-group vitamins, such as folate, riboflavin, cobalamin, pyridoxine, thymine, niacin, and nicotinic acid, are produced by lactic acid bacteria and Bifidobacterium sp. [150][55]. Numerous fermented foods, including fermented milk, yogurt, and cheese, are major sources of these vitamins, which help the digestive system. In addition to being essential for producing energy, controlling genes, and changing intestinal immunity, B-group vitamins, including B12, B2, B6, B9, and vitamin K, may all be synthesized by the gut microbiome on their own. For example, vitamins B2, B6, and B9 exerted anti-tumorigenic effects against pro-monocytic lymphoma cells [151][56].Cobalamin, generally known as vitamin B12 (B12), is a water-soluble vitamin essential for maintaining hematopoiesis and neuronal health. It is also an essential nutrient in animal products. Probiotics such as L. sanfranciscensis, L. reuteri, L. rossiae, and L. fermentum, which have been shown to synthesize vitamin B12 and could be useful substitutes for industrial production, have recently been found to contain genes encoding enzymes necessary for cobalamin (B12) synthesis [152,153,154][57][58][59]. In contrast to MK-6, MK-8, and MK-9, which are produced by Bacteroides fragilis, MK-10, MK-11, and MK-12 are produced by Eubacterium lentum, Lactococcus lactis ssp. lactis, and Lactococcus lactiscremoris [155][60]. Cortés-Martin et al. [156][61] found that the gut microbiota also produces dietary polyphenols. Aromatic amino acids are generated and metabolized in the gut to function as bioactive molecules in circulatory, renal, and brain systems [157][62].

10. Neurotransmitters

Neurotransmitters, such as serotonin, dopamine, norepinephrine, catecholamines, and acetylcholines, are produced by gut bacteria such as Bifidobacterium, Lactobacillus plantarum, Lactobacillus brevis, and Bacillus subtilis. These neurotransmitters play a major role in brain function via the gut–brain axis through the modulation of enteric nerve signaling. Tryptophan is an amino acid that is transformed into serotonin, which is responsible for mood improvement. Gamma-aminobutyric acid inhibits neurotransmission, and when it does not work, anxiety and depression result. Acetylcholine and catecholamines are essential for CNS activities, such as emotion, memory, learning, and motor control [157,158,159][62][63][64]. According to Patterson et al. [159][64], microbiome management can cure mental conditions linked to depression, and these compounds appear to have antidepressant potential.

11. Extracellular Vesicles

EVs are spherical, lipid bilayer, membrane-bound particles that release commensal bacteria, such as E. coli and Akkermansia muciniphila, into the environment. They are involved in the horizontal transfer of genetic material across bacterial species and contain a variety of substances, including proteins, DNA, RNA, glycolipids, polysaccharides, enzymes, and toxins. According to studies by Ahmadi Badi et al. and Chelakkot et al. [159[64][65],160], these substances are thought to regulate the permeability of the gut barrier and signaling pathways, maintain intestinal homeostasis, improve lipid profiles, and facilitate communication between the gut and brain. Survival, competitiveness, pathogenesis, and immunomodulation are some mechanisms regulated by bacterial EVs. They can also swiftly cross the mucosal barrier and interact with the host, thereby lowering the risk of sepsis. Previous studies have shown an association between obesity and reduced barrier integrity. Increased intestinal barrier permeability causes metabolic endotoxemia, which is the primary contributing factor to obesity-related metabolic diseases [161,162,163][66][67][68]. EVs derived from Akkermansia muciniphila reduced fat accumulation, body weight gain, and pathological abnormalities in high-fat diet (HFD)-fed mice; the tested EVs had the most significant effects on adipocyte size, epididymal white adipose tissue (eWAT) weight, lipid balance, and expression of inflammatory cytokines in the adipose tissue and glucose tolerance in diabetic mice. EVs derived from Propionibacterium freudenreichii can mitigate inflammation by modulating the NF-B pathway [161,164,165,166,167][66][69][70][71][72].Recently, Gurunathan et al. reported that Pseudomonas aeruginosa-derived outer membrane vesicles exhibited antibacterial and antibiofilm effects against Streptococcus mutans. Extracellular nanovesicles produced by Bacillus licheniformis showed anticancer effects against breast and lung cancer cells [167][72].

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