Open access peer-reviewed chapter

Perspective Chapter: Role of Probiotics in the Intestinal Ecosystem and the Immune System

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Ivanna Novotny Núñez, Eva Vélez, Silvia I. Cazorla and Carolina Maldonado Galdeano

Submitted: 24 July 2024 Reviewed: 20 September 2024 Published: 24 October 2024

DOI: 10.5772/intechopen.1007436

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Abstract

The microbial colonizers of the intestine, collectively known as microbiota, are an essential and irreplaceable component of the human organism. They provide valuable functions and genetic resources (the microbiome) and play a critical role in various physiological processes, including somatic development, nutrition, and immunity. Maintaining intestinal homeostasis requires a delicate balance between the diverse array of microorganisms within the intestinal microbiota and the host cells, all within an environment constantly influenced by numerous stimuli from both external and internal sources. Disruption of this balance, known as dysbiosis, is characterized by reduced microbial diversity and deviation from the ancestral microbial environment. Dysbiosis is linked to several chronic non-communicable diseases prevalent in developed societies, such as atopic conditions, metabolic syndrome, inflammatory diseases, cancer, and certain behavioral disorders. The increasing focus on the intestinal microbiota and its interaction with the immune system has spurred the development of new strategies to maintain intestinal balance and enhance overall health. Among these approaches, dietary interventions involving probiotics, prebiotics, synbiotics, and postbiotics hold significant promise for providing substantial health benefits to consumers.

Keywords

  • probiotics
  • prebiotics
  • synbiotics
  • posbiotics
  • intestinal immune system
  • epithelial cells (IECs)
  • immune cells

1. Introduction

It is known that diet plays a fundamental role in the health of the intestinal microbiota. Its diversity depends largely on the variety and quality of the foods consumed. In addition to diet, probiotics and prebiotics are widely used to maintain a healthy microbiome.

There are numerous studies demonstrating the health benefits attributed to the consumption of probiotics. Probiotics are defined by the Food and Agriculture Organization of the United Nations (FAO) and the World Health Organization (WHO) as “live microorganisms which, when administered in adequate amounts, confer health benefits on the host” [1]. Currently, there is a growing interest in their use, as a strategy to improve the intestinal barrier and the health of the consumer. Probiotics are known to have numerous benefits such as modulation of the immune system, reinforcement of the intestinal barrier, improvement of the intestinal microbiome, reduction of serum cholesterol, alleviation of allergic processes and symptoms of inflammatory bowel disease (IBD), as well as anticancer activity [2, 3, 4, 5, 6, 7]. Lactic acid bacteria, including species of lactobacilli, bifidobacteria, streptococci, lactococci and some strains of yeast (Saccharomyces) are the most widely used microorganisms for the development of probiotic products [8].

Prebiotics have been defined as “a non-digestible food ingredient that beneficially affects the host by selectively stimulating the growth and/or the activity of one or a limited number of bacteria in the colon” [9]. Prebiotics are substrates that are selectively utilized by host microorganisms, conferring a health benefit. Selectivity plays a key role in the prebiotic concept. Prebiotics such as fructooligosaccharides (FOS) and galactooligosaccharides (GOS) primarily stimulate the proliferation of Lactobacilli and Bifidobacteria, unlike fibers (cellulose, pectins and xylans), which promote the growth of many microorganisms in the intestine. There are different prebiotic effects, such as defense against pathogens, immune modulation, mineral absorption, intestinal function, metabolic effects and satiety [10].

Synbiotics refer to the combination of a probiotic with a prebiotic with the aim of improving human or animal health [11]. They are used to amplify the benefits of the probiotic as well as to stimulate the growth of indigenous beneficial microorganisms [12]. In synbiotic products, probiotic bacteria selectively use prebiotics as a substrate for their growth [13]. Synbiotics can be of two types: (1) complementary synbiotics: which consist of a probiotic and a prebiotic together, which confer one or more health benefits but do not require codependent functions; (2) synergistic synbiotics: they contain a substrate, which is selectively used by the co-administered microorganisms, according to the International Scientific Association of Probiotics and Prebiotics [14].

Postbiotic refers to a term derived from the Greek “post,” meaning after, and “bios,” meaning life. Therefore, the term postbiotic refers to substances derived after the microorganisms are no longer alive, that is, they are dead or inactivated and confer health benefits. A postbiotic was defined 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”. Postbiotics may be composed of intact inanimate cells or may be structural fragments of microorganisms, such as cell walls. Many postbiotic preparations may contain substances produced by microorganisms (metabolites, proteins or peptides), which although not essential for a postbiotic may contribute to the health effect elicited by the postbiotic itself (Figure 1) [15].

Figure 1.

A stable gut microbiome is essential for defending the host against harmful microorganisms and maintaining homeostasis, while also playing a critical role in balancing the gut microbiota with immune system. Disruptions to this balance can occur due to dietary changes, antibiotic use, aging, or infections, leading to alterations in the gut microbiota. These disturbances are often linked to inflammatory, pathogenic, and metabolic conditions. In this context, dietary interventions-such as the use of probiotics, prebiotics, synbiotics, or postbiotics-are crucial for restoring microbiota balance.

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2. Probiotics

The human intestine is known to be a complex ecosystem, where microbiota, nutrients and host cells interact to maintain intestinal homeostasis and host development. The intestinal microbiota is composed of different bacteria, which carry out certain functions, such as metabolic functions and barrier effect, among others [16].

The intestinal microbiome can be altered by diet, lifestyle, exposure to toxins and the use of antibiotics. This is why the microbiota can play a fundamental role in gastrointestinal disorders such as inflammatory bowel disease, celiac disease, functional and motility disorders, metabolic and immune functions, among others [12].

These close relationships between the intestinal microbiota, health and disease have generated great interest in the use of probiotics. In recent years, various mechanisms have been described on probiotics maintenance of intestinal homeostasis and immune system modulation [8].

The imbalance of the structure and function of the intestinal microbiota is known as microbial dysbiosis. Recently, it has been shown that intestinal microbiota dysbiosis is associated with intestinal disorders such as IBD, irritable bowel syndrome (IBS) and celiac disease, being probiotics an alternative to restore intestinal microbial balance and prevent infections in patients after treatment with antibiotics, which induces intestinal microbiota dysbiosis [17].

Intestinal microbiota is also modified in metabolic disorders as obesity [18]. There are studies in animal and human models where it has been shown that the intestinal microbiota is different in lean and obese hosts. Therefore, the modification of the intestinal microbiota could have a beneficial effect and be used as a tool for future treatments [19].

Obesity is a chronic and multifactorial disease. It is strongly associated with an inflammatory process in which adipose tissue plays an important role, as well as hepatic steatosis and insulin resistance [20, 21, 22]. In a mouse model of obesity induced by a high-fat diet, the probiotic administration improved the intestinal microbiota and mucosal immunity, downregulated some blood biochemical parameters associated with metabolic syndrome, and decreased hepatic steatosis. Administration of probiotics, as fermented milk, was associated with a decrease in proinflammatory cytokines, in the small intestine and liver of diet-induced obese mice. The authors demonstrated the potential of probiotics in obese individuals to reduce body weight and improve biochemical and immunological parameters that are altered in obesity. Therefore, due to the anti-inflammatory effects of probiotic microorganisms, they could be used as dietary supplements to combat obesity and its related disorders [23, 24]. There are studies in which the administration of probiotics to mice was evaluated in two experimental models: obesity and senescence, including mice of different ages (21, 28, 45, 90 and 180 days). Authors observed that probiotic consumption improved the cortical/medullary ratio, cytokine production and regulation, as well as the recovery of mature T cell populations in thymus, in both obese and aged mice. Authors concluded that probiotics incorporation into diet could modulate the immune system and lead to the recovery of thymus function, thus improving the quality of life [25].

It is known that malnutrition, both by excess and deficiency, can negatively affect the number and activity of the immune cells [26, 27]. Malnutrition is a systemic disorder caused by an imbalance between nutrient intake and energy requirements, which causes a significant deterioration of the immune system. The architecture of the intestinal mucosa and the thymus is one of the most affected organs. Malnutrition can be reversed with adequate renutrition. In this sense, the administration of probiotics as a renutrition supplement could be useful to restore gastrointestinal and immune functions, regenerate the intestinal mucosa and improve its microbiota.

In a study carried out on malnourished mice, the administration of probiotics, such as probiotic fermented milk, restored the number of immune cells in the lamina propria of the small intestine, its functionality, reconstituted the architecture of the intestinal mucosa and stimulated local and systemic immunity. The importance of probiotic supplementation in the histological and functional recovery of the thymus has also been demonstrated in a model of non-severe protein-energy malnutrition in mice [28, 29].

The beneficial effect of probiotics in allergic processes has also been described. One of the most important signs that can be distinguished in this process is the increase of immunoglobulin E (IgE) [30]. It has been shown that probiotics could be effective in decreasing this immunoglobulin and in alleviating symptoms. In an experimental model of respiratory allergy, it was shown that probiotics induced a clear balance of T helper 1 (Th1) cells, favoring the production of IgG immunoglobulin instead of IgE and increased the levels of anti-inflammatory cytokines. The consumption of probiotics could be a strategy to improve respiratory tract allergies, mediating by the production of IgG [31].

It is known that probiotics have an effect on the functioning of the immune system. Probiotics are able to interact with intestinal epithelial cells (IECs) through their surface molecules; these cells establish a dialog between the host and the external environment. Immune cells associated with the intestinal epithelial can be activated after the internalization of the probiotic bacteria fragments in IECs, thus prolonging the survival of the gastrointestinal immune system and promoting the activation of immune cells in other distant organs (Figure 2) [32].

Figure 2.

Principal effects of probiotics.

Lemme Dumit et al. [33] evaluated the effect of oral administration of probiotic bacteria cell walls (PBCW) in healthy mice, mainly on intestinal epithelial cells (IECs). Probiotic bacteria and their cell walls stimulate IECs, exhibiting significant activation and release of cytokines. Probiotic bacteria and their cell walls have an important immunoregulatory effect on IECs without altering the homeostatic environment. These findings on the ability of probiotic bacteria cell walls to stimulate IECs and macrophages, as well as improve the functioning of the immune system, suggest that such structures could be applied as a new oral adjuvant [33].

Other important cells that play a fundamental role in the epithelial barrier are Paneth cells, which produce antimicrobial peptides (AMPs) that act in innate immunity. A study by Cazorla et al. [34] evaluated whether the antimicrobial activity against the pathogens Staphylococcus aureus and Salmonella Typhimurium, and Paneth cells are influenced by the probiotics administration, in a mouse model. The authors demonstrated that oral administration of probiotics can increase intestinal antimicrobial activity and Paneth cells, thereby strengthening the epithelial barrier against pathogens. They concluded that this could be another mechanism by which probiotics protect the host against infectious diseases [34].

However, mechanisms by which probiotics can modulate the immune system are not fully known.

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3. Prebiotics

Prebiotics were recognized over 20 years ago as a class of compounds capable of manipulating the host microbiota for the benefit of the host [9]. At that time, fructans, fructooligosaccharides, inulin and galactooligosaccharides fit that category, by an enrichment of Lactobacillus and/or Bifidobacterium spp intestinal microbiota. This definition has been reviewed several times until 2016, when the International Scientific Association for Probiotics and Prebiotics set prebiotics as a substrate that is selectively utilized by host microorganisms, conferring a health benefit [35].

While probiotics are live microorganisms, prebiotics are non-viable substrates that will boost the growth of beneficial microorganisms present in the host. This latest definition enlarges the benefit action of prebiotics to other body sites and not exclusively to the gastrointestinal tract [36]. Even more important, this last definition points to other microorganisms like Roseburia, Eubacterium or Faecalibacterium spp. as the drivers of the health-beneficial effects [37]. It was not until molecular-based methods replaced culture ones that employment of prebiotic substrates by these other bacteria genera was determined.

Prebiotics are early in life introduced to the human through breast milk. Currently, prebiotics include galactooligosaccharides (GOSs), mannan oligosaccharide (MOS), xylooligosaccharide (XOS), fructooligosaccharides (FOSs), inulin, as well as human milk oligosaccharides (HMO) [38, 39]. Plant polyphenols and other phytochemicals, pyrodextrins, conjugated linolenic acid (CLA), and PUFA (polyunsaturated fatty acids) constitute a class of compounds that can also meet the criteria of prebiotics [40, 41, 42]. Since oligosaccharides exhibit resistance to digestion, over 95% of HMOs reach the intestine, where they play their qualities.

Prebiotics elicit their effects through multiple mechanisms:

  1. Promote the proliferation of beneficial microorganisms and inhibit the growth of detrimental microorganisms.

    HMOs, through a competitive mechanism, inhibit the adhesion of pathogens to the neonate intestinal epithelium and avoid infections [43]. GOSs, also limit the growth of pathogens such as Staphylococcus aureus and Pseudomonas aeruginosa [44] and the adherence of Escherichia coli E2348/69 [45]. Additionally, GOS, by selectivity, increases the abundance of Bifidobacterium, leading to large concentrations of colonic short-chain fatty acids (SCFAs), particularly butyrate, which promotes the intestinal homeostasis through effects on the integrity of the colonic epithelium, metabolic and immunological actions [12]. Recent studies demonstrated that the production of biofilms, a mechanism displayed by the bacteria to adhere to various surfaces, was significantly decreased in the presence of prebiotics [46].

    Studies in mice have shown that oligofructose (a fructan) reduced inflammation by mechanisms linked with changes in specific gut microorganisms [35].

  2. Contribute to gut maturation and strengthen the intestinal barrier.

    In vitro, Kuntz et al. reported the growth inhibition of intestinal cells by MOS [47]. Similarly, Roselli et al., described that GOS inhibited an inflammatory response induced by dextran sulfate sodium through the NF-κB pathway in Caco-2 cells [48]. GOS has also modulated the function of intestinal Goblet cells by the regulation of the following genes: muc2, tff3, and retnlb [49].

  3. Play a role in shaping the responses and development of the immune system.

    Eiwegger et al. [50] revealed that sialylated MOS diminishes postnatal allergen-specific immune responses by shifting the Th-2 phenotype toward a more balanced Th-1/Th-2 response. Additionally, MOS suppressed the production of IL-6 and IL-1β, and decreased the overexpression of Th17 [50]. Zhou P has also reported that prebiotics stimulate mucosal immunity by increasing IgA antibody production [51].

    Prebiotics are used to treat a wide variety of disease, such as obesity, chronic enteritis, skin disease, autism spectrum disorders, and ulcerative colitis [52, 53, 54]. The mechanism of prebiotics in alleviating UC in mice seems to be through the inhibition of the TLR4/NF-κB signaling pathway, the JAK2/STAT3 signaling pathway, the inhibition of T cells naive conversion into Th17 cells and their conversion into Treg cells [55].

  4. Confer positive effects beyond the intestinal tract (Figure 3).

    Prebiotics elicited beneficial properties at different levels: mental, cardiovascular, the brain, the bones, and the bile acid metabolism [41, 56].

    Compared to infants, studies of prebiotics’ effects in older are relatively underexplored. Recently, Hu et al. reviewed the current knowledge on the immunomodulatory mechanisms elicited by GOS to maintain immune homeostasis in elders [57]. Prebiotics have also been probed to reduce the age-associated compromised intestinal permeability by increasing muc2 expression and mucus thickness [49, 58, 59] in aged mice. Additionally, GOS modulates the intestinal microbiota by increasing Bifidobacterium, Lactobacillus-Enterococcus spp., and Clostridium coccoidesEubacterium rectale in older individuals [6061]. The increases of Bifidobacterium protected against irritable bowel syndrome, pouchitis and Clostridium difficile infection [62, 63]. In older individuals, GOS also increases phagocytosis, NK cell activity and IL-10 production and decreases proinflammatory cytokines [64].

Figure 3.

Summary of the main effects that highlight the importance of including foods rich in prebiotics in the diet for general health and well-being.

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4. Synbiotics

A stable gut community plays a crucial role in protecting the host against invading microorganisms, maintaining homeostasis, and regulating immune function [64]. However, disruptions can occur due to dietary changes, antibiotic use, aging, or infection, resulting in an altered gut microbiota linked to inflammatory, pathogenic, and metabolic conditions such as inflammatory bowel diseases, colorectal cancer, metabolic syndrome, and atopic disorders [65]. Various strategies have been proposed to modulate the composition and function of the gut microbiota. These include fecal microbiota transplants, probiotics, other live microorganisms, and non-digestible dietary substrates such as prebiotics. More recently, the use of synbiotic has also emerged as a promising approach. The concept of synbiotic, introduced 25 years ago, involves combining selectively fermentable non-digestible food ingredients (prebiotics) with probiotics. Recently, a panel of experts from the International Scientific Association for Probiotics and Prebiotics (ISAPP) updated the definition of synbiotic, describing them as: “A mixture comprising live microorganisms and substrates selectively utilized by host microorganisms that confer a health benefit on the host.” Host microorganisms are understood to include both those naturally occurring in the host microbiota and those introduced as probiotics.

According to this definition, synbiotic are divided into two categories: complementary and synergistic. A synergistic synbiotic is characterized by a substrate designed to counteract potential difficulties in the survival of co-administered probiotics in the gastrointestinal tract. In contrast, a complementary synbiotic combines a probiotic and a prebiotic to jointly confer one or more health benefits without the need for interdependent functions [66]. However, these definitions still present some ambiguity. For a microorganism to be considered a probiotic, it must be able to withstand passage through the gastrointestinal tract, meaning it does not necessarily require the co-administration of a prebiotic to reach the intestine intact. In contrast, a synbiotic is expected to be more effective than the use of prebiotics or probiotics alone.

Central to formulating a synbiotic is the careful selection of the appropriate probiotic microorganism and prebiotic. The prebiotic must not only protect the probiotic in the harsh gastrointestinal environment but also promote the growth of microorganisms that confer beneficial health effects. Furthermore, an essential characteristic of a synbiotic is that its live microbial components must include strains with verified identity, potency, and safety deposited in an internationally recognized collection. Additionally, the structure and purity of the prebiotic substrate used are crucial factors [67].

One of the most commonly used combinations in synbiotic includes bacteria from the Bifidobacterium, Streptococcus, Lactobacillus or Propionibacterium genus along with fructooligosaccharides.

Early reports indicated that probiotics or synbiotic have a beneficial effect on gut microflora, intestinal structure, function, and local immune response. However, the mechanisms through which synbiotic exert these effects are not fully understood. It is hypothesized that these benefits are mediated by the combined contributions of both probiotic and prebiotic components [68].

The literature describes various beneficial effects of synbiotics on human health. These include balancing the intestinal microbiota by increasing bifidobacteria and lactobacillus species, improving liver function in patients with cirrhosis, and enhancing immune system status [69, 70].

Several authors have reported on the effects of synbiotics in specifically modulating the immune system. For instance, in an experimental rat model, the administration of a synbiotic blend consisting of two probiotic bacteria (Lactobacillus rhamnosus and Bifidobacterium lactis), along with two prebiotics (inulin and oligofructose), resulted in increased levels of intestinal IgA, as well as reductions in blood cholesterol levels and blood pressure [71].

In a randomized controlled trial involving 120 patients with remission or active ulcerative colitis (UC), participants were divided into three groups receiving either a probiotic, a prebiotic, or a combination of both (synbiotic). At the end of the treatment period, various parameters were evaluated to assess the inflammatory status. The authors concluded that the administration of synbiotics was more effective than administering probiotics or prebiotics alone in maintaining UC remission [72].

In another study involving a synbiotic mixture of Bifidobacterium longum and fructo-oligosaccharide/inulin administered to patients with active ulcerative colitis (UC), a significant decrease in TNF-α and IL-1α was observed after 4 weeks compared to the placebo group. Additionally, there was a notable increase in mucosal bifidobacteria in the synbiotic group [73].

Recent studies conducted on a large cohort of patients with IBD have demonstrated the effectiveness of synbiotic administration in reducing inflammatory parameters [74]. Other studies have also shown that synbiotics can induce changes in TCD4+ cells and increase intestinal concentrations of short-chain fatty acids [75].

Danq et al. [76] conducted an investigation into several published studies on the efficacy of bacterial strains and synbiotics in altering the allergy status of children. Their analysis revealed that probiotics or synbiotics may reduce the incidence of eczema in infants aged less than 2 years [76].

Synbiotics have shown beneficial effects in the treatment of individuals with depression and in dental caries prevention [77, 78]. Studies in animal models and among patients with IBD are promising; however, data are still limited, and only a few placebo-controlled trials have been conducted.

Future studies are likely to explore combinations of probiotics and prebiotics, further advancing the development of synbiotics and elucidating the mechanisms of action of these components. This research may uncover their beneficial effects on human health.

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5. Postbiotics

5.1 Definition

A new category has emerged in the past years that join the already well-described probiotics, prebiotics, and synbiotics, named “postbiotics”. The current definition proposed in 2021 by de ISAPP establishes postbiotics as a: “preparation of inanimate microorganisms and/or their components that confers a health benefit on the host” [8, 12, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78].

Reports of postbiotics use in human health are varied and increasing; they can be found in literature mentioned as parabiotics, ghostbiotics and tyndalized probiotics, among other names. Here, the discussion of the beneficial effects will consider only those that strictly apply to the postbiotics definition proposed by de ISAPP [8, 12, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78].

5.2 Postbiotics beneficial effects in the intestinal ecosystem and the immune system

Postbiotics are not able to colonize the host intestine, however they can still induce changes in the microbiota composition or its function or directly stimulate the immune system, the lack of living cells makes it easier to interact with the intestinal surface, for example, it does not need to compete with the local microbiota to reach and penetrate the mucosal barrier and interact with the epithelial cells or to be previously processed to induce signaling [79, 80]. The possible changes may affect the local immune response as well as the homeostasis, and in distant sites such as the respiratory tract or the brain (gut-lung axis or gut-brain axis, etc).

A study published in 2020 by Zhang et al. reported that mice with depleted microbiota using a mix of antibiotics and treated with heat-killed Lactobacillus paracasei N1115 maintained similar values of IL-6 and corticosterone to those observed in normal mice which were completely altered in mice only administered with the antibiotic mix. Treatment with postbiotic led to an improvement in the intestinal crypts depth and the expression of γ-aminobutyric acid type A receptor α1 (GABAAα1), γ-aminobutyric acid type B receptor 1 (GABAb1) in the brain (gut-brain axis) [81].

As said before, not only the inactivated microbial cell can act as a postbiotic but also parts of the cell. The component HM0539 from Lactobacillus rhamnosus GG (a soluble protein) was reported to prevent infection mediated by E. coli O157: H7 in mice. This postbiotic can to induce the expression of tight junction proteins such as ZO-1 (zonula occludens-1) and intestinal mucin MUC2 in vitro, blocking E. coli O157: H7 adhesion and invasion process; in vivo, it prevented body weight loss after pathogen challenge and jejunal damage [82].

Another work showed that this same postbiotic HM0539 had inhibitory effects over the inflammatory response induced by LSP on RAW264.7 cells (in vitro) and DSS-induced murine colitis (in vivo); in vitro HM0539 inhibited the expression of COX-2 and iNOS (cyclooxygenase-2 and inducible nitric oxide synthase enzymes) and in consequence reducing the release of prostaglandin E2 and nitric oxide. In vivo it reduced the expression of TLR4 (TLR4/MyD88/NF-кB Axis) and could be a promising therapy treatment for IBD [83].

In humans a clinical trial was published in 2020 and evaluated the use of heat-inactivated Bifidobacterium bifidum MIMBb75 for IBD treatment. The most important finding was that the group receiving MIMBb75 had a good tolerance to treatment (no adverse effects) and reduced the symptoms in all the subtypes of IBS. This is important because heat-inactivated Bifidobacterium bifidum MIMBb75 was originally a probiotic, with a positive effect on IBS in its live and inactivated form [84].

At the metabolic level, probiotics and prebiotics have a proven effect. In the case of postbiotics, a human proof-of-concept exploratory study was carried out with obese and overweight patients using Akkermansia muciniphila, a resident commensal bacteria in the intestine. This bacterial strain was used in its live form and pasteurized for comparison. Both forms were proven to be safe; however, the pasteurized supplement showed better performance, improving insulin sensitivity and reducing insulinemia and total plasma cholesterol, among other parameters. Over time, it also reduced inflammation and liver dysfunction [85].

Regarding the microbiota, it was observed that healthy mice administered with ADR-159 (a heat-killed fermented product containing two Lactobacillus strains) had a subtle variation in the microbiota, mainly affecting the less abundant taxa; in addition, ADR-159-fed mice were more social and had lower corticosterone level [86].

There are several works published about the use of postbiotics that present immunomodulatory effects whether it directly affects the innate and adaptive immune response, or indirectly improves the mucosal barrier. For example, in children, a double-blind trial studied heat-killed Pediococcus acidilactici K15 in respiratory infections. Children from pre-scholar were given the K15 formula and showed increased levels of secretory IgA in saliva, and fever events duration was shortened [87].

In a pilot trial with adult volunteers who were intranasally challenged with human rhinovirus (HRV A39) that previously consumed juice enriched with live or heat-inactivated L. rhamnosus GG showed a tendency to have a lower HRV load from intranasal lavage, however, these results were not significantly higher than the placebo group. However, these results were not conclusive, and the possibility of a clinical trial should be evaluated [88].

Ou et al. [89] showed in research using 11 lactic acid bacteria (LAB) killed with four different heat treatments that two of the selected strains E. faecalis YM-73 and L. salivarius AP-32 had good immunomodulatory activity in vitro, after heat treatment. Th1 response was favored over Th2 response by increasing the release of IFN-γ and IL12p70 [89]. It is important to mention that the immunomodulatory activity can change when different killing techniques are applied.

When using a mice infection model with Salmonella, feeding mice with heat-killed multispecies combination of LAB (HMLAB) and the cell walls from HMLAB resulted in the reduction of proinflammatory cytokines (TNF-α and IL-6) and enhanced level of IL-10; also, HMLAB significantly inhibited Salmonella invasion [90].

Salmonella infection model has been widely used. Dunand et al. demonstrated that postbiotic cell-free supernatant produced at laboratory and industrial scale increases the release of secretory IgA in feces of adult BALB/c mice and prevents Salmonella infection [91].

Finally, at the cellular level, the secreted metabolite (MET) fraction of Ganeden Bacillus coagulans 30 (GBC30) bacterial cultures were proven to induce maturation of peripheral blood mononuclear cells (PBMC) such as mononuclear phagocytes (to macrophage stage) and dendritic cells from healthy human donors in vitro [92].

5.3 Discussion

The term postbiotic has brought controversies into a discussion as it must contain inactivated microbial cells or parts of it (like cell wall, cytoplasmic content, etc), and it may or may not contain products of their metabolism that are released into the culture media (whether it comes from pure culture or as a fermented product), as these products may enhance their effect but are not essential to achieve them [15, 78]. The controversy arises as most of the probiotics preparations, for example, fermented products, contain live and dead cells and their metabolism products. To induce a beneficial effect, a probiotic must be administered in a certain amount of live cells, which is often higher in the product (whether it is on a functional food or a pharmaceutical preparation), only to ensure that the amount of live cells that reach the intestines is the minimum required [78]. In this scenario, microbial cells die within time; however, the preparation remains as a probiotic product and does not turn into a postbiotic just because there are inactivated cells. Another limitation is the origin; a postbiotic does not necessarily need to be a probiotic in its live form but needs to have a confirmed beneficial effect when administered to the host and most importantly derived from a “well-defined microorganism or combined microorganisms.” Further investigations should focus on these particular points [15, 78].

It is important to mention some differences between postbiotics and probiotics in terms of use and production. Probiotics must have living cells in the preparation and an appropriate legal regulation regarding the safety of the product, the route of administration, and the concentration, whereas postbiotics are composed of inactivated cells or parts of it having an intrinsic safety in comparison to probiotics (postbiotics do not colonize the intestine), however, the manufacturing process must be specifically described and reproducible [15, 78, 79].

Currently, reports on the effects of postbiotics and health claims are increasing. The complete underlying mechanisms are still unknown, and we cannot assume they work in the same way as probiotics do, even if the origin of the postbiotic is a probiotic microorganism.

More research is needed in this field, and should focus on critical points: the origin of the posbiotic (nature of the microorganism), processing (growing, obtaining, the specific killing or inactivating process), and clinical trials.

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6. Conclusions

The growing interest in the intestinal microbiota and its interaction with the intestinal immune system has contributed to the attention paid to the use of probiotics, prebiotics, synbiotics and postbiotics, due to their potential benefits for host health. The clue by which prebiotics elicited their beneficial effects on the host is the shift of the microbiota toward beneficial microorganisms that diminishes inflammatory environments and increases the levels of SCFA. One limitation of prebiotics is that they can only promote the growth of bacteria present in the ecosystem. Interesting, this drawback has already been overcome by the administration of probiotics on food matrices. Growing evidences indicate that the beneficial effects of probiotics, prebiotics, synbiotics and postbiotics go beyond the intestinal tract, reaching several organs and system of the host. Postbiotics can be an interesting alternative for live probiotics for immunocompromised people.

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Acknowledgments

The authors thank the Immunology Laboratory, Reference Center for Lactobacilli (CERELA-CONICET) and Food Research and Development Laboratory (LABIDAL), Santo Tomas de Aquino University of the North (UNSTA-CONICET) and CONICET.

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Conflict of interest

The authors declare that the chapter of the book was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Written By

Ivanna Novotny Núñez, Eva Vélez, Silvia I. Cazorla and Carolina Maldonado Galdeano

Submitted: 24 July 2024 Reviewed: 20 September 2024 Published: 24 October 2024