Next Article in Journal
Study of Copper/Aluminum Bimetallic Tube Rotary Ring Spinning Composite Forming Characteristics
Previous Article in Journal
QUIC Network Traffic Classification Using Ensemble Machine Learning Techniques
Previous Article in Special Issue
Association of Serum 25-Hydroxyvitamin D and Vitamin D Intake with the Prevalence of Metabolic Syndrome in Korean Adults: 2013–2014 Korea National Health and Nutrition Examination Survey
 
 
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Immunomodulatory Properties of Probiotics and Their Derived Bioactive Compounds

Laboratory of General Biology, Department of Genetics, Development and Molecular Biology, School of Biology, Faculty of Sciences, Aristotle University of Thessaloniki, 54 124 Thessaloniki, Greece
*
Author to whom correspondence should be addressed.
Appl. Sci. 2023, 13(8), 4726; https://doi.org/10.3390/app13084726
Submission received: 7 March 2023 / Revised: 3 April 2023 / Accepted: 7 April 2023 / Published: 9 April 2023
(This article belongs to the Special Issue Functional Food and Chronic Disease II)

Abstract

:
Immune system modulation is an intriguing part of scientific research. It is well established that the immune system plays a crucial role in orchestrating cellular and molecular key mediators, thus establishing a powerful defense barrier against infectious pathogens. Gut microbiota represent a complex community of approximately a hundred trillion microorganisms that live in the mammalian gastrointestinal (GI) tract, contributing to the maintenance of gut homeostasis via regulation of the innate and adaptive immune responses. However, impairment in the crosstalk between intestinal immunity and gut microbiota may reflect on detrimental health issues. In this context, many studies have indicated that probiotics and their bioactive compounds, such as bacteriocins and short chain fatty acids (SCFAs), display distinct immunomodulatory properties through which they suppress inflammation and enhance the restoration of microbial diversity in pathological states. This review highlights the fundamental features of probiotics, bacteriocins, and SCFAs, which make them ideal therapeutic agents for the amelioration of inflammatory and autoimmune diseases. It also describes their underlying mechanisms on gut microbiota modulation and emphasizes how they influence the function of immune cells involved in regulating gut homeostasis. Finally, it discusses the future perspectives and challenges of their administration to individuals.

1. Introduction

The intestine provides a fruitful environment for the establishment of balanced relationships between commensal bacteria and immune cells [1]. The evolution of this diverse ecosystem over time has occurred through consecutive exposures to multiple antigens. The cellular and molecular components comprising the gut immunity are constantly under intimate interaction with intestinal commensal microbes, thus contributing to the modulation of immune responses as well as the maintenance of gut homeostasis [2]. Alterations in gut microbiota composition may lead to gut dysbiosis, thereby activating various signaling cascades that are implicated in the maturation, differentiation, and proliferation of gut immune cells. Disturbance of this complex microbial community has been directly associated with the development of severe health issues [3], including metabolic disorders [4], chronic inflammation [5], cancer [6], cardiovascular diseases through the gut–heart axis [7], and neurodegenerative diseases through the gut–brain axis [8]. In this context, probiotics have been suggested as a promising treatment strategy for the restoration of the intestinal microbial diversity [9].
Probiotics are microorganisms that confer health benefits to the host when administered in adequate amounts [10]. Bacterial strains with accredited probiotic properties, which include tolerance to intestinal conditions, ability of adherence to epithelial cells, and cell-surface hydrophobicity [11], were found to counteract infections through modulation of gut immunity [12]. Probiotics exert their immunomodulatory properties on the host in several ways, including colonization of the perturbed mucosal barrier, competitive exclusion and inhibition of harmful invading pathogens, production of bioactive compounds [13], enhancement of anti-inflammatory cytokine production [14], detoxification of virulent substances [15], and recruitment of various immune cells [16].
Bioactive probiotic molecules include amino acids, vitamins, exopolysaccharides, enzymes, short chain fatty acids (SCFAs), and bacteriocins [16,17]. SCFAs are metabolic by-products of non-digestible fiber fermentation [18], while bacteriocins comprise a heterogeneous group of peptides with antimicrobial activity against pathogens [13]. The profound effect of SCFAs, tryptophan catabolic products, and secondary bile acids originating from bacterial metabolism on the immune system–gut microbiota crosstalk has recently been reviewed [1,3]. Although studies on bacteriocins mainly focus on particular commercially available forms and their effects on host health [19], their contribution in the modulation of the immune system has also been reported [20,21]. Therefore, the utilization of bioactive compounds for therapeutic purposes comprises a new field of research investigations.
This review focuses on the underlying mechanisms that configure the intricate interaction between probiotics, bacteriocins, and SCFAs with the host immune cells. Understanding the impact of probiotics and probiotic derived compounds on gut immunity is challenging as well as extremely significant in order to develop efficient therapeutic strategies for the amelioration of life-threatening diseases.

2. Hallmarks of Innate and Adaptive Immunity

The first step in host immunoprotection from invading pathogens is their identification, conducted by the pattern recognition receptors (PRRs) [22], which, based on their localization, are classified into transmembrane receptors (toll-like receptors, TLRs), and intracellular receptors (NOD-like receptors, NLRs) [23]. Their action is related to the recognition of miscellaneous signaling molecules, including microbe-associated molecular patterns (MAMPs) on pathogens and endogenous damage-associated molecular patterns (DAMPs) on host cells [24,25]. PRRs bridge innate (nonspecific) and adaptive (specific) immunity [26], with both immunity types functioning as reciprocal defense mechanisms to provide protection against inflammatory or autoimmune diseases [27].
The innate immunity mainly involves anatomical and physical barriers such as skin and mucous membranes, the microbiota, chemical barriers such as antimicrobial molecules and enzymes, and specialized effector cells promoting phagocytosis of foreign pathogens, rendering it the first line of defense [27,28]. Innate immune response distinguishes normal host cells from intruding pathogens via the identification of pathogen-associated molecular patterns (PAMPs) and of endogenous molecules released from damaged cells (DAMPs), a process mediated by PRRs [27]. The interaction of PAMPs with PRRs elicits an intracellular signal transduction in immune cells [29]. A great variety of components, including antimicrobial enzymes (e.g., lysozyme), acute phase proteins in blood serum (e.g., complement factors, C-reactive protein), antimicrobial peptides (AMPs) (e.g., defensins), cells with phagocytic capacity (i.e., neutrophils, monocytes, macrophages, and dendritic cells (DCs)), and pro-inflammatory cytokine producing cells (e.g., macrophages, mast cells, natural-killer (NK) cells) act in synergy in addition to physical barriers [14,27]. If pathogens manage to penetrate the first line of defense, the adaptive immunity is activated [28].
Adaptive immunity, as a second line of defense against pathogens, is related to antigen-specific responses and provides long-lasting immunological memory to the host [28]. Unlike the immediate action of innate immunity from minutes to hours, the maximum response of adaptive immunity is observed days after exposure to an antigen [14]. The connection between innate and adaptive immunity depends on the activation of professional antigen-presenting cells (APCs), which include DCs, macrophages, and B cells [28,30]. The two main classes of adaptive immunity, humoral and cell-mediated immune response, are mediated by B cells and T cells, respectively [31]. B cells, following maturation, migrate through blood to lymph nodes, where they are bound to foreign antigens, proliferate, and further differentiate into antibody-secreting plasma cells and memory B cells [28,32]. Plasma cells secrete five distinct types of immunoglobulins (Ig) to directly neutralize antigens or indirectly mark the pathogens for destruction. Memory B cells present extended survival and immediately respond upon re-exposure to the same antigen [32,33]. T cells, the mediators of cell-mediated immunity, mature in thymus to naïve T cells [33], which interact with the major histocompatibility complex (MHC) expressed on the surface of APCs [32]. Following this interaction, they proliferate and differentiate into CD4+ T helper cells (Th cells) and CD8+ cytotoxic T cells. Although CD8+ T cells are critical for the host defense against virally infected cells and tumor cells, those that carry out the action of stimulating other immune cell types are CD4+ T cells [28,32]. The latter can differentiate into seven major subtypes [34], namely Th1 [35], Th2 [35,36], Th9 [37], Th17 [38], Th22 [39], T regulatory (Treg) cells [36,40], and T follicular helper (Tfh) cells [41], and are distinguished by the expression of specific cytokines and transcription factors [33]. The uncontrolled Th cell-mediated immune responses have been linked to the appearance of autoimmune disorders and other diseases. The balanced regulation of particular T cell subtypes comprises an important key element in the maintenance of a strengthened immune system [34,38].

3. Gut Microbiota and Immunity Crosstalk in Health and Disease

The gut microbiota represents a group of microorganisms that are strictly compartmentalized to the intestinal lumen of the mammalian gastrointestinal (GI) tract [42]. This complex microbial community that harbors the gut involves more than 1000 bacterial species [43] which contribute to the maintenance of host health. A balanced gut microbiota combats harmful opportunistic pathogens while showing tolerance to beneficial commensal bacteria, and thus it is directly associated with the establishment of gut homeostasis [44]. Gut microbiota has a prominent participation in the execution of various gut functions, such as degradation of unmetabolized dietary components, production of essential nutrients, and secretion of bioactive compounds with anti-inflammatory and immunomodulatory properties, such as SCFAs and bacteriocins [3,45]. Gut microbiota imbalance, known as gut dysbiosis, is often implicated in the development of acute or chronic inflammation and oxidative stress, provoking grievous health disorders [24]. Changes in the composition and diversity of the gut microbiota are associated with increased susceptibility to non-communicable gastrointestinal diseases [42], such as inflammatory bowel disease (IBD) or colorectal cancer (CRC), metabolic disorders including obesity or type 2 diabetes [46], and cardiovascular and neurodegenerative diseases [47].
Although the connection between diseases and disrupted gut microbiota composition has been documented [47,48], it is still ambiguous whether gut dysbiosis is the cause or consequence for the development of detrimental health issues [49]. It is generally argued that resilience, defined as the ability of an ecosystem to return to its original state after perturbation caused by drug administration, invasion of pathogens, and unhealthy lifestyle habits, constitutes the preponderant factor for a healthy gut microbiota [50]. Resilient microbiota is often associated with increased complexity and diversity of gut microbial communities [51]. However, the determination of a healthy gut microbiota, which might contribute to personalized medicine approaches, has not been achieved yet. This lack of evidence is due to the microbiome diversity among individuals and age groups, as demonstrated by the Human Microbiome Project, rendering the need for further research imperative [52].
Considering the fact that approximately 70% of immune cells reside in the gut [51], the interaction of gut microbiota with the intestinal immune system is a prerequisite towards the achievement of a balance between inflammation and immune tolerance [48]. The intestinal immune system comprises four main compartments: the gut-associated lymphoid tissue (GALT), the mesenteric lymph nodes (MLN), the lamina propria (LP), and the epithelial tissue [53]. GALT utilizes multiple mechanisms in order to eliminate the presence of pathogens in the intestinal lumen of mammals [54] and consists mostly of aggregated lymphoid follicles, the Peyer’s patches, which are characterized as the immune sensors of the intestine [55]. Peyer’s patches contribute to the generation of IgA-producing B cells [2] and are covered by the follicle-associated epithelium (FAE), the interface between the intestinal lumen and the GALT [55]. Except for the intestinal epithelial cells (IECs), two distinct types of specialized epithelial cells are incorporated in the FAE: microfold (M) cells, which recognize various mucosal antigens and transfer them to the LP, where the underlying APCs stimulate the adaptive immune response [54,55], and goblet cells, which are involved in the secretion of mucus [3]. The FAE serves as an effective barrier which enhances the isolation of host immune cells residing in the LP from commensal or pathogenic bacteria [3] and may be disrupted in case of gut dysbiosis [51].
Several studies in germ-free (GF) mice, a representative model system of immunodeficiency, have indicated the supreme impact of gut microbiota on the development of the immune system [44,48]. In comparison to GF mice, which are known to exhibit low concentrations of secretory IgA [3], wild-type mice administered intragastrically with commensal bacteria were found to produce great amounts [56]. Additionally, GF mice have poorly developed GALT, including fewer and smaller Peyer’s patches and MLNs, while their mucosal barrier is thinner compared to wild-type animals [3,57]. In this context, the necessity of intestinal commensal bacteria in defining the differentiation of immune cellular components has been demonstrated [58,59]. Impairment in immune system–gut microbiota crosstalk may result in serious repercussions, such as deviant immune responses, systemic distribution of commensal microbes, and vulnerability to pathogenic infiltration [60].

4. Immunomodulatory Properties of Probiotics

Probiotics are non-pathogenic distinct microorganisms, which provide health benefits when administered in adequate amounts to the host [10], contributing to the maintenance of gut microbiota homeostasis [61]. They are considered to be one of the most valuable options regarding the restoration of microbial diversity [61] and the treatment of infections caused by antibiotic resistant bacteria or invading viruses [24,54]. However, the precise molecular mechanisms via which they confer their positive effects have not been completely elucidated [9].
The effects of probiotic bacteria on immunity are exerted through epithelial colonization with simultaneous induction of mucin secretion [61], production of several bioactive compounds [24], competitive exclusion of pathogens by preventing their adherence on the intestinal epithelial surface [54], and inhibition of pathogens’ proliferation through competition for essential nutrients [2,61,62]. The immunomodulatory properties of probiotics vary between individuals and are mostly attributed to the release of cytokines and chemokines from immune cells [14], the activation of TLRs [2,63], or the inhibition of the nuclear factor-κB (NF-κB) pathway [64,65]. Probiotics are also involved in the regulation of the JAK/STAT and the mitogen-activated protein kinase (MAPK) signaling pathways via the secretion of cytokines and AMPs, thus promoting the mucosal and systemic immune response [64,66]. It is well established that cellular fragments or surface molecules of probiotics can trigger the phagocytic capacity of macrophages and DCs [67,68,69] while contributing to the enhancement of NK cells [70,71] and CD8+ T cells’ cytotoxic activity [72]. The significance of probiotics in inducing the maturation and differentiation of adaptive immune cells through modulation of innate immune cells has been designated [73,74]. Upon adherence to the IECs, probiotics induce the secretion of cytokines leading to the activation of Tregs, the key mediators in maintaining gut homeostasis [2,51,75]. The increased production of the anti-inflammatory cytokine interleukin (IL)-10 by Tregs to the detriment of pro-inflammatory cytokines in the colonic mucosa may suppress inflammatory responses [51] and stimulate immune tolerance to commensal microbes [2,75]. In regard to the required balance of T cell subtypes for the proper function of gut immunity [44], probiotics promote a shift from Th2 to Th1 cells, in order to restrict allergic reactions and control autoimmune disorders [51,54]. Furthermore, the association of probiotics with IECs triggers the maturation of DCs and the subsequent induction of Tregs, thus promoting the immunoglobulin class switching by mature B cells, in the Peyer’s patches, towards the secretory IgA [76]. The secretory IgA plays a significant role in preventing the interaction of pathogens with epithelial receptors, preserving the integrity of the mucosal barrier, and neutralizing bacterial toxins on the mucous membrane [77,78].

5. Probiotic Derived Bioactive Compounds and Immunity

Probiotics produce a great variety of substances, which exhibit growth-inhibitory action against several pathogens and present a distinct effect on the microenvironment abiotic factors [79]. The metabolic products secreted by probiotic bacteria, also known as postbiotics, include vitamins, organic acids, SCFAs, neurotransmitters, flavonoids, amino acids, enzymes, bacteriocins, exopolysaccharides, cell wall fragments, teichoic acids, and biosurfactants [24,80]. A concise summary has recently highlighted some general features of postbiotics in immune response stimulation [24], and the immunomodulatory properties of exopolysaccharides and cell-envelope components [81,82], bacterial lysates, and cell-free supernatants [83,84] have been extensively reviewed. This review emphasizes the current knowledge regarding the effect of bacteriocins and SCFAs on immune cells.

5.1. Bacteriocins

5.1.1. General Features of Bacteriocins

Bacteriocins comprise a miscellaneous group of bacterial peptides, which display antimicrobial activity against other bacteria. Their inhibitory activity can range from narrow to wide, whether they eliminate only bacterial strains that are closely related to the producer bacterium or non-related species [85]. Both Gram-positive and Gram-negative bacteria can secrete bacteriocins [86,87]. To protect themselves from being killed by their own bacteriocins, most of bacterial strains have developed self-defense mechanisms, such as the production of self-immunity proteins and the utilization of efflux pumps [13].
Bacteriocins are small proteinaceous molecules, mostly ribosomally synthesized, with extraordinary and diverse characteristics in terms of molecular weight, net charge, pH, and heat tolerance, as well as physicochemical properties [88]. The secretion of bacteriocins can be modified by several abiotic factors, as well as the producer bacterial strain [89], and takes place mainly in the late exponential growth phase and the early stationary phase [88]. Bacteriocins are considered to be potential candidates for therapeutic use, due to their effectiveness against multidrug resistant bacteria (MDR) [87], since they form pores on the cell membrane of the target cell, a process that contributes to the induction of cell death and prevention of drug resistance development [90]. Bacteriocins bind directly on the cell membrane presumably in the absence of a specific receptor [91].
The predominant producers of bacteriocins are lactic acid bacteria (LAB), a distinct group of Gram-positive bacteria with particular interest due to their “generally recognized as safe” (GRAS) status [79,92]. LAB strains produce lactic acid as a main product of carbohydrate fermentation and include various genera, such as Pediococcus, Leuconostoc, Lactococcus, Enterococcus, Streptococcus, Lactobacillus, and Bifidobacterium [21,88]. They share common metabolic characteristics, including the ability of bacteriocins and SCFAs production [92,93]. LAB bacteriocins present great variety, specificity, potential in co-administration with other drugs [87,94], and stability in a wide range of physicochemical conditions. The lack of toxicity of bacteriocins and the absence of bacterial resistance to them has been attributed to their short biological half-life in the human body [88,92]. Bacteriocins selectively target pathogens, but not commensal microbiota [87], and present cytotoxic activity against cancer cells [95,96]. Finally, certain bacteriocins exhibit anti-inflammatory and immunomodulatory properties, thus participating in the maintenance of a balanced crosstalk between gut microbiota and immunity [90] (Figure 1).

5.1.2. Classification of LAB Bacteriocins

Bacteriocins of LAB are currently categorized into three major classes [97,98] based on their size, structure, and biochemical composition (Figure 2). Class I bacteriocins (lantibiotics) are small-sized (<5 kDa), membrane-active peptides with extensive post-translational modifications, containing uncommon dehydrated amino acids and displaying stability to heat, pH, and proteolysis [87]. Class I includes Subclass Ia, Subclass Ib, and Subclass Ic [21,86,87]. Class I bacteriocins use the peptidoglycan cell wall precursor lipid II as a docking molecule and induce pore formation on the target cell membrane to penetrate the phospholipid bilayer, leading to ion efflux and death. Additionally, they can disrupt the cell wall biosynthesis [92,94]. Class II bacteriocins are small (<10 kDa), heat-stable, non-lanthionine-containing peptides that mainly cause permeabilization of the target cell membranes [87]. This group is subdivided into four subclasses, namely Subclass IIa, Subclass IIb, Subclass IIc, and Subclass IId [21,86,87]. Class II bacteriocins, following docking on the mannose permease of the phosphotransferase system (Man-PTS), create intrinsic channels on the target cell membrane, allowing ion diffusion and leading to cell death [87,94]. Class III bacteriocins are larger (>30 kDa), heat-labile peptides and are subdivided into subclass IIIa (bacteriolysins) and subclass IIIb (non-lytic peptides) [21,87]. Their antimicrobial activity correlates with their endopeptidase enzymatic activity, leading to loss of the bacterial cell wall integrity [87,96].

5.1.3. Bacteriocins as Immunomodulatory Molecules

Although the immunomodulatory properties of bacteriocins have not been completely elucidated, their role as signaling peptides [99] affecting host immunity has been reported [91] (Table 1). A recent study has shown that bacteriocins, including nisin A, plantaricin 423, and bacST4SA, can migrate across endothelial and epithelial cells in vitro without causing toxicity, and they display stability in blood plasma [100]. The above observations provide strong evidence which supports the ability of bacteriocins to cross the gut–blood barrier, thereby affecting local and systemic immunity [101]. It is also suggested that bacteriocins may contribute to the stimulation of IECs which, in turn, produce antimicrobial substances to eradicate the colonization of intruding pathogens [90].
Researchers have mainly focused their interest on how nisin, a lantibiotic used in food preservation (E234), commercially available as Nisaplin [87], may affect immune responses [20]. Nisin was found to promote the production of anti-inflammatory cytokines at the expense of pro-inflammatory cytokines to inhibit inflammation in vivo [102]. Additionally, investigations on the effect of nisin on the immune system of mice showed that short-term nisin consumption induces an increase in the number of CD4+ and CD8+ T cells, as well as a significant reduction in the percentage of B cells. Following long-term nisin-consumption, T cells and B cells return to normal levels, and the population of macrophages/monocytes isolated from peripheral blood increases [103]. Similarly, a recent study which evaluated the effect of various nisin concentrations on porcine peripheral blood mononuclear cells (PBMC) in vitro, found that a high dose of nisin induces the proliferation of CD4+ and CD8+ T cells and the secretion of IL-1β and IL-6 in PBMCs, thus indicating the enhancement of immune response against potential infections [104]. Moreover, the nisin Z variant can promote the secretion of the chemokines monocyte chemoattractant protein-1 (MCP-1), IL-8, and growth regulated oncogene-alpha (Gro-α), as well as suppress the production of tumor necrosis factor-alpha (TNF-α) in human LPS-stimulated PBMCs [105]. Nisin can also enhance the function of phagocytes that comprise an important part of innate immunity, including neutrophils and macrophages. Nisin activates the formation of neutrophil extracellular traps (NETs) by neutrophils in vitro [106], a process probably attributed to the increased production of IL-8 [107], and therefore inhibits pathogen infiltration in host cells. Treating macrophage cells with a synthesized nanoparticle containing nisin was shown to increase the levels of IL-12 without causing any effects on IL-10 and TNF-α levels [108].
Generally, bacteriocins have the ability to modulate the cytokine levels via controlling various signaling cascades (e.g., TLR, NF-κB, MAPK) in order to exert their immunomodulatory properties in case of inflammation [90]. It is reported that bacteriocins can elicit innate immune response upon viral infection via the inflammasome activation [109]. Sublancin, an antimicrobial peptide originated from Bacillus subtilis, was found to stimulate innate immune response via IL-1β, IL-6, TNF-α, and nitric oxide (NO) production in both RAW264.7 cells and mouse peritoneal macrophages [110]. The enhanced phagocytic capacity of macrophages was correlated with the TLR4 and the NF-κB [111] and MAPK signaling pathways, while the oral administration of sublancin increased the number of CD4+ and CD8+ T cells in MLNs in vivo [110]. Treatment of human PBMCs with acidocin A, a pediocin-like bacteriocin, resulted in increased production of multiple cytokines and chemokines, including MIG, MCP-1, MCP-3, macrophage inflammatory protein (MIP)-1α, MIP-1β, IL-6, and TNF-α [112]. Moreover, Lactobacillus plantarum genes encoding production or secretion of bacteriocins [113] were reported to enhance production of IL-10 over IL-12 and possibly TNF-a induction in DCs [114] and in PBMCs [115].
Table 1. The effects of probiotic derived bacteriocins on immune cells.
Table 1. The effects of probiotic derived bacteriocins on immune cells.
Cell TypeCompoundImmunomodulatory EffectReferences
IECsSublancinInhibition of NF-κB activation[90]
BacteriocinsStimulation of host immunity as signaling peptides[13,99]
NeutrophilsNisinNETs formation, IL-8 production[106,107]
MacrophagesNisinIL-12 increase[108]
SublancinIL-1β, IL-6, TNF-α, and NO production, TLR, NF-κB, and MAPK signaling pathways modulation[110]
DCsL. plantarum
bacteriocin-like
peptide
Genes encoding bacteriocin secretion enhance IL-10 over IL-12[114]
PBMCsNisinCD4+ and CD8+ T cell proliferation, macrophages/monocytes
increase
[103,104]
Nisin ZIL-1β, IL-6, IL-8, MCP-1, Gro-α secretion, TNF-α suppression[105]
Acidocin ACytokines- chemokines production[112]
L. plantarum
bacteriocin-like
peptide
Genes encoding bacteriocin secretion enhance IL-10 over IL-12[115]
IECs: intestinal epithelial cells, NF-κB: nuclear factor-κB, NETs: neutrophil extracellular traps, IL-8: Interleukin-8, IL-12: Interleukin-12, IL-1β: Interleukin-1β, IL-6: Interleukin-6, TNF-α: Tumor necrosis factor-α, NO: nitric oxide, TLR: Toll-like receptor, MAPK: mitogen-activated protein kinase, DCs: dendritic cells, L. plantarum: Lactobacillus plantarum, IL-10: Interleukin-10, MCP-1: monocyte chemoattractant protein-1, Gro-α: Growth regulated oncogene-alpha, PBMCs: peripheral blood mononuclear cells.

5.2. SCFAs

5.2.1. Overview of SCFAs

Specific commensal anaerobic bacteria residing in the intestinal lumen are major contributors in the fermentation of non-digestible complex carbohydrates, thus producing a great amount of SCFAs [116]. SCFAs are saturated fatty acids containing six or fewer carbon atoms, including: formate (C1), acetate (C2), propionate (C3), butyrate (C4), valerate (C5), and caproate (C6) [117]. The most abundant SCFAs found in colon are acetate, propionate, and butyrate. SCFAs are released longitudinally in the intestine in different concentrations, with a maximum level in the proximal colon (100 mM) [1,118]. The fatty acids acetate, propionate, butyrate, isobutyrate, 2-methylbutyrate, isovalerate, and valerate have been detected in human feces, in decreasing order of abundance [119]. The branched SCFAs isovalerate and isobutyrate are produced in lower amounts in the gut and have been associated with aging [120]. Members of the Firmicutes phylum mostly synthesize butyrate, while members of the Bacteroidetes phylum mainly synthesize acetate and propionate [121]. Upon production in colon, SCFAs are disseminated into the bloodstream with the aim of being delivered to distant tissues, thereby exerting their beneficial effects [122].
SCFAs exhibit distinct anti-inflammatory and immunomodulatory properties and play a fundamental role in gut homeostasis, serving as the interface between gut microbiota and immunity [123]. IECs metabolize SCFAs into acetyl coenzyme A (acetyl-CoA) via the tricarboxylic acid (TCA) cycle, thus promoting cell metabolism and acquiring the essential energy for multiple cellular functions, including proliferation and activation of immune cells [124]. Butyrate serves as the primary substrate for energy production and corresponds to approximately 60–70% of total energy consumption in IECs [125,126]. Moreover, SCFAs promote the differentiation of the goblet cells involved in the secretion of mucus, thus having a well-appreciated role in maintaining mucosal barrier integrity [3]. Collectively, SCFAs perform a great variety of functions, which include protection and restoration of the intestinal epithelial barrier [125,127], prevention of gut dysbiosis via inhibition of harmful pathogens [124,128], regulation of intestinal immunity [129,130], maintenance of a balanced crosstalk between gut microbiota and extraintestinal tissues [18], and inhibition of gut inflammation through reduction in the levels of pro-inflammatory cytokines produced by immune cells [131].
In addition to the common SCFAs produced upon microbial fermentation, the presence of lactate in the intestinal lumen is considered to be a critical indicator for the preservation of gut integrity [132]. Lactate, a short chain hydroxy-carboxylic acid examined separately from SCFAs [133,134], serves as an energy substrate for a subgroup of lactate-utilizing bacterial species [132]. Under normal conditions, it is metabolized to acetate, propionate, and butyrate via distinct biochemical pathways employed by gut microbes. Therefore, the colonic concentrations of lactate are relatively low, ranging from 5 to 10 mM, in comparison to the major SCFAs [134]. On the other hand, lactate accumulation in the gut has been associated with inflammatory gastrointestinal disorders [132,134]. Lactate is not only considered as an important intermediate in cell metabolism [135,136,137], but also a multifunctional signaling molecule [138] with profound immunomodulatory properties both in physiological and pathological states [139].

5.2.2. SCFAs as Immunomodulatory Molecules

SCFAs play a significant role in modulating innate and adaptive immune response (Table 2, Figure 3). They are mainly recognized by three distinct G-protein-coupled receptors (GPR41, GPR43, and GPR109A) found on the surface of host IECs. Following activation of GPRs, SCFAs can modulate various signaling cascades, including MAPK, the signal transducer and activator of transcription 3 (STAT3) and the mammalian target of rapamycin (mTOR) pathways [140].
Additionally, SCFAs are involved in cell proliferation and programmed cell death via the inhibition of the enzyme histone deacetylase (HDAC) [141], and they participate in inflammasome activation, a key element of innate immune response [140]. Butyrate or acetate-GPR43-mediated signaling facilitates the activation of the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome in IECs, thereby resulting in the production of IL-18, which has been linked to intestinal epithelial barrier maintenance [142]. A recent study indicated the importance of three SCFAs in restoring the reduced mucin levels in Caco-2 cells and mouse IECs previously treated with the chemotherapeutic 5- Fluorouracil (5-FU) [131]. It is speculated that SCFAs activate the NLRP6 inflammasome in order to enhance the secretion of mucin 2 by the intestinal goblet cells [1] in a similar way to other microbiota-associated metabolites [143]. Furthermore, it is reported that SCFAs inhibit the production of pro-inflammatory cytokines, including interferon-gamma (IFN-γ), TNF-α, IL-6, IL-1β, and IL-8, and they favor the production of anti-inflammatory cytokines such as IL-10 and TGF-β, via suppression of the NF-κB pathway in IECs [127,144]. Butyrate induces the activation of nuclear peroxisome proliferator-activated receptor gamma (PPAR-γ) [145], thus enhancing the β-oxidation of SCFAs and oxidative phosphorylation, contributing to the maintenance of hypoxic conditions in the microenvironment of IECs [16,17]. Under these conditions, commensal obligate anaerobic SCFA-producing bacteria thrive, while pathogenic facultative anaerobic bacteria are eliminated [1].
The development of augmented inflammation in GPR43-deficient mice confirmed that GPR43-mediated signaling pathway leading to the activation of p38 MAPK [3] is directly associated with neutrophils chemotaxis [146,147]. Interestingly, upon exposure of LPS-stimulated neutrophils to SCFAs, the levels of NO, TNF-α, and cytokine-induced neutrophil chemoattractant-2 alpha beta (CINC-2αβ) decreased, resulting in inhibition of HDAC activity [148]. Treatment of LPS-induced THP-1 macrophages with SCFAs secreted by E. coli KUB-36 resulted in reduction of pro-inflammatory cytokines, and anti-inflammatory cytokine IL-10 production was triggered [149]. A recent study has also highlighted the role of butyrate in promoting M2 macrophage polarization both in vitro and in vivo in mice with dextran sulfate sodium (DSS)-induced colitis. The reduced transcription of pro-inflammatory genes in bone-marrow-derived macrophages was attributed to butyrate-induced epigenetic modulations, thus indicating the significant impact of butyrate on immune tolerance enhancement [150]. Accumulating evidence underlines the role of SCFAs in regulating the maturation and stimulation of DCs, which primarily express GPR41 and GPR109 receptors on their surface [140]. Butyrate activates GPR109A in colonic DCs, which, in turn, induces IL-10-producing Tregs, as well as the secretion of IL-18 in the intestinal epithelium of mice, providing protection against inflammation and tumorigenesis [151]. Additionally, butyrate promotes naïve T-cell differentiation to Tregs or Th1 and Th17 cells, ensuring their balance, which is a significant prerequisite to the elimination of gut inflammation [152,153]. Both butyrate and propionate were found to exert immunomodulatory properties via modulation of gene expression in DCs [154]. Supplementation with SCFAs has been proved to enhance the cytotoxic capacity of NK cells in rats while boosting the secretion of IFN-γ, the predominant cytokine produced in response to inflammatory signals [155]. Gut-associated NK cells detect invading pathogens, as well as cancer cells, and induce the recruitment of various immune cells to elicit the innate and/or adaptive immunity [140].
SCFAs are implicated in the differentiation of naïve CD4+ T cells into Tregs expressing the forkhead box protein (Foxp3) through the activation of GPR43 or GPR41 in vivo [130]. A similar increase in Tregs has been observed following oral administration of SCFAs, individually or in combination, to GF mice [156]. In vitro studies have also confirmed that butyrate and propionate favor the polarization of naïve CD4+ T cells toward IL-10+ Tregs, thus promoting resilience in the gut microbiota [140]. Upon interaction with GPR43, SCFAs activate Th1 cells and induce the mTOR and STAT3 pathways, resulting in upregulation of B lymphocyte-induced maturation protein 1 (Blimp-1) expression and IL-10 secretion in vivo [157].
Butyrate and propionate promote IFN-γ secretion, thus enhancing the cytotoxic activity of CD8+ T cells, the preponderant effector cells found in the tumor microenvironment [1,158]. Interestingly, the administration of butyrate, both in vitro and in vivo, enhanced the efficacy of the chemotherapeutic oxaliplatin via amplification of CD8+ T cell responses [159]. Moreover, the presence of SCFAs is associated with increased levels of intestinal IgA in mice. It has been confirmed that acetate activates GPR43 in intestinal DCs, thus triggering IgA secretion by B cells [1]. Alternatively, SCFA attachment to GPRs activates DCs to produce class 1A acetaldehyde dehydrogenase (ALDH1a). ALDH1a catalyzes the conversion of vitamin A into retinoid acid, thereby causing the IgA isotype switching towards secretory IgA production [1,3]. The increased energy requirements of B cells due to their multifaceted cellular processes are met by enhancement of oxidative phosphorylation and fatty acid synthesis induced by SCFAs [1,160]. Furthermore, differentiation of B cells into plasma cells in Peyer’s patches is enhanced by SCFAs, which activate the mTOR pathway [160]. SCFAs employ multiple mechanisms in order to boost B cell differentiation into plasma cells and antibody production, including epigenetic regulation of specific genes such as Aicda, Xbp1, and Irf4, production of IL-6, and activation of Tfh cells [160,161].
Table 2. The effects of probiotic derived SCFAs on immune cells.
Table 2. The effects of probiotic derived SCFAs on immune cells.
Cell TypeCompoundImmunomodulatory EffectReferences
IECsAcetateGPR43 and NLRP3 activation, IL-18 production,
maintenance of epithelial barrier
[142]
ButyratePPAR-γ activation, β-oxidation and OXPHOS induction, conditions
favoring SCFA-producing bacteria
[1,16,17]
NF-κB pathway suppression, anti-inflammatory cytokines increase[127,144]
Acetate,
propionate,
butyrate
Restoration of mucosal barrier integrity (5-FU treated
Caco-2 and IECs)
[131]
NeutrophilsAcetate, butyrateGPR43 activation, chemotaxis induction,
p38 MAPK activation
[3,146]
Acetate,
propionate,
butyrate
Inhibition of ROS and NO production, NF-κB pathway suppression,
HDAC inhibition
[3,148]
MacrophagesAcetate, butyratePro-inflammatory cytokines reduction, anti-inflammatory cytokine IL-10 increase[149]
ButyrateEpigenetic modulations, M2 macrophage polarization,
immune tolerance enhancement
[150]
DCsButyrateGPR109A activation, Tregs differentiation, IL-18 secretion, protection
against inflammation–tumorigenesis
[151]
Balance in Tregs and Th1-Th17 cells population, modulation
of gene expression
[152]
Acetate, butyrateActivation of GPRs, ALDH1a production, increased secretion
of IgA by plasma cells
[1,3]
NK cellsButyrate, acetateNK recruitment, increased IFN-γ production[140,155]
CD4+ T cells ButyrateGPR43/GPR41 activation, differentiation to Tregs
expressing Foxp3
[130]
Butyrate, acetateTh1 activation, mTOR, STAT3 pathways induction, Blimp-1
and IL-10 production
[1]
CD8+ T cellsButyrateEnhancement of memory CD8+ responses[158]
Enhancement of the efficacy of oxaliplatin, amplification of
CD8+ T cell responses
[159]
B cellsAcetate,
propionate,
butyrate
OXPHOS- fatty acid synthesis enhancement, differentiation
into plasma cells, epigenetic regulation, IL-6 production, activation of Tfh
[160,161]
IECs: intestinal epithelial cells, GPR43: G-protein-coupled receptor 43, NLRP3: NOD-like receptor family pyrin domain containing 3, IL-18: Interleukin-18, PPAR-γ: peroxisome proliferator-activated receptor-γ, OXPHOS: oxidative phosphorylation, SCFA: short chain fatty acid, NF-κB: nuclear factor-κB, 5-FU: 5-Fluorouracil, MAPK: mitogen-activated protein kinase, ROS: reactive oxygen species, NO: nitric oxide, HDAC: histone deacetylase, IL-10: Interleukin-10, DCs: dendritic cells, GPR109A: G-protein-coupled receptor 101A, Tregs: T regulatory cells, Th1: T helper 1, Th17: T helper 17, GPRs: G-protein-coupled receptors, ALDH1a: acetaldehyde dehydrogenase class 1A, IgA: immunoglobulin A, NK: Natural killer cells, GPR41: G-protein-coupled receptor 41, Foxp3: forkhead box protein, mTOR: mammalian target of rapamycin, STAT3: signal transducer and activator of transcription 3, Blimp-1: B lymphocyte-induced maturation protein 1, IL-6: Interleukin-6, Tfh: T follicular helper cells.
Lactate also exhibits a great variety of immunomodulatory properties (Table 3). Lactate plays a critical role in abrogating TLR and IL-1β dependent IECs activation [162], and it downregulates the expression of pro-inflammatory cytokines in IECs [133,136]. Interestingly, lactate has been found to induce NETs formation when administered to neutrophils [139,163]. Activation of GPR81-mediated signaling by lactate in colonic DCs and macrophages contributes to the suppression of colonic inflammation [137,164]. However, lactate can also enhance GPR81-independent metabolic changes in LPS-activated macrophages, thus inducing a reduction in pro-inflammatory cytokine levels [133,165]. Furthermore, lactate promotes M2 polarization of macrophages producing IL-10 and inhibits IL-12 production [166]. An in vitro study has also indicated that lactate is involved in the suppression of TNF-α secretion in LPS-stimulated monocytes in the tumor microenvironment (TME) [167]. The significant immunomodulatory role of lactate in TME has been extensively reviewed [168,169]. Lactate has been shown to inhibit the motility of CD4+ and CD8+ T cells [170]. In the case of CD4+ T cells it induces Th17 differentiation [168] and Tregs proliferation [171], whereas it promotes the loss of cytolytic function in CD8+ T cells [170].

6. Challenges and Future Perspectives

The contribution of probiotics in the maintenance of a healthy gut microbiota and a balanced interaction between commensal bacteria and immune cells is noteworthy. However, a few studies have highlighted impediments in probiotic utilization, despite their accredited beneficial effects on human health. For instance, it has been reported that probiotics administered to eliminate common treatment-related side effects in adult cancer patients led to the development of undesired health issues, including bacteremia, endocarditis, sepsis, and pneumonia [172]. Several factors could account for the initiation of inflammatory responses upon probiotic treatment, such as: significant gut microbiota variability between individuals, probiotic strain-specific function, and bacterial translocation to remote tissues or into the bloodstream [24]. Therefore, it is important to evaluate the risk–benefit ratio prior to probiotic administration to individuals with increased intestinal permeability and immunocompromised patients. Additionally, clarification of the exact molecular mechanisms of probiotic action, selection of the appropriate bacterial strain for targeted therapy, and determination of the most efficient dose remain necessary [173].
It is hypothesized that specific probiotic-derived compounds, mainly bacteriocins and SCFAs, are involved in the improvement of gut immunity without causing the undesirable side effects related to living microorganisms in high-risk patients [51]. Bacteriocins could be a promising therapeutic approach for the eradication of harmful pathogens showing resistance to conventional antibiotics [88,174]. Nevertheless, there is limited in vitro and in vivo evidence regarding their efficacy and safety as a treatment option for various human diseases [90]. In order to determine their efficiency, pharmacokinetic parameters, including solubility, bioavailability, and biodegradation, must be evaluated [175]. A few studies have indicated that bacteriocins may aggregate in vivo due to disturbance of their physical stability or alterations of their biochemical properties during their exposure in the GI tract. This could lead to low bioactivity and a subsequent immune response [91]. In this context, the encapsulation of purified bacteriocins into a protective matrix or the application of bioengineering methods [176] could be efficient approaches in order to improve their stability when orally administrated [175]. Further studies should be conducted to determine the action of purified bacteriocins since the presence of other postbiotics may mask their actual effects, as well as the combined action of their mixtures, since probiotics produce a variety of them. Thus, it is still challenging to develop more advanced, efficient, and affordable methods for the purification of bacteriocins from cell free supernatants to ideal concentrations for therapeutic applications [176] or the discovery of new bacteriocins [177].
In general, SCFAs comprise the largest group of bioactive compounds residing in the gut lumen, thus participating vigorously in the stimulation of gut immunity synergistically with other endogenous metabolites or exogenously administered drugs [1,146]. Additionally, SCFAs are endowed with the capacity to promote immune response, not only locally, but also systemically, due to their dissemination to distant tissues and organs [18,178]. To date, there are limited in vivo studies focusing mostly on the impact of SCFAs administration in chemically induced colitis animal models. The design of randomized controlled trials is required to fully understand the clinical impact of SCFAs in host health [116]. Several factors could affect the efficacy of SCFAs, including their route of administration, their dynamic interactions with commensal bacteria or other metabolites, and the variability in gut microbiota composition between individuals. It still remains a major challenge to determine the in vivo production of SCFAs in tissues other than the gut [179]. In this context, further investigations are necessary to extrapolate conclusions regarding the optimal dose and composition of SCFAs, and comparative analysis experiments could configure the criteria of SCFAs utilization based on the distinctiveness of each individual. Finally, there is lack of evidence regarding the combined action of purified bacteriocins and SCFAs. Further studies are warranted to ascertain their optimal ratio as therapeutics.

Author Contributions

Conceptualization, M.T.; writing—original draft preparation, C.T.; writing—review and editing, M.T. and C.T.; figure editing, C.T. and M.T.; supervision, M.T. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Acknowledgments

The authors express their gratitude to Kontoyiannis D.L. for the critical reading of the MS. This study was partially financially supported by the Graduate Program “Applications of Biology” of the School of Biology, Aristotle University of Thessaloniki.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Zhang, Z.; Tang, H.; Chen, P.; Xie, H.; Tao, Y. Demystifying the manipulation of host immunity, metabolism, and extraintestinal tumors by the gut microbiome. Signal Transduct. Target. Ther. 2019, 4, 41. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  2. Mazziotta, C.; Tognon, M.; Martini, F.; Torreggiani, E.; Rotondo, J.C. Probiotics Mechanism of Action on Immune Cells and Beneficial Effects on Human Health. Cells 2023, 12, 184. [Google Scholar] [CrossRef] [PubMed]
  3. Wang, G.; Huang, S.; Wang, Y.; Cai, S.; Yu, H.; Liu, H.; Zeng, X.; Zhang, G.; Qiao, S. Bridging intestinal immunity and gut microbiota by metabolites. Cell Mol. Life Sci. 2019, 76, 3917–3937. [Google Scholar] [CrossRef] [Green Version]
  4. Martinez, K.B.; Leone, V.; Chang, E.B. Western diets, gut dysbiosis, and metabolic diseases: Are they linked? Gut Microbes 2017, 8, 130–142. [Google Scholar] [CrossRef] [Green Version]
  5. Wang, J.; Chen, W.D.; Wang, Y.D. The Relationship Between Gut Microbiota and Inflammatory Diseases: The Role of Macrophages. Front. Microbiol. 2020, 11, 1065. [Google Scholar] [CrossRef] [PubMed]
  6. Sharma, V.R.; Singh, M.; Kumar, V.; Yadav, M.; Sehrawat, N.; Sharma, D.K.; Sharma, A.K. Microbiome dysbiosis in cancer: Exploring therapeutic strategies to counter the disease. Semin. Cancer Biol. 2021, 70, 61–70. [Google Scholar] [CrossRef]
  7. Bartolomaeus, H.; McParland, V.; Wilck, N. Darm-Herz-Achse: Wie Darmbakterien kardiovaskuläre Erkrankungen beeinflussen [Gut-heart axis: How gut bacteria influence cardiovascular diseases]. Herz 2020, 45, 134–141. [Google Scholar] [CrossRef]
  8. Rutsch, A.; Kantsjö, J.B.; Ronchi, F. The Gut-Brain Axis: How Microbiota and Host Inflammasome Influence Brain Physiology and Pathology. Front. Immunol. 2020, 11, 604179. [Google Scholar] [CrossRef]
  9. Plaza-Diaz, J.; Ruiz-Ojeda, F.J.; Gil-Campos, M.; Gil, A. Mechanisms of Action of Probiotics. Adv. Nutr. 2019, 10, S49–S66. [Google Scholar] [CrossRef] [Green Version]
  10. Hill, C.; Guarner, F.; Reid, G.; Gibson, G.R.; Merenstein, D.J.; Pot, B.; Morelli, L.; Canani, R.B.; Flint, H.J.; Salminen, S.; et al. Expert Consensus Document: The International Scientific Association for Probiotics and Prebiotics Consensus Statement on the Scope and Appropriate Use of the Term Probiotic. Nat. Rev. Gastroenterol. Hepatol. 2014, 11, 506–514. [Google Scholar] [CrossRef] [Green Version]
  11. Bao, Y.; Zhang, Y.; Zhang, Y.; Liu, Y.; Wang, S.; Dong, X.; Wang, Y.; Zhang, H. Screening of potential probiotic properties of Lactobacillus fermentum isolated from traditional dairy products. Food Control. 2010, 21, 695–701. [Google Scholar] [CrossRef]
  12. Nagpal, R.; Wang, S.; Ahmadi, S.; Hayes, J.; Gagliano, J.; Subashchandrabose, S.; Kitzman, D.W.; Becton, T.; Read, R.; Yadav, H. Human-origin probiotic cocktail increases short-chain fatty acid production via modulation of mice and human gut microbiome. Sci. Rep. 2018, 8, 12649. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  13. Soltani, S.; Hammami, R.; Cotter, P.D.; Rebuffat, S.; Said, L.B.; Gaudreau, H.; Bédard, F.; Biron, E.; Drider, D.; Fliss, I. Bacteriocins as a new generation of antimicrobials: Toxicity aspects and regulations. FEMS Microbiol. Rev. 2021, 45, fuaa039. [Google Scholar] [CrossRef]
  14. Azad, M.A.K.; Sarker, M.; Wan, D. Immunomodulatory Effects of Probiotics on Cytokine Profiles. BioMed Res. Int. 2018, 2018, 8063647. [Google Scholar] [CrossRef] [Green Version]
  15. Nagpal, R.; Kumar, A.; Kumar, M.; Behare, P.V.; Jain, S.; Yadav, H. Probiotics, their health benefits and applications for developing healthier foods: A review. FEMS Microbiol. Lett. 2012, 334, 1–15. [Google Scholar] [CrossRef] [Green Version]
  16. Chugh, B.; Kamal-Eldin, A. Bioactive compounds produced by probiotics in food products. Curr. Opin. Food Sci. 2020, 32, 76–82. [Google Scholar] [CrossRef]
  17. Indira, M.; Venkateswarulu, T.C.; Abraham Peele, K.; Nazneen Bobby, M.; Krupanidhi, S. Bioactive molecules of probiotic bacteria and their mechanism of action: A review. 3 Biotech 2019, 9, 306. [Google Scholar] [CrossRef]
  18. Blacher, E.; Levy, M.; Tatirovsky, E.; Elinav, E. Microbiome-Modulated Metabolites at the Interface of Host Immunity. J. Immunol. 2017, 198, 572–580. [Google Scholar] [CrossRef] [Green Version]
  19. Shin, J.M.; Gwak, J.W.; Kamarajan, P.; Fenno, J.C.; Rickard, A.H.; Kapila, Y.L. Biomedical applications of nisin. J. Appl. Microbiol. 2016, 120, 1449–1465. [Google Scholar] [CrossRef] [Green Version]
  20. Małaczewska, J.; Kaczorek-Łukowska, E. Nisin-A lantibiotic with immunomodulatory properties: A review. Peptides 2021, 137, 170479. [Google Scholar] [CrossRef] [PubMed]
  21. Hernández-González, J.C.; Martínez-Tapia, A.; Lazcano-Hernández, G.; García-Pérez, B.E.; Castrejón-Jiménez, N.S. Bacteriocins from Lactic Acid Bacteria. A Powerful Alternative as Antimicrobials, Probiotics, and Immunomodulators in Veterinary Medicine. Animals 2021, 11, 979. [Google Scholar] [CrossRef] [PubMed]
  22. Śliżewska, K.; Markowiak-Kopeć, P.; Śliżewska, W. The Role of Probiotics in Cancer Prevention. Cancers 2021, 13, 20. [Google Scholar] [CrossRef] [PubMed]
  23. Alexopoulou, L.; Kontoyiannis, D. Contribution of microbial-associated molecules in innate mucosal responses. Cell Mol. Life Sci. 2005, 62, 1349–1358. [Google Scholar] [CrossRef]
  24. Yeşilyurt, N.; Yılmaz, B.; Ağagündüz, D.; Capasso, R. Involvement of Probiotics and Postbiotics in the Immune System Modulation. Biologics 2021, 1, 89–110. [Google Scholar] [CrossRef]
  25. Amarante-Mendes, G.P.; Adjemian, S.; Branco, L.M.; Zanetti, L.C.; Weinlich, R.; Bortoluci, K.R. Pattern Recognition Receptors and the Host Cell Death Molecular Machinery. Front. Immunol. 2018, 9, 2379. [Google Scholar] [CrossRef] [Green Version]
  26. Li, D.; Wu, M. Pattern recognition receptors in health and diseases. Signal Transduct. Target. Ther. 2021, 6, 291. [Google Scholar] [CrossRef] [PubMed]
  27. Cano, R.L.E.; Lopera, H.D.E. Introduction to T and B lymphocytes. In Autoimmunity: From Bench to Bedside; Anaya, J.M., Shoenfeld, Y., Rojas-Villarraga, A., Eds.; El Rosario University Press: Bogota, Colombia, 2013. Available online: https://www.ncbi.nlm.nih.gov/books/NBK459471/ (accessed on 25 January 2023).
  28. Marshall, J.S.; Warrington, R.; Watson, W.; Kim, H.L. An introduction to immunology and immunopathology. Allergy Asthma Clin. Immunol. 2018, 14, 49. [Google Scholar] [CrossRef] [Green Version]
  29. Silva-Gomes, S.; Decout, A.; Nigou, J. Pathogen-Associated Molecular Patterns (PAMPs). In Encyclopedia of Inflammatory Diseases; Parnham, M., Ed.; Birkhäuser: Basel, Switzerland, 2014. [Google Scholar] [CrossRef]
  30. Netea, M.G.; Schlitzer, A.; Placek, K.; Joosten, L.A.B.; Schultze, J.L. Innate and Adaptive Immune Memory: An Evolutionary Continuum in the Host’s Response to Pathogens. Cell Host Microbe 2019, 25, 13–26. [Google Scholar] [CrossRef] [Green Version]
  31. Alberts, B.; Johnson, A.; Lewis, J.; Raff, M.; Roberts, K.; Walter, P. The Adaptive Immune System. In Molecular Biology of the Cell, 4th ed.; Garland Science: New York, NY, USA, 2002. Available online: https://www.ncbi.nlm.nih.gov/books/NBK21070/ (accessed on 25 January 2023).
  32. Chaplin, D.D. Overview of the immune response. J. Allergy Clin. Immunol. 2010, 125, S3–S23. [Google Scholar] [CrossRef]
  33. Bonilla, F.A.; Oettgen, H.C. Adaptive immunity. J. Allergy Clin. Immunol. 2010, 125, S33–S40. [Google Scholar] [CrossRef]
  34. Luckheeram, R.V.; Zhou, R.; Verma, A.D.; Xia, B. CD4+T cells: Differentiation and functions. Clin. Dev. Immunol. 2012, 2012, 925135. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  35. Hirahara, K.; Nakayama, T. CD4+ T-cell subsets in inflammatory diseases: Beyond the Th1/Th2 paradigm. Int. Immunol. 2016, 28, 163–171. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  36. Golubovskaya, V.; Wu, L. Different Subsets of T Cells, Memory, Effector Functions, and CAR-T Immunotherapy. Cancers 2016, 8, 36. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  37. Vyas, S.P.; Goswami, R. A Decade of Th9 Cells: Role of Th9 Cells in Inflammatory Bowel Disease. Front. Immunol. 2018, 9, 1139. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  38. Imam, T.; Park, S.; Kaplan, M.H.; Olson, M.R. Effector T Helper Cell Subsets in Inflammatory Bowel Diseases. Front. Immunol. 2018, 9, 1212. [Google Scholar] [CrossRef] [PubMed]
  39. Keir, M.; Yi, Y.; Lu, T.; Ghilardi, N. The role of IL-22 in intestinal health and disease. J. Exp. Med. 2020, 217, e20192195. [Google Scholar] [CrossRef]
  40. Cosovanu, C.; Neumann, C. The Many Functions of Foxp3+ Regulatory T Cells in the Intestine. Front. Immunol. 2020, 11, 600973. [Google Scholar] [CrossRef]
  41. Krishnaswamy, J.K.; Alsén, S.; Yrlid, U.; Eisenbarth, S.C.; Williams, A. Determination of T Follicular Helper Cell Fate by Dendritic Cells. Front. Immunol. 2018, 9, 2169. [Google Scholar] [CrossRef]
  42. Olvera-Rosales, L.B.; Cruz-Guerrero, A.E.; Ramírez-Moreno, E.; Quintero-Lira, A.; Contreras-López, E.; Jaimez-Ordaz, J.; Castañeda-Ovando, A.; Añorve-Morga, J.; Calderón-Ramos, Z.G.; Arias-Rico, J.; et al. Impact of the Gut Microbiota Balance on the Health-Disease Relationship: The Importance of Consuming Probiotics and Prebiotics. Foods 2021, 10, 1261. [Google Scholar] [CrossRef]
  43. Liu, Y.; Wang, J.; Wu, C. Modulation of Gut Microbiota and Immune System by Probiotics, Pre-biotics, and Post-biotics. Front. Nutr. 2022, 8, 634897. [Google Scholar] [CrossRef]
  44. Wu, H.J.; Wu, E. The role of gut microbiota in immune homeostasis and autoimmunity. Gut Microbes. 2012, 3, 4–14. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  45. Peluzio, M.D.C.G.; Martinez, J.A.; Milagro, F.I. Postbiotics: Metabolites and mechanisms involved in microbiota-host interactions. Trends Food Sci. Technol. 2021, 108, 11–26. [Google Scholar] [CrossRef]
  46. Fan, Y.; Pedersen, O. Gut microbiota in human metabolic health and disease. Nat. Rev. Microbiol. 2021, 19, 55–71. [Google Scholar] [CrossRef]
  47. Chen, Y.; Zhou, J.; Wang, L. Role and Mechanism of Gut Microbiota in Human Disease. Front. Cell. Infect. Microbiol. 2021, 11, 625913. [Google Scholar] [CrossRef] [PubMed]
  48. Zheng, D.; Liwinski, T.; Elinav, E. Interaction between microbiota and immunity in health and disease. Cell Res. 2020, 30, 492–506. [Google Scholar] [CrossRef] [PubMed]
  49. McBurney, M.I.; Davis, C.; Fraser, C.M.; Schneeman, B.O.; Huttenhower, C.; Verbeke, K.; Walter, J.; Latulippe, M.E. Establishing What Constitutes a Healthy Human Gut Microbiome: State of the Science, Regulatory Considerations, and Future Directions. J. Nutr. 2019, 149, 1882–1895. [Google Scholar] [CrossRef] [Green Version]
  50. Dogra, S.K.; Doré, J.; Damak, S. Gut Microbiota Resilience: Definition, Link to Health and Strategies for Intervention. Front. Microbiol. 2020, 11, 572921. [Google Scholar] [CrossRef]
  51. Cristofori, F.; Dargenio, V.N.; Dargenio, C.; Miniello, V.L.; Barone, M.; Francavilla, R. Anti-Inflammatory and Immunomodulatory Effects of Probiotics in Gut Inflammation: A Door to the Body. Front. Immunol. 2021, 12, 578386. [Google Scholar] [CrossRef]
  52. Integrative HMP (iHMP) Research Network Consortium. The Integrative Human Microbiome Project. Nature 2019, 569, 641–648. [Google Scholar] [CrossRef] [Green Version]
  53. Mörbe, U.M.; Jørgensen, P.B.; Fenton, T.M.; von Burg, N.; Riis, L.B.; Spencer, J.; Agace, W.W. Human gut-associated lymphoid tissues (GALT); diversity, structure, and function. Mucosal Immunol. 2021, 14, 793–802. [Google Scholar] [CrossRef]
  54. Yadav, M.K.; Kumari, I.; Singh, B.; Sharma, K.K.; Tiwari, S.K. Probiotics, prebiotics and synbiotics: Safe options for next-generation therapeutics. Appl. Microbiol. Biotechnol. 2022, 106, 505–521. [Google Scholar] [CrossRef] [PubMed]
  55. Jung, C.; Hugot, J.P.; Barreau, F. Peyer’s Patches: The Immune Sensors of the Intestine. Int. J. Inflam. 2010, 2010, 823710. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  56. Macpherson, A.J.; Harris, N.L. Interactions between commensal intestinal bacteria and the immune system. Nat. Rev. Immunol. 2004, 4, 478–485. [Google Scholar] [CrossRef]
  57. Round, J.L.; Mazmanian, S.K. The gut microbiota shapes intestinal immune responses during health and disease. Nat. Rev. Immunol. 2009, 9, 313–323. [Google Scholar] [CrossRef] [PubMed]
  58. Mazmanian, S.K.; Liu, C.H.; Tzianabos, A.O.; Kasper, D.L. An immunomodulatory molecule of symbiotic bacteria directs maturation of the host immune system. Cell 2005, 122, 107–118. [Google Scholar] [CrossRef] [Green Version]
  59. Ivanov, I.I.; Atarashi, K.; Manel, N.; Brodie, E.L.; Shima, T.; Karaoz, U.; Wei, D.; Goldfarb, K.C.; Santee, C.A.; Lynch, S.V.; et al. Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell 2009, 139, 485–498. [Google Scholar] [CrossRef] [Green Version]
  60. Zheng, Y.; Fang, Z.; Xue, Y.; Zhang, J.; Zhu, J.; Gao, R.; Yao, S.; Ye, Y.; Wang, S.; Lin, C.; et al. Specific gut microbiome signature predicts the early-stage lung cancer. Gut Microbes 2020, 11, 1030–1042. [Google Scholar] [CrossRef]
  61. Youssef, M.; Ahmed, H.Y.; Zongo, A.; Korin, A.; Zhan, F.; Hady, E.; Umair, M.; Shahid Riaz Rajoka, M.; Xiong, Y.; Li, B. Probiotic Supplements: Their Strategies in the Therapeutic and Prophylactic of Human Life-Threatening Diseases. Int. J. Mol. Sci. 2021, 22, 11290. [Google Scholar] [CrossRef]
  62. Raheem, A.; Liang, L.; Zhang, G.; Cui, S. Modulatory Effects of Probiotics During Pathogenic Infections with Emphasis on Immune Regulation. Front. Immunol. 2021, 12, 616713. [Google Scholar] [CrossRef]
  63. Kaur, H.; Ali, S.A. Probiotics and gut microbiota: Mechanistic insights into gut immune homeostasis through TLR pathway regulation. Food Funct. 2022, 13, 7423–7447. [Google Scholar] [CrossRef]
  64. Aghamohammad, S.; Sepehr, A.; Miri, S.T.; Najafi, S.; Rohani, M.; Pourshafiea, M.R. The effects of the probiotic cocktail on modulation of the NF-kB and JAK/STAT signaling pathways involved in the inflammatory response in bowel disease model. BMC Immunol. 2022, 23, 8. [Google Scholar] [CrossRef] [PubMed]
  65. Bhardwaj, R.; Singh, B.P.; Sandhu, N.; Singh, N.; Kaur, R.; Rokana, N.; Singh, K.S.; Chaudhary, V.; Panwar, H. Probiotic mediated NF-κB regulation for prospective management of type 2 diabetes. Mol. Biol. Rep. 2020, 47, 2301–2313. [Google Scholar] [CrossRef]
  66. Dinić, M.; Jakovljević, S.; Đokić, J.; Popović, N.; Radojević, D.; Strahinić, I.; Golić, N. Probiotic-mediated p38 MAPK immune signaling prolongs the survival of Caenorhabditis elegans exposed to pathogenic bacteria. Sci. Rep. 2021, 11, 21258. [Google Scholar] [CrossRef] [PubMed]
  67. Liu, Q.; Yu, Z.; Tian, F.; Zhao, J.; Zhang, H.; Zhai, Q.; Chen, W. Surface components and metabolites of probiotics for regulation of intestinal epithelial barrier. Microb. Cell Fact. 2020, 19, 23. [Google Scholar] [CrossRef] [Green Version]
  68. Gill, H.S.; Rutherfurd, K.J.; Prasad, J.; Gopal, P.K. Enhancement of natural and acquired immunity by Lactobacillus rhamnosus (HN001), Lactobacillus acidophilus (HN017) and Bifidobacterium lactis (HN019). Br. J. Nutr. 2000, 83, 167–176. [Google Scholar] [CrossRef] [Green Version]
  69. Rocha-Ramírez, L.M.; Pérez-Solano, R.A.; Castañón-Alonso, S.L.; Moreno Guerrero, S.S.; Ramírez Pacheco, A.; García Garibay, M.; Eslava, C. Probiotic Lactobacillus Strains Stimulate the Inflammatory Response and Activate Human Macrophages. J. Immunol. Res. 2017, 2017, 4607491. [Google Scholar] [CrossRef] [Green Version]
  70. Yousefi, B.; Eslami, M.; Ghasemian, A.; Kokhaei, P.; Salek Farrokhi, A.; Darabi, N. Probiotics importance and their immunomodulatory properties. J. Cell Physiol. 2019, 234, 8008–8018. [Google Scholar] [CrossRef] [PubMed]
  71. Aziz, N.; Bonavida, B. Activation of Natural Killer Cells by Probiotics. Onco Ther. 2016, 7, 41–55. [Google Scholar] [CrossRef] [Green Version]
  72. Mao, J.; Zhang, S.Z.; Du, P.; Cheng, Z.B.; Hu, H.; Wang, S.Y. Probiotics Can Boost the Antitumor Immunity of CD8+T Cells in BALB/c Mice and Patients with Colorectal Carcinoma. J. Immunol. Res. 2020, 2020, 4092472. [Google Scholar] [CrossRef] [PubMed]
  73. Maldonado Galdeano, C.; Cazorla, S.I.; Lemme Dumit, J.M.; Vélez, E.; Perdigón, G. Beneficial Effects of Probiotic Consumption on the Immune System. Ann. Nutr. Metab. 2019, 74, 115–124. [Google Scholar] [CrossRef] [Green Version]
  74. Javanshir, N.; Hosseini, G.N.G.; Sadeghi, M.; Esmaeili, R.; Satarikia, F.; Ahmadian, G.; Allahyari, N. Evaluation of the Function of Probiotics, Emphasizing the Role of their Binding to the Intestinal Epithelium in the Stability and their Effects on the Immune System. Biol. Proced. Online 2021, 23, 23. [Google Scholar] [CrossRef] [PubMed]
  75. Tripathy, A.; Dash, J.; Kancharla, S.; Kolli, P.; Mahajan, D.; Senapati, S.; Jena, M.K. Probiotics: A Promising Candidate for Management of Colorectal Cancer. Cancers 2021, 13, 3178. [Google Scholar] [CrossRef] [PubMed]
  76. Rousseaux, A.; Brosseau, C.; Bodinier, M. Immunomodulation of B Lymphocytes by Prebiotics, Probiotics and Synbiotics: Application in Pathologies. Nutrients 2023, 15, 269. [Google Scholar] [CrossRef]
  77. Pietrzak, B.; Tomela, K.; Olejnik-Schmidt, A.; Mackiewicz, A.; Schmidt, M. Secretory IgA in Intestinal Mucosal Secretions as an Adaptive Barrier against Microbial Cells. Int. J. Mol. Sci. 2020, 21, 9254. [Google Scholar] [CrossRef] [PubMed]
  78. Sakai, F.; Hosoya, T.; Ono-Ohmachi, A.; Ukibe, K.; Ogawa, A.; Moriya, T.; Kadooka, Y.; Shiozaki, T.; Nakagawa, H.; Nakayama, Y.; et al. Lactobacillus gasseri SBT2055 induces TGF-β expression in dendritic cells and activates TLR2 signal to produce IgA in the small intestine. PLoS ONE 2014, 9, e105370. [Google Scholar] [CrossRef] [PubMed]
  79. Tiwari, S.K. Bacteriocin-Producing Probiotic Lactic Acid Bacteria in Controlling Dysbiosis of the Gut Microbiota. Front. Cell. Infect. Microbiol. 2022, 12, 851140. [Google Scholar] [CrossRef]
  80. Nataraj, B.H.; Ali, S.A.; Behare, P.V.; Yadav, H. Postbiotics-parabiotics: The new horizons in microbial biotherapy and functional foods. Microb. Cell Fact. 2020, 19, 168. [Google Scholar] [CrossRef]
  81. Ma, L.; Tu, H.; Chen, T. Postbiotics in Human Health: A Narrative Review. Nutrients 2023, 15, 291. [Google Scholar] [CrossRef]
  82. Zamora-Pineda, J.; Kalinina, O.; Osborne, B.A.; Knight, K.L. Probiotic Molecules That Inhibit Inflammatory Diseases. Appl. Sci. 2022, 12, 1147. [Google Scholar] [CrossRef]
  83. Thorakkattu, P.; Khanashyam, A.C.; Shah, K.; Babu, K.S.; Mundanat, A.S.; Deliephan, A.; Deokar, G.S.; Santivarangkna, C.; Nirmal, N.P. Postbiotics: Current Trends in Food and Pharmaceutical Industry. Foods 2022, 11, 3094. [Google Scholar] [CrossRef]
  84. Aggarwal, S.; Sabharwal, V.; Kaushik, P.; Joshi, A.; Aayushi, A.; Suri, M. Postbiotics: From emerging concept to application. Front. Sustain. Food Syst. 2022, 6, 887642. [Google Scholar] [CrossRef]
  85. Klaenhammer, T.R. Bacteriocins of lactic acid bacteria. Biochimie 1988, 70, 337–349. [Google Scholar] [CrossRef]
  86. Zimina, M.; Babich, O.; Prosekov, A.; Sukhikh, S.; Ivanova, S.; Shevchenko, M.; Noskova, S. Overview of Global Trends in Classification, Methods of Preparation and Application of Bacteriocins. Antibiotics 2020, 9, 553. [Google Scholar] [CrossRef] [PubMed]
  87. Simons, A.; Alhanout, K.; Duval, R.E. Bacteriocins, Antimicrobial Peptides from Bacterial Origin: Overview of Their Biology and Their Impact against Multidrug-Resistant Bacteria. Microorganisms 2020, 8, 639. [Google Scholar] [CrossRef] [PubMed]
  88. Darbandi, A.; Asadi, A.; Mahdizade Ari, M.; Ohadi, E.; Talebi, M.; Halaj Zadeh, M.; Darb Emamie, A.; Ghanavati, R.; Kakanj, M. Bacteriocins: Properties and potential use as antimicrobials. J. Clin. Lab. Anal. 2022, 36, e24093. [Google Scholar] [CrossRef]
  89. Brogden, K.A. Classification of Bacteriocins from Gram-Positive Bacteria. In Prokaryotic Antimicrobial Peptides: From Genes to Applications; Drider, D., Rebuffat, S., Eds.; Springer: New York, NY, USA, 2011; pp. 29–54. [Google Scholar] [CrossRef]
  90. Huang, F.; Teng, K.; Liu, Y.; Cao, Y.; Wang, T.; Ma, C.; Zhang, J.; Zhong, J. Bacteriocins: Potential for Human Health. Oxidative Med. Cell. Longev. 2021, 2021, 5518825. [Google Scholar] [CrossRef]
  91. Benítez-Chao, D.F.; León-Buitimea, A.; Lerma-Escalera, J.A.; Morones-Ramírez, J.R. Bacteriocins: An Overview of Antimicrobial, Toxicity, and Biosafety Assessment by in vivo Models. Front Microbiol. 2021, 12, 630695. [Google Scholar] [CrossRef]
  92. Fernandes, A.; Jobby, R. Bacteriocins from lactic acid bacteria and their potential clinical applications. Appl. Biochem. Biotechnol. 2022, 194, 4377–4399. [Google Scholar] [CrossRef]
  93. Doublier, S.; Cirrincione, S.; Scardaci, R.; Botta, C.; Lamberti, C.; Giuseppe, F.D.; Angelucci, S.; Rantsiou, K.; Cocolin, L.; Pessione, E. Putative probiotics decrease cell viability and enhance chemotherapy effectiveness in human cancer cells: Role of butyrate and secreted proteins. Microbiol. Res. 2022, 260, 127012. [Google Scholar] [CrossRef]
  94. Rani, A.; Saini, K.C.; Bast, F.; Varjani, S.; Mehariya, S.; Bhatia, S.K.; Sharma, N.; Funk, C. A Review on Microbial Products and Their Perspective Application as Antimicrobial Agents. Biomolecules 2021, 11, 1860. [Google Scholar] [CrossRef] [PubMed]
  95. Kaur, S.; Kaur, S. Bacteriocins as Potential Anticancer Agents. Front. Pharmacol. 2015, 6, 272. [Google Scholar] [CrossRef] [Green Version]
  96. Cesa-Luna, C.; Alatorre-Cruz, J.M.; Carreño-López, R.; Quintero-Hernández, V.; Baez, A. Emerging Applications of Bacteriocins as Antimicrobials, Anticancer Drugs, and Modulators of The Gastrointestinal Microbiota. Pol. J. Microbiol. 2021, 70, 143–159. [Google Scholar] [CrossRef] [PubMed]
  97. Alvarez-Sieiro, P.; Montalbán-López, M.; Mu, D.; Kuipers, O.P. Bacteriocins of lactic acid bacteria: Extending the family. Appl. Microbiol. Biotechnol. 2016, 100, 2939–2951. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  98. Acedo, J.Z.; Chiorean, S.; Vederas, J.C.; van Belkum, M.J. The expanding structural variety among bacteriocins from Gram-positive bacteria. FEMS Microbiol. Rev. 2018, 42, 805–828. [Google Scholar] [CrossRef]
  99. Dobson, A.; Cotter, P.D.; Ross, R.P.; Hill, C. Bacteriocin production: A probiotic trait? Appl. Environ. Microbiol. 2012, 78, 1–6. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  100. Dreyer, L.; Smith, C.; Deane, S.M.; Dicks, L.M.T.; van Staden, A.D. Migration of Bacteriocins Across Gastrointestinal Epithelial and Vascular Endothelial Cells, as Determined Using In Vitro Simulations. Sci. Rep. 2019, 9, 11481. [Google Scholar] [CrossRef] [Green Version]
  101. Dicks, L.M.T.; Dreyer, L.; Smith, C.; van Staden, A.D. A Review: The Fate of Bacteriocins in the Human Gastro-Intestinal Tract: Do They Cross the Gut-Blood Barrier? Front. Microbiol. 2018, 9, 2297. [Google Scholar] [CrossRef] [Green Version]
  102. Jia, Z.; He, M.; Wang, C.; Chen, A.; Zhang, X.; Xu, J.; Fu, H.; Liu, B. Nisin reduces uterine inflammation in rats by modulating concentrations of pro- and anti-inflammatory cytokines. Am. J. Reprod. Immunol. 2019, 81, e13096. [Google Scholar] [CrossRef]
  103. De Pablo, M.A.; Gaforio, J.J.; Gallego, A.M.; Ortega, E.; Gálvez, A.M.; Alvarez de Cienfuegos López, G. Evaluation of immunomodulatory effects of nisin-containing diets on mice. FEMS Immunol. Med. Microbiol. 1999, 24, 35–42. [Google Scholar] [CrossRef] [Green Version]
  104. Małaczewska, J.; Kaczorek-Łukowska, E.; Wójcik, R.; Rękawek, W.; Siwicki, A.K. In vitro immunomodulatory effect of nisin on porcine leucocytes. J. Anim. Physiol. Anim. Nutr. 2019, 103, 882–893. [Google Scholar] [CrossRef]
  105. Kindrachuk, J.; Jenssen, H.; Elliott, M.; Nijnik, A.; Magrangeas-Janot, L.; Pasupuleti, M.; Thorson, L.; Ma, S.; Easton, D.M.; Bains, M.; et al. Manipulation of innate immunity by a bacterial secreted peptide: Lantibiotic nisin Z is selectively immunomodulatory. Innate Immun. 2013, 19, 315–327. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  106. Begde, D.; Bundale, S.; Mashitha, P.; Rudra, J.; Nashikkar, N.; Upadhyay, A. Immunomodulatory efficacy of nisin--a bacterial lantibiotic peptide. J. Pept. Sci. 2011, 17, 438–444. [Google Scholar] [CrossRef] [PubMed]
  107. Lewies, A.; Du Plessis, L.H.; Wentzel, J.F. Antimicrobial Peptides: The Achilles’ Heel of Antibiotic Resistance? Probiotics Antimicrob. Proteins 2019, 11, 370–381. [Google Scholar] [CrossRef] [PubMed]
  108. Moein, M.; Imani Fooladi, A.A.; Mahmoodzadeh Hosseini, H. Determining the effects of green chemistry synthesized Ag-nisin nanoparticle on macrophage cells. Microb. Pathog. 2018, 114, 414–419. [Google Scholar] [CrossRef] [PubMed]
  109. Umair, M.; Jabbar, S.; Zhaoxin, L.; Jianhao, Z.; Abid, M.; Khan, K.R.; Korma, S.A.; Alghamdi, M.A.; El-Saadony, M.T.; Abd El-Hack, M.E.; et al. Probiotic-Based Bacteriocin: Immunity Supplementation Against Viruses. An Updated Review. Front. Microbiol. 2022, 13, 876058. [Google Scholar] [CrossRef]
  110. Wang, S.; Ye, Q.; Wang, K.; Zeng, X.; Huang, S.; Yu, H.; Ge, Q.; Qi, D.; Qiao, S. Enhancement of Macrophage Function by the Antimicrobial Peptide Sublancin Protects Mice from Methicillin-Resistant Staphylococcus aureus. J. Immunol. Res. 2019, 2019, 3979352. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  111. Wang, S.; Wang, Q.; Zeng, X.; Ye, Q.; Huang, S.; Yu, H.; Yang, T.; Qiao, S. Use of the Antimicrobial Peptide Sublancin with Combined Antibacterial and Immunomodulatory Activities to Protect against Methicillin-Resistant Staphylococcus aureus Infection in Mice. J. Agric. Food Chem. 2017, 65, 8595–8605. [Google Scholar] [CrossRef]
  112. Antoshina, D.V.; Balandin, S.V.; Bogdanov, I.V.; Vershinina, M.A.; Sheremeteva, E.V.; Toropygin, I.Y.; Finkina, E.I.; Ovchinnikova, T.V. Antimicrobial Activity and Immunomodulatory Properties of Acidocin A, the Pediocin-like Bacteriocin with the Non-Canonical Structure. Membranes 2022, 12, 1253. [Google Scholar] [CrossRef]
  113. Cotter, P.D.; Ross, R.P.; Hill, C. Bacteriocins—a viable alternative to antibiotics? Nat. Rev. Microbiol. 2013, 11, 95–105. [Google Scholar] [CrossRef]
  114. Meijerink, M.; van Hemert, S.; Taverne, N.; Wels, M.; de Vos, P.; Bron, P.A.; Savelkoul, H.F.; van Bilsen, J.; Kleerebezem, M.; Wells, J.M. Identification of genetic loci in Lactobacillus plantarum that modulate the immune response of dendritic cells using comparative genome hybridization. PLoS ONE 2010, 5, e10632. [Google Scholar] [CrossRef] [Green Version]
  115. Van Hemert, S.; Meijerink, M.; Molenaar, D.; Bron, P.A.; de Vos, P.; Kleerebezem, M.; Wells, J.M.; Marco, M.L. Identification of Lactobacillus plantarum genes modulating the cytokine response of human peripheral blood mononuclear cells. BMC Microbiol. 2010, 10, 293. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  116. Cong, J.; Zhou, P.; Zhang, R. Intestinal Microbiota-Derived Short Chain Fatty Acids in Host Health and Disease. Nutrients 2022, 14, 1977. [Google Scholar] [CrossRef]
  117. Akhtar, M.; Chen, Y.; Ma, Z.; Zhang, X.; Shi, D.; Khan, J.A.; Liu, H. Gut microbiota-derived short chain fatty acids are potential mediators in gut inflammation. Anim. Nutr. 2021, 8, 350–360. [Google Scholar] [CrossRef] [PubMed]
  118. Cummings, J.H.; Pomare, E.W.; Branch, W.J.; Naylor, C.P.; Macfarlane, G.T. Short chain fatty acids in human large intestine, portal, hepatic and venous blood. Gut 1987, 28, 1221–1227. [Google Scholar] [CrossRef] [Green Version]
  119. Wang, H.Y.; Wang, C.; Guo, L.X.; Zheng, Y.F.; Hu, W.H.; Dong, T.T.X.; Wang, T.J.; Tsim, K.W.K. Simultaneous determination of short-chain fatty acids in human feces by HPLC with ultraviolet detection following chemical derivatization and solid-phase extraction segmental elution. J. Sep. Sci. 2019, 42, 2500–2509. [Google Scholar] [CrossRef]
  120. Rios-Covian, D.; González, S.; Nogacka, A.M.; Arboleya, S.; Salazar, N.; Gueimonde, M.; de Los Reyes-Gavilán, C.G. An Overview on Fecal Branched Short-Chain Fatty Acids Along Human Life and as Related with Body Mass Index: Associated Dietary and Anthropometric Factors. Front. Microbiol. 2020, 11, 973. [Google Scholar] [CrossRef] [PubMed]
  121. Zhang, Z.; Zhang, H.; Chen, T.; Shi, L.; Wang, D.; Tang, D. Regulatory role of short-chain fatty acids in inflammatory bowel disease. Cell Commun. Signal. 2022, 20, 64. [Google Scholar] [CrossRef]
  122. Hanus, M.; Parada-Venegas, D.; Landskron, G.; Wielandt, A.M.; Hurtado, C.; Alvarez, K.; Hermoso, M.A.; López-Köstner, F.; De la Fuente, M. Immune System, Microbiota, and Microbial Metabolites: The Unresolved Triad in Colorectal Cancer Microenvironment. Front. Immunol. 2021, 12, 612826. [Google Scholar] [CrossRef]
  123. Gill, P.A.; van Zelm, M.C.; Muir, J.G.; Gibson, P.R. Review article: Short chain fatty acids as potential therapeutic agents in human gastrointestinal and inflammatory disorders. Aliment Pharmacol. Ther. 2018, 48, 15–34. [Google Scholar] [CrossRef] [Green Version]
  124. Parada Venegas, D.; De la Fuente, M.K.; Landskron, G.; González, M.J.; Quera, R.; Dijkstra, G.; Harmsen, H.J.M.; Faber, K.N.; Hermoso, M.A. Short Chain Fatty Acids (SCFAs)-Mediated Gut Epithelial and Immune Regulation and Its Relevance for Inflammatory Bowel Diseases. Front. Immunol. 2019, 10, 277. [Google Scholar] [CrossRef] [Green Version]
  125. Van der Hee, B.; Wells, J.M. Microbial Regulation of Host Physiology by Short-chain Fatty Acids. Trends Microbiol. 2021, 29, 700–712. [Google Scholar] [CrossRef] [PubMed]
  126. Ramos Meyers, G.; Samouda, H.; Bohn, T. Short Chain Fatty Acid Metabolism in Relation to Gut Microbiota and Genetic Variability. Nutrients 2022, 14, 5361. [Google Scholar] [CrossRef]
  127. Siddiqui, M.T.; Cresci, G.A.M. The Immunomodulatory Functions of Butyrate. J. Inflamm. Res. 2021, 14, 6025–6041. [Google Scholar] [CrossRef] [PubMed]
  128. Jenab, A.; Roghanian, R.; Emtiazi, G. Bacterial Natural Compounds with Anti-Inflammatory and Immunomodulatory Properties (Mini Review). Drug Des. Dev. Ther. 2020, 14, 3787–3801. [Google Scholar] [CrossRef] [PubMed]
  129. Ranjbar, R.; Vahdati, S.N.; Tavakoli, S.; Khodaie, R.; Behboudi, H. Immunomodulatory roles of microbiota-derived short-chain fatty acids in bacterial infections. Biomed. Pharmacother. 2021, 141, 111817. [Google Scholar] [CrossRef]
  130. Kim, C.H. Control of lymphocyte functions by gut microbiota-derived short-chain fatty acids. Cell Mol. Immunol. 2021, 18, 1161–1171. [Google Scholar] [CrossRef]
  131. Yue, X.; Wen, S.; Long-Kun, D.; Man, Y.; Chang, S.; Min, Z.; Shuang-Yu, L.; Xin, Q.; Jie, M.; Liang, W. Three important short-chain fatty acids (SCFAs) attenuate the inflammatory response induced by 5-FU and maintain the integrity of intestinal mucosal tight junction. BMC Immunol. 2022, 23, 19. [Google Scholar] [CrossRef]
  132. Louis, P.; Duncan, S.; Sheridan, P.; Walker, A.; Flint, H. Microbial lactate utilisation and the stability of the gut microbiome. Gut Microbiome 2022, 3, E3. [Google Scholar] [CrossRef]
  133. Iraporda, C.; Errea, A.; Romanin, D.E.; Cayet, D.; Pereyra, E.; Pignataro, O.; Sirard, J.C.; Garrote, G.L.; Abraham, A.G.; Rumbo, M. Lactate and short chain fatty acids produced by microbial fermentation downregulate proinflammatory responses in intestinal epithelial cells and myeloid cells. Immunobiology 2015, 220, 1161–1169. [Google Scholar] [CrossRef]
  134. Caffaratti, C.; Plazy, C.; Mery, G.; Tidjani, A.R.; Fiorini, F.; Thiroux, S.; Toussaint, B.; Hannani, D.; Le Gouellec, A. What We Know So Far about the Metabolite-Mediated Microbiota-Intestinal Immunity Dialogue and How to Hear the Sound of This Crosstalk. Metabolites 2021, 11, 406. [Google Scholar] [CrossRef]
  135. Garrote, G.L.; Abraham, A.G.; Rumbo, M. Is lactate an undervalued functional component of fermented food products? Front. Microbiol. 2015, 6, 629. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  136. Iraporda, C.; Romanin, D.E.; Bengoa, A.A.; Errea, A.J.; Cayet, D.; Foligné, B.; Sirard, J.C.; Garrote, G.L.; Abraham, A.G.; Rumbo, M. Local Treatment with Lactate Prevents Intestinal Inflammation in the TNBS-Induced Colitis Model. Front. Immunol. 2016, 7, 651. [Google Scholar] [CrossRef]
  137. Manoharan, I.; Prasad, P.D.; Thangaraju, M.; Manicassamy, S. Lactate-Dependent Regulation of Immune Responses by Dendritic Cells and Macrophages. Front. Immunol. 2021, 12, 691134. [Google Scholar] [CrossRef]
  138. Lee, T.Y. Lactate: A multifunctional signaling molecule. Yeungnam Univ. J. Med. 2021, 38, 183–193. [Google Scholar] [CrossRef] [PubMed]
  139. Caslin, H.L.; Abebayehu, D.; Pinette, J.A.; Ryan, J.J. Lactate Is a Metabolic Mediator That Shapes Immune Cell Fate and Function. Front. Physiol. 2021, 12, 688485. [Google Scholar] [CrossRef]
  140. Pujari, R.; Banerjee, G. Impact of prebiotics on immune response: From the bench to the clinic. Immunol. Cell Biol. 2021, 99, 255–273. [Google Scholar] [CrossRef]
  141. Mirzaei, R.; Afaghi, A.; Babakhani, S.; Sohrabi, M.R.; Hosseini-Fard, S.R.; Babolhavaeji, K.; Khani Ali Akbari, S.; Yousefimashouf, R.; Karampoor, S. Role of microbiota-derived short-chain fatty acids in cancer development and prevention. Biomed. Pharmacother. 2021, 139, 111619. [Google Scholar] [CrossRef]
  142. Li, C.; Liang, Y.; Qiao, Y. Messengers from the Gut: Gut Microbiota-Derived Metabolites on Host Regulation. Front. Microbiol. 2022, 13, 863407. [Google Scholar] [CrossRef]
  143. Levy, M.; Thaiss, C.A.; Zeevi, D.; Dohnalová, L.; Zilberman-Schapira, G.; Mahdi, J.A.; David, E.; Savidor, A.; Korem, T.; Herzig, Y.; et al. Microbiota-Modulated Metabolites Shape the Intestinal Microenvironment by Regulating NLRP6 Inflammasome Signaling. Cell 2015, 163, 1428–1443. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  144. Russo, E.; Giudici, F.; Fiorindi, C.; Ficari, F.; Scaringi, S.; Amedei, A. Immunomodulating Activity and Therapeutic Effects of Short Chain Fatty Acids and Tryptophan Post-biotics in Inflammatory Bowel Disease. Front. Immunol. 2019, 10, 2754. [Google Scholar] [CrossRef] [Green Version]
  145. Kinoshita, M.; Suzuki, Y.; Saito, Y. Butyrate reduces colonic paracellular permeability by enhancing PPARgamma activation. Biochem. Biophys. Res. Commun. 2002, 293, 827–831. [Google Scholar] [CrossRef]
  146. Deleu, S.; Machiels, K.; Raes, J.; Verbeke, K.; Vermeire, S. Short chain fatty acids and its producing organisms: An overlooked therapy for IBD? EBioMedicine 2021, 66, 103293. [Google Scholar] [CrossRef]
  147. Kamp, M.E.; Shim, R.; Nicholls, A.J.; Oliveira, A.C.; Mason, L.J.; Binge, L.; Mackay, C.R.; Wong, C.H. G Protein-Coupled Receptor 43 Modulates Neutrophil Recruitment during Acute Inflammation. PLoS ONE 2016, 11, e0163750. [Google Scholar] [CrossRef] [Green Version]
  148. Maslowski, K.M.; Vieira, A.T.; Ng, A.; Kranich, J.; Sierro, F.; Yu, D.; Schilter, H.C.; Rolph, M.S.; Mackay, F.; Artis, D.; et al. Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43. Nature 2009, 461, 1282–1286. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  149. Nakkarach, A.; Foo, H.L.; Song, A.A.L.; Mutalib, N.E.A.; Nitisinprasert, S.; Withayagiat, U. Anti-cancer and anti-inflammatory effects elicited by short chain fatty acids produced by Escherichia coli isolated from healthy human gut microbiota. Microb. Cell Factories 2021, 20, 36. [Google Scholar] [CrossRef]
  150. Ji, J.; Shu, D.; Zheng, M.; Wang, J.; Luo, C.; Wang, Y.; Guo, F.; Zou, X.; Lv, X.; Li, Y.; et al. Microbial metabolite butyrate facilitates M2 macrophage polarization and function. Sci. Rep. 2016, 6, 24838. [Google Scholar] [CrossRef]
  151. Singh, N.; Gurav, A.; Sivaprakasam, S.; Brady, E.; Padia, R.; Shi, H.; Thangaraju, M.; Prasad, P.D.; Manicassamy, S.; Munn, D.H.; et al. Activation of Gpr109a, receptor for niacin and the commensal metabolite butyrate, suppresses colonic inflammation and carcinogenesis. Immunity 2014, 40, 128–139. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  152. Arpaia, N.; Campbell, C.; Fan, X.; Dikiy, S.; van der Veeken, J.; deRoos, P.; Liu, H.; Cross, J.R.; Pfeffer, K.; Coffer, P.J.; et al. Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation. Nature 2013, 504, 451–455. [Google Scholar] [CrossRef] [Green Version]
  153. Park, J.; Kim, M.; Kang, S.G.; Jannasch, A.H.; Cooper, B.; Patterson, J.; Kim, C.H. Short-chain fatty acids induce both effector and regulatory T cells by suppression of histone deacetylases and regulation of the mTOR-S6K pathway. Mucosal Immunol. 2015, 8, 80–93. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  154. Nastasi, C.; Candela, M.; Bonefeld, C.M.; Geisler, C.; Hansen, M.; Krejsgaard, T.; Biagi, E.; Andersen, M.H.; Brigidi, P.; Ødum, N.; et al. The effect of short-chain fatty acids on human monocyte-derived dendritic cells. Sci. Rep. 2015, 5, 16148. [Google Scholar] [CrossRef] [Green Version]
  155. Poggi, A.; Benelli, R.; Venè, R.; Costa, D.; Ferrari, N.; Tosetti, F.; Zocchi, M.R. Human Gut-Associated Natural Killer Cells in Health and Disease. Front. Immunol. 2019, 10, 961. [Google Scholar] [CrossRef] [Green Version]
  156. Smith, P.M.; Howitt, M.R.; Panikov, N.; Michaud, M.; Gallini, C.A.; Bohlooly-y, M.; Glickman, J.N.; Garrett, W.S. The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis. Science 2013, 341, 569–573. [Google Scholar] [CrossRef] [Green Version]
  157. Sun, M.; Wu, W.; Liu, Z.; Cong, Y. Microbiota metabolite short chain fatty acids, GPCR, and inflammatory bowel diseases. J. Gastroenterol. 2017, 52, 1–8. [Google Scholar] [CrossRef] [PubMed]
  158. Yang, W.; Cong, Y. Gut microbiota-derived metabolites in the regulation of host immune responses and immune-related inflammatory diseases. Cell. Mol. Immunol. 2021, 18, 866–877. [Google Scholar] [CrossRef] [PubMed]
  159. He, Y.; Fu, L.; Li, Y.; Wang, W.; Gong, M.; Zhang, J.; Dong, X.; Huang, J.; Wang, Q.; Mackay, C.R.; et al. Gut microbial metabolites facilitate anticancer therapy efficacy by modulating cytotoxic CD8+ T cell immunity. Cell Metab. 2021, 33, 988–1000.e7. [Google Scholar] [CrossRef]
  160. Kim, M.; Qie, Y.; Park, J.; Kim, C.H. Gut Microbial Metabolites Fuel Host Antibody Responses. Cell Host Microbe 2016, 20, 202–214. [Google Scholar] [CrossRef] [Green Version]
  161. Kim, C.H. B cell-helping functions of gut microbial metabolites. Microb. Cell. 2016, 3, 529–531. [Google Scholar] [CrossRef] [Green Version]
  162. Iraporda, C.; Romanin, D.; Rumbo, M.; Garrote, G.; Abraham, A. The role of lactate in the immunomodulatory properties of kefir non bacterial fraction. Food Res. Int. 2014, 62, 247–253. [Google Scholar] [CrossRef]
  163. Awasthi, D.; Nagarkoti, S.; Sadaf, S.; Chandra, T.; Kumar, S.; Dikshit, M. Glycolysis dependent lactate formation in neutrophils: A metabolic link between NOX-dependent and independent NETosis. Biochim. Biophys. Acta (BBA) Mol. Basis Dis. 2019, 1865, 165542. [Google Scholar] [CrossRef]
  164. Ranganathan, P.; Shanmugam, A.; Swafford, D.; Suryawanshi, A.; Bhattacharjee, P.; Hussein, M.S.; Koni, P.A.; Prasad, P.D.; Kurago, Z.B.; Thangaraju, M.; et al. GPR81, a Cell-Surface Receptor for Lactate, Regulates Intestinal Homeostasis and Protects Mice from Experimental Colitis. J. Immunol. 2018, 200, 1781–1789. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  165. Errea, A.; Cayet, D.; Marchetti, P.; Tang, C.; Kluza, J.; Offermanns, S.; Sirard, J.-C.; Rumbo, M. Lactate Inhibits the Pro-Inflammatory Response and Metabolic Reprogramming in Murine Macrophages in a GPR81-Independent Manner. PLoS ONE 2016, 11, e0163694. [Google Scholar] [CrossRef] [Green Version]
  166. Shan, T.; Chen, S.; Chen, X.; Wu, T.; Yang, Y.; Li, S.; Ma, J.; Zhao, J.; Lin, W.; Li, W.; et al. M2-TAM subsets altered by lactic acid promote T-cell apoptosis through the PD-L1/PD-1 pathway. Oncol. Rep. 2020, 44, 1885–1894. [Google Scholar] [CrossRef] [PubMed]
  167. Dietl, K.; Renner, K.; Dettmer, K.; Timischl, B.; Eberhart, K.; Dorn, C.; Hellerbrand, C.; Kastenberger, M.; Kunz-Schughart, L.A.; Oefner, P.J.; et al. Lactic Acid and Acidification Inhibit TNF Secretion and Glycolysis of Human Monocytes. J. Immunol. 2010, 184, 1200–1209. [Google Scholar] [CrossRef] [Green Version]
  168. Wang, Ζ.H.; Peng, W.B.; Zhang, P.; Yang, X.P.; Zhou, Q. Lactate in the tumour microenvironment: From immune modulation to therapy. EBioMedicine 2021, 73, 103627. [Google Scholar] [CrossRef]
  169. Apostolova, P.; Pearce, E.L. Lactic acid and lactate: Revisiting the physiological roles in the tumor microenvironment. Trends Immunol. 2022, 43, 969–977. [Google Scholar] [CrossRef]
  170. Haas, R.; Smith, J.; Rocher-Ros, V.; Nadkarni, S.; Montero-Melendez, T.; D’Acquisto, F.; Bland, E.J.; Bombardieri, M.; Pitzalis, C.; Perretti, M.; et al. Lactate regulates metabolic and proinflammatory circuits in control of T cell migration and effector functions. PLoS Biol. 2015, 13, e1002202. [Google Scholar] [CrossRef] [PubMed]
  171. Angelin, A.; Gil-de-Gómez, L.; Dahiya, S.; Jiao, J.; Guo, L.; Levine, M.H.; Wang, Z.; Quinn, W.J.; Kopinski, P.K.; Wang, L.; et al. Foxp3 Reprograms T Cell Metabolism to Function in Low-Glucose, High-Lactate Environments. Cell Metab. 2017, 25, 1282–1293.e7. [Google Scholar] [CrossRef] [Green Version]
  172. Rodriguez-Arrastia, M.; Martinez-Ortigosa, A.; Rueda-Ruzafa, L.; Folch Ayora, A.; Ropero-Padilla, C. Probiotic Supplements on Oncology Patients’ Treatment-Related Side Effects: A Systematic Review of Randomized Controlled Trials. Int. J. Environ. Res. Public Health. 2021, 18, 4265. [Google Scholar] [CrossRef] [PubMed]
  173. Sanders, M.E.; Akkermans, L.M.; Haller, D.; Hammerman, C.; Heimbach, J.; Hörmannsperger, G.; Huys, G.; Levy, D.D.; Lutgendorff, F.; Mack, D.; et al. Safety assessment of probiotics for human use. Gut Microbes 2010, 1, 164–185. [Google Scholar] [CrossRef]
  174. Heilbronner, S.; Krismer, B.; Brötz-Oesterhelt, H.; Peschel, A. The microbiome-shaping roles of bacteriocins. Nat. Rev. Microbiol. 2021, 19, 726–739. [Google Scholar] [CrossRef]
  175. Flynn, J.; Ryan, A.; Hudson, S.P. Pre-formulation and delivery strategies for the development of bacteriocins as next generation antibiotics. Eur. J. Pharm. Biopharm. 2021, 165, 149–163. [Google Scholar] [CrossRef]
  176. Todorov, S.D.; Popov, I.; Weeks, R.; Chikindas, M.L. Use of Bacteriocins and Bacteriocinogenic Beneficial Organisms in Food Products: Benefits, Challenges, Concerns. Foods 2022, 11, 3145. [Google Scholar] [CrossRef]
  177. Zou, J.; Jiang, H.; Cheng, H.; Fang, J.; Huang, G. Strategies for screening, purification and characterization of bacteriocins. Int. J. Biol. Macromol. 2018, 117, 781–789. [Google Scholar] [CrossRef] [PubMed]
  178. Xiong, R.-G.; Zhou, D.-D.; Wu, S.-X.; Huang, S.-Y.; Saimaiti, A.; Yang, Z.-J.; Shang, A.; Zhao, C.-N.; Gan, R.-Y.; Li, H.-B. Health Benefits and Side Effects of Short-Chain Fatty Acids. Foods 2022, 11, 2863. [Google Scholar] [CrossRef] [PubMed]
  179. Koh, A.; De Vadder, F.; Kovatcheva-Datchary, P.; Bäckhed, F. From Dietary Fiber to Host Physiology: Short-Chain Fatty Acids as Key Bacterial Metabolites. Cell 2016, 165, 1332–1345. [Google Scholar] [CrossRef] [PubMed] [Green Version]
Figure 1. Bacteriocins mechanism of action.
Figure 1. Bacteriocins mechanism of action.
Applsci 13 04726 g001
Figure 2. Classification of LAB bacteriocins.
Figure 2. Classification of LAB bacteriocins.
Applsci 13 04726 g002
Figure 3. SCFAs modulate innate and adaptive immune cells residing in the gut. SCFAs exert their immunomodulatory properties via activation of GPRs (namely GPR41, GPR43, and GPR101A) on the IECs surface. As a result, they induce: (1) naïve CD4+ T cells differentiation towards Th1, Th17, and IL-10 producing Tregs, (2) activation of DCs, which in turn trigger IL-10 producing Tregs, (3) secretion of mucin by intestinal goblet cells, (4) M2 macrophage polarization with subsequent production of IL-10, (5) secretion of IL-18 via activation of the NLRP3 inflammasome, (6) chemotaxis of neutrophils at inflammation sites, and (7) activation of DCs which produce ALDH1a causing IgA secretion by plasma cells.
Figure 3. SCFAs modulate innate and adaptive immune cells residing in the gut. SCFAs exert their immunomodulatory properties via activation of GPRs (namely GPR41, GPR43, and GPR101A) on the IECs surface. As a result, they induce: (1) naïve CD4+ T cells differentiation towards Th1, Th17, and IL-10 producing Tregs, (2) activation of DCs, which in turn trigger IL-10 producing Tregs, (3) secretion of mucin by intestinal goblet cells, (4) M2 macrophage polarization with subsequent production of IL-10, (5) secretion of IL-18 via activation of the NLRP3 inflammasome, (6) chemotaxis of neutrophils at inflammation sites, and (7) activation of DCs which produce ALDH1a causing IgA secretion by plasma cells.
Applsci 13 04726 g003
Table 3. The effects of probiotic-derived lactate on immune cells.
Table 3. The effects of probiotic-derived lactate on immune cells.
Cell TypeImmunomodulatory EffectReferences
IECsDownregulation of pro-inflammatory cytokines[133,136]
Abrogation of IECs activation depending on TLRs and IL-1β[162]
NeutrophilsNETs formation[139,163]
DCsGPR81 activation, suppression of colonic inflammation[137,164]
Cell surface markers modulation and cytokine secretion in
LPS-activated DCs
[133,137]
Macrophages GPR81-independent metabolic changes, pro-inflammatory
cytokines reduction
[165]
GPR81 activation, suppression of colonic inflammation[137,164]
M2 macrophage polarization, IL-10 increase, IL-12 decrease[166]
Downregulation of cytokine secretion in LPS-activated macrophages[133]
MonocytesInhibition of glycolysis, suppression of TNF-α secretion in the TME[167]
CD4+ T cellsGlycolysis-dependent inhibition of motility, Th17 differentiation,
increased IL-17 levels
[170]
Tregs proliferation[171]
CD8+ T cellsGlycolysis-independent inhibition of motility, loss of cytolytic function[170]
IECs: intestinal epithelial cells, TLR: Toll-like receptor, IL-1β: Interleukin-1β, NETs: neutrophil extracellular traps, DCs: dendritic cells, GPR81: G-protein-coupled receptor 81, LPS: Lipopolysaccharide, IL-10: Interleukin-10, IL-12: Interleukin- 12, TNF-α: Tumor necrosis factor-α, TME: tumor microenvironment, Th17: T helper 17, IL-17: Interleukin-17, Tregs: T regulatory cells.
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Thoda, C.; Touraki, M. Immunomodulatory Properties of Probiotics and Their Derived Bioactive Compounds. Appl. Sci. 2023, 13, 4726. https://doi.org/10.3390/app13084726

AMA Style

Thoda C, Touraki M. Immunomodulatory Properties of Probiotics and Their Derived Bioactive Compounds. Applied Sciences. 2023; 13(8):4726. https://doi.org/10.3390/app13084726

Chicago/Turabian Style

Thoda, Christina, and Maria Touraki. 2023. "Immunomodulatory Properties of Probiotics and Their Derived Bioactive Compounds" Applied Sciences 13, no. 8: 4726. https://doi.org/10.3390/app13084726

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop