Next Article in Journal
Human Resources Churning
Previous Article in Journal
Experiences of Parenting Multiple Expressions of Relationally Challenging Childhood Behaviours across Contexts
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:

Probiotics as Antibiotic Alternatives for Human and Animal Applications

Holy N. Rabetafika
Aurélie Razafindralambo
Bassey Ebenso
2 and
Hary L. Razafindralambo
ProBioLab, Campus Universitaire de la Faculté de Gembloux Agro-Bio Tech, Université de Liège, B-5030 Gembloux, Belgium
Leeds Institute of Health Sciences, University of Leeds, Leeds LS2 9NL, UK
BioEcoAgro Joint Research Unit, TERRA Teaching and Research Centre, Microbial Processes and Interactions, Gembloux AgroBio Tech, Université de Liège, B-5030 Gembloux, Belgium
Author to whom correspondence should be addressed.
Encyclopedia 2023, 3(2), 561-581;
Submission received: 25 March 2023 / Revised: 20 April 2023 / Accepted: 28 April 2023 / Published: 30 April 2023
(This article belongs to the Section Biology & Life Sciences)


Probiotics are live microorganisms recognized as natural candidates to substitute antibiotic substances, usually used to treat bacterial infections responsible for numerous human and animal diseases. Antibiotics are mostly prescribed for treating infections caused by bacteria. However, their excessive and inappropriate use has resulted in the increase of bacterial antimicrobial resistance (AMR) and host microbiota imbalance or dysbiosis phenomena. Even though antibiotics are the most well-known lifesaving substances, the AMR within the bacterial community has become a growing threat to global health, with the potential to cause millions of deaths each year in the future. Faced with these worldwide issues, it is high time to discover and develop antibiotic alternatives. There exists some evidence of probiotic roles in antagonizing pathogens, modulating immune systems, and maintaining general host health by restoring the gut microbiota balance. The multi-antimicrobial action mechanisms of such beneficial living microorganisms are one approach to practicing the “prevention is better than cure” concept to avoid antibiotics. The current review proposes a comprehensive description of antibiotic-related AMR issues and the potential of probiotics as antibiotic alternatives, while discussing pros and cons, as well as some evidence of beneficial uses of probiotics for human and animal health protection through recent results of experimental models and clinical trials.

1. Introduction

The use of antibiotics has a long history of applications in bacterial infection treatment, owing to their ability to inhibit the growth of or kill living microorganisms [1]. However, the current dissemination of antibiotic resistance genes into pathogenic bacteria has raised concern about the effectiveness of today’s antibiotic repertoire in the near future. Antimicrobial and antibiotic resistance problems have spread worldwide and have prompted the World Health Organization to classify such issues as an unpredictable global health threat with broad, multiple-sector impacts to human, animal, food, and environment safety [2]. Antibiotic-resistant pathogen-related deaths are projected to rise to 10 million per year worldwide by the year 2050 [3]. Therefore, alternative approaches to target bacterial pathogens have been advocated, such as directly treating diseases with therapeutic agents or indirectly modulating the gut microbial community with beneficial live microorganisms, the so-called probiotics [4]. In fact, probiotics play a key role in the microbiota equilibrium by re-populating, for instance, a gut in dysbiosis [5].
The mammalian gut microbiota confers health-promoting benefits to the host by modulating the immune system, by increasing the efficiency of nutrient utilization, and by eliminating the presence of pathogens [6]. An overall balance in the proportion of gut microbiota is essential in maintaining the healthy condition of the host [7]. The intestinal microbiome is unique in each individual and may be affected by genetic and environmental factors. Inappropriate and systematic administration of antibiotics is one of the environmental factors that cause alteration of gut microbiota (dysbiosis), leading to a deficiency of beneficial microorganisms in favor of potentially harmful microorganisms, as well as lower microbial diversity [8].
Probiotics are well-known as “good microorganisms” as opposed to “bad or harmful microbes” like pathogens. The term probiotic comes from the Latin “pro” and Greek “bios”, literally meaning “for life”, whereas antibiotic signifies “against life”. The most common probiotic definition is a live microorganism with beneficial effects when provided in appropriate conditions to a host. [9]. By possessing antagonistic properties, probiotics have been found to hinder the growth of gut pathogens through (i) the production of bioactive metabolites such as bacteriocins, hydrogen peroxide, organic acids, antioxidants, and antimicrobial peptides [10,11]; (ii) competition for nutrients and attachment sites [12]; and (iii) the modulation of immune system functions [13]. The first antimicrobial activity mechanism of probiotics is comparable to the direct antibiotic molecular reactivity against pathogens, whereas the second and third ones are inherent to probiotic cells, owing to their adhesion and colonization capacities, and indirect mechanisms through immune cells, respectively. By developing multi-antimicrobial mechanisms, probiotics induce low risks of resistance to pathogens, aside from transferring resistance genes which are normally verified before any microorganisms are recognized as probiotics. Some experimental studies and clinical trials on humans and animals have been reported in the literature, indicating some evidence of probiotic applications as alternatives of antibiotics to inhibit or/and destroy pathogens responsible for various diseases [14,15].
This review proposes a comprehensive description of antibiotic-related antimicrobial resistance issues, states the potential of probiotics as antibiotic alternatives while discussing pros and cons of their uses, and illustrates with recent examples some evidence of probiotic applications instead of antibiotics in human and animal health protection.

2. Antibiotics: Antimicrobial Resistance Causes and Potential Alternatives

2.1. Basic Concept of Antibiotics

Etymologically, the notion of antibiotics comes from “antibiosis”, which describes antagonistic effects among microorganisms [16]. The term “antibiotics” refers to naturally derived substances that inhibit or kill bacteria [17], whereas “antimicrobials” emerged with the development of natural, semi-synthetic and synthetic substances capable of inhibiting the proliferation of bacteria, viruses, fungi, and parasites [1]. According to Smith et al. (1998), antibiotics are low-molecular-weight substances produced by live microorganisms and plants, capable of selectively killing or hindering the growth of other organisms at low concentrations. These include synthetic organic compounds with identical antimicrobial activities [18].
Antibiotics can be classified according to their molecular structures, action mode, activity spectrum, origins, or administration route [17]. Most antibiotics are produced by filamentous actinomycetes (Streptomyces spp.). Other bacteria (Bacillus and Pseudomonas) and fungi (Penicillium) also synthesize antibiotic molecules [19]. A list of the major classes of antibiotics is provided in Table 1.
Antibiotics are currently used to treat infections and inhibit the growth of pathogenic microbes in the context of human health. The main antibiotic action mechanisms include cell wall synthesis inhibition, cell membrane structure or function breakdown, nucleic acid structure and function inhibition, protein synthesis inhibition, and key metabolic pathway blockage of folate synthesis [29].

2.2. Antimicrobial Resistance (AMR) Issues

AMR is the ability of microorganisms to resist and grow in the presence of antimicrobial agents [30]. The emergence of antibiotic resistance is a major global health challenge. The possible causes of its apparition include poor hygiene and misuse and overuse of antibiotics [31]. Moreover, animal farms have been identified as a potential source of antibiotic resistance genes (ARGs) and antibiotic-resistant bacteria (ARB) [32]. Therefore, the consumption of antibiotic-treated animal products constitutes a potential risk of resistant bacteria transfer [33]. For example, methicillin-resistant Staphylococcus aureus (MRSA) has been detected in farm equipment, livestock, and dairy farmers [34]. Bacteria can insert their genetic information into another organism via horizontal gene transfer mechanisms such as conjugation, phage transduction, plasmid mobility, and natural transformation, which facilitate bacteria niche expansion and functional diversification [35]. Human-associated bacteria have been found to have a 25-times higher chance of exchanging genetic material than bacteria from other environments [36]. Under the selective pressure exerted by antibiotic treatment, evolving microbial communities result from the altered population structure of the indigenous microbiota, which have endured stress perturbation and acquisition of resistance enrichment. Antibiotics also favor antibiotic-resistant communities, enriching the presence of resistance genes in the microbiome. For instance, a study has showed an increased exchange of integrating conjugative genes that encode multidrug resistance by interspecies DNA-synthesis-inhibiting antibiotics. The ability of commensals to outcompete pathogens for space and nutrients, as well as enhancing the host defense of the colonic epithelium, actively protect the host against infections [37,38]. Administration of antibiotics can disrupt the population structure of the gut environment, which then compromises the defenses, thus opening new niches for intrusion. The mobility of antibiotic-induced resistance genes encourages co-localization of pathogenic and commensal bacteria, which thus provides opportunities for the transfer of resistance to harmful pathogens [35]. This can be exemplified by methicillin-resistant S. aureus (MRSA), which acquired a gene that improved its colonization in the host from Staphylococcus epidermis [39].
The main AMR mechanisms developed by resistant pathogens (Figure 1) include the presence of resistance genes in transposable elements such as in plasmids, reduction in uptake of antimicrobial agents (efflux of the antibiotic from the cell, biofilm formation, and permeability reduction), the presence of factors that affect the target antibiotic like enzymes, and mutation or alteration in the target site of antibiotics [40]. Table 2 lists the action modes and the resistance mechanisms of principal antibiotic classes.

2.3. Alternatives to Antibiotics

Considering the alarming consequences of AMR, new antibiotic alternative treatments which are more specific while eliminating deleterious side effects on the gut microbiota are crucial. These alternatives aim at maximally reducing the inappropriate and excessive use of antibiotics and should produce the same beneficial effects of such active molecules. Among the alternative candidates include molecular substitute classes such as bacteriocins, antimicrobial peptides, medicinal plants, and nanoparticles, which directly act by inhibiting or destroying pathogens, and microbial-based substitute classes such as bacteriophages, probiotics, and some vaccines [50]. The antibacterial mechanisms of the latter are based on either direct or indirect activities. For instance, bacteriophages are viruses that release their genetic material into bacteria, degrading the bacterial DNA, and ultimately killing them. Probiotics may directly act through antibiosis by producing metabolites such as bacteriocins, organic acids, antioxidant compounds, and nutrient-space competition, or indirectly by modulating the host’s gut microbiota and immune system, and can in this way reduce dysbiosis and bacterial infections, respectively. Figure 2 summarizes the main potential alternatives that have been considered to reduce the use of or even replace conventional antibiotics, and thus fight against AMR phenomena. Two alternative groups are distinguished according to their functions: (i) disease prevention through gut microbiota and immune system modulation (e.g., probiotics) and immune stimulation (e.g., vaccines), and (ii) disease treatment by reducing or suppressing bacterial infections (e.g., phage therapy, bacteriocins, nanoparticles, antibodies, and quorum-sensing anti-virulence inhibitors) [50].

3. Probiotics as Potential Alternative to Antibiotics

The probiotic-based approach represents a potential effective strategy to counter the emergence of antibiotic-resistant bacteria [51]. Probiotics consist of live microorganisms that are beneficial to the host when used under adequate conditions [9].
There exists evidence to support the idea that probiotics can be used for treating and preventing infectious diseases in human and animal health [4,52]. For instance, several clinical trials demonstrate the positive effect of the probiotic yeast Saccharomyces boulardii on Candida infection complications [53]. Lacticaseibacillus casei ATTC334, Bifidobacterium breve JCM1192, and Bifidobacterium infantis BL2416 are able to decrease the harmful effects and mortality in chicks due to Salmonella infections by competitive exclusion and cytokine release promotion mechanisms [54].
The main antimicrobial mechanisms of probiotics include competitive exclusion, intestinal barrier function improvement by enhancing mucin and tight junction protein expression, antimicrobial molecule secretion, and immune system regulation [55]. Figure 3 outlines the principal antimicrobial mechanisms employed by probiotics.

3.1. Competitive Exclusion of Pathogens

The establishment of a probiotic bacterial population in the gastrointestinal tract creates competition for nutrients or adhesion sites to prevent the overgrowth of potential pathogens. Two competitive strategies, namely, exploitation and interference competition, exist [12]. Exploitation competition for both nutrients and space is an indirect mechanism. It results from rapid nutrient consumption due to the secretion of extracellular molecules (e.g., proteases, iron-chelating siderophores), which are able to hydrolyze complex macromolecules, thus restricting resources for competitors. Probiotics also can rapidly colonize uninhabited niches or compete with pathogens through the production of adhesins and receptors that bind to specific surface features [56]. Several experimental studies reported the antagonistic effects of lactic acid bacteria (LAB) on the adhesion of pathogens [57,58,59].
Interference competition acts directly on potential pathogens by the production of antimicrobial compounds, for example, bacteriocins that harm pathogens. Furthermore, it reduces antibiotic-induced superinfections and aids in the restoration of the desired microbial numbers inside the body [7]. Probiotic Lactiplantibacillus plantarum strains effectively compete with, exclude, and displace the adhesion of pathogenic Escherichia coli and Salmonella enterica [60].

3.2. Improvement of Intestinal Barriers

The intestinal barrier has a fundamental role in health and disease. It constitutes an important line of defense in order to maintain intestinal homeostasis by ensuring mechanical, chemical, immune, and microbial barrier functions. These functions can be compromised when the mucosa suffers structural damage and dysregulation [61]. The use of probiotics represents a potentially effective strategy for the mucosal barrier function to out-compete pathogenic organisms. The mechanical barrier is ensured by the intestinal epithelial cells (IECs) and intercellular junction complexes. The tight junctions (TJs) at the IECs’ apical side regulate small and ionic molecules to maintain normal intestinal barrier function with regard to pathogenic bacteria and harmful substances [62]. Probiotics are able to restore the gut barrier by enhancing the expression of genes and proteins involved in tight junction (TJ) signaling and regulating the intestinal epithelial cells’ apoptosis and the proliferation of IECs. As an example, Lactobacillus acidophilus causes a strain-specific and rapid enhancement of intestinal epithelial TJ barrier function, mediated by the Toll-like receptor-2 (TLR-2) heterodimeric complexes TLR-2/TLR-1 and TLR-2/TLR-6, which leads to protection against intestinal inflammation [63].
Moreover, a mucus layer is secreted by goblet cells in the intestinal epithelium. The mucus, mainly composed of high-molecular-weight glycoproteins called mucins, enhances nutrient uptake, provides adhesion sites for resident bacteria, and prevents microbial penetration [61,62,64].
Probiotics are also able to elicit mucin expression and mucus secretion from the goblet cells. Treatment of mucus-secreting colon epithelial cells (HT29-MTX) with probiotic mix yogurt supernatants (Streptococcus thermophilus, Lactobacillus bulgaricus, and Bifidobacterium bifidum (C-Bb); S. thermophilus, L. bulgaricus, and L. acidophilus (C-La); and S. thermophilus, L. bulgaricus, and Lactobacillus gasseri (C-Lg)) increased the expression of MUC2 and CDX2, as well as the production of mucin proteins. MUC2 is a major mucin protein in the mucus layer, whereas CDX2 regulates the expression of MUC2 [65].

3.3. Secretion of Antimicrobial Peptides (AMPs)

Probiotic bacteria can produce and release antimicrobial molecules such as organic acid compounds [66,67], diacetyl [68], hydrogen peroxide [69], and peptides [70], which have selective activity against numerous strains of microbes commonly found in the gut. Bacterial AMPs are often referred to as bacteriocins, which are a heterogenous group of ribosomally synthetized peptides. These peptides directly kill or inhibit the growth of pathogens in the lumen [71]. Bacteriocins are generally categorized into three classes: (1) heat-stable peptides of class I are lantibiotics with characteristic polycyclic thioether amino acids (e.g., lanthionine, <5 kDa), with linear (A-lantibiotics) or globular (B-lantibiotics) structures; (2) heat-stable peptides of class II are bacteriocins containing no lanthionine (<10 kDa); and (3) heat-labile high-molecular-weight molecules are class III bacteriocins (>30 kDa) [72].
The antimicrobial mechanisms of probiotic bacteriocins are structure-dependent (e.g., amino acid sequence and net charge) and include pore formation and enzyme activity modulation, as well as quorum sensing, i.e., the ability to detect and respond to cell population density with gene regulation [73].
Bacteriocins of class I have detrimental effects on cell integrity, owing to their ability to enter the cell membrane. Another action mechanism of class I bacteriocins is cell wall synthesis inhibition. Those of class II have the ability to depolarize cell membranes by binding to the membrane pore receptor system, such as mannose phosphotransferase, while those of class III directly lyse cells [74].
The AMP named nisin is, for instance, able to interact with membrane-bound lipid II proteins and cause pore formation in the cell membrane, leading to the lysis of the bacterium [75,76]. Such bacteriocins are produced by Lactococcus lactis and belong to the class of A-lantibiotics with a positive charge.
The class I B-lantibiotic named mersacidin from Bacillus spp. is a globular-shaped and neutral or negatively charged peptide that is able to interfere with cell wall biosynthesis [77].
The class II bacteriocin named pediocin from Pediococcus pentosaceus GS4 (MTCC 12683) has antibacterial and antagonistic potential against S. aureus (ATCC 25923), E. coli (ATCC 25922), Pseudomonas aeruginosa (ATCC 25619), and Listeria monocytogenes (ATCC 15313) [78].
The AMPs colicin, megacin, klebicin, helveticin I, and enterolysin from Bacillus megaterium, Klebsiella pneumonia, Lactobacillus helveticus, and Enterococcus faecalis, respectively, are categorized as class III bacteriocins. They are able to catalyze cell wall hydrolysis [73]. A few examples of probiotic bacteriocins and their target microorganisms are listed in Table 3.

3.4. Modulation of Host Immune System

Probiotic bacteria may exert their immunomodulatory effect by increasing the growth of healthy components in the gut microecology. By restoring the normal ecological niche, a probiotic can give rise to better nutritional and environmental proto-cooperation that enables the body to regulate all the specific and nonspecific immune responses [84].
The nonspecific immune response (innate immunity) is the first line of defense and is composed of chemical and physical barriers (skin and mucous membranes), immune cells (dendritic cells, macrophages, monocytes, neutrophils, and natural killers), and immunomodulatory agent cytokines.
The specific immune response (adaptive immunity) is induced toward offensive targets by lymphocytes (B and T cells) and through antibody responses, immunoglobulin production, and the cell-mediated immune response [85].
Probiotics have an impact on innate immunity by enhancing the cytotoxicity of natural killer (NK) cells and the phagocytosis of macrophages. They modulate the adaptive immunity by interacting with intestinal immune cells such as enterocytes, dendritic cells, and regulatory T cells [13].
The replenishing of the gut population through probiotics has gone beyond the benefits of maintaining a balanced gut ecosystem by recuperating the immune system. Probiotics affect the host defense mechanisms in several ways such as the stimulation of phagocytic activity, balancing pro-inflammatory and anti-inflammatory cytokines, and enhancing the production of cytokines and immunoglobulin IgA.

3.4.1. Stimulation of Phagocytic Activity

Probiotic bacteria are able to enhance nonspecific immune responses. Among the possible mechanisms is the promotion of phagocytic activity through macrophage activation [86]. Activated macrophages enhance phagocytosis by promoting the production of cytotoxic molecules such as nitric oxide (NO) and secrete immunoregulatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-6, IL-10, and interferon-γ (IFN-γ) in order to initiate the destruction of pathogens [87]. At the same time, they express receptors for a variety of cytokines such as IFN-γ, IL-4, IL-10, and TNF-α [88].
Specific receptors (pattern recognition receptors, or PRRs) of macrophages can bind to the surface components of probiotic LABs, such as flagella, proteins, capsular polysaccharides (CPSs), lipopolysaccharide (LPS), and peptidoglycan (PG), which represent microbial-associated molecular patterns (MAMPs) [89].
The probiotic strains Lacticaseibacillus rhamnosus GG, L. rhamnosus KLDS, L. helveticus IMAU70129, and L. casei IMAU60214 have been shown to stimulate inflammatory responses and activate human macrophages. Pretreatment with Lactobacillus enhanced phagocytosis and the antimicrobial activity of macrophages against S. aureus, S. typhimurium, and E. coli [90].
It has been proposed that consumption of fermented milk containing Lactobacillus johnsonii and S. thermophilus enhances the phagocytic activity of peripheral blood leukocytes in healthy adult volunteers [91]. In another study, an improvement of phagocytic activity of peritoneal macrophages in a murine model was shown after feeding with fermented fish protein concentrate (FPC) at 0.3 mg/mL for 7 consecutive days. This finding indicates that fermented fish proteins regulate nonspecific host defense mechanisms by enhancing the phagocytosis of pathogens [88].

3.4.2. Balancing of Pro- and Anti-Inflammatory Cytokines

Cytokines are small proteins released by immune cells such as macrophages, T cells, B cells, and natural killers in order to regulate and influence the immune response [92]. Cytokine production can lead to the modulation of the host immune system, as it is involved in the regulation of cell activation, growth, and differentiation, as well as inflammation [86]. The inflammatory process depends on the balance between pro-inflammatory and anti-inflammatory cytokines. Interleukin-1 (IL-1), IL-2, IL-6, IL-12, IL-18, gamma interferon (IFN-γ), and tumor necrosis factor alpha (TNF-α) are involved in pro-inflammatory action. The anti-inflammatory cytokines such as IL-10, transforming growth factor-β (TGF-β) produced by monocytes, T cells, B cells, macrophages, natural killer cells, and dendritic cells inhibit pro-inflammatory cytokines, chemokines, and chemokine receptors [93].
Probiotics regulate the innate and adaptive immune systems by interacting with enterocytes and dendritic cells, Th1, Th2, and Treg cells in the intestine, thus inducing the release of cytokines [13]. Streptococcus thermophilus ST285 has been shown to significatively increase the expression of anti-inflammatory IL-4, IL-5, and IL-10 cytokines, and decrease the secretion of pro-inflammatory IL-1β and IFN-γ, thus altering pro-inflammatory secretion to anti-inflammatory secretion against multiple sclerosis peptide in mice [94].
Moreover, S. thermophilus ST285 increased the anti-inflammatory cytokine production by human monocytes (IL-4, IFN-γ, and TNF-α) [95].
As the most generally accepted cultured dairy product, yogurt has been amended with specific strains of lactic acid bacteria to stimulate cytokine production, such as interferon γ (IFN-γ) by human blood mononuclear cells and also by monocytes [96].
Probiotic Lactobacillus kefiri CIDCA 8348 isolated from kefir induced immunomodulatory effects on CD4+ T lymphocytes from the lamina propria of intestinal bowel disease (IBD) patients. L. kefiri decreased the secretion of IL-6 and IL-8 from inflamed biopsies ex vivo and reduced the secretion of TNF-α, IL-6, IFN-γ, and IL-13. In addition, L. kefiri induced an increased frequency of activated CD4+ with high levels of IL-10 [97].

3.4.3. Enhancing Immunoglobulin A (IgA) Production

IgA is produced by the plasma cells while representing the first-line defense against infection in the digestive tract. Secretory IgA (SIgA) protects against the adhesion of pathogens and their penetration into the intestinal barrier. In contact with bacteria present in the digestive tract, SIgA traps pathogens and pathogenic material through agglutination, disrupting adhesive complex substances, and also by setting adhesive proteins on the surface of bacteria [98].
Probiotics are able to improve host defense by enhancing the production of specific antibodies against pathogens and total IgA. It has been demonstrated that LABs induced IL-6 and IL-10 production by dendritic cells, which contribute to upregulating the secretory IgA concentration at mucosal sites in humans [99]. For example, L. gasseri SBT2055 induced TGF-β expression in dendritic cells and activated TLR2 signaling to produce IgA in the small intestine [100].
Evidence of the immune-stimulating effect of fermented milk kefir made with a wide variety of bacteria such as lactobacilli, lactococci, leuconostocs, aceterobacteria, as well as some potentially beneficial yeast has been reported. After the ingestion of kefir by young and senescent rats, a significant increase in IgA antibody titers in young rats was noticed [101]. Furthermore, it has also been shown that IgA production by plasma cells can be altered in a dose-dependent manner by consuming yogurt [102].
Administration of viable (L. salivarius subsp. salicinius AP-32, B. animalis subsp. lactis CP-9, and Lacticaseibacillus paracasei ET-66) and heat-killed (L. salivarius subsp. salicinius AP-32 and L. paracasei ET-66) probiotics in healthy adults increased salivary IgA levels after 6 weeks and inhibited oral pathogens such as S. mutans, P. gingivalis, F. nucleatum subsp. polymorphum, and A. actinomycetemcomitans [103].
A study conducted on children with acute rotavirus diarrhea showed that administration of L. rhamnosus GG fermented milk product caused stimulatory effects on IgA-specific antibody-secreting cells [104]. Table 4 lists recent in/ex vivo studies on probiotic effects on the immune system.

4. Advantages and Disadvantages of Probiotics as Antibiotic Alternatives

While antibiotics are active substances directly used to fight pathogens, probiotics are live microorganisms that can act directly by producing antimicrobial metabolites and competing microbes for sites/nutrients, or/and indirectly by stimulating host immune systems. In addition, probiotics help to repopulate the gut with healthy microbiota and reduce dysbiosis caused by antibiotics. In this situation, probiotics can compensate for antibiotic side effects. Moreover, probiotic activities are multiple and may include antibacterial, antifungal, and antiviral effects, whereas those of antibiotics are only intended to inhibit or destroy bacteria [17,111,112,113]. Other aspects distinguishing them arise from their status. Antibiotics are used as drugs requiring medical prescription, while probiotics are freely available and mainly consumed as diet supplements or through fermented products, even if some strains are prescribed as drugs, such as S. boulardii as an antidiarrheal [114]. In terms of dose, effects, and treatment duration, an effective antibiotic is a short-time and low-dose-acting antimicrobial, but it might cause progressive antimicrobial resistance and host microbiota imbalance by inducing a pathogen’s defense mechanisms and killing also good microbes. Conversely, the positive effects of probiotics are often perceptible after long-term uptake, without the side effects observed after antibiotic treatment. In fact, probiotics can control pathogenic targets through competitive exclusion of nutrients and space, and ensure the host’s microbiota balance. Among probiotics’ disadvantages are their sensitivity under extreme stress conditions (e.g., temperature, acidity, moisture, etc.), which reduce their survival rate and therefore their capacity to colonize the gut. Table 5 compares the strengths and weaknesses of antibiotics and probiotics regarding their usage for fighting pathogen growth and infections.

5. Human Applications

The potential use of probiotics as antibiotic alternatives for human applications has been shown through many in and ex vivo experiments reported in the literature, as illustrated in Table 6. For instance, lactic acid- and soil-based bacteria are capable of exerting bacteriostatic and bactericidal activities to certain pathogens such as S. aureus, L. monocytogenes, P. aeruginosa, and Candida albicans, reducing their colonization of the human body. Some clinical trials have also proven their efficacy for disease treatments (Table 7). However, it is important to distinguish different scenarios where probiotics are used for supporting antibiotics from other situations where they are used as substitute options. For many situations in human health, the use of antibiotics remains the first choice for controlling bacterial infections, and probiotics are useful for repopulating the gut microbiota [115]. Other situations indicate no clear or controversial use of antibiotics, whereas the use of probiotics may constitute an alternative in cases such as periodontal disease, acne, recurrent infections with Helicobacter pilori, and bacterial vaginosis [116,117,118,119]. Finally, there are other situations for which the antibiotic use is non-indicated and probiotics appear as an appropriate option, such as in the case of acute and Clostridium difficile-associated diarrhea [120,121].

6. Animal Applications

Antibiotics are often used in animal farming as antimicrobial agents for enhancing animal growth and production, as well as controlling diseases [138]. An evident use of probiotics instead of antibiotics is supported in the case of promoting animal growth, for which the goal consists of health development without specific infection targets [139,140]. A considerable number of probiotic strains are also capable of inhibiting diverse animal pathogens and may be potentially used as antibiotic alternatives in the farming sectors of poultry, swine, cattle, and others for enhancing immune function and disease prevention [10]. The benefits and inputs from probiotics as alternatives to antibiotics in animal health are outlined in Figure 4.
Table 8 illustrates some recent examples of animal feed being supplemented with lactic acid and soil-based bacteria, the form of administration, and the probiotic strain effects. The use of probiotics as feed supplements in animal farming allows not only the reduction of AMR apparition due to the excessive use of antibiotics, but also the diminution of the residue transfer risk to animal products such as eggs, milk, and meat.

7. Conclusions

Inappropriate and excessive use of antibiotics increases pathogen resistance cases and dysbiosis phenomena, which constitute a real threat to human and animal health and wellbeing. As alternatives, probiotics appear to be reliable candidates, owing to numerous features and functions that these live and multifunctional microorganisms possess compared to antibacterial substances. In addition to their capacity to produce multiple antimicrobial metabolites comparable to antibiotics, probiotics have other mechanisms of action against pathogens, including nutrient competition and space exclusion, as well as immunomodulation activities. Such multi-action mechanisms minimize the risk of pathogen AMR and increase the potential for the use of probiotics as substitutes for antibiotics. Moreover, the use of probiotics as antimicrobials is not limited to bacteria but is also applicable to viruses. Plentiful evidence indicates their efficacy in inhibiting human and animal pathogens through experimental models and clinical trials and confirms their potential applications to prevent diseases, treat infections, and promote growth performance, immune systems, and nutrient efficiency. Despite such advantages, the maintenance of cell viability and dose optimization remain industrial challenges to achieving high specificity and short-time treatment with probiotics compared to antibiotics.

Author Contributions

H.L.R. conceptualized and outlined the manuscript. H.N.R. searched the literature, created figures, and prepared tables. H.N.R., A.R., B.E. and H.L.R. contributed to the manuscript writing and have read and agreed to the final version. All authors have read and agreed to the published version of the manuscript.


This research received no external funding.

Data Availability Statement

No new data were created or analyzed.

Conflicts of Interest

The authors declare no conflict of interest.


  1. Kourkouta, L.; Koukourikos, K.; Iliadis, C.; Plati, P.; Dimitriadou, A. History of Antibiotics. Sumer. J. Med. Healthc. 2018, 1, 51–55. [Google Scholar]
  2. World Health Organization. Antimicrobial Resistance: Global Report on Surveillance; World Health Organization: Geneva, Switzerland, 2014; ISBN 92-4-156474-1. [Google Scholar]
  3. O’Neill, J. Tackling Drug-Resistant Infections Globally: Final Report and Recommendations. 2016. Available online: (accessed on 24 March 2023).
  4. Tegegne, B.A.; Kebede, B. Probiotics, their prophylactic and therapeutic applications in human health development: A review of the literature. Heliyon 2022, 8, e09725. [Google Scholar] [CrossRef] [PubMed]
  5. Kumar, R.; Sood, U.; Gupta, V.; Singh, M.; Scaria, J.; Lal, R. Recent Advancements in the Development of Modern Probiotics for Restoring Human Gut Microbiome Dysbiosis. Indian J. Microbiol. 2020, 60, 12–25. [Google Scholar] [CrossRef] [PubMed]
  6. Allen, H.K.; Trachsel, J.; Looft, T.; Casey, T.A. Finding alternatives to antibiotics. Ann. N. Y. Acad. Sci. 2014, 1323, 91–100. [Google Scholar] [CrossRef]
  7. Reid, G. Probiotics to Prevent the Need for, and Augment the Use of, Antibiotics. Can. J. Infect. Dis. Med Microbiol. 2006, 17, 291–295. [Google Scholar] [CrossRef]
  8. Petersen, C.; Round, J.L. Defining dysbiosis and its influence on host immunity and disease. Cell. Microbiol. 2014, 16, 1024–1033. [Google Scholar] [CrossRef]
  9. 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]
  10. Vieco-Saiz, N.; Belguesmia, Y.; Raspoet, R.; Auclair, E.; Gancel, F.; Kempf, I.; Drider, D. Benefits and Inputs from Lactic Acid Bacteria and Their Bacteriocins as Alternatives to Antibiotic Growth Promoters during Food-Animal Production. Front. Microbiol. 2019, 10, 57. [Google Scholar] [CrossRef]
  11. Aghebati-Maleki, L.; Hasannezhad, P.; Abbasi, A.; Khani, N. Antibacterial, Antiviral, Antioxidant, and Anticancer Activities of Postbiotics: A Review of Mechanisms and Therapeutic Perspectives. Biointerface Res. Appl. Chem. 2021, 12, 2629–2645. [Google Scholar]
  12. Knipe, H.; Temperton, B.; Lange, A.; Bass, D.; Tyler, C.R. Probiotics and competitive exclusion of pathogens in shrimp aquaculture. Rev. Aquac. 2021, 13, 324–352. [Google Scholar] [CrossRef]
  13. Azad, M.; Kalam, A.; Sarker, M.; Wan, D. Immunomodulatory Effects of Probiotics on Cytokine Profiles. BioMed Res. Int. 2018, 2018, 8063647. [Google Scholar] [CrossRef] [PubMed]
  14. Yaqoob, M.U.; Wang, G.; Wang, M. An updated review on probiotics as an alternative of antibiotics in poultry—A review. Anim. Biosci. 2022, 35, 1109–1120. [Google Scholar] [CrossRef] [PubMed]
  15. Saettone, V.; Biasato, I.; Radice, E.; Schiavone, A.; Bergero, D.; Meineri, G. State-of-the-Art of the Nutritional Alternatives to the Use of Antibiotics in Humans and Monogastric Animals. Animals 2020, 10, 2199. [Google Scholar] [CrossRef] [PubMed]
  16. Bentley, R.; Bennett, J.W. What Is an Antibiotic? Revisited. Adv. Appl. Microbiol. 2003, 52, 303–332. [Google Scholar] [CrossRef] [PubMed]
  17. Etebu, E.; Arikekpar, I. Antibiotics: Classification and Mechanisms of Action with Emphasis on Molecular Perspectives. Int. J. Appl. Microbiol. Biotechnol. Res. 2016, 4, 90–101. [Google Scholar]
  18. Smith, A.D.; Datta, S.P.; Smith, G.H.; Campbell, P.N.; Bentley, R.; McKenzie, H.A.; Jakoby, W.B. Oxford Dictionary of Biochemistry and Molecular Biology. Trends Biochem. Sci. 1998, 23, 228. [Google Scholar]
  19. Hutchings, M.I.; Truman, A.W.; Wilkinson, B. Antibiotics: Past, Present and Future. Curr. Opin. Microbiol. 2019, 51, 72–80. [Google Scholar] [CrossRef]
  20. Pissowotzki, K.; Mansouri, K.; Piepersberg, W. Genetics of streptomycin production in Streptomyces griseus: Molecular structure and putative function of genes strELMB2N. Mol. Gen. Genet. MGG 1991, 231, 113–123. [Google Scholar] [CrossRef]
  21. Laich, F.; Fierro, F.; Martín, J.F. Production of Penicillin by Fungi Growing on Food Products: Identification of a Complete Penicillin Gene Cluster in Penicillium griseofulvum and a Truncated Cluster in Penicillium verrucosum. Appl. Environ. Microbiol. 2002, 68, 1211–1219. [Google Scholar] [CrossRef]
  22. Jung, H.-M.; Kim, S.-Y.; Moon, H.-J.; Oh, D.-K.; Lee, J.-K. Optimization of culture conditions and scale-up to pilot and plant scales for vancomycin production by Amycolatopsis orientalis. Appl. Microbiol. Biotechnol. 2007, 77, 789–795. [Google Scholar] [CrossRef]
  23. Miao, V.; Coëffet-LeGal, M.-F.; Brian, P.; Brost, R.; Penn, J.; Whiting, A.; Martin, S.; Ford, R.; Parr, I.; Bouchard, M.; et al. Daptomycin biosynthesis in Streptomyces roseosporus: Cloning and analysis of the gene cluster and revision of peptide stereochemistry. Microbiology 2005, 151, 1507–1523. [Google Scholar] [CrossRef] [PubMed]
  24. Weber, J.M.; Wierman, C.K.; Hutchinson, C.R. Genetic analysis of erythromycin production in Streptomyces erythreus. J. Bacteriol. 1985, 164, 425–433. [Google Scholar] [CrossRef] [PubMed]
  25. Fernández-Martínez, L.T.; Borsetto, C.; Gomez-Escribano, J.P.; Bibb, M.J.; Al-Bassam, M.M.; Chandra, G.; Bibb, M.J. New Insights into Chloramphenicol Biosynthesis in Streptomyces venezuelae ATCC 10712. Antimicrob. Agents Chemother. 2014, 58, 7441–7450. [Google Scholar] [CrossRef] [PubMed]
  26. Fang, A.; Pierson, D.L.; Mishra, S.K.; Koenig, D.W.; Demain, A.L. Gramicidin S Production by Bacillus brevis in Simulated Microgravity. Curr. Microbiol. 1997, 34, 199–204. [Google Scholar] [CrossRef] [PubMed]
  27. Naghmouchi, K.; Hammami, R.; Fliss, I.; Teather, R.; Baah, J.; Drider, D. Colistin A and colistin B among inhibitory substances of Paenibacillus polymyxa JB05-01-1. Arch. Microbiol. 2012, 194, 363–370. [Google Scholar] [CrossRef]
  28. Petković, H.; Lukežič, T.; Šušković, J. Biosynthesis of Oxytetracycline by Streptomyces rimosus: Past, Present and Future Directions in the Development of Tetracycline Antibiotics. Food Technol. Biotechnol. 2017, 55, 3–13. [Google Scholar] [CrossRef]
  29. Dowling, A.; O’dwyer, J.; Adley, C. Antibiotics: Mode of Action and Mechanisms of Resistance. Antimicrob. Res. Nov. Bioknowledge Educ. Programs 2017, 1, 536–545. [Google Scholar]
  30. Abushaheen, M.A.; Fatani, A.J.; Alosaimi, M.; Mansy, W.; George, M.; Acharya, S.; Rathod, S.; Divakar, D.D.; Jhugroo, C.; Vellappally, S. Antimicrobial Resistance, Mechanisms and Its Clinical Significance. Dis. Mon. 2020, 66, 100971. [Google Scholar] [CrossRef]
  31. Aghamohammad, S.; Rohani, M. Antibiotic resistance and the alternatives to conventional antibiotics: The role of probiotics and microbiota in combating antimicrobial resistance. Microbiol. Res. 2022, 267, 127275. [Google Scholar] [CrossRef]
  32. Bai, H.; He, L.-Y.; Wu, D.-L.; Gao, F.-Z.; Zhang, M.; Zou, H.-Y.; Yao, M.-S.; Ying, G.-G. Spread of airborne antibiotic resistance from animal farms to the environment: Dispersal pattern and exposure risk. Environ. Int. 2021, 158, 106927. [Google Scholar] [CrossRef]
  33. Ma, F.; Xu, S.; Tang, Z.; Li, Z.; Zhang, L. Use of antimicrobials in food animals and impact of transmission of antimicrobial resistance on humans. Biosaf. Health 2021, 3, 32–38. [Google Scholar] [CrossRef]
  34. Papadopoulos, P.; Angelidis, A.S.; Papadopoulos, T.; Kotzamanidis, C.; Zdragas, A.; Papa, A.; Filioussis, G.; Sergelidis, D. Staphylococcus aureus and methicillin-resistant S. aureus (MRSA) in bulk tank milk, livestock and dairy-farm personnel in north-central and north-eastern Greece: Prevalence, characterization and genetic relatedness. Food Microbiol. 2019, 84, 103249. [Google Scholar] [CrossRef] [PubMed]
  35. Modi, S.R.; Collins, J.J.; Relman, D.A. Antibiotics and the Gut Microbiota. J. Clin. Investig. 2014, 124, 4212–4218. [Google Scholar] [CrossRef]
  36. Smillie, C.S.; Smith, M.B.; Friedman, J.; Cordero, O.X.; David, L.A.; Alm, E.J. Ecology drives a global network of gene exchange connecting the human microbiome. Nature 2011, 480, 241–244. [Google Scholar] [CrossRef] [PubMed]
  37. Brandl, K.; Plitas, G.; Mihu, C.N.; Ubeda, C.; Jia, T.; Fleisher, M.; Schnabl, B.; DeMatteo, R.P.; Pamer, E.G. Vancomycin-resistant enterococci exploit antibiotic-induced innate immune deficits. Nature 2008, 455, 804–807. [Google Scholar] [CrossRef]
  38. Fukuda, S.; Toh, H.; Hase, K.; Oshima, K.; Nakanishi, Y.; Yoshimura, K.; Tobe, T.; Clarke, J.M.; Topping, D.L.; Suzuki, T.; et al. Bifidobacteria can protect from enteropathogenic infection through production of acetate. Nature 2011, 469, 543–547. [Google Scholar] [CrossRef]
  39. Diep, B.A.; Gill, S.R.; Chang, R.F.; Phan, T.H.; Chen, J.H.; Davidson, M.G.; Lin, F.; Lin, J.; Carleton, H.A.; Mongodin, E.F.; et al. Complete genome sequence of USA300, an epidemic clone of community-acquired meticillin-resistant Staphylococcus aureus. Lancet 2006, 367, 731–739. [Google Scholar] [CrossRef]
  40. Darby, E.M.; Trampari, E.; Siasat, P.; Gaya, M.S.; Alav, I.; Webber, M.A.; Blair, J.M.A. Molecular mechanisms of antibiotic resistance revisited. Nat. Rev. Microbiol. 2022, 21, 280–295. [Google Scholar] [CrossRef]
  41. Singh, S.P.; Qureshi, A.; Hassan, W. Mechanisms of action by antimicrobial agents: A review. McGill J. Med. 2021, 19, 1–10. [Google Scholar] [CrossRef]
  42. Uddin, T.M.; Chakraborty, A.J.; Khusro, A.; Zidan, B.R.M.; Mitra, S.; Bin Emran, T.; Dhama, K.; Ripon, K.H.; Gajdács, M.; Sahibzada, M.U.K.; et al. Antibiotic resistance in microbes: History, mechanisms, therapeutic strategies and future prospects. J. Infect. Public Health 2021, 14, 1750–1766. [Google Scholar] [CrossRef]
  43. Krause, K.M.; Serio, A.W.; Kane, T.R.; Connolly, L.E. Aminoglycosides: An Overview. Cold Spring Harb. Perspect. Med. 2016, 6, a027029. [Google Scholar] [CrossRef] [PubMed]
  44. Fernandes, R.; Amador, P.; Prudêncio, C. β-Lactams: Chemical Structure, Mode of Action and Mechanisms of Resistance. Rev. Res. Med. Microbiol. 2013, 24, 7–17. [Google Scholar] [CrossRef]
  45. Zeng, D.; Debabov, D.; Hartsell, T.L.; Cano, R.J.; Adams, S.; Schuyler, J.A.; McMillan, R.; Pace, J.L. Approved Glycopeptide Antibacterial Drugs: Mechanism of Action and Resistance. Cold Spring Harb. Perspect. Med. 2016, 6, a026989. [Google Scholar] [CrossRef] [PubMed]
  46. Redgrave, L.S.; Sutton, S.B.; Webber, M.A.; Piddock, L.J. Fluoroquinolone resistance: Mechanisms, impact on bacteria, and role in evolutionary success. Trends Microbiol. 2014, 22, 438–445. [Google Scholar] [CrossRef] [PubMed]
  47. Kim, D.-W.; Thawng, C.N.; Lee, K.; Wellington, E.M.; Cha, C.-J. A novel sulfonamide resistance mechanism by two-component flavin-dependent monooxygenase system in sulfonamide-degrading actinobacteria. Environ. Int. 2019, 127, 206–215. [Google Scholar] [CrossRef]
  48. Grossman, T.H. Tetracycline Antibiotics and Resistance. Cold Spring Harb. Perspect. Med. 2016, 6, a025387. [Google Scholar] [CrossRef]
  49. Schwarz, S.; Shen, J.; Kadlec, K.; Wang, Y.; Michael, G.B.; Feßler, A.T.; Vester, B. Lincosamides, Streptogramins, Phenicols, and Pleuromutilins: Mode of Action and Mechanisms of Resistance. Cold Spring Harb. Perspect. Med. 2016, 6, a027037. [Google Scholar] [CrossRef]
  50. Helmy, Y.A.; Taha-Abdelaziz, K.; Hawwas, H.A.E.-H.; Ghosh, S.; AlKafaas, S.S.; Moawad, M.M.M.; Saied, E.M.; Kassem, I.I.; Mawad, A.M.M. Antimicrobial Resistance and Recent Alternatives to Antibiotics for the Control of Bacterial Pathogens with an Emphasis on Foodborne Pathogens. Antibiotics 2023, 12, 274. [Google Scholar] [CrossRef]
  51. Silva, D.R.; Sardi, J.D.C.O.; de Souza Pitangui, N.; Roque, S.M.; da Silva, A.C.B.; Rosalen, P.L. Probiotics as an alternative antimicrobial therapy: Current reality and future directions. J. Funct. Foods 2020, 73, 104080. [Google Scholar] [CrossRef]
  52. Zamojska, D.; Nowak, A.; Nowak, I.; Macierzyńska-Piotrowska, E. Probiotics and Postbiotics as Substitutes of Antibiotics in Farm Animals: A Review. Animals 2021, 11, 3431. [Google Scholar] [CrossRef]
  53. Kunyeit, L.; K A, A.-A.; Rao, R.P. Application of Probiotic Yeasts on Candida Species Associated Infection. J. Fungi 2020, 6, 189. [Google Scholar] [CrossRef] [PubMed]
  54. El-Sharkawy, H.; Tahoun, A.; Rizk, A.M.; Suzuki, T.; Elmonir, W.; Nassef, E.; Shukry, M.; Germoush, M.O.; Farrag, F.; Bin-Jumah, M.; et al. Evaluation of Bifidobacteria and Lactobacillus Probiotics as Alternative Therapy for Salmonella typhimurium Infection in Broiler Chickens. Animals 2020, 10, 1023. [Google Scholar] [CrossRef]
  55. 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]
  56. Schluter, J.; Nadell, C.D.; Bassler, B.L.; Foster, K.R. Adhesion as a weapon in microbial competition. ISME J. 2015, 9, 139–149. [Google Scholar] [CrossRef] [PubMed]
  57. Siedler, S.; Rau, M.H.; Bidstrup, S.; Vento, J.M.; Aunsbjerg, S.D.; Bosma, E.F.; McNair, L.M.; Beisel, C.L.; Neves, A.R. Competitive exclusion is a major bioprotective mechanism of lactobacilli against fungal spoilage in fermented milk products. Appl. Environ. Microbiol. 2020, 86, e02312-19. [Google Scholar] [CrossRef] [PubMed]
  58. Zuo, F.; Appaswamy, A.; Gebremariam, H.G.; Jonsson, A.-B. Role of Sortase A in Lactobacillus gasseri Kx110A1 Adhesion to Gastric Epithelial Cells and Competitive Exclusion of Helicobacter pylori. Front. Microbiol. 2019, 10, 2770. [Google Scholar] [CrossRef] [PubMed]
  59. Lau, L.Y.J.; Chye, F.Y. Antagonistic effects of Lactobacillus plantarum 0612 on the adhesion of selected foodborne enteropathogens in various colonic environments. Food Control 2018, 91, 237–247. [Google Scholar] [CrossRef]
  60. Dhanani, A.; Bagchi, T. The expression of adhesin EF-Tu in response to mucin and its role in Lactobacillus adhesion and competitive inhibition of enteropathogens to mucin. J. Appl. Microbiol. 2013, 115, 546–554. [Google Scholar] [CrossRef]
  61. Vancamelbeke, M.; Vermeire, S. The intestinal barrier: A fundamental role in health and disease. Expert Rev. Gastroenterol. Hepatol. 2017, 11, 821–834. [Google Scholar] [CrossRef]
  62. Gou, H.-Z.; Zhang, Y.-L.; Ren, L.-F.; Li, Z.-J.; Zhang, L. How Do Intestinal Probiotics Restore the Intestinal Barrier? Front. Microbiol. 2022, 13, 929346. [Google Scholar] [CrossRef]
  63. Al-Sadi, R.; Nighot, P.; Nighot, M.; Haque, M.; Rawat, M.; Ma, T.Y. Lactobacillus acidophilus Induces a Strain-specific and Toll-Like Receptor 2–Dependent Enhancement of Intestinal Epithelial Tight Junction Barrier and Protection against Intestinal Inflammation. Am. J. Pathol. 2021, 191, 872–884. [Google Scholar] [CrossRef] [PubMed]
  64. La Fata, G.; Weber, P.; Mohajeri, M.H. Probiotics and the Gut Immune System: Indirect Regulation. Probiotics Antimicrob. Proteins 2018, 10, 11–21. [Google Scholar] [CrossRef] [PubMed]
  65. Chang, Y.H.; Jeong, C.H.; Cheng, W.N.; Choi, Y.; Shin, D.M.; Lee, S.; Han, S.G. Quality characteristics of yogurts fermented with short-chain fatty acid-producing probiotics and their effects on mucin production and probiotic adhesion onto human colon epithelial cells. J. Dairy Sci. 2021, 104, 7415–7425. [Google Scholar] [CrossRef] [PubMed]
  66. Szczerbiec, D.; Piechocka, J.; Głowacki, R.; Torzewska, A. Organic Acids Secreted by Lactobacillus spp. Isolated from Urine and Their Antimicrobial Activity against Uropathogenic Proteus mirabilis. Molecules 2022, 27, 5557. [Google Scholar] [CrossRef]
  67. Huang, C.B.; Alimova, Y.; Myers, T.M.; Ebersole, J.L. Short- and medium-chain fatty acids exhibit antimicrobial activity for oral microorganisms. Arch. Oral Biol. 2011, 56, 650–654. [Google Scholar] [CrossRef]
  68. Kim, Y.; Yoon, S.; Shin, H.; Jo, M.; Lee, S.; Kim, S.-H. Isolation of Lactococcus lactis ssp. cremoris LRCC5306 and Optimization of Diacetyl Production Conditions for Manufacturing Sour Cream. Food Sci. Anim. Resour. 2021, 41, 373–385. [Google Scholar] [CrossRef]
  69. Tomás, M.S.J.; Otero, M.C.; Ocaña, V.; Nader-Macías, M.E. Production of Antimicrobial Substances by Lactic Acid Bacteria I: Determination of Hydrogen Peroxide. Public Health Microbiol. Methods Protoc. 2004, 268, 337–346. [Google Scholar] [CrossRef]
  70. Mejía-Pitta, A.; Broset, E.; de la Fuente-Nunez, C. Probiotic engineering strategies for the heterologous production of antimicrobial peptides. Adv. Drug Deliv. Rev. 2021, 176, 113863. [Google Scholar] [CrossRef]
  71. Hassan, M.; Kjos, M.; Nes, I.F.; Diep, D.B.; Lotfipour, F. Natural antimicrobial peptides from bacteria: Characteristics and potential applications to fight against antibiotic resistance. J. Appl. Microbiol. 2012, 113, 723–736. [Google Scholar] [CrossRef]
  72. Negash, A.W.; Tsehai, B.A. Current Applications of Bacteriocin. Int. J. Microbiol. 2020, 2020, 4374891. [Google Scholar] [CrossRef]
  73. Bharti, V.; Mehta, A.; Singh, S.; Jain, N.; Ahirwal, L.; Mehta, S. Bacteriocin: A Novel Approach for Preservation of Food. Int. J. Pharm. Pharm. Sci. 2015, 7, 20–29. [Google Scholar]
  74. Darvishi, N.; Fard, N.A.; Sadrnia, M. Genomic and proteomic comparisons of bacteriocins in probiotic species Lactobacillus and Bifidobacterium and inhibitory ability of Escherichia coli MG 1655. Biotechnol. Rep. 2021, 31, e00654. [Google Scholar] [CrossRef] [PubMed]
  75. Brötz, H.; Josten, M.; Wiedemann, I.; Schneider, U.; Götz, F.; Bierbaum, G.; Sahl, H.-G. Role of Lipid-bound Peptidoglycan Precursors in the Formation of Pores by Nisin, Epidermin and Other Lantibiotics. Mol. Microbiol. 1998, 30, 317–327. [Google Scholar] [CrossRef] [PubMed]
  76. Panina, I.; Taldaev, A.; Efremov, R.; Chugunov, A. Molecular Dynamics Insight into the Lipid II Recognition by Type a Lantibiotics: Nisin, Epidermin, and Gallidermin. Micromachines 2021, 12, 1169. [Google Scholar] [CrossRef]
  77. Wang, X.; Gu, Q.; Breukink, E. Non-lipid II targeting lantibiotics. Biochim. Biophys. Acta (BBA)-Biomembr. 2020, 1862, 183244. [Google Scholar] [CrossRef] [PubMed]
  78. Ghosh, B.; Sukumar, G.; Ghosh, A.R. Purification and characterization of pediocin from probiotic Pediococcus pentosaceus GS4, MTCC 12683. Folia Microbiol. 2019, 64, 765–778. [Google Scholar] [CrossRef]
  79. Gaspar, C.; Donders, G.G.; Palmeira-De-Oliveira, R.; Queiroz, J.A.; Tomaz, C.; Martinez-De-Oliveira, J. Bacteriocin production of the probiotic Lactobacillus acidophilus KS400. AMB Express 2018, 8, 153. [Google Scholar] [CrossRef]
  80. Lauková, A.; Styková, E.; Kubašová, I.; Gancarčíková, S.; Plachá, I.; Mudroňová, D.; Kandričáková, A.; Miltko, R.; Belzecki, G.; Valocký, I.; et al. Enterocin M and its Beneficial Effects in Horses—A Pilot Experiment. Probiotics Antimicrob. Proteins 2018, 10, 420–426. [Google Scholar] [CrossRef]
  81. Lei, W.; Hao, L.; You, S.; Yao, H.; Liu, C.; Zhou, H. Partial purification and application of a bacteriocin produced by probiotic Lactococcus lactis C15 isolated from raw milk. LWT 2022, 169, 113917. [Google Scholar] [CrossRef]
  82. De Giani, A.; Bovio, F.; Forcella, M.; Fusi, P.; Sello, G.; Di Gennaro, P. Identification of a bacteriocin-like compound from Lactobacillus plantarum with antimicrobial activity and effects on normal and cancerogenic human intestinal cells. AMB Express 2019, 9, 88. [Google Scholar] [CrossRef]
  83. Wei, Z.; Shan, C.; Zhang, L.; Wang, Y.; Xia, X.; Liu, X.; Zhou, J. A novel subtilin-like lantibiotics subtilin JS-4 produced by Bacillus subtilis JS-4, and its antibacterial mechanism against Listeria monocytogenes. LWT 2021, 142, 110993. [Google Scholar] [CrossRef]
  84. Zambori, C.; Cumpănăşoiu, C.; Moţ, D.; Huţu, I.; Gurban, C.; Tîrziu, E. The Antimicrobial Role of Probiotics in the Oral Cavity in Humans and Dogs. Anim. Sci. Biotechnol. 2014, 47, 126–130. [Google Scholar]
  85. 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]
  86. Jha, A.; Mishra, V.K.; Mohammad, G. Immunomodulation and anticancer potentials of yogurt probiotic. 2008. EXCLI J. 2008, 7, 177–184. [Google Scholar]
  87. Noh, H.-J.; Park, J.M.; Kwon, Y.J.; Kim, K.; Park, S.Y.; Kim, I.; Lim, J.H.; Kim, B.K.; Kim, B.-Y. Immunostimulatory Effect of Heat-Killed Probiotics on RAW264. 7 Macrophages. J. Microbiol. Biotechnol. 2022, 32, 638–644. [Google Scholar] [CrossRef]
  88. Duarte, J.; Vinderola, G.; Ritz, B.; Perdigón, G.; Matar, C. Immunomodulating capacity of commercial fish protein hydrolysate for diet supplementation. Immunobiology 2006, 211, 341–350. [Google Scholar] [CrossRef]
  89. Lebeer, S.; Vanderleyden, J.; De Keersmaecker, S.C. Host interactions of probiotic bacterial surface molecules: Comparison with commensals and pathogens. Nat. Rev. Microbiol. 2010, 8, 171–184. [Google Scholar] [CrossRef]
  90. 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]
  91. Donnet-Hughes, A.; Rochat, F.; Serrant, P.; Aeschlimann, J.M.; Schiffrin, E.J. Modulation of Nonspecific Mechanisms of Defense by Lactic Acid Bacteria: Effective Dose. J. Dairy Sci. 1999, 82, 863–869. [Google Scholar] [CrossRef]
  92. Kany, S.; Vollrath, J.T.; Relja, B. Cytokines in Inflammatory Disease. Int. J. Mol. Sci. 2019, 20, 6008. [Google Scholar] [CrossRef]
  93. Cavaillon, J.M. Pro- versus anti-inflammatory cytokines: Myth or reality. Cell. Mol. Biol.-Paris-Wegmann 2001, 47, 695–702. [Google Scholar]
  94. Dargahi, N.; Matsoukas, J.; Apostolopoulos, V. Streptococcus thermophilus ST285 Alters Pro-Inflammatory to Anti-Inflammatory Cytokine Secretion against Multiple Sclerosis Peptide in Mice. Brain Sci. 2020, 10, 126. [Google Scholar] [CrossRef] [PubMed]
  95. Dargahi, N.; Johnson, J.C.; Apostolopoulos, V. Immune Modulatory Effects of Probiotic Streptococcus thermophilus on Human Monocytes. Biologics 2021, 1, 396–415. [Google Scholar] [CrossRef]
  96. López-Varela, S.; Gonzalez-Gross, M.; Marcos, A. Functional foods and the immune system: A review. Eur. J. Clin. Nutr. 2002, 56, S29–S33. [Google Scholar] [CrossRef]
  97. Curciarello, R.; Canziani, K.E.; Salto, I.; Romero, E.B.; Rocca, A.; Doldan, I.; Peton, E.; Brayer, S.; Sambuelli, A.M.; Goncalves, S.; et al. Probiotic Lactobacilli Isolated from Kefir Promote Down-Regulation of Inflammatory Lamina Propria T Cells from Patients with Active IBD. Front. Pharmacol. 2021, 12, 658026. [Google Scholar] [CrossRef]
  98. 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]
  99. Kawashima, T.; Ikari, N.; Kouchi, T.; Kowatari, Y.; Kubota, Y.; Shimojo, N.; Tsuji, N.M. The molecular mechanism for activating IgA production by Pediococcus acidilactici K15 and the clinical impact in a randomized trial. Sci. Rep. 2018, 8, 5065. [Google Scholar] [CrossRef]
  100. 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]
  101. Thoreux, K.; Owen, R.; Schmucker, D.L. Functional Foods, Mucosal Immunity and Aging: Effect of Probiotics on Intestinal Immunity in Young and Old Rats. Commun. Curr. Res. Educ. Top. Trends Appl. Microbiol. 2007, 1, 458–465. [Google Scholar]
  102. Perdigon, G.; Alvarez, S.; Rachid, M.; Agüero, G.; Gobbato, N. Immune System Stimulation by Probiotics. J. Dairy Sci. 1995, 78, 1597–1606. [Google Scholar] [CrossRef]
  103. Lin, W.-Y.; Kuo, Y.-W.; Chen, C.-W.; Huang, Y.-F.; Hsu, C.-H.; Lin, J.-H.; Liu, C.-R.; Chen, J.-F.; Hsia, K.-C.; Ho, H.-H. Viable and Heat-Killed Probiotic Strains Improve Oral Immunity by Elevating the IgA Concentration in the Oral Mucosa. Curr. Microbiol. 2021, 78, 3541–3549. [Google Scholar] [CrossRef] [PubMed]
  104. Kaila, M.; Isolauri, E.; Soppi, E.S.A.; Virtanen, E.; Laine, S.; Arvilommi, H. Enhancement of the Circulating Antibody Secreting Cell Response in Human Diarrhea by a Human Lactobacillus Strain. Pediatr. Res. 1992, 32, 141–144. [Google Scholar] [CrossRef] [PubMed]
  105. Finamore, A.; Roselli, M.; Donini, L.M.; Brasili, E.; Rami, R.; Carnevali, P.; Mistura, L.; Pinto, A.; Giusti, A.; Mengheri, E. Supplementation with Bifidobacterium longum Bar33 and Lactobacillus helveticus Bar13 mixture improves immunity in elderly humans (over 75 years) and aged mice. Nutrition 2019, 63–64, 184–192. [Google Scholar] [CrossRef] [PubMed]
  106. Pahumunto, N.; Sophatha, B.; Piwat, S.; Teanpaisan, R. Increasing salivary IgA and reducing Streptococcus mutans by probiotic Lactobacillus paracasei SD1: A double-blind, randomized, controlled study. J. Dent. Sci. 2019, 14, 178–184. [Google Scholar] [CrossRef]
  107. Wang, M.; Wu, H.; Lu, L.; Jiang, L.; Yu, Q. Lactobacillus reuteri Promotes Intestinal Development and Regulates Mucosal Immune Function in Newborn Piglets. Front. Veter Sci. 2020, 7, 42. [Google Scholar] [CrossRef]
  108. Garcia-Castillo, V.; Komatsu, R.; Clua, P.; Indo, Y.; Takagi, M.; Salva, S.; Islam, A.; Alvarez, S.; Takahashi, H.; Garcia-Cancino, A.; et al. Evaluation of the Immunomodulatory Activities of the Probiotic Strain Lactobacillus fermentum UCO-979C. Front. Immunol. 2019, 10, 1376. [Google Scholar] [CrossRef]
  109. Foysal, J.; Fotedar, R.; Siddik, M.A.B.; Tay, A. Lactobacillus acidophilus and L. plantarum improve health status, modulate gut microbiota and innate immune response of marron (Cherax cainii). Sci. Rep. 2020, 10, 1–13. [Google Scholar] [CrossRef]
  110. Wu, Z.; Yang, K.; Zhang, A.; Chang, W.; Zheng, A.; Chen, Z.; Cai, H.; Liu, G. Effects of Lactobacillus acidophilus on the growth performance, immune response, and intestinal barrier function of broiler chickens challenged with Escherichia coli O157. Poult. Sci. 2021, 100, 101323. [Google Scholar] [CrossRef]
  111. Kosgey, J.C.; Jia, L.; Fang, Y.; Yang, J.; Gao, L.; Wang, J.; Nyamao, R.; Cheteu, M.; Tong, D.; Wekesa, V.; et al. Probiotics as antifungal agents: Experimental confirmation and future prospects. J. Microbiol. Methods 2019, 162, 28–37. [Google Scholar] [CrossRef]
  112. Kesika, P.; Sivamaruthi, B.S.; Thangaleela, S.; Chaiyasut, C. The Antiviral Potential of Probiotics—A Review on Scientific Outcomes. Appl. Sci. 2021, 11, 8687. [Google Scholar] [CrossRef]
  113. Rezaee, P.; Kermanshahi, R.K.; Falsafi, T. Antibacterial activity of lactobacilli probiotics on clinical strains of Helicobacter pylori. Iran. J. Basic Med. Sci. 2019, 22, 1118–1124. [Google Scholar] [CrossRef] [PubMed]
  114. I Moré, M.; Vandenplas, Y. Saccharomyces boulardii CNCM I-745 Improves Intestinal Enzyme Function: A Trophic Effects Review. Clin. Med. Insights: Gastroenterol. 2018, 11, 1179552217752679. [Google Scholar] [CrossRef] [PubMed]
  115. Dahiya, D.; Nigam, P.S. Antibiotic-Therapy-Induced Gut Dysbiosis Affecting Gut Microbiota—Brain Axis and Cognition: Restoration by Intake of Probiotics and Synbiotics. Int. J. Mol. Sci. 2023, 24, 3074. [Google Scholar] [CrossRef] [PubMed]
  116. Matsubara, V.H.; Fakhruddin, K.S.; Ngo, H.; Samaranayake, L.P. Probiotic Bifidobacteria in Managing Periodontal Disease: A Systematic Review. Int. Dent. J. 2022, 73, 11–20. [Google Scholar] [CrossRef]
  117. Knackstedt, R.; Knackstedt, T.; Gatherwright, J. The role of topical probiotics in skin conditions: A systematic review of animal and human studies and implications for future therapies. Exp. Dermatol. 2020, 29, 15–21. [Google Scholar] [CrossRef]
  118. Pourmasoumi, M.; Najafgholizadeh, A.; Hadi, A.; Mansour-Ghanaei, F.; Joukar, F. The effect of synbiotics in improving Helicobacter pylori eradication: A systematic review and meta-analysis. Complement. Ther. Med. 2019, 43, 36–43. [Google Scholar] [CrossRef]
  119. Tidbury, F.D.; Langhart, A.; Weidlinger, S.; Stute, P. Non-antibiotic treatment of bacterial vaginosis—A systematic review. Arch. Gynecol. Obstet. 2021, 303, 37–45. [Google Scholar] [CrossRef]
  120. Huang, R.; Xing, H.-Y.; Liu, H.-J.; Chen, Z.-F.; Tang, B.-B. Efficacy of probiotics in the treatment of acute diarrhea in children: A systematic review and meta-analysis of clinical trials. Transl. Pediatr. 2021, 10, 3248–3260. [Google Scholar] [CrossRef]
  121. Ma, Y.; Yang, J.Y.; Peng, X.; Xiao, K.Y.; Xu, Q.; Wang, C. Which probiotic has the best effect on preventing Clostridium difficile-associated diarrhea? A systematic review and network meta-analysis. J. Dig. Dis. 2020, 21, 69–80. [Google Scholar] [CrossRef]
  122. Piewngam, P.; Khongthong, S.; Roekngam, N.; Theapparat, Y.; Sunpaweravong, S.; Faroongsarng, D.; Otto, M. Probiotic for pathogen-specific Staphylococcus aureus decolonisation in Thailand: A phase 2, double-blind, randomised, placebo-controlled trial. Lancet Microbe 2023, 4, e75–e83. [Google Scholar] [CrossRef]
  123. Liao, H.; Liu, S.; Wang, H.; Su, H.; Liu, Z. Enhanced antifungal activity of bovine lactoferrin-producing probiotic Lactobacillus casei in the murine model of vulvovaginal candidiasis. BMC Microbiol. 2019, 19, 7. [Google Scholar] [CrossRef] [PubMed]
  124. Khmaladze, I.; Butler, É.; Fabre, S.; Gillbro, J.M. Lactobacillus reuteri DSM 17938—A comparative study on the effect of probiotics and lysates on human skin. Exp. Dermatol. 2019, 28, 822–828. [Google Scholar] [CrossRef] [PubMed]
  125. Lee, D.-H.; Kim, B.S.; Kang, S.-S. Bacteriocin of Pediococcus acidilactici HW01 Inhibits Biofilm Formation and Virulence Factor Production by Pseudomonas aeruginosa. Probiotics Antimicrob. Proteins 2020, 12, 73–81. [Google Scholar] [CrossRef] [PubMed]
  126. Bin Lee, H.; Kim, K.H.; Kang, G.A.; Lee, K.-G.; Kang, S.-S. Antibiofilm, AntiAdhesive and Anti-Invasive Activities of Bacterial Lysates Extracted from Pediococcus acidilactici against Listeria monocytogenes. Foods 2022, 11, 2948. [Google Scholar] [CrossRef]
  127. Invernici, M.M.; Salvador, S.L.; Silva, P.H.; Soares, M.S.; Casarin, R.; Palioto, D.B.; Souza, S.L.; Taba, M., Jr.; Novaes, A.B., Jr.; Furlaneto, F.A. Effects of Bifidobacterium Probiotic on the Treatment of Chronic Periodontitis: A Randomized Clinical Trial. J. Clin. Periodontol. 2018, 45, 1198–1210. [Google Scholar] [CrossRef]
  128. Michelotti, A.; Cestone, E.; De Ponti, I.; Giardina, S.; Pisati, M.; Spartà, E.; Tursi, F. Efficacy of a probiotic supplement in patients with atopic dermatitis: A randomized, double-blind, placebo-controlled clinical trial. Eur. J. Dermatol. 2021, 31, 225–232. [Google Scholar] [CrossRef]
  129. Rahmayani, T.; Putra, I.B.; Jusuf, N.K. The Effect of Oral Probiotic on the Interleukin-10 Serum Levels of Acne Vulgaris. Open Access Maced. J. Med Sci. 2019, 7, 3249–3252. [Google Scholar] [CrossRef]
  130. Zaharuddin, L.; Mokhtar, N.M.; Nawawi, K.N.M.; Ali, R.A.R. A randomized double-blind placebo-controlled trial of probiotics in post-surgical colorectal cancer. BMC Gastroenterol. 2019, 19, 131. [Google Scholar] [CrossRef]
  131. Tsilika, M.; Thoma, G.; Aidoni, Z.; Tsaousi, G.; Fotiadis, K.; Stavrou, G.; Malliou, P.; Chorti, A.; Massa, H.; Antypa, E.; et al. A four-probiotic preparation for ventilator-associated pneumonia in multi-trauma patients: Results of a randomized clinical trial. Int. J. Antimicrob. Agents 2022, 59, 106471. [Google Scholar] [CrossRef]
  132. Mageswary, M.U.; Ang, X.-Y.; Lee, B.-K.; Chung, Y.-L.F.; Azhar, S.N.A.; Hamid, I.J.A.; Abu Bakar, H.; Roslan, N.S.; Liu, X.; Kang, X.; et al. Probiotic Bifidobacterium lactis Probio-M8 treated and prevented acute RTI, reduced antibiotic use and hospital stay in hospitalized young children: A randomized, double-blind, placebo-controlled study. Eur. J. Nutr. 2022, 61, 1679–1691. [Google Scholar] [CrossRef]
  133. Ahrén, I.L.; Hillman, M.; Nordström, E.A.; Larsson, N.; Niskanen, T.M. Fewer Fewer community-acquired colds with daily consumption of Lactiplantibacillus plantarum HEAL9 and Lacticaseibacillus paracasei 8700: 2. A randomized, placebo-controlled clinical trial. J. Nutr. 2021, 151, 214–222. [Google Scholar] [CrossRef] [PubMed]
  134. Liang, B.; Yuan, Y.; Peng, X.-J.; Liu, X.-L.; Hu, X.-K.; Xing, D.-M. Current and future perspectives for Helicobacter pylori treatment and management: From antibiotics to probiotics. Front. Cell. Infect. Microbiol. 2022, 12, 1740. [Google Scholar] [CrossRef] [PubMed]
  135. Oh, J.H.; Jang, Y.S.; Kang, D.; Chang, D.K.; Min, Y.W. Efficacy and Safety of New Lactobacilli Probiotics for Unconstipated Irritable Bowel Syndrome: A Randomized, Double-Blind, Placebo-Controlled Trial. Nutrients 2019, 11, 2887. [Google Scholar] [CrossRef] [PubMed]
  136. Wang, G.; Feng, D. Therapeutic effect of Saccharomyces boulardii combined with Bifidobacterium and on cellular immune function in children with acute diarrhea. Exp. Ther. Med. 2019, 18, 2653–2659. [Google Scholar] [CrossRef]
  137. Cohen, C.R.; Wierzbicki, M.R.; French, A.L.; Morris, S.; Newmann, S.; Reno, H.; Green, L.; Miller, S.; Powell, J.; Parks, T.; et al. Randomized Trial of Lactin-V to Prevent Recurrence of Bacterial Vaginosis. N. Engl. J. Med. 2020, 382, 1906–1915. [Google Scholar] [CrossRef]
  138. Roth, N.; Käsbohrer, A.; Mayrhofer, S.; Zitz, U.; Hofacre, C.; Domig, K.J. The application of antibiotics in broiler production and the resulting antibiotic resistance in Escherichia coli: A global overview. Poult. Sci. 2019, 98, 1791–1804. [Google Scholar] [CrossRef]
  139. Zhang, L.; Zhang, R.; Jia, H.; Zhu, Z.; Li, H.; Ma, Y. Supplementation of probiotics in water beneficial growth performance, carcass traits, immune function, and antioxidant capacity in broiler chickens. Open Life Sci. 2021, 16, 311–322. [Google Scholar] [CrossRef]
  140. Lokapirnasari, W.P.; Pribadi, T.B.; Al Arif, A.; Soeharsono, S.; Hidanah, S.; Harijani, N.; Najwan, R.; Huda, K.; Wardhani, H.C.P.; Rahman, N.F.N.; et al. Potency of probiotics Bifidobacterium spp. and Lactobacillus casei to improve growth performance and business analysis in organic laying hens. Veter World 2019, 12, 860–867. [Google Scholar] [CrossRef]
  141. Wang, L.; Li, L.; Lv, Y.; Chen, Q.; Feng, J.; Zhao, X. Lactobacillus plantarum Restores Intestinal Permeability Disrupted by Salmonella Infection in Newly-hatched Chicks. Sci. Rep. 2018, 8, 2229. [Google Scholar] [CrossRef]
  142. Fesseha, H.; Demlie, T.; Mathewos, M.; Eshetu, E. Effect of Lactobacillus Species Probiotics on Growth Performance of Dual-Purpose Chicken. Veter Med. Res. Rep. 2021, 12, 75–83. [Google Scholar] [CrossRef]
  143. Wang, H.; Ni, X.; Qing, X.; Liu, L.; Xin, J.; Luo, M.; Khalique, A.; Dan, Y.; Pan, K.; Jing, B.; et al. Probiotic Lactobacillus johnsonii BS15 Improves Blood Parameters Related to Immunity in Broilers Experimentally Infected with Subclinical Necrotic Enteritis. Front. Microbiol. 2018, 9, 49. [Google Scholar] [CrossRef] [PubMed]
  144. Kan, L.; Guo, F.; Liu, Y.; Pham, V.H.; Guo, Y.; Wang, Z. Probiotics Bacillus licheniformis Improves Intestinal Health of Subclinical Necrotic Enteritis-Challenged Broilers. Front. Microbiol. 2021, 12, 623739. [Google Scholar] [CrossRef] [PubMed]
  145. Huang, T.; Peng, X.-Y.; Gao, B.; Wei, Q.-L.; Xiang, R.; Yuan, M.-G.; Xu, Z.-H. The Effect of Clostridium butyricum on Gut Microbiota, Immune Response and Intestinal Barrier Function during the Development of Necrotic Enteritis in Chickens. Front. Microbiol. 2019, 10, 2309. [Google Scholar] [CrossRef] [PubMed]
  146. Zhang, S.; Yoo, D.H.; Ao, X.; Kim, I.H. Effects of dietary probiotic, liquid feed and nutritional concentration on the growth performance, nutrient digestibility and fecal score of weaning piglets. Asian-Australas. J. Anim. Sci. 2020, 33, 1617–1623. [Google Scholar] [CrossRef]
  147. Pupa, P.; Apiwatsiri, P.; Sirichokchatchawan, W.; Pirarat, N.; Nedumpun, T.; Hampson, D.J.; Muangsin, N.; Prapasarakul, N. Microencapsulated probiotic Lactiplantibacillus plantarum and/or Pediococcus acidilactici strains ameliorate diarrhoea in piglets challenged with enterotoxigenic Escherichia coli. Sci. Rep. 2022, 12, 7210. [Google Scholar] [CrossRef]
  148. Yasmin, F.; Alam, M.J.; Kabir, M.E.; Al Maruf, A.; Islam, M.A.; Hossain, M.M. Influence of Probiotics supplementation on Growth and Haemato-biochemical Parameters in Growing Cattle. Int. J. Livest. Res. 2021, 11, 36–42. [Google Scholar] [CrossRef]
  149. Merati, Z.; Towhidi, A. Effect of a Multispecies Probiotics on Productive and Reproductive Performance of Holstein Cows. Iran. J. Appl. Anim. Sci. 2022, 12, 237–247. [Google Scholar]
  150. Genís, S.; Sánchez-Chardi, A.; Bach, À.; Fàbregas, F.; Arís, A. A combination of lactic acid bacteria regulates Escherichia coli infection and inflammation of the bovine endometrium. J. Dairy Sci. 2017, 100, 479–492. [Google Scholar] [CrossRef]
  151. Devyatkin, V.; Mishurov, A.; Kolodina, E. Probiotic effect of Bacillus subtilis B-2998D, B-3057D, and Bacillus licheniformis B-2999D complex on sheep and lambs. J. Adv. Veter Anim. Res. 2021, 8, 146–157. [Google Scholar] [CrossRef]
  152. Islam, S.M.; Rohani, F. Shahjahan Probiotic yeast enhances growth performance of Nile tilapia (Oreochromis niloticus) through morphological modifications of intestine. Aquac. Rep. 2021, 21, 100800. [Google Scholar] [CrossRef]
  153. Cavalcante, R.B.; Telli, G.S.; Tachibana, L.; Dias, D.D.C.; Oshiro, E.; Natori, M.M.; da Silva, W.F.; Ranzani-Paiva, M.J. Probiotics, Prebiotics and Synbiotics for Nile tilapia: Growth performance and protection against Aeromonas hydrophila infection. Aquac. Rep. 2020, 17, 100343. [Google Scholar] [CrossRef]
  154. Ahmadifar, E.; Sadegh, T.H.; Dawood, M.A.; Dadar, M.; Sheikhzadeh, N. The effects of dietary Pediococcus pentosaceus on growth performance, hemato-immunological parameters and digestive enzyme activities of common carp (Cyprinus carpio). Aquaculture 2020, 516, 734656. [Google Scholar] [CrossRef]
  155. Saravanan, K.; Sivaramakrishnan, T.; Praveenraj, J.; Kiruba-Sankar, R.; Haridas, H.; Kumar, S.; Varghese, B. Effects of single and multi-strain probiotics on the growth, hemato-immunological, enzymatic activity, gut morphology and disease resistance in Rohu, Labeo rohita. Aquaculture 2021, 540, 736749. [Google Scholar] [CrossRef]
  156. Won, S.; Hamidoghli, A.; Choi, W.; Bae, J.; Jang, W.J.; Lee, S.; Bai, S.C. Evaluation of Potential Probiotics Bacillus subtilis WB60, Pediococcus pentosaceus, and Lactococcus lactis on Growth Performance, Immune Response, Gut Histology and Immune-Related Genes in Whiteleg Shrimp, Litopenaeus vannamei. Microorganisms 2020, 8, 281. [Google Scholar] [CrossRef] [PubMed]
  157. Kewcharoen, W.; Srisapoome, P. Probiotic effects of Bacillus spp. from Pacific white shrimp (Litopenaeus vannamei) on water quality and shrimp growth, immune responses, and resistance to Vibrio parahaemolyticus (AHPND strains). Fish Shellfish. Immunol. 2019, 94, 175–189. [Google Scholar] [CrossRef]
Figure 1. Illustration of antibiotic action modes (left side) and antibiotic resistance mechanisms (right side) of pathogens.
Figure 1. Illustration of antibiotic action modes (left side) and antibiotic resistance mechanisms (right side) of pathogens.
Encyclopedia 03 00040 g001
Figure 2. Antibiotic alternative classes.
Figure 2. Antibiotic alternative classes.
Encyclopedia 03 00040 g002
Figure 3. Antimicrobial mechanisms of probiotics against pathogens.
Figure 3. Antimicrobial mechanisms of probiotics against pathogens.
Encyclopedia 03 00040 g003
Figure 4. Impacts of probiotics as antibiotic alternatives in animals.
Figure 4. Impacts of probiotics as antibiotic alternatives in animals.
Encyclopedia 03 00040 g004
Table 1. Main classes of antibiotics and their sources.
Table 1. Main classes of antibiotics and their sources.
AminoglycosidesStreptomycinStreptomyces griseus[20]
Β-LactamsPenicillinPenicillium griseofulvum[21]
GlycopeptidesVancomycinAmycolatopsis orientalis[22]
LipopetidesDaptomycinStreptomyces roseosporus[23]
MacrolidesErythromycinStreptomyces erythreus[24]
OxazolidinonesLinezolidChemical synthesis[19]
PhenicolsChloramphenicolStreptomyces venezuelae[25]
PolypeptidesGramicidinBacillus brevis[26]
PolymixinColistinPaenibacillus polymyxa[27]
QuinolonesCiproxacinChemical synthesis[19]
SulfonamidesMafenideChemical synthesis[19]
TetracyclinesOxytetracyclinesStreptomyces rimosus[28]
Table 2. Action modes and resistance mechanisms of main antibiotic classes.
Table 2. Action modes and resistance mechanisms of main antibiotic classes.
ClassMode of ActionResistance MechanismReference
AminoglycosidesInhibition of protein synthesis (30S ribosomal subunit inhibitor)Binding inhibition by phosphorylation, adenylation, and acetylation of aminoglycosides
Aminoglycoside-modifying enzymes (e.g., acetyltransferases, phosphotransferases)
16S rRNA methylation
Efflux-mediated resistance
β-LactamsInhibition of cell wall synthesis (peptidoglycan)Production of β-Lactamases
Permeability change (Efflux)
GlycopeptidesInhibition of cell wall synthesis (peptidoglycans)Intrinsic resistance in Gram-negative cells by impermeable outer membrane
Presence of enzymes that modify and hydrolyze peptidoglycan precursors
Low permeability
FluoroquinolonesInhibition of nucleic acid synthesisMutations in DNA gyrase or topoisomerase IV[41,42,46]
SulfonamidesBlockage of key metabolic pathways (folate synthesis inhibitors)Mutations in folP gene encoding dihydropteroate synthase, sul1, sul2 genes, sulfonamide monooxygenase gene sulX[41,42,47]
TetracyclinesInhibition of protein synthesis (30S-ribosomal subunit inhibitor)Enzymatic inactivation
Binding site mutation
ChloramphenicolsInhibition of protein synthesis (50S-ribosomal subunit inhibitor)Mutations within 23S rRNA of the 50S ribosomal subunit
Enzymatic inactivation via acetyltransferases
Active efflux
Table 3. Antimicrobial activity of some probiotic bacteriocins.
Table 3. Antimicrobial activity of some probiotic bacteriocins.
BacteriocinsProbioticTarget MicroorganismsReference
BacteriocinL. acidophilus KS400Gardnerella vaginalis, Streptococcus agalactiae, P. aeruginosa[79]
Enterocin MEnterococcus faecium AL41Campylobacter spp.
Clostridium spp.
Nisin-like bacteriocinL. lactis C15E. coli[81]
PediocinPed. pentosaceus GS4 (MTCC 12683)S. aureus (ATCC 25923), E. coli (ATCC 25922), P. aeruginosa (ATCC 25619), and L. monocytogenes (ATCC 15313)[78]
Plantaricin P1053L. plantarum PBS067S. aureus and E. coli[82]
Subtilin-like bacteriocin—Subtilin JS-4Bacillus subtilis JS-4L. monocytogenes[83]
Table 4. In/ex vivo immunomodulation effects of probiotics.
Table 4. In/ex vivo immunomodulation effects of probiotics.
ProbioticsStudied ModelEffects on ImmunityReference
Bifidobacterium longum Bar33 and L. helveticus Bar13Older adults (over 75 years)Increase naive T cells
Increase activated memory, regulatory T cells, B cells, and natural killer (NK) activity
Decrease memory T cells
L. paracasei SD1ChildrenDecrease of Streptococcus mutans pathogens
Increase of salivary IgA
Limosilactobacillus reuteri D8PigletsIncrease of goblet cells and antimicrobial peptides (AMPs), expressions of Muc2, Lyz1, and porcine β-defensins 1 (pBD1)
Increase of CD3+ T cells, combined with increased expression of IL-4 and IFN-γ
Lactobacillus fermentum UCO-979CMiceIncrease the production of intestinal IFN-γ, stimulate intestinal and peritoneal macrophages, increase the number of Peyer’s patches CD4+ T cells
Increase intestinal IL-6, intestinal IgA, and the number of mature B cells
L. acidophilus and L. plantarumFreshwater crayfishUpregulation of cytokine gene families (IL1β, IL8, IL10, and IL17F), proPO, and cytMnSOD[109]
L. acidophilusBroilers challenged with E. coliReduce the mortality rate caused by E. coli challenge
Decrease the serum C-reactive protein, diamine oxydase, and endotoxin lipopolysaccharide levels at 14 days and 21 days
Upregulate the mRNA expression of occludin and zona occludens protein 1 (ZO-1) in the jejunum and ileum (tight junction)
Downregulate the mRNA expression of inducible nitric oxide synthase (iNOS), IL-8, and IL-1β in the jejunum in E. coli challenged birds at 21 days
Table 5. Comparison between antibiotics and probiotics: characteristic features, action mechanisms, strengths, and weakness.
Table 5. Comparison between antibiotics and probiotics: characteristic features, action mechanisms, strengths, and weakness.
Characteristic featuresActive substance
Natural or synthetic
One function
Non-growth over time
(static process)
Live microorganism
Growth over time
(dynamic process)
Action mechanismsCell membrane breakdown
Cell wall synthesis inhibition
Nucleic acid structure/function and protein synthesis inhibition
Key metabolic pathway blockage
Gut barrier protection
Nutrient/space competitive exclusion
Antimicrobial substance secretion
Short-time treatment
No side effects
Antibacterial and antiviral properties
Generally recognized as safe (GRAS)
Natural and biodegradable
WeaknessDestroy beneficial microbes
Antimicrobial resistance induction
Not effective on viruses
Low biodegradability for synthetic compounds
Cell viability maintaining challenge
Long-term treatment
Sensitivity under stress conditions
Antimicrobial resistance risk if genes transfer
Table 6. In vivo antimicrobial activity of probiotics against human pathogens.
Table 6. In vivo antimicrobial activity of probiotics against human pathogens.
B. subtilis MB40S. aureusSignificant reduction of S. aureus colonization in body human without modification of microbiome[122]
L. caseiC. albicansFungicidal effect in vulvovaginal candidiasis (VVC) murine model[123]
L. reuteri DSM 17938S. aureus, S. pyogenes M1, Cutibacterium acnes AS12, P. aeruginosaAntimicrobial action against pathogenic skin bacteria and reduction of proinflammatory IL-6 and IL-8 in reconstructed human epidermis and native skin models[124]
Pediococcus acidilactici HW01P. aeruginosaInhibition of biofilm formation by bacteriocin and decrease of the production of virulence factors, such as pyocyanin, protease, and rhamnolipid[125]
Ped. acidilactici HW01L. monocytogenesInhibition of biofilm formation, adhesion, and invasion of HT-29 cells (human-intestinal-epithelial cell line) by bacterial lysate[126]
Table 7. Some clinical trials and uses of probiotics in human health.
Table 7. Some clinical trials and uses of probiotics in human health.
Oral and dental healthChronic periodontitisB. animalis subsp. lactis (B. lactis) HN019Decreasing significantly the periodontal pathogens of red and orange complexes;
reducing proinflammatory cytokine levels; promoting clinical, microbiological, and immunological benefits in the treatment of chronic periodontitis
SkinAtopic dermatitisL. plantarum PBS067
L. reuteri PBS072
L. rhamnosus LRH020
Improvement in skin smoothness, skin moisturization, self-perception, and decrease in scoring atopic dermatitis (SCORAD) index and levels of inflammatory markers[128]
Acne vulgarisB. lactis W51, B. lactis W52, L. acidophilus W55, L. casei W56, L. salivarius W57, L. lactis W58 combined with rice starch and maltodextrinIncreasing serum IL-10 levels after oral probiotic in acne vulgaris[129]
Surgical wound infection L. acidophilus BCMC® 12130 L. lactis BCMC® 12451, L. casei subsp BCMC® 12313, B. longum BCMC® 02120, B. bifidum BCMC® 02290, and B. infantis BCMC® 02129Reduction of pro-inflammatory cytokines (except for IFN-gamma) in colorectal cancer patients after consumption for 4 weeks[130]
Respiratory tractVentilator-associated pneumonia (VAP)L. acidophilus LA-5, L. plantarum UBLP-40, B. animalis subsp. lactis BB-12, and S. boulardiiDecreasing the incidence of VAP induced by Acinobacter baumannii and P. aeruginosa
in patients subjected to prolonged mechanical ventilation for severe multiple trauma, including brain injury
Acute respiratory tract infectionB. lactis Probio-M8Reducing antibiotic prescription, preventing antibiotic new prescription in non-prescribed patients,
decreasing oral cytokine levels of TNF-α, and increased IL-10 (over 4 weeks post-discharge)
Virus associated respiratory tract infectionL. plantarum HEAL9 L. paracasei 8700No effect on symptom severity but significantly fewer colds[133]
StomachHelicobacter pylori infection, gastritisL. reuteri DSM 17648Effectively reducing H. pylori load and improving gastrointestinal symptoms in adults and children[134]
IntestinesInflammatory bowel syndrome (IBS)L. paracasei, L. salivarius, and L. plantarumEffective global relief of IBS symptoms and abdominal pain without significant adverse events[135]
C. difficile-associated diarrhea (CDAD)L. caseiReduction of the incidence rates of CDAD[121]
Acute diarrheaS. boulardii combined with bifidobacteriumShortening the duration of diarrhea and hospital stay,
reducing the number of diarrhea,
enhancing cellular immune function
Female urogenital tractBacterial vaginosisL. crispatus CTV-05 (Lactin-V)Prevention of the recurrence of bacterial vaginosis[137]
Table 8. Animal applications of antimicrobial probiotics.
Table 8. Animal applications of antimicrobial probiotics.
AnimalsProbioticsForm of
BroilersL. casei, L. acidophilus, and BifidobacteriumSupplementing 1% of probiotics in waterIncreasing growth performance, carcass traits, immune function, gut microbial population, and antioxidant capacity[139]
Laying hensBifidobacterium spp. and L. caseiFeedingImproving the growth performance, increase of egg weight, and feed efficiency[140]
Newly hatched chicksL. plantarum LTC-113Oral vaccinationProtection from Salmonella colonization by regulating expression of tight junction genes and inflammatory mediators[141]
ChickensL. paracasei ssp. paracasei and L. rhamnosusFeedingImproving growth performance[142]
BroilerL. johnsonii BS15FeedingPreventing subclinical necrotic enteritis[143]
Bacillus licheniformisFeedingAlleviating intestinal damage caused by SNE challenge, modulating intestinal microflora structure and barrier function, and regulating intestinal mucosal immune responses[144]
ChickensC. butyricumFeedingPromoting anti-inflammatory expression and tight junction protein genes
Inhibiting pro-inflammatory genes in C. perfringens-challenged chickens
Weaning pigletsB. subtilis, E. faeciumLiquid feedImprove growth performance[146]
PigletsL. plantarum (strains 22F and 25F) and Ped. acidilactici (strain 72N)FeedingReducing the infection severity with enterotoxigenic E. coli (ETEC) in weaned pigs[147]
CattleL. gallinarum JCM 2011(T), S. infantarius subsp. coli HDP90246 (T), S. salivarius subsp. thermophilus ATCC 19258(T), and S. equinus ATCC 9812(T)
Saccharomyces cerevisiae
Improving the growth and haemato-biochemical parameters of growing cattle[148]
Dairy cowsS. cerevisiae, B. subtilis, B. lichenformis, E. faecium, L. acidophilus, L. plantarum, B. tedium and calcium carbonateFeedingImproving reproductive performance
Increasing milk yield and milk fat and protein percentage
L. rhamnosus, P. acidilactici, and L. reuteriEx vivo bovine endometrial explantsReducing acute inflammation under E. coli infection, decreasing IL-8, IL-1β, and IL-6[150]
Sheep, LambEnzimsporin™
(B. subtilis B-2998D, B-3057D, and B. licheniformis B-2999D)
FeedingIncreasing body weight gain and improving intestinal microbiota[151]
Nile Tilapia
(Oreochromis niloticus)
S. cerevisiaeFeedingIncreasing growth performance and feed utilization indices[152]
Nile Tilapia
(Oreochromis niloticus)
DBA® (B. sp., L. acidophilus and E. faecium)FeedingProtection against A. hydrophila infection without growth reduction[153]
Common carp
(Cyprinus carpio)
Ped. pentosaceusFeedingImproving growth performance, digestive enzyme activity, and haemato-immunological responses[154]
Rohu fingerlings (Labeo rohita)B. amyloliquefaciens BN06, B. subtilis WN07, and B. megateriumFeedingImproving growth and haemato-immunological parameters[155]
Whiteleg shrimp, (Litopenaeus vannamei)B. subtilis, Ped. pentosaceus, and L. lactisFeedingImproving growth, immunity, histology, gene expression, digestive enzyme activity, and disease resistance[156]
Pacific white shrimp (Litopenaeus vannamei)B. subtilis AQAHBS001FeedingImproving the growth performance, immune response, and resistance to Vibrio parahaemolyticus[157]
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

Rabetafika, H.N.; Razafindralambo, A.; Ebenso, B.; Razafindralambo, H.L. Probiotics as Antibiotic Alternatives for Human and Animal Applications. Encyclopedia 2023, 3, 561-581.

AMA Style

Rabetafika HN, Razafindralambo A, Ebenso B, Razafindralambo HL. Probiotics as Antibiotic Alternatives for Human and Animal Applications. Encyclopedia. 2023; 3(2):561-581.

Chicago/Turabian Style

Rabetafika, Holy N., Aurélie Razafindralambo, Bassey Ebenso, and Hary L. Razafindralambo. 2023. "Probiotics as Antibiotic Alternatives for Human and Animal Applications" Encyclopedia 3, no. 2: 561-581.

Article Metrics

Back to TopTop