Improving Antimicrobial Stewardship in Human Health Using Probiotics and Their Derivatives

Abstract

Since antimicrobial resistance poses the biggest risks to human health, antimicrobial stewardship implies a strategy of responsible management. To lessen antimicrobial resistance and its impacts, a number of antimicrobial stewardship strategies are being used. One such crucial tactic is the use of probiotics and their derivatives, which directly affect the gut microbiota and have been linked to the development and management of a number of human diseases. Undoubtedly, the gut microbiota has a significant impact on the host immunological response, defense against pathogen overgrowth, biosynthesis, and metabolism. There is a rising need to incorporate strategies for altering the gut microbiota as a means of therapy or infection prevention in routine clinical practice as our understanding of the connections between the gut microbiota and host immunity and infectious illnesses deepens. Probiotics and their derivatives influence the development of various species in the gut microbiome to support the host’s health. This review aims to investigate how the gut microbiota is modulated by probiotics, ghost probiotics, postbiotics, and synbiotics, and what this means for infection prevention and antibiotic stewardship.

1. Introduction

The maintenance of a healthy and diverse gut microbiota plays an important role in the prevention and acquisition of antimicrobial resistance, and strategies that modulate its composition have great potential in impacting human health [1]. By limiting the detrimental effects of antimicrobials on the gut flora, the principles of antimicrobial stewardship are strengthened. Antimicrobial stewardship refers to a logical sequence of steps that confirms the effective therapeutic availability of antimicrobials when required [1]. Antimicrobial stewardship has three objectives. The first objective is to collaborate with medical professionals to ensure that each patient receives the best antibiotic at the right dosage and for the right amount of time. The correct drug, dose, de-escalation to pathogen-directed therapy, and length of therapy are essential components of the best antimicrobial therapy [2]. Preventing misuse, abuse, and overuse of antibiotics is the second objective. Reduction of the emergence of antimicrobial resistance is the third objective [3].

Antimicrobials are the foundation upon which the health system is standing and are regarded as a global public good that has boosted health care, saved lives, and increased economic advantages [4]. Antimicrobial stewardship optimizes patient antimicrobial functioning to enhance outcomes and lowers antimicrobial resistance. In addition to encouraging the use of agents that are less likely to select for resistant microorganisms, it aids in the development of techniques and interventions that aim to reduce the unnecessary use of antimicrobials. Its initiatives lower prices, antimicrobial resistance, and toxicity [5]. According to Shiffen et al. [6], antimicrobial resistance is the modification of bacteria that renders them resistant to an antimicrobial. Antimicrobial resistance is one of the top ten global public health problems now facing the world [7].

In order to maintain antibiotic effectiveness and prevent the emergence and spread of infections that are antibiotic-resistant, antimicrobial stewardship promotes the cautious application of antimicrobials [8]. Antimicrobial treatments can cause microbes including viruses, fungi, and parasites to adapt and develop resistance. For instance, bacteria that are exposed to antibiotics develop a resistance that allows them to proliferate in the presence of antibiotics and pass on their resistance genes to their progeny [9]. As time goes on, highly resistant strains of microbes develop which are difficult or impossible to treat with available antimicrobials [10]. For antimicrobial therapies to be effective, antimicrobial stewardship programs promote the appropriate use of antibiotics, which includes proper prescription of drugs, the right dose for the right duration, and only when it is necessary [11]. As a result, the selective pressure driving the formation of antimicrobial resistance is reduced. It ensures that these drugs successfully treat infections and reduces the risk of microbial resistance, which is connected to morbidity and mortality [12].

Focus should be placed on the antimicrobial potential of probiotics against pathogenic microbes and host immunity when considering the current pandemic scenario. It has been said that the gut microbiota is an underappreciated organ that constantly establishes bi- or multidirectional interactions with other organs [13]. Therefore, the modification of the human immune system, gut microbiota, and treatment of illness by probiotics and their derivatives has a strong positive impact on reducing antimicrobial resistance and thereby increasing antimicrobial stewardship. The capacity of a healthy microbiota to limit the spread of potentially harmful bacteria is known as colonization resistance [1]. Probiotics play a crucial role in antimicrobial stewardship by maintaining or re-establishing colonization resistance by regulating the gut microbiota to prevent infection [6].

2. Probiotics

Probiotics are living organisms that, when consumed in sufficient proportions, help the host’s health, however, the dead bacteria and their components can also exhibit probiotic properties [14]. They help with gastrointestinal health, immune system stimulation, and infection risk reduction [15]. By upsetting the normal equilibrium of gut flora, they reduce antibiotic-associated diarrhea [16]. Additionally, they prevent an infection, which is an objective of antimicrobial stewardship, which reduces the need for antimicrobials. Microbiome therapy aims to modify the gut microbiome by applying native or artificially created bacteria in an additive, subtractive, or modulatory manner. [17]. Probiotic bacteria have the additional capacity to create and release antimicrobial substances like chemical compounds [7].

2.1 Mechanisms of action of probiotics

Probiotics function by:

• Strengthening the epithelial barrier. The gut barrier plays a crucial role in preventing the entry of harmful substances into the bloodstream. Probiotics can enhance the integrity of the intestinal barrier by strengthening the tight junctions between intestinal cells. This helps to maintain a healthy gut lining and reduces the risk of harmful substances crossing into the body [13],

• Boosting adherence to the intestinal mucosa,

• Blocking pathogen adhesion. Probiotics can influence the composition and activity of the gut microbiota. They compete with harmful bacteria for resources and adhesion sites in the gut, effectively crowding out pathogenic microorganisms. Probiotics can also produce antimicrobial substances that inhibit the growth of harmful bacteria [14].

• Eliminating harmful bacteria through competition, creating anti-microbe compounds, and altering the immune system. The colonization of intestinal microbe communities, competitive exclusion of pathogens [18].

• Modulating the immune response. They interact with immune cells in the gut-associated lymphoid tissue (GALT) and stimulate the production of beneficial cytokines, such as interleukin-10 (IL-10), which helps to regulate the immune system and reduce inflammation. This immunomodulatory effect may be beneficial in conditions such as allergies, autoimmune diseases, and certain gastrointestinal disorders [19],

• Production of bioactive compounds: Probiotics can produce bioactive compounds such as vitamins (such as vitamin K and some B vitamins), enzymes, and antimicrobial substances. These compounds can have direct health benefits and contribute to overall production of bacteriocins, modulation of enzymatic activities related to metabolization of specific carcinogens, and production of volatile fatty acids [14]. Probiotics boost the formation of mucin and cell adhesion.

2.2 Effects of probiotics on the gut microbiota

By encouraging the growth of helpful bacteria like Lactobacillus and Bifidobacterium and suppressing the growth of pathogenic bacteria like Clostridium difficile, probiotics can alter the balance of bacteria in the gut [20]. This can help safeguard against certain illnesses while enhancing intestinal health. Depending on the probiotic, harmful bacteria may be killed or its growth may be inhibited [19]. By doing so, the danger of infection can be decreased and pathogenic bacteria in the gut cannot develop [21]. By encouraging the creation of mucus and tight junction proteins, which can help stop harmful bacteria from entering the bloodstream, probiotics can enhance the intestinal barrier [19]. By increasing the production of anti-inflammatory cytokines and decreasing the production of pro-inflammatory cytokines, probiotics can also modify the immune system [20]. This may lessen intestinal inflammation and enhance gut health. A number of infectious and non-infectious diseases can be effectively treated using probiotics and their derivatives.

2.3 Role of probiotics in antimicrobial stewardship

The World Health Organization [11] has come to the conclusion that probiotics are the second-most important immune defense mechanism when frequently advised antimicrobials are unsuccessful against a limited number of pathogens. A number of beneficial intestinal bacteria, including Lactobacillus, Bifidobacterium, and Enterococcus, as shown in Table 1, contribute to the improvement of gut microbiota stability [28]. Probiotics can be found in food, beverages, and dietary supplements. Additionally, consuming fermented foods, which are probiotic bacteria’s natural habitat, is of immense importance which eventually helps in the better treatment of several diseases, including gut-related disorders [28].

Probiotic	Reported effects	References
Lactobacillus rhamnosus GG	Improved gut health, reduced diarrhea	[22]
Bifidobacterium animalis DN-173010	Enhanced immune response - They can boost antibody synthesis, amplify immune cell activity, and fortify the intestinal barrier, lowering the risk of opportunistic infections while using antibiotics; fewer stomach aches and pains	[23]
Saccharomyces boulardii	AAD (antibiotic-associated diarrhea) prevention and treatment. The natural balance of benevolent bacteria in the stomach can be upset by antibiotics, which can result in diseases like AAD. When given simultaneously with antibiotics, probiotics can aid in microbial restoration and lower the risk of AAD.	[22]
Lactobacillus acidophilus NCFM	Reduction of lactose intolerance	[24]
Streptococcus thermophilus	Enhanced digestion of lactose	[22]
Lactobacillus plantarum 299v	Improved symptoms of irritable bowel syndrome	[25]
Bifidobacterium bifidum	Enhanced immune function	[25]
Lactobacillus; Streptococcus	Treatment Adherence - Probiotics may improve a patient’s treatment adherence with antibiotics. Probiotics have been shown to improve treatment compliance, decrease side effects, and improve patient satisfaction when added to antibiotic regimens.	[26]
Lactobacillus; Saccharomyces	Inhibiting the growth and colonization of Clostridium difficile	[27]

Table 1.

Roles of probiotics.

If it happens that once in the human body the probiotics die, they can no longer have a positive effect on health therefore scientists are conducting research to formulate technologies that produce dead and broken-down bacteria which are like probiotics or better in terms of immune enhancing properties [29].

3. Ghost probiotics

It has recently been discovered that ghost probiotics, or inactivated or heat-killed probiotic cells, can be used in place of live probiotics. In both animals and people, they have demonstrated effectiveness in modifying anti-inflammatory and pro-inflammatory immune responses [30]. Ghost probiotics, commonly referred to as para-probiotics, are beneficial microorganisms that have been rendered inactive. They can either be whole or broken [8]. Provoking the human immune system, promoting a favorable immunological response, and having anti-inflammatory effects in both people and animals are all impacts of ghost probiotics [31]. They are favored because they have a longer shelf life, which makes it easier to distribute them without refrigeration to various locations. In immune-compromised people, the use of ghost probiotics lowers the likelihood of contamination, microbial translocation, or heightened inflammatory immune responses [8, 32].

3.1 Mechanisms of action of ghost probiotics

Probiotics that have been inactivated may influence immunological responses by interacting with the immune system. A study suggested that the beneficial effects of ghost probiotics on gut microbiota may be due to the release of soluble factors such as cell membrane fragments and metabolites that can modulate immune function and promote the growth of beneficial bacteria [4]. These immuno-modulatory actions might suppress immune-related disorders and control immune response and inflammation. In the stomach, they fight against harmful microbes for adhesion sites and nutrition. They might hinder the attachment and proliferation of harmful bacteria by occupying these locations. In another study, researchers discovered that supplementation with ghost probiotics derived from Lactobacillus plantarum had positive effects on gut microbiota, including an increase in beneficial bacteria such as Bifidobacterium and Lactobacillus and a decrease in potentially harmful bacteria such as Clostridium [17].

They might help keep the intestinal barrier healthy and functioning properly. They are able to interact with gut epithelial cells, enhancing tight junction protein production and preserving the integrity of the gut barrier. Inactivated probiotics can aid in preventing the transfer of hazardous chemicals from the gut into the circulation by enhancing the barrier function [33]. Even in their non-viable state, inactivated probiotics may retain some antimicrobial properties. They may produce antimicrobial compounds such as organic acids, bacteriocins, or antimicrobial peptides that can inhibit the growth of pathogenic bacteria in the gut. These antimicrobial effects contribute to maintaining a balanced gut microbiota [8]. Inactivated probiotics may still have metabolic effects. They can interact with dietary components and release bioactive compounds such as short-chain fatty acids (SCFAs) or other metabolites. SCFAs, for example, can provide energy to colon cells, support the gut barrier function, and have systemic effects on metabolism [32].

3.2 Roles of ghost probiotics in antimicrobial stewardship

In antimicrobial stewardship, ghost probiotics are used as a possible remedy in fighting against antimicrobial resistance [34], as illustrated in Table 2. A study by Thursby and Juge [40], revealed a significant decrease in the number of infections in the treatment group compared to the control group when the efficacy of a ghost probiotic formula in preventing respiratory tract infections in a population of elderly individuals in a nursing home was tested. In 2019, another study investigated the potential use of ghost probiotics as a preventive strategy against Clostridium difficile infections in a mouse model. Researchers found that a ghost probiotic formula of Lactobacillus reuteri DSM 17938 significantly shortens the duration of acute infectious diarrhea and reduces abdominal pain in patients with colitis [19, 41].

Ghost probiotic	Reported effects	References
Non-pathogenic Escherichia coli Nissle 1917	Competitive exclusion of pathogenic bacteria. They compete with pathogenic bacteria for binding sites and nutrients in the gut. This competitive exclusion mechanism can help prevent the attachment and colonization of harmful bacteria, reducing the risk of infections.	[26]
Lactobacillus rhamnosus GG	Reduced inflammatory response in the gut. When it comes to viral disorders, where inflammation can cause tissue damage, they can help regulate immune responses and minimize excessive inflammation.	[35]
Bacillus subtilis	Enhanced immune response; inhibition of pathogens	[36]
Lactobacillus acidophilus	Modulation of immune responses. Similar to living probiotics, they influence the immune system by promoting the synthesis of substances that modulate the immune system. They have the power to affect immune cell activity and cytokine synthesis, which can strengthen immunological responses and promote the body’s fight against infections.	[37]
Bifidobacterium	Boost intestinal health and aid in keeping the intestinal barrier’s integrity. They can strengthen tight connections between cells, increase mucus production, and improve the gut epithelium’s defensive capabilities. This may help lower the possibility of bacterial translocation and ensuing illnesses.	[24]
Streptococcus	Treat and prevent infections	[38]
Lactobacillus; Streptococcus; Bifidobacterium	Reduce use of antibiotics. In some circumstances, they might act as an additional therapy to lessen the requirement for antibiotics. Ghost probiotics may enhance the body’s natural defense mechanisms by boosting the immune system and encouraging a healthy gut flora, potentially lowering the need for antibiotics and limiting the emergence of antibiotic resistance.	[39]

Table 2.

Roles of ghost probiotics.

4. Synbiotics

The term synbiotics describes probiotics and prebiotics that have been combined in dietary supplements or food ingredients to create a synergistic effect. According to Wang et al. [42], prebiotics are common foods that strengthen the immune system while encouraging the development of probiotic bacteria in the human stomach. Prebiotics, which are necessary for the development and function of microorganisms, should not be mistaken with probiotics. Supplements and specific foods like yogurt, whole grains, and sauerkraut contain synbiotics [43]. Bifidobacterium, Lactobacillus, Saccharomyces boulardii, Bacillus cougulans, and prebiotics like Inulin and XOS are the most widely utilized synbiotics [44]. The most popular fibers that are typically utilized in conjunction with probiotics are fructans. Synbiotics were created in order to get over potential probiotic survival issues [43]. Synbiotics play a significant role in gut bacterial balance, which benefits the human immune system, metabolism, and gut health [43].

4.1 Effects of synbiotics on gut microbiota

The gut microbiota appears to play a role in the pathogenesis of obesity and associated diseases. Therefore, gut microbiota can also be considered a promising target in the comprehensive dietary approach to the prevention and treatment of obesity, including weight loss and weight maintenance [45]. Synbiotic supplementation increases the abundance of gut bacteria associated with positive health effects, especially Bifidobacterium and Lactobacillus, and it also appears to increase the gut microbiota richness [45].

According to Roy and Dhaneshwar [46], synbiotics can aid in enhancing the integrity of the intestinal barrier, which may lessen intestinal inflammation and enhance immunological function. Short chain fatty acids (SCFAs) are vital energy sources for colonocytes and have anti-inflammatory characteristics. Synbiotics help to boost production of SCFAs [47]. According to Phavichitr et al. [45], synbiotics can determine the abundance of harmful bacteria in the stomach, including Escherichia coli and Clostridium difficile. Additionally, synbiotics may enhance cholesterol, glucose, and inflammation metabolism, which could be advantageous for metabolic health [44].

4.2 How do synbiotics work?

Synbiotics work by combining prebiotics and probiotics to provide a synergistic effect that promotes optimal gut health. The probiotic adds beneficial bacteria that greatly benefit the gut microbiome. The prebiotic fuels the beneficial bacteria that is already present in the gut microbiome. There are two types of synbiotics which are synergistic synobiotics and complementary synbiotics [43]. Synergistic synbiotics are formulated to have live probiotics fueled by the prebiotic substrate that is co-administered in the product, allowing the two elements to work together as a self-contained whole [44]. Complementary synbiotics are formulated so that both elements work independently, with the prebiotic chosen to target resident microorganisms in the gut [44].

Synbiotics help to promote the growth of beneficial bacteria in the gut, leading to improved gut microbiome balance and overall gut health. A study by Palai et al. [43], supported that symbiotic supplements used in clinical trial modulate human gut microbiota by increasing abundance of potentially beneficial microbial species. Synbiotics have been shown to boost immune function by promoting the growth of beneficial bacteria that can help fight off harmful pathogens. A study showed that a synbiotic consisting of Lactobacillus acidophilus and Inulin improved the immune response in elderly individuals by increasing the production of immunoglobulin A and reducing the levels of pro-inflammatory cytokines such as interleukin-6 and tumor necrosis factor-alpha [44].

Synbiotics can improve digestion by promoting the growth of beneficial bacteria that aid in the breakdown and absorption of nutrients. They display positive effects on digestion and enzymatic activity, which may help alleviate many of the symptoms associated with lactose intolerance. For instance, the synbiotic of Lactobacillius acidophilus and Inulin improves the digestion of lactose in lactose-intolerant individuals by increasing the population of lactase-producing bacteria in the gut [47]. Also, probiotics like Bifidobacterium lactis combined together with fructooligosaccharides (FOS) improve the digestion of protein and fat in healthy adults by enhancing the production of pancreatic enzymes. Synbiotics have been shown to have anti-inflammatory effects, which can help to reduce inflammation in the gut and throughout the body. For example, research showed that a synbiotic consisting of Lactobacillus acidophilus and FOS reduces levels of C-reactive protein, a cause of inflammation [48].

4.3 Roles of synbiotics in antimicrobial stewardship

Synbiotics play a valuable role in antimicrobial stewardship by reducing the need for antimicrobial agents and preventing the development of antibiotic resistance. Synbiotics can be used to prevent and treat a number of conditions that are often treated with antimicrobials, such as Clostridium difficile infection, inflammatory bowel disease, and irritable bowel syndrome [49]. Lactobacillus acidophilus and Bifidobacterium lactis with FOS have been shown to reduce the incidence of antibiotic-associated diarrhea and Clostridium difficile infection in hospitalized patients efficiently [47]. Lactobacillus rhamnosus GG and inulin have been shown to reduce the incidence of antibiotic-associated diarrhea in children [47]. Akkermansia muciniphila and prebiotic fibers have been shown to improve gut barrier function and reduce inflammation in obese and overweight adults [49].

5. Postbiotics

Postbiotics are metabolic by-products of probiotic bacteria [34]. These byproducts include short-chain fatty acids, enzymes, peptides, and other compounds that can have various health benefits. Postbiotics play a role in maintaining gut health, regulating the immune system, providing anti-inflammatory effects and potentially reducing the risk of certain diseases [2]. Postbiotics can be naturally produced by the probiotic bacteria that live in our gut and they can also be produced through fermentation of certain foods such as yogurt, kefir, sauerkraut, and kimchi [50].

5.1 Roles of postbiotics in antimicrobial stewardship

Postbiotics, such as peptides and organic acids, have been shown to have beneficial effects on gut microbiota as shown in Table 3. Certain peptides produced by Lactobacillus species have been shown to inhibit the growth of pathogenic bacteria such as Escherichia coli and Salmonella enteritidis [9]. Organic acids such as acetic acid and lactic acid, which are produced by some probiotic bacteria, can help to lower the pH of the gut, creating an environment that is less favorable for the growth of harmful bacteria [2]. Short-chain fatty acids (SCFAs) are produced by the fermentation of dietary fiber by gut bacteria and have been shown to have antimicrobial properties. They can help to inhibit the growth of harmful bacteria such as Clostridium difficile, which is a common cause of antibiotic-associated diarrhea. By promoting the growth of beneficial bacteria and reducing the need for antibiotics, SCFAs can help to reduce the overall use of antimicrobials and limit the development of antimicrobial resistance [50].

Postbiotic	Reported effects	References
Short chain fatty acids from gut microbiota fermentation	Enhanced gut barrier function; anti-inflammatory effects. They can reduce the production of pro-inflammatory molecules, promote the production of anti-inflammatory substances, and help alleviate inflammation associated with infections.	[51]
Lactic acid bacteria metabolites	Modulation of immune responses; antimicrobial properties	[52]
Bacteriocins	Inhibition of pathogenic bacteria	[53]
Extracellular vesicles	Cellular communication; immune regulation	[54]
Organic acids	pH regulation; antimicrobial effects	[55]
Peptidoglycan derived muropeptides	The intestinal barrier’s integrity and functionality can be supported by immunomodulation. They can improve the protective qualities of the barrier, encourage mucus secretion, and fortify the tight junctions between intestinal cells. This aids in stopping dangerous bacteria and poisons from crossing the intestinal barrier.	[51]
	They can aid in forming and preserving a balanced makeup of the gut flora. They can support a healthy microbial environment by selectively promoting the development of advantageous bacteria, preventing the growth of diseases, and both. This may improve infection resistance and intestinal health.	[56]
	Reduction of negative Effects Related to Antibiotic Use - They might help to lessen the negative effects related to antibiotic use. They can aid in reducing antibiotic-associated diarrhea, maintain gut health while taking antibiotics, and hasten recovery by encouraging a balanced gut flora.	[35]

Table 3.

Roles of postbiotics.

Bacteriocins are antimicrobial peptides produced by some probiotic bacteria that can help to inhibit the growth of pathogenic bacteria. For example, nisin, a bacteriocin produced by Lactococcus lactis, has been shown to be effective against a range of Gram-positive bacteria, including Staphylococcus aureus and Streptococcus pneumoniae [57]. By using bacteriocins instead of antimicrobials to target specific pathogens, postbiotics can help to reduce the overall use of antimicrobials and limit the development of antimicrobial resistance.

Exopolysaccharides are complex carbohydrates produced by some probiotic bacteria that can have prebiotic effects, meaning they can promote the growth of beneficial bacteria in the gut [50]. Peptidoglycans are complex molecules found in the cell walls of bacteria that can modulate the immune system and have anti-inflammatory effects. Cell surface proteins are proteins found on the surface of probiotic bacteria that can interact with host cells and modulate immune responses [33].

6. Issues surrounding the use of probiotics and their derivatives in antimicrobial stewardship

To be considered a probiotic, a supplement needs to meet all the requirements set forth by the 2002 Food and Agriculture Organization/World Health [57]. The requirements stipulate that a probiotic must be a live microorganism, needs to be administered and should have a health benefit. Additionally, a probiotic must be safe and void of vectors that can transfer resistance to antibiotics [14]. One issue surrounding the use of probiotics in antimicrobial stewardship is the potential for interactions between probiotics and antibiotics. Some studies have suggested that probiotics may reduce the effectiveness of antibiotics by competing with them for absorption in the gut or by producing antibacterial substances that can neutralize antibiotics. This could lead to suboptimal treatment outcomes and the emergence of antibiotic-resistant strains of bacteria [58]. However, other studies have shown that probiotics can enhance the effectiveness of antibiotics by improving the gut microbiota and reducing the risk of antibiotic-associated diarrhea and other side effects. Another issue is the lack of standardization in the production and labeling of probiotics [57]. There is significant variability in the quality and efficacy of probiotic products, and there are currently no widely accepted standards for the selection, testing, and labeling of probiotics. This makes it difficult for healthcare providers to make informed decisions about which probiotics to use and for what indications [59].

7. Conclusion and future perspectives

In the midst of the ongoing antibiotic resistance challenge, using probiotics, postbiotics, ghost probiotics, and synbiotics offers a secure alternative to treating microbial infections. In order to research future potential uses of probiotics in both human and animal diseases, it is vital to update our knowledge in this area. As a result, this work may be used as a reference to understand naturally occurring probiotic compounds and their prospective applications for the treatment and management of numerous human diseases, providing a significant contribution to antimicrobial stewardship. Probiotics and their derivatives that exhibit powerful activity, both alone and in combination, must therefore be researched in the future.