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Novel Dietary Approach with Probiotics, Prebiotics, and Synbiotics to Mitigate Antimicrobial Resistance and Subsequent Out Marketplace of Antimicrobial Agents: A Review
Authors Habteweld HA , Asfaw T
Received 3 April 2023
Accepted for publication 16 May 2023
Published 23 May 2023 Volume 2023:16 Pages 3191—3211
DOI https://doi.org/10.2147/IDR.S413416
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 2
Editor who approved publication: Prof. Dr. Héctor Mora-Montes
Habtemariam Alekaw Habteweld,1 Tsegahun Asfaw2
1Department of Pharmacy, Debre Berhan University, Debre Berhan, Ethiopia; 2Department of Medical Laboratory Science, Debre Berhan University, Debre Berhan, Ethiopia
Correspondence: Habtemariam Alekaw Habteweld, Tel +251-961-285-631, Email [email protected]
Abstract: Antimicrobial resistance (AMR) is a significant public health concern worldwide. The continuous use and misuse of antimicrobial agents have led to the emergence and spread of resistant strains of bacteria, which can cause severe infections that are difficult to treat. One of the reasons for the constant development of new antimicrobial agents is the need to overcome the resistance that has developed against existing drugs. However, this approach is not sustainable in the long term, as bacteria can quickly develop resistance to new drugs as well. Additionally, the development of new drugs is costly and time-consuming, and there is no guarantee that new drugs will be effective or safe. An alternative approach to combat AMR is to focus on improving the body’s natural defenses against infections by using probiotics, prebiotics, and synbiotics, which are helpful to restore and maintain a healthy balance of bacteria in the body. Probiotics are live microorganisms that can be consumed as food or supplements to promote gut health and improve the body’s natural defenses against infections. Prebiotics are non-digestible fibers that stimulate the growth of beneficial bacteria in the gut, while synbiotics are a combination of probiotics and prebiotics that work together to improve gut health. By promoting a healthy balance of bacteria in the body, these can help to reduce the risk of infections and the need for antimicrobial agents. Additionally, these approaches are generally safe and well tolerated, and they do not contribute to the development of AMR. In conclusion, the continuous development of new antimicrobial agents is not a sustainable approach to combat AMR. Instead, alternative approaches such as probiotics, prebiotics, and synbiotics should be considered as they can help to promote a healthy balance of bacteria in the body and reduce the need for antibiotics.
Keywords: antimicrobial resistance, probiotics, prebiotics, synbiotics
Introduction
The continual emergence of antimicrobial resistance (AMR) from unchecked and unregulated antimicrobial usage has posed a higher influence on the world population’s health and development plan. Drug-resistant pathogens have a multifaceted problem and could result in prolonged illness, disability, and death, as well as worldwide economic loss. Globally, there is an estimated annual death rate of 700,000 people from antimicrobial-resistant infections. Antimicrobial-resistant infections have become a major source of worldwide economic loss in searching for more expensive medicines. The consequences and burdens of these drug-resistant pathogens are particularly significant in developing nations where poor sanitation, inadequate infection prevention and control, and sophisticated healthcare problems are dominated.1–3
An increase in the occurrence of infections with increased morbidity, mortality, and readmissions is the common fearful consequence of multidrug-resistant pathogens as compared to susceptible ones. The insusceptibility of these pathogenic microbes to the currently available antimicrobial agents calls many researchers to stand for action for searching non‐antimicrobial therapeutic alternatives which is useful for preventing and treating infectious disease conditions from those resistant pathogens. Many of the non‐antibiotic therapeutic options explored include the use of probiotics, prebiotics, synbiotics, phytocompounds, vaccines, Clustered Regularly Interspaced Short Palindromic Repeats-Cas (CRISPR-Cas), nucleic acid-based anti-bacterial treatments, bacteriocins, antimicrobial peptides, phage therapy, immunostimulants, cytokines, Quorum Quenchers (QQ) or Quorum Sensing Inhibitors (QSI), feed enzymes, Nanoparticles (NPs), and Chicken Egg Yolk Antibodies (IgY).4–6
Of these various approaches, the probiotics, prebiotics, and synbiotics dietary-based non-antibiotic alternative approach is by far the most promising ones due to their convenient availability as a dietary supplement, their ability to mitigate the risk of antimicrobial resistance in the natural way of living making them host and environmentally friendly approaches, their ability to replenish washed-out endogenous gut flora associated with antibiotic treatment, their antagonistic activity against a varied number of resistant strains and their several mechanisms involved in the prevention of emergence of antimicrobial resistance and infections, their applicability as prophylactic and therapeutic approaches, and their wider applicability to improve general health beyond their antagonistic activity on pathogens.4,7
However, other approaches like Clustered Regularly Interspaced Short Palindromic Repeats-Cas (CRISPR-Cas) are associated with many drawbacks like higher cost and time-consuming to formulate these novel methods, probability of off-target effects, lack of on-target editing efficiency, incomplete editing (mosaicism), Cas9 toxicity, difficulty of targeting intracellular infections with this technology, genome instability which may not be an effective barrier to plasmid and drug resistance spread, delivery inefficiency and inability to use conventional approaches like nanoparticles when phages are non-symmetrical and large.4,6
The probiotics, prebiotics, and synbiotics dietary-based non-antibiotic alternative approach aimed to switch the intestinal bacterial makeup of humans, involving the replacement of important beneficial bacteria by out-competing colonization of harmful pathogenic bacteria to regrow and establish a healthy microbiome.7 In this approach, clinically important established promising outcomes were observed when these products are incorporated as a formulation into our day-to-day life helping in modulating an optimal balance of the human gut microbiome and possibly preventing the development of AMR.
Probiotics
Probiotics are live microbial species of bacteria or yeasts that resemble important functional microorganisms residing inside the human intestine. Under properly controlled studies, these live microbial species have been shown to have a health-promoting property for humans when taken in sufficient quantity as dietary supplements or found in foods.8 Broad-spectrum antagonistic activity on the vast majority of microbes is especially an important health-promoting benefit of probiotics. Probiotics (yeasts or bacteria) are becoming the most popular, less expensive, and environmentally friendly novel therapeutic options to antibiotics to overcome the problems of antimicrobial resistance by direct inhibition of drug resistance pathogens or indirectly by reducing the risk of infections.9,10
The most common and well-investigated probiotics include many bacterial species of Bifidobacterium (ie, B. longum, B. animalis subsp. lactis, B. infantis, etc.) and Lactobacillus (ie, L. plantarum, L. casei, L. acidophilus, L. rhamnosus etc.). Some other bacterial species like Lactococcus lactis subsp. lactis, Pediococcus acidilactici, Streptococcus thermophilus, Leuconostoc mesenteroides, Bacillus subtilis, Escherichia coli Nissle 1917, Enterococcus faecium, etc.), and yeasts (S. boulardii) are also probiotics.9–11
Mechanism of Actions of Probiotics Against Antimicrobial-Resistant Pathogens
Probiotics have an enormous function for humans, mainly in the improvement of the intestinal microflora, making sure stability between harmful pathogens and bacteria essential for everyday functioning. The antagonistic activity of probiotics against antimicrobial-resistant pathogens can be by competitive exclusion through the creation of a hostile environment, blocking harmful pathogens from their adhesion sites,12 toxin receptor blockage and degradation, outcompeting pathogenic microbes for nutrients, modulating the host immunity and expression of genes,13,14 and producing substances (H2O2, bacteriocins, organic acids, and antioxidants) with inhibitory and antagonistic potential against the vast majority of pathogenic microbes.15–20
Substances like benzoic acid, formic acid, lactic acid, phenylacetic acid, acetic acid, carbon dioxide, hydrogen peroxide, acetoin, short-chain fatty acids, diacetyl, acetaldehyde, and bacteriocin substances of enterocin, enterolysin, lacticin plantaricin, nisin pisciolin, lactocin, reuterin, and pediocin are among the commonest chemical substance with the antimicrobial property.
These usually produced bacteriocins can effectively improve the host mucosal integrity by disrupting surface-associated microbial cells and decreasing the number of harmful microorganisms residing at the intestinal epithelium. This can further aid to reduce the pathogenic bacterial population and promote “colonization resistance”.21
Probiotics at the intestinal epithelial cells can initiate cells in producing mucus and antimicrobial substances and thereby aid in improving intestinal barrier functions.22 Production of immunoglobulins, macrophages, lymphocytes, and γ- interferon can also be their mechanism of improving mucosal immunity which could possibly reduce and eradicate harmful pathogenic microorganisms and opportunistic microbes in the human gut.23 Probiotic microorganisms can efficiently protect the adhesion and colonization of pathogenic microbes to the surface of intestinal epithelial cells. They can also trigger and illicit a series of signaling pathways that can activate the various immunological cells which aid in preventing infectious diseases.
Several ex vivo and in vivo testing approaches have been employed for investigating the potential effects of probiotics as an alternative antimicrobial agent against harmful pathogens. The ex vivo (in-vitro) testing method uses different assay techniques like agar well diffusion/paper disc, microtiter plate, co-culturing, cell-line assays, and spot-on lawn/agar spot for determining antimicrobial activity.11 Table 1 shows many established antimicrobial activities of many investigated probiotics against harmful microbes. The in vivo method uses animal studies, placebo-controlled human trials, and randomized double-blind studies to investigate the apparent ability of probiotic formulations against other microorganisms (Table 2).
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Table 1 Current Evidence Revealing in vitro Antimicrobial Activity of Probiotics |
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Table 2 Current Evidence Revealing in vivo Antimicrobial Activity of Probiotics |
Prebiotics
Prebiotics are carbohydrate-based polysaccharide food components that are selectively utilized by human or animal hosts. They are known for providing health-promoting effects to the host.91 Carbohydrate-based glucans and fructans are known for their proven prebiotic potentials from other substances like starches, glucose, pectin, oligomers of mannose, human milk, xylose, and polyphenols.91,92 In common practice, prebiotics are given to the host through orally,91 however, direct application of the products to other microbially colonized body sites is also investigated as a possible method of administration. For instance, they can be directly applied to the vaginal tract93 and skin.94 Studies have outlined numerous investigated health benefits of prebiotics, including defending microbes,95,96 modulating immunity,97,98 absorbing minerals,99–101 proper bowel functioning,102,103 cardiovascular disease,104,105 and assuring satiety.106,107
Mechanism of Action of Prebiotics in Defense Against Antimicrobial-Resistant Pathogens
Colonic bacteria utilize prebiotics as substrates of their fermentation products, resulting in the production of short-chain fatty acids (ie propionic acid, butyric acid, and lactic acid) which decreases pH in the colon. This lowering in colonic pH level will create acidic surroundings that are less suitable for the existence of harmful and pathogenic microorganisms which could result in the reduction of their numbers.23,108 This change in the composition of the intestinal microbiome is helpful in reducing the risk of antimicrobial resistance. Moreover, the reduction in the pH of the colon can aid calcium and other minerals absorption, which can in turn help in limiting the growth of yeasts, and other harmful microorganisms.19
Prebiotics may also act by aiding epithelial cells functioning and supporting the gut microbiota by providing metabolic energy and thereby affecting the composition and function of these beneficial microorganisms. Establishing an optimal balance of beneficial microorganisms will help in reducing the availability of nutrient food components for the invading pathogenic microbes, and therefore inhibit epithelial invasion and colonization.92,108 Moreover, prebiotics may also affect the intestinal epithelial absorption of nutrients and the level of host immune system efficiency.102 Table 3 summarizes the currently available evidence on the antimicrobial activity of prebiotics through these different proposed mechanisms of action.
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Table 3 Current Evidence Revealing Antimicrobial Activity of Selected Prebiotics |
Synbiotics
Synbiotics are a combination product of live microorganisms and substrate(s) that are selectively taken and utilized by human or animal hosts to impart a health-promoting benefit. Those products can be complementary synbiotics where they are selectively used by either the endogenous microbiota or synergistic types where they are utilized by the live microorganism in the formulation, and therefore having proof of conferring health benefit is not merely sufficient to prepare and formulate a synbiotic product. As for probiotics, the application of synbiotics inside or outside the intestine is also possible and promising. Synbiotics might be formulated into a variety of suitable and convenient products, such as drugs, foods, or nutritional supplements.118
Species from the genera Lactobacillus, Bifidobacterium, and Streptococcus with variable doses of either galactooligosaccharides, inulin, or fructo-oligosaccharides are the most commonly used to test live microorganisms and substrate components in synbiotic formulations, respectively.11
Many trials have claimed the potential health benefits of synbiotics in preventing and treating various infectious disease conditions like eradicating infection induced by Helicobacter pylori bacteria,119,120 and preventing the occurrence of surgical site infections.121–125 The result reported from various systematic review and meta-analysis studies done at different times also revealed the effectiveness of synbiotics in reducing surgery-related complications like sepsis, diarrhea, urinary tract infection, pneumonia, abdominal distention, duration of postoperative fever, surgical site infection, and duration of antimicrobial therapy and subsequent duration of hospitalization.126,127
Mechanism of Actions of Synbiotics in Defense Against Antimicrobial-Resistant Pathogens
There are many proposed mechanisms of action for synbiotics in defending against many harmful resistant pathogens. The presence of substrate components in a synbiotic formulation provides a favorable condition for living microorganisms to help in competing with the pathogenic microorganisms inside the gut environment and thereby improving the growth and number of useful microflora which supports intestinal homeostasis.128 Host immune system modulation and microbial toxin neutralization through the production of metabolites like short-chain fatty acids are also their mechanisms to fight against resistant pathogens.126 Synbiotics-based natural way inhibition of such pathogenesis can significantly reduce the high burden of antimicrobial pills use and subsequent antimicrobial resistance resulting from antimicrobial-induced selection pressure.128 Some studies129–131 have established the potential of synbiotics for restoring unbalanced gut microbiome by enhancing the growth and number of gut-useful microbes which can serve as a promising option for the antimicrobial treatment of various infectious diseases. Table 4 summarizes the currently available evidence on the in vivo and in vitro antimicrobial potential of synbiotics.
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Table 4 Current Evidence Revealing in vivo or ex vivo Antimicrobial Activity of Synbiotics |
Summary and Future Prospects of Probiotics, Prebiotics, and Synbiotics as Alternative Sources for Antimicrobial Agents and Prevention of Antimicrobial Resistance
The potential benefits of using probiotics, prebiotics, and synbiotics as alternative therapies to combat antimicrobial-resistant infections are promising. These natural agents have been shown to have antimicrobial properties and can help to restore and maintain a healthy balance of bacteria in the body, which can reduce the risk of infections and minimize the need for antimicrobial agents. However, the effective means of administering these natural agents to the site of action is still a topic of investigation. Nanotechnology formulations with a biocompatible matrix encapsulation of probiotics with polysaccharide prebiotics can be a promising approach to delivering these agents to the site of action. The use of polysaccharides with prebiotics potential as a matrix polymer is an innovative approach that can provide a dual benefit as a delivery agent and an effective synbiotics formulation. It is also important to note that probiotics, prebiotics, and synbiotics should be used as adjuvants or synergistic agents to conventional antimicrobial therapies, rather than a replacement. This approach can aid in fostering healing and eradication rates of pathogenic microbial infections, reduce the cumulative dose and side effects of conventional antimicrobials, and minimize the development of antimicrobial resistance. It is crucial for stakeholders and government health policies to give special emphasis to formulating individualized dosage forms with established safety and efficacy of these therapeutic biologic agents, taking into account various factors like the disease condition, ways of administration/delivery, storage conditions, and facilities, and host innate and physiologic conditions. All these factors need to be considered and standardized. Furthermore, the theoretical side effects from the consumption of probiotics, such as transferring antimicrobial-resistant genes to pathogens, should be considered. An investigation of antimicrobial susceptibility of the strains to identify potential drug-resistant plasmids and assure that no transferable antimicrobial-resistant gene is present should also be performed to ensure safety and efficacy. Efforts should be put in to assure market availability of these products in the most cost-effective manner so that every society across the world can get benefited. Like the conventional pharmaceutical products being marketed, these products should also be procured at each distribution and retail outlet and should be advertised through television, radio, newsletters web banners, social media, email, blogs, public gatherings, conferences, and pay per click ads for assuring products continual future utilization.
Funding
This review work received no specific grant from any funding agency.
Disclosure
The authors declare that they have no conflicts of interest in this work.
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