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REVIEW ARTICLE
Year : 2022 | Volume
: 21
| Issue : 1 | Page : 1-8
Therapeutic impact of probiotics in various aspects: a novel prospective strategy
Rehab M Abdel-Megeed
Department of Therapeutic Chemistry, National Research Centre, Cairo, Egypt
Correspondence Address:
PhD Rehab M Abdel-Megeed
Assistant Professor, Department of Therapeutic Chemistry, National Research Centre, El-Buhouth Street, Cairo
Egypt
Source of Support: None, Conflict of Interest: None
CheckDOI: 10.4103/epj.epj_66_21
Probiotics are viable microorganisms that intentionally provide health benefits when consumed through restoring the gut microflora. Mainly, it is used as a successful approach for the treatment of gastrointestinal upset. Probiotics were initially used as a biotherapeutic regimen around the turn of the century. Probiotics stimulate the immune system that plays an important role in defense response against harmful microflora. Consumption of probiotics improves health against numerous diseases such as colorectal cancer, viral infection, allergies, stress, and different gastrointestinal disorders. This evidence suggests that the functions of commensal bacterial-derived factors are affected by host genetics and the discovery of links between susceptibility gene polymorphisms and protective microbial effects on the host, which might include probiotic-induced host responses. However, while probiotics’ prospective health-boosting effects have been explored in many studies, further study is needed to fully understand the processes and agents that promote their beneficial effects. The current review briefly discusses the beneficial effect of probiotics as a promising biotherapeutic approach focusing on the therapeutic properties of probiotics and its role to enhance the treatment of numerous diseases. Furthermore, the current review discusses the challenges and future insights into the development of genetically engineered probiotics and their application for the treatment of various diseases or as a novel nano-drug delivery system that will be a promising regimen for human health and biotherapy.
Keywords: biotherapy, health benefits, Lactobacillus, probiotics
Probiotics are microorganisms that participate in the microbial intestinal balance and play an essential role in health maintenance. Probiotics as a definition came from an assent panel held by the International Scientific Association of Probiotics and Prebiotics (ISAPP), 2001 Food and Agriculture Organization and WHO for the definition of probiotics [1].
These microorganisms include mostly different strains such as Lactobacillus, Bifidobacterium, Bacillus, Pediococcus, and some yeast. Probiotics are mainly common in dairy products but they can also be located in nondairy products [2].
Probiotics have an important role in the industry that is predominated by food companies, specified probiotic production companies, and nutritional supplement companies. The majority of commercially traded probiotics originated from a limited list of Lactobacillus spp. and Bifidobacterium spp. [3]. These strains have been previously accepted as generally regarded as safe (GRAS) status in the United States (http://www.accessdata.fda.gov/scripts/fdcc/?set=GRASNotices) and by the European Food Safety Authority [4].
Furthermore, other probiotics are available in the market such as Saccharomyces, Bacillus spp., Escherichia coli, Enterococci, and Weissella spp.
Probiotics have gained an increased attention in pharmaceutics for the health of different organs in addition to their benefit in heavy metal detoxification [5],[6]. Clinically, the health utility of probiotics has started since the 1990s. It is well known that the microbiota colonies in the healthy body seem to be different from those found in diseased conditions. Moreover, nutritional status is influenced by the role of the gut microbial community [7].
The current review focuses on the therapeutic role of probiotics as a promising biotherapeutic approach, as well as the challenges and future prospects of genetically engineered probiotics and their use for the treatment of a variety of diseases or as a novel nano-drug delivery system that could be a promising health biotherapy regime.
Probiotics: definition
Probiotic is the Greek words ‘pro and bios,’ meaning ‘of life.’ First, Lilly and Stillwell [8] described probiotics as the ‘substances produced by any microorganism to promote another to grow.’ Accordingly, probiotics are defined as ‘substances and microorganisms that collaborate in microbial balance in the gastrointestinal tract.’. Furthermore, probiotics are termed microbial cells that have beneficial effects on the maintenance of health [9].
History of probiotics
The essential benefit of the gut microbiota was completely unknown until the beginning of the 20th century. Elie Metchnikoff (a Russian scientist, Nobel laureate, and professor at the Pasteur Institute in Paris) detected that lactic acid bacteria (LAB) has health benefits and the ability to promote longevity. He detected a significantly low number of microbiota specified morphologically by a foreign Y-shaped cells that appeared in the stool of children with diarrhea [10]. Tissier discovered a type of bacteria in breastfed infants, who played an important role in establishing the concept that these bacteria take part in the maintenance of children’s health. By modulating the flora in infants, those suffered from infections in their intestines were relieved [10]. Elie Metchnikoff also investigated antioxidants that could suppress aging through some modified gut microbiota, which could replace proteolytic microbes as Clostridium, which produces toxic substances including phenols, indoles, and ammonia from the digestion of proteins with beneficial microbes. He advanced a diet containing probiotics such as Lactobacillus bulgaricus and Streptococcus thermophilus in milk fermentation; this fermented milk played a role in maintaining health [11].
Types of probiotics and their health benefits
Different types of probiotics have been investigated and listed as helpful microorganisms to human health [2],[12]:
Lactobacilli: are the common bacteria in the small intestine and essential to initiate digestion and absorption of food. Lactobacilli give numerous benefits to intestinal mucosa health conditions.Lactobacilli acidophilus: it can be found at the end of the small intestine and the colon. It helps in the inhibition of vaginal inflammation occurred by Candida albicans. It also helps in the development of natural defenses against harmful bacteria as well as viral infections.Lactobacilli rhamnosus: it is normally common in the intestine and the vagina as it can grow well in acidic media.Bifidobacteria: this type of probiotics is abundant in the colon and the vagina. Bifidobacteria synthesize short-chain fatty acids, such as propionic, lactic, acetic, formic, and butyric acids, with acetic acids. These acids have antimicrobial activity against harmful bacteria, molds, and yeasts.Bifidobacteria bifidum: it is mainly found in both the vagina and the lower part of the small intestine with an essential role for vitamin production and protection of candida infection. Furthermore, it is able to inhibit baleful enzymes and modulate the pH level. It has antibacterial activity against E. coli, Shigella, and Salmonella.Bifidobacteria breve: it is the main enhancer for immunity that protects against rotavirus and stabilizes the microflora.Bifidobacteria infantis: mainly found in infants’ gastrointestinal tract keeping it very healthy.Bifidobacteria longum: it improves the intestinal environment and defecation frequency.Saccharomyces: Saccharomyces are microorganisms from the yeast family. It is used in the treatment of diarrhea associated with antibiotic administration.Streptococcus thermophilus was defined as LAB, which is mainly found in milk and milk products and used in yogurt production.Enterococcus: they are Gram-positive, facultative anaerobic cocci. It is useful in the treatment of diarrhea.Mechanism of action of probiotics and immune response
The main role of probiotics is to stimulate the immune system enabling it to cope with harmful microflora. The immune system may be innate or adaptive systems. The main role of adaptive immunity is dependent on B and T lymphocytes that are specific to a responsible antigen. However, innate immunity responds to pathogen-associated molecular patterns. Toll-like receptors are a good example of immunity [13],[14],[15],[16].
Numerous studies have demonstrated the mechanisms by which probiotics can regulate the immune response. Indole derivatives were stimulated by Lactobacillus reuteri for the activation of aryl-hydrocarbon receptor leading to the reduction of gene expression of Thpok in CD4 and intraepithelial lymphocytes and reprogramming CD4+ IELs into CD4+CD8aa+ IELs [17].
Probiotics enhance gastrointestinal immune response during infection [18]. Probiotics are reported to prevent colitis induced by Citrobacter rodentium in mice by the downregulation of interferon-γ and tumor necrosis factor-α. Moreover, upregulation of interleukin (IL)-10 and FOXP3 transcription increases follicular T-regulatory cells [19]. Immunological role of bifidobacterium has been investigated through Foxp3 and IL-10 secreting T cells, which requires toll-like receptor signaling pathways [20] ([Table 1]).
Probiotics as a promising biotherapeutic regimen
Intolerance of lactose
Nearly 70% of people suffer from an intolerance of lactose and it is most predominant in kids. Lactose intolerance is associated with several gastrointestinal symptoms such as diarrhea, flatulence, vomiting, and abdominal pain resulting from colon fermentation of undigested lactose [25].
Previous investigations declared the superiority of yogurt to improve lactose absorption [26]. Furthermore, living bacteria that contain β-galactosidase improves lactose digestion [21].
Various studies have demonstrated the impact of probiotic administration including Lactobacillus spp. such as L. acidophilus, L. bulgaricus, B. longum, L. reuteri, L. rhamnosus, and Streptococcus spp. such as S. thermophilus to attenuate the pathological effect of lactose intolerance both in vivo and in vitro. These bacteria species are characterized by powerful mucus adhesion properties, inhibiting pathogens, and evolving barrier function, as well as improving lactose absorption [27].
Antibiotic-associated diarrhea
Some antibiotic-treated patients suffered from antibiotic-associated diarrhea (5–39%). Antibiotics such as cephalosporins and aminopenicillins are associated with a high risk of antibiotic-associated diarrhea [28]. Severe diarrhea is associated with Clostridium difficile infections due to antibiotic consumption. Reports suggested that inappropriate antibiotic use should be reduced and replaced by target antibiotics. However, if antibiotic treatment is deemed urgent, it is useful to create a safe method to prevent side effects associated with the issued antibiotic. Probiotics in marketing could be important and effective drugs for antibiotic-associated diarrhea treatment [29]. Different species of probiotics such as as Lactobacillus genus, Bifidobacterium genus, and Saccharomyces genus are recorded to be useful in the prevention of antibiotic-associated diarrhea [30].
Gastroenteritis
Gastroenteritis or acute diarrhea is a disease that results from viral, bacterial, or parasitic infection causing dehydration. Rehydration strategy can reduce the incidence of mortality and morbidity but does not shorten diarrhea duration or normalization of gastrointestinal microbiota [22].
Administration of some probiotic strains (as L. rhamnosus, L. acidophilus, Bifidobacterium lactis, B. infantis, and S. thermophilus) in combination with the standard oral rehydration solution treatment was recorded to improve acute diarrhea in children [31].
Viral infections and rotavirus gastroenteritis in children
Probiotics are effective in confronting viral infections by stimulating the immune system that has different mechanisms of action. Lactobacilli can increase serum IgA and promotion of phagocytosis in leukocytes. Furthermore, it was clear that probiotics have a vital role in stimulating the immune response of vaccines against rotavirus and Salmonella typhi [32].
Rotavirus is the most recorded virus causing gastrointestinal infections and is responsible for 453 000 deaths of children worldwide [33].
The essential role of CD4+ cells was previously recorded for the promotion of protective response and rotavirus-specific IgA development [34]. Moreover, CD8+ T cells are associated with the protection of rotavirus reinfection [35].
Prevention and treatment of rotavirus diarrhea were effective using L. rhamnosus. Enterococcus faecium SF68 were effective in rotavirus treatment. This strain is mainly found in yogurt [36].
Bacterial overgrowth
Bacterial overgrowth in the small intestine is defined as an abnormal growth of colonized bacteria in the small intestine associated with different gastrointestinal syndromes. Abdominal pain, diarrhea, and flatulence are the main abounding characters in the digestion process in bacterial overgrowth. This abnormality of intestinal colonies seems to be more prevalent in older individuals and women [37].
Recently, probiotics therapy has been reported to enhance clearance of bacterial overgrowth as compared with nonprobiotic therapy, although probiotics were not efficient in bacterial overgrowth prevention [38]. However, it has been observed that treatment of bacterial overgrowth and chronic diarrhea can occur with Lactobacillus bacteria [39].
Inflammatory bowel disease and irritable bowel syndrome
A combination of environmental, genetic, and intestinal microbial factors can cause inflammatory bowel disease [40]. Cocktails of probiotic intake may be important to improve inflammatory bowel disease.
Administration of a combination of eight strains of Lactobacillus bacteria (Lactobacillus plantarum, Lactobacillus delbrueckii subsp. bulgaricus, Lactobacillus casei, L. acidophilus, Bifidobacteria breve, B. longum, B. infantis, and Streptococcus salivarius) was commonly applied in inflammatory bowel disease therapy [41]. This formulation increased the levels of regulatory cytokines and downregulated proinflammatory cytokines and toll-like receptor gene expression [42]. Furthermore, tumor necrosis factor-α and NF-κB gene expression was modulated in the presence of Lactobacillus and Bifidobacterium of affected individuals [43].
Irritable bowel syndrome is a gastrointestinal disorder recording 20% of the population suffered from it due to increasing abnormal microflora such as Klebsiella spp. and Enterococci in addition to decreasing numbers of Lactobacilli and Bifidobacteria [44]. Furthermore, probiotic supplementation has demonstrated clinical improvements in up to 80% of the treated patients [45].
Reduction of allergy
Gut microbiota plays a remarkable role in the development of mucosal immune system and environmental factors in the development of allergic diseases [46]. Infants who suffered from pathogenic bacteria such as C. difficile and Staphylococcus aureus in the gastrointestinal tract are at more risk of developing the allergy. On the other hand, more colonies by different species of Lactobacillus bacteria and other Bifidobacteria were seen in gastrointestinal tracts of nonallergic children. This finding suggested that the presence of microbiota of the described species in the gastrointestinal tract might protect against allergic diseases [47].
Newborns with allergies depend on immune response due to placental immune regulation across feto-paternal antigens [48]. After a neonate is born, this response is reduced due to the activation of some microbiota [49]. Moreover, gastrointestinal probiotics regulate immune response due to their impact on the development of gut-associated lymphoid tissue. Therefore, probiotic supplementation during the pregnancy period decreases risk factors whereas probiotics may be a good modulator of cytokine balance [50].
Colon cancer
Colorectal cancer (CRC) estimates nearly 9.2% of all cancers recording 1.096 million cases and is the second leading cause of cancer morbidity and mortality worldwide [51].
The gut microbiome plays a crucial role in host health [23]; meanwhile, an imbalance in the gut microbiome can influence bacterial toxin secretions leading to carcinogenic metabolites such as hydrogen sulfide in addition to lowering beneficial metabolites as butyrate. These metabolic disorders cause dysregulation of the immune system and lead to CRC [52].
Numerous studies have assessed the gut microbiome of CRC patients, revealing several patterns [53]. CRC patients revealed an increment in the abundances of the genus Fusobacterium in their gut microbiomes [54],[55],[56],[57],[58],[59]. On the other hand, tissue and stool specimens of CRC revealed several harmful bacterial species such as Streptococcus [58], Peptostreptococcus [54],[55],[56], Selenomonas [56],[57], and Porphyromonas [56],[57],[58],[59]. Microbial composition of CRC patients as compared with healthy individuals based on the analysis of 16 S rRNA amplicon (V3) declared an increment in the above-mentioned genera besides a remarkable decrease in butyrate-producing bacteria. Another study investigated similar results using compositional 16 S rDNA sequencing of CRC specimens [54]. The relative abundances of Fusobacterium bacteria in carcinogenic colon tissue observed a significant difference as compared with noncancerous mucosa, with 8.5 and 4.13%, respectively [55].
Exposure to probiotics could activate caspase-3 besides the inhibition of p21 gene expression. This result suggested that probiotic supplementation improves cell apoptosis [60].
Furthermore, L. casei and L. rhamnosus recorded an ability to reduce the invasion of human CRC cell line (HCT-116) [61] in addition to an observed downregulation of matrix metalloproteinase-9 gene expression.
The therapeutic impact of probiotics was investigated in vivo and in vitro. Gao et al. [57] proved the effect of probiotic supplementation by regulating microRNA in CRC-induced mice. The result declared that miR-135b, miR-155, and KRAS expression have been downregulated; meanwhile, there was an obvious upregulation of miR-26b, miR-18a, APC, PU.1, and PTEN in the probiotic-treated group as compared with the nontreated group [62]. Furthermore, the prophylactic effect of probiotics was demonstrated along with the anti-inflammatory standard drug celecoxib in the CRC rat model. Daily supplementation of probiotic strains for 18 weeks reduced the tumor burden, downregulate Bcl-2 and K-ras and anti-apoptotic genes and upregulate p53 and Bax tumor-suppressor genes [63],[64].
Clinically, the protective effect of probiotics and dietary fiber was conducted on some volunteers with CRC who had colorectal removal surgery. Atypia of colorectal tumors has been prevented [65],[66]. Another study investigated the changes in the microbiota, DNA methylation, epithelial proliferation, and biomarkers of CRC in probiotic supplementation [67]. Gianotti et al. [68] studied the impact of B. longum and Lactobacilli johnsonii with two different doses when supplemented perioperatively to CRC patients. High-dose supplementation significantly modulated the expression of CD3, CD4, CD8, and lymphocytes. This study suggested that probiotic supplementation could modulate the health status of CRC patients.
Cholesterol-lowering effects
The relationship between consuming Lactobacilli and cholesterol level was previously investigated. Moreover, L. acidophilus can remove cholesterol from tissue culture media.
Cholesterol concentration decreased upon intake of a large quantity of yogurt [24]. In the animal model, hypercholesterolemia declared a significant decrease in serum cholesterol levels after Lactobacilli administration [69].
Heavy meatal detoxification
Probiotics are a promising generation of microorganisms that have the capacity to mitigate toxicity of heavy metals. As previously reported, probiotics could modulate oxidative stress, modify, and adjust pH levels [7],[70]. Furthermore, they modulate the expression of enzymes and proteins that are related to heavy metal toxicity [71]. Moreover, it has a vigorous antioxidative and immune modulatory ability, sustain fluid of the gut, and suppress microflora overgrowth [72]. L. plantarum was recorded to modulate cadmium, lead, and chromium toxicity [73]. Moreover, Lactobacillus brevis (23017) could modulate mercury toxicity. Probiotic strains are able to get rid of heavy metals through fecal excretion [74]. Lactobacillus and Acidobacillus strains were used in our previously published article to detoxify cadmium chloride in mice [6].
Therapeutic application of genetically engineered probiotics
However, host responses to the harmful microbes are carefully studied; the major attention is to discover novel and safe therapies using the helpful bacteria. Novel production of bioengineered probiotics is established through genetic modulation to improve the efficiency of conventional probiotics in addition to reduce the pathogenic potential of target strains. These strains are used for different applications such as a drug delivery system vaccine or to simulate surface receptors, targeting specified pathogens or toxins, and to improve the host immune response [75].
In view of the removal of beneficial microbiota associated with antibiotic treatment, unique antimicrobial drugs that are environment-friendly and seem riskless have been developed [76]. Genetic-engineered probiotics have numerous advantages, as they are more stable and lower in cost.
Genetically modified LAB was previously used to improve its therapeutic potential against CRC. The modified strain of Pediococcus pentosaceus, SL4 has a significant antitumor effect after oral administration in mice [77].
Furthermore, cotreatment of IL-10 and genetically engineered Lactococcus lactis declared a significant reduction (50%) in colitis incidence inflammatory bowel disease in a mouse model [78]. Moreover, another study suggested that IL-10 efficacy can be improved through the integration of recombinant L. lactis [79].
LAB is the best-characterized model organism used for the production and delivery of antigens and cytokines [80] and DNA delivery system [81]. In a previous study, DNA delivery into mammalian cells with LAB through invading target genes such as fibronectin-binding protein A is derived from S. aureus and was expressed in L. lactis by vector transformation to increase target gene expression [82],[83].
Probiotica as a drug delivery system
It was indicated that probiotics can intermediate the synthesis of selenium nanoparticles biologically. However, biogenic synthesis of selenium nanoparticles by probiotics is usually observed to be eco-friendly, of low-cost, safe, and nontoxic. Therefore, selenium-enriched probiotica approach attracted wide interests and attention due to the above advantages. Selenium loaded in L. casei can synthesize lactomicroselenium particles (85–200 nm) [84].
The therapeutic effect of probiotic strains is summarized in [Table 2].
ConclusionProbiotics have opened a new drift on the correlation between nutrition and health. Different studies prove that the intake of probiotics is effective in the treatment of numerous diseases and stimulates the immune system. Furthermore, it could be a promising generation of biotherapy. Gastrointestinal microbiota eventually manipulate all health directions including drug metabolism, toxicology, and improvement of creative therapies. Their combined benefits include antagonistic response against microflora in addition to their immunomodulatory impact against numerous diseases, such as pathogenic bacteria, cancers, and metabolic disorders, can be assessed. In particular, the combined therapeutic approach including immunomodulatory, antimicrobial, and anti-inflammatory role of genetically engineered probiotics could be beneficial to overcome the progression of different diseases and metabolic disorders Furthermore, probiotics are used for various applications such as the nano-drug delivery system to target specific pathogens or toxins and for improving host immune response. However, up to now, the mechanism of probiotic-mediated synthesis of nanoprticles is still unclear. Moreover, the potential biological activity and application effect of different promising drug-enriched probiotics need further investigation.
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Conflicts of interest
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