Sanjukta Mishra¹  and Swastik Acharya²

¹Department of Biochemistry, Kalinga Institute of Medical Science, KIIT University, Bhubaneswar, Odisha, India

²Department of Medicine, Kalinga Institute of Medical Science, KIIT University, Bhubaneswar, Odisha, India

Corresponding Author E-mail: drmsanjukta@gmail.com

DOI : https://dx.doi.org/10.13005/bpj/2285

Abstract

Probiotics are defined as non-pathogenic live microorganisms that, when administered in adequate amounts, confer health benefits on the host. Association of probiotics with human beings has a lot of history. Well known as 'health-friendly bacteria', they are widely used commercially as a functional food. The popularity of probiotics has gone exponentially high due to an increasing number of clinical trials, supporting their beneficial effects. Several in vivo and in-vitro experimental evidence supports strain-specific and disease-specific probiotic efficacy to prevent and ameliorate antibiotic-associated diarrhoea, traveller's diarrhoea, ulcerative colitis, and many more.  Besides, numerous recent studies have reported that probiotics could have a significant effect in alleviating various metabolic, lifestyle and diet-related disorders like obesity, type 2 diabetes, metabolic syndrome, irritable bowel syndrome Strains of Bifidobacterium, Lactobacillus and Saccharomyces boulardii are the most commonly used as probiotics. Safety, efficacy, pathogenicity, infectivity, intrinsic property, virulence factors are to be addressed during probiotic selection. The underlying mechanisms of probiotics effects are still not fully elucidated and have been under intensive research. Numerous diverse, strain-specific probiotic mechanisms have been proposed, which include early colonization of perturbed microbes, competitive exclusion of pathogens, short-chain volatile fatty acid production, alteration of gut pH, immunomodulation and many more. Considering the remarkable influence on human health, probiotics seem to be alluring attractive agents to promote human health conditions and to improve the quality of life against several diseases. This review discusses the current documentation and recent advances on probiotics and their possible health attributes, in scientific literature, focusing on diverse, heterogeneous, and strain-specific mechanisms of action. Randomised human controlled clinical trials are needed to reconfirm its safety and beneficial effects.

Keywords

Bifidobacteria; Health; Lactobacillus; Microorganism; Probiotics; Saccharomyces

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Introduction

Human beings are a natural habitat for a large, complex, dynamic microbial ecosystem. Bacterial colonization of the gut begins in early life, which imitates that of its mother^1. In healthy adults, gut microbiota show higher complexity and diversity. Diet, genome, the lifestyle of host, use of antibiotics and ageing process may influence microbiota composition.² These microbes form a population density gradient ranging from about 10² /ml in the stomach to about 10¹¹ – 10¹² /ml in the colon.³ Gut microbiota can accomplish metabolic (ferment non-digestible dietary residues) as well as protective function (via immunomodulation).^4,5 Alteration in microbiome diversity (dysbiosis) and composition are studied to be related to chronic diseases like obesity, type 2 diabetes mellitus, oxidative stress-related diseases, non-alcoholic fatty liver disease, cardiovascular disease and immune-mediated diseases.^6,7 Due to the emergence of bacterial resistance against antibiotics, the therapeutic use of medicines would provide limited efficacy. In this regard, probiotics and their relationship with human health have been an area of interest in recent years. Probiotics can be defined as non-pathogenic live microorganisms that exert health benefits to host upon ingestion. Probiotics exhibit this unique ability to promote human health by s  colonization and normalization of a perturbed intestinal microbial community. Moreover, they should be able to express their activities against pathogens and should be able to stimulate the immune system.⁸ They are being implicated clinically as co-adjuvants for the elite properties like anti-diabetic, anti-obesity, anti-inflammatory, anti-angiogenic activities.^9,10 Most of the probiotics are available commercially as foodstuff or drugs containing live microbes. Therefore, consideration of the safety assessment of probiotics is of utmost importance before use.¹¹ Looking at the long list of health benefits, it may be considered as a biotherapeutic agent. A comprehensive review of the relevant literature was performed to reiterate the factual findings. Present review article provides a current understanding of different aspects of probiotics, highlighting the historical prospectus, compliance to the global scientific definition, criteria for safety selection, brief mechanism of action, and its role towards human health. This may result in establishing validation of probiotic therapies in application to human beings.

Origin and Historical perspectives

Etymologically, the term “Probiotic” comes from the Greek word “pro-bios” which means “for life”. It has long been integral since ancient times when fermented products had been used for nutritional and therapeutic purposes. A century ago, the journey of probiotics was started when scientist Henry Tessler (1899), Pasteur Institute of Paris, discovered Bifidobacterium in the intestine of breastfed infants and found it useful for diarrhoeal episodes in those infants.¹²

However, Nobel laureate Russian scientist Elie Metchnikoff (1907), first introduced the hypothesis of using microorganisms for health benefit by replacement of gut flora with useful ones.¹³ In the early 1930s, Shirota reported the survival of intestinal bacteria through the gut passage. He developed fermented milk containing Lactobacillus acidophilus Shirota, which is still popular today as Yakult.¹⁴  Lilly and Stillwell (1965) then first introduced the term “Probiotic” to describe a substance which stimulates the growth of other microorganisms.¹⁵

Next supporting evidence came from Parker (1974), who gave a new definition to probiotics as ‘microorganism and substances responsible for intestinal microbial homeostasis.¹⁶ Following which, many scientists widened the definition of probiotics, including health benefits of the host.^17,18,19 Subsequently, Food and agricultural   organization of United Nations and World Health Organisation [FAO/WHO,2002], explained probiotics as “live microorganisms which when administered in adequate amounts, confer health to the host”.²⁰ This recommended definition and guidelines have been popularly adopted and proven to be useful to researchers. Since then, research in the field of probiotics has grown exponentially high, and it has been strengthened considerably to understand the role of a wide range of probiotics in enhancing or preventing chronic diseases.

Microbial species as probiotics

Contemporary probiotics research aims at the characterization and composition of gut microbiota, which functions as a microbial ecosystem. It is worth mentioning here that probiotic effects are strain specific. So health claim is distinctive for each probiotic strain, and probiotic prospective of bacterial strains varies significantly within the same species.^21,22 That is why strain identification is recommended to characterize the functions of each probiotic to the specific strain. This could be achieved by genetic recognition using molecular approaches like DNA-DNA hybridization, 16SRNA sequencing, and pulsed-field gel electrophoresis for strain typing.^23,24 That apart polymerase chain reaction(PCR) method can come up with fast quantitative and qualitative information on the constitution of the intestinal microbiome.²⁵ It is also reported that several probiotic products contain more than one strain. A single strain may exhibit different benefits when used individually and in combination.^26,27 Every individual is bestowed with exclusive gut microbiota that take part in distinctive functions like nutrient metabolism, continuance of structural coherence of gut mucosal barrier, and immunomodulation. Traditionally, the term probiotics are more related to most popular strains of Lactobacillus and Bifidobacterium (Table-1), but it can be extended to other microorganisms like Streptococcus, Saccharomyces (yeast strain), Enterococcus and  Bacillus.^28,29,30 Many of these probiotics strains have been preferred based on selection criteria^.31

Table 1: Commonly used probiotic microorganism

Lactobacillus	Acidophilus, Plantarum, Crispatus Rhamnosus, Paracasei, Fermentum Reuteri, Johnsonii, Breves, Casei Delbrueckii gasseri, Salivarus Gallinarum, Crispatus, Bulgaricus
Bifidobacterium	Breve, Bifidum, Infantis, Longum Thermophilus, Animalis Adoloscentis
Bacillus   Lactococcus      Saccharomyces   Streptococcus   Enterococcus   Pedicoccus   Bacteroids    Others	Sereus, coagulans, subtilis   Lactis, reuteri, rhamnosus Casei, acidophillus   Cervisiae, boulardii   Thermophilus, salivarius, sanguis   Faecium SF 68,  faecalis   Acidilactici, pentosaceus   Uniformis Leuconostoc mesenteroides E.Coli strain Nissle Weissella cibaria, confusa Pediococcus acidilactici

Some bacterias that do not normally colonize the intestinal tract, may also come under the category of probiotics that include Lactobacillus bulgaricus, streptococcus thermophilus, and Leuconostoc species. Neither these bacterias colonize nor exert any significant effect on intestinal microbial balance.³² But they do play an important role in the food industry.  There are several studies in progress to recognize the futuristic genre and new strains for probable use as probiotics. These new strains need to be appraised and analyzed based on accepted and confirmed selection criteria before implication.

Requisites for selection of safe and effective probiotics

Eighteen years before, scientific definition of probiotics was conceived, along with the guidelines warranting pertinent use of them. The aim of administering live microbes can assist therapeutic function is achieving precedence. Most of the probiotics are promoted as foodstuff or drugs (tablets, powder, and other formulations) containing live microbes. The variety of food products accommodating probiotic strain is wide such as fermented milk, cheese, ice cream, buttermilk, milk powder, yogurt, and many more. The viability and feasibility of probiotics is a fundamental parameter for developing probiotic food, as probiotics are certainly very fragile to many environmental burdens such as acidity, oxygen, heat, etc.³³ Probiotic food products are widened worldwide due to never ending steady generation of research confirmations, indicating their likely health benefits to consumers. Consideration of safety of probiotics and compatibility of the product with the microbes are very important because of the frequent isolation of widely used bacteria (Table-1) from clinical infection sites. This has raised debate over their infectiveness and safety. However, it is unlikely that they require generalized infectivity as their separation is the result of opportunistic infection, which might be caused by chronic diseases, skin injury, cancer, or drug induced abnormality.³⁴  Practically, lactobacillus and Bifidobacterium are an  infrequent cause of infection to humans. This lack of pathogenicity perpetuates all age groups and also to the immunosuppressed individual.³⁵ Assessment of the safety of probiotics from various angles is not a simple task. However, it is relatively easy for an in vitro study of several factors. Several such studies in animal and human beings have been proposed to assess the safety standards of probiotics by studying on an intrinsic property of the strain, the pharmacokinetics of the strain (survival, activity in intestine, faecal and mucosal recovery) and interaction between strain and host.³⁶ But the values of these parameters are under debate due to discrepancies and lack of standardization of operating procedures. So, the best-proposed approach should be the target population and function-specific studies. Although, many probiotic strains are well described as safe, risk-free and reports of harmful effects to the host are rare, the following factors need to be evaluated to assess its safety and effectiveness:

Identified genetically at genus, species and strain level [whole genome strain characterisation]³⁷

Non-pathogenic, non-infective.^38,39,40

should not carry transferable antibiotic resistance gene.⁴¹

Non toxic [no formation of any harmful substances like ammonia, indole, phenol, amines]⁴²

Able to survive in adequate number during intestinal transit [ acid, bile tolerant]⁴³

Bile salt hydrolase activity [ deconjugation of biliary salt, prevents carcinogenesis].^44,45

Antimicrobial activity [able to adhere to the mucosal epithelium, able to colonize and competitive exclusion of pathogen]⁴⁶

Able to antagonize pathogenic bacteria [in vitro culture study depends on microbial cell mass, buffer component, fermentation span, and growth medium]⁴⁷

Stable and capable of remaining viable under storage condition [potentiates gut adherence, immunomodulation and can lower gut permeability]⁴⁸

Clinically documented and validated health effects [strain to be tested in randomized controlled human trial]⁴⁹

Designated strain-specific for human use and animals⁴⁹

That apart, several other determinants that must be described during the analysis of safety are   Platelet aggregation activity and mucus degradation activity. Harry et al. could isolate different strains of L. Rhamnosus from infective endocarditis, which is having higher activity than laboratory strains.⁵⁰  This suggests that they may have an infective property in contributing to the progression of endocarditis.  Mucous degradation activity is because of the production of enzymes glycosidase and protease, which might break intestinal mucous glycoproteins, so causing infective endocarditis.⁵¹  Ruserler et al. in his study lactobacillus and bifidobacterium did not find the efficacy of this proposed mechanism.⁵² Therefore, it is critical to establish the infectivity related to the outer layer structure containing glycoproteins and lectins.

Mechanism of action of probiotics

Probiotics are safe microbes that confer beneficial effects to the host when administered in an adequate dose and at an appropriate period. The consequences of probiotics on host well-being have been communicated in many reports, articles, reviews, systematic meta-analysis, though many studies lack insight into the potential mechanism of action.^53,54,55 The underlying mechanism on why and how the bacterial strains work to achieve such effect, has been under intensive study. Numerous probiotic mechanisms have been proposed, which are diverse, heterogeneous, and strain-specific such as modulation of host defence, antagonist to pathogenic bacteria, and effect through microbial toxins.⁵⁶ After a thorough comprehensive search of relevant literature, elaborated mechanisms from in vivo and in vitro studies are given below:          

Colonization and normalization of the perturbed intestinal microbes.⁵⁷

Competitive exclusion of pathogens.⁵⁸

Enzyme activity [beta galactosidase, beta glucuronidase].^59,60

Production of bacteriocin, mucin and volatile fatty acid.⁶⁰

Cell adhesion and cell antagonism.⁶¹

Modulation of immune system.⁶²

Interaction of brain-gut axis.^63,64,65

Currently, it is accepted that early colonization of probiotic strain and normalization of the perturbed intestinal microbial community is the key mechanism that confers health benefits to the host. Normally intestinal microflora exhibits colonization resistance or barrier effect, an indigenous mechanism to inhibit colonization of harmful enteric pathogen, which is attained by complex interactions among the bacterial community.^66,67 Adhesion of bacteria to host surfaces prevents mechanical clearing of pathogens. The anti-pathogenic activity of probiotics has been a topic of research as a wide variety of such compounds (bacteriocin, ethanol, organic acid, hydrogen peroxide, acetaldehyde, peptides, etc) are produced by them.⁶⁸ Some lactobacillus and bifidobacterium produce bacteriocin,  which prevents proliferation by competitive exclusion of selected pathogen and can increases membrane permeability, that leads to depolarisation of membrane potential.⁶⁹ Enzymatic activity of probiotic specifically beta-glucuronidase hydrolyses glucuronidated metabolite in their toxic form, causing intestinal damage. More so it has been linked to an early pre-neoplasticism marker for colon carcinoma.⁷⁰ Agreeing with in vitro and in vivo study information, volatile fatty acids have been documented to have numerous biochemical, physiological and molecular effects.  It is a useful source of energy for enterocytes and it acts as a key signalling molecule for maintenance of gut health.²⁵

Evidence for probiotic effectiveness [in vivo and in vitro studies]

The association between lifestyle, diet, and well-being has increased the requirement for products, which can build up health beyond rendering basic nourishment. The conglomeration of probiotics on human health goes back to the long past when people were using fermented milk for their well-being.⁷¹The detailed review of literature by WHO/FAO illustrated a comparatively small number of areas in which probiotics have shown their positive effect, which will be presented below.

Probiotics for newborn and children

Intestinal infection in neonates is very frequent and is the leading cause of death in developing countries.⁷² Necrotizing enterocolitis is a devastating intestinal condition, mostly seen in preterm infants, where intestinal microbiota will be dominated by many pathogens like Enterococcus faecalis, E.Coli, Staphylococcus epidermidis, Klebsiella pneumonia etc.⁷³ However, the study has indicated a low incidence of the said condition if premature infants were given breast milk, which may allow non-pathogens like lactobacillus and bifidobacterium to organize within the premature intestine. Recent meta-analysis has identified the specific strain Lactobacillus rhamnosus GG ATCC53103 or combination of Bifidobacterium infantis Bb-02, Bifidobacterium lactis Bb-12, and Streptococcus  thermophilus TH-4 in order to reduce necrotizing enterocolitis.⁷⁴  This suggests a correlation between the reduction in Lactobacillus and the increased risk of necrotizing enterocolitis. That apart, in a review on mucosal immunity starting at birth, Walker outlined a correlation between the normal intestinal microbiome, early intestinal colonisation, and subsequent defence from several disorders.⁷⁵ In another meta-analysis, the author briefly discussed the effect of probiotic and conventional oral rehydration therapy, which reduces the extent of acute diarrhoea in one day in the case of little ones under 5 years of age.⁷⁶  Cochrane review  involving infant and children also reported beneficial effects of probiotics as the reduced duration of diarrhoea and diminished stool frequency.⁷⁷

Probiotics for Antibiotic-associated diarrhoea and Traveller’s diarrhoea

There is considerable evidence to encourage probiotic use in GIT illness like acute diarrhoeal disease and amelioration of antibiotic linked diarrhea.^78,79,80 Treatment and improvement of infectious diarrhoea are presumably the most comprehensively accepted health asset of probiotic microorganisms.  Rotavirus is the commonest source, which replicates in the highly differentiated absorptive columnar cells of the small intestine. Evidence suggests the effectiveness of L. Rhamnous, B.animalis, L. Casei Shirota in diminishing the span of acute rotavirus infection by immunomodulation, competitive hindrance of receptor sites, and by yielding substances that inactivated viral particle.⁸¹  Moreover Rotavirus protein NSP1 may be linked to inhibition of interferon production by stimulating the degradation of interferon regulatory factor. ⁸² Recent systematic review and meta-analysis explained the positive effect exerted by probiotics Lactobacillus rhamnosus GG in reducing the duration of acute rotavirus diarrhea.⁸³ Randomised control trial by Allen et al. to assess the probiotic efficacy in proven acute infectious diarrhoea showed the reduced mean duration of diarrhoea and reduced stool frequency after the intervention.⁸⁴ Several incidents of diarrhoea are the usual after-effects of antibiotic therapy. This is due to suppressing GI microflora that encourages overgrowth of opportunistic infections like clostridium difficile. A meta-analysis by Hempel et al have evaluated the evidence of probiotic administration in reducing the risk of the condition.⁸⁵ The majority of traveller’s diarrhoea is triggered by bacteria E.Coli and rest by virus and Protozoa. The 2017 guidelines for prevention of traveller’s diarrhoea [TD] by International society of travel medicine proposed inadequate affirmation to suggest the use of probiotics for treatment. A meta-analysis of randomised control trials by Jong-Myon Bae showed statistically significant efficacy in prevention of TD ⁸⁶ Another study by Hilton et al on randomised American tourists with an intake of a probiotic placebo showed a reduced daily risk of developing diarrhea.⁸⁷ Interpreting the details from several blinded, randomised, placebo-controlled trials, sazawal et al. established that the use of probiotics in antibiotic-associated diarrhoea decreases the probability of diarrhoea by 52%, traveller’s diarrhoea by 8%.⁸⁸ Furthermore, numerous other study results have indicated contradictory findings owing to the difference in the study population and species of probiotic being used.^89,90

Probiotics for Inflammatory Bowel Disease [IBD]

Ulcerative colitis and Chron’s disease are the two important bowel diseases, where a change in normal intestinal flora has been associated with gut microbial genetic susceptibility and its ambience. Change in the normal intestinal flora and subsequent breaking in the uniformity between intestinal immune status and microbiome may lead to IBD.⁹¹ It is worth mentioning here that Probiotics are progressively known for its potentiality to impede and handle intestinal disorders and enhance the immune system in both in vitro and animal model research. Several clinical review articles demonstrated the efficacy of probiotics in IBD.^92,93 Though the exact mechanism of action is not known, probiotics are thought to utilise their effect by modulating and harmonising intestinal flora and intestinal immune response.⁹³ Enteric bacteria may alter the balance of pro-inflammatory and anti-inflammatory cytokine levels (secreted by T helper cells-1 and T- helper cells-2 respectively) of the intestine that predisposes for intestinal disorders.⁹⁴ These two are important in maintaining the homeostasis of the immune system in the intestinal barrier. A preliminary study investigating the efficacy of probiotics suggests that a high dose of a combination of strains may alleviate symptoms of a disease, as compared to placebo.⁹⁵ This improvement in the severity of the disease might be due to a decrease in inflammation. But still, there are inadequate confirmations to conclude about the potency as there is the fear of opportunistic by modulating inflammatory status.⁹⁶ Several animal trials also conducted to investigate the effects of probiotics on IBD showing its anti colitis effects via downregulation of TNF-alpha, COX-2, and upregulating anti-inflammatory cytokines.^97,98,99 Although probiotic treatment improves the severity of disease by diminishing inflammation; it did not treat the source. So definitely more clinical trials of longer duration studies are required to understand safety, effectiveness and to prove sustainability of the positive results.

Probiotics for Hypercholesterolemia:^{100,101,102,103}

Specific strains of Probiotic like b.adolescentis  have been claimed to exhibit possible therapy for reducing cholesterol levels. The possible mechanisms include:

Bile salt hydrolase activity, which is considered by many scientists to be a prerequisite for the selection of probiotics.

Deconjugation of bile salt in enterohepatic circulation that makes it less soluble, so can be excreted via feces. This mechanism exhibited by Lactobacillus has drawn attention

The accumulation of cholesterol into bacterial cell membranes. E.faceium CRL183 strain has already been experimented to reduce lipid parameters, so it could prevent atherosclerosis development in rabbit with induced hypercholesterolemia¹⁰⁴

Much work has already been accomplished using bile salt deconjugation by Lactobacillus to treat hypercholesterolemia.¹⁰⁵ Another study by Lye et al also reported experimental evidence of cholesterol-reducing property of Lactobacillus, where cholesterol was found to get converted into coprostanol with the help of cholesterol reductase produced by the probiotic strain.¹⁰⁶ Probiotics may also produce short-chain fatty acids, which can inhibit HMG CoA activity and subsequently can decrease the transformation of primary to secondary bile acid due to colonic acidification.^{100, 107}

Probiotics for Cancer

In vivo and in vitro experimental data supported the anti-carcinogenic effect of probiotics, which may be attributed to pro-inflammatory, anti-inflammatory response.^33,108 Lactobacillus, Bifidobacterium and E.Coli strain of Nissle have shown antimutagenic activity in-vitro due to inactivation of the mutagenic compound.¹⁰⁹ Roller et al. in his animal study on rats could correlate inhibition of carcinogenesis with a change in immune activity on probiotic consumption.¹¹⁰ Precise mechanism remains unclear due to a lack of human experimental evidence. The proposed mode of action includes immunomodulation, production of antimutagenic substances, which alter the physicochemical and metabolic effect.¹¹¹

Other health benefits of probiotics

Apart from these conventional beneficial effects, the role of probiotics in diabetes, inflammation, allergy, cardiovascular diseases, and neurodegenerative diseases has been a fascinating area of research. It has been reported that probiotics by improving mucosal barrier function, might help to protect against allergies.¹¹² They are found to have cardiovascular protection via antihypertensive action.¹¹³  Accumulating pieces of evidence prove the beneficial dermal effects of probiotics such as a wound, scar healing, skin rejuvenation.^114,115 Many other effects include a reduction in body and abdominals mass,¹¹⁶ lactose intolerance,¹¹⁷ periodontal infections,^118,119 women’s reproductive and bladder health^{120, 121} and modulation of the gut-brain axis.^{122, 123} Undoubtedly, the current research progress toward healthful effects has been encouraging.

Probiotic: hope or hype

Researchers and clinicians used probiotics in a variety of medical conditions, taking into account safety guidelines and scientific requirements. Different new technologies like microencapsulation, cell immobilisation have been developed to enhance its stability and viability in functional food. That apart, molecular technology is already being tried to manipulate Lactobacillus by replacing it with its active ingredient or metabolite to produce new improvised products, which are clinically proven safe. It is suggested that these new ways of handling gut microbe-host interaction offer hope for the therapeutic effects of probiotics. Consumption of probiotics as dietary supplements may potentiate health benefits as human gut microbiome functions like a microbial ecosystem to boost the immune system by preventing the growth of other pathogenic bacteria.¹²⁴ A scientific question arises here whether probiotics can modify dysbiosis or not. According to many recent scientific observations, the mode of the impact of probiotics on gut microbiome composition is not significant.^{41, 44,47,48}  Lerner et al. did an extensive study on several systemic reviews and meta-analysis and concluded that there are limited experimental design, precision, and incomplete reporting with variation in strain, which might lead to lack of safety and transparency in research design.¹²⁵ Safety is further complicated by the use of duplicate cultures of original strain by DNA fingerprinting technique which increases the risk of side effects.¹²⁵  The common systemic and intestinal side effects of probiotics consumption include Lactic acidosis, brain fogginess, hostile gene transfer, the introduction of specific bacteriophages, virulence factors, intestinal probiotic overgrowth, and many others.¹²⁶  Antibiotic resistance determinants question the safety issues, as it can be passed to resident gut bacterial by horizontal gene transfer, which in turn is responsible for opportunistic infection.^{126, 127} Use of Polymerase chain reaction[PCR] technique and microarray analysis can detect acquired resistance. Nevertheless, more safety and toxicity-defined study is needed in the future to reveal the sombre side of probiotic use and to highlight the potential detrimental effects. Moreover, consideration of the risk-benefit ratio should be recommended before suggesting the use of probiotics.

Conclusion

Probiotics may be considered as a functional food as they provide health benefits beyond the traditional nutritional functions. Safe and health-friendly bacterial species come under the probiotics category. Association of probiotics with human beings has a long history.  Probiotics have become increasingly popular as there is documented evidence of health benefits. The capability of probiotics to ameliorate different health aspects with utmost safety is the basis of the selection of probiotics. Safety assessment should be the screening tool to identify potential probiotics.  Lactobacillus and Bifidobacterium genera are reported to be used widely as probiotic food supplements due to their therapeutic benefits.   Recent research explorations suggest that probiotics can modify the composition and few metabolic activities of the microbiota.  Probiotic clinical effects are still controversial, as several results obtained are heterogeneous. So, sustainability of the desired results is a matter of conflict. Despite the strong scientific evidence of various health benefits of probiotics, further intensive research with well-designed randomised clinical trials is needed to justify the safety and efficacy.

References

1. Dreyer J.L., Liebl A.L. Early colonization of the gut microbiome and its relationship with obesity. Human Microbiome Journal. 2018;10:1-5
   CrossRef
2. Bäckhed F., Ley R.E., Sonnenburg J.L, Peterson D.A., Gordon J.I. Host-bacterial mutualism in the human intestine. Science. 2005;307(5717):1915-1920.
   CrossRef
3. Guarner F., Malagelada J.R. Gut flora in health and disease. Lancet. 2003;361(9356):512-519.
   CrossRef
4. Tsai Y.L., Lin T.L., Chang C.J., et al. Probiotics, prebiotics and amelioration of diseases. J Biomed Sci. 2019;26(1):3.
   CrossRef
5. Jandhyala S.M., Talukdar R., Subramanyam C., Vuyyuru H., Sasikala M., Nageshwar Reddy D. Role of the normal gut microbiota. World J Gastroenterol. 2015;21(29):8787-8803.
   CrossRef
6. Qin J., Li Y., Cai Z, et al. A metagenome-wide association study of gut microbiota in type 2 diabetes. Nature. 2012;490(7418):55-60.
   CrossRef
7. Selvanantham T., Lin Q., Guo C.X., et al. NKT Cell-Deficient Mice Harbor an Altered Microbiota That Fuels Intestinal Inflammation during Chemically Induced Colitis. J Immunol. 2016;197(11):4464-4472.
   CrossRef
8. Moal V.L., Servin A.L. Anti-infective activities of Lactobacillus strains in the human intestinal microbiota: from probiotics to gastrointestinal anti-infectious biotherapeutic agent. Clinical Microbiology reviews. 2014;27(2): 167-199
   CrossRef
9. Le Barz M., Anhê F.F., Varin T.V., et al. Probiotics as Complementary Treatment for Metabolic Disorders. Diabetes Metab J. 2015;39(4):291-303.
   CrossRef
10. Palumbo V.D., Romeo M., Marino Gammazza A., et al. The long-term effects of probiotics in the therapy of ulcerative colitis: A clinical study. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2016;160(3):372-377.
    CrossRef
11. Ishibashi N., Yamazaki S. Probiotics and safety. Am J Clin Nutr. 2001;73(2 Suppl):465S-470S.
    CrossRef
12. Tissier H. Traitement des infections intestinales par la methode de la flore bacterienne de l’intestin. 1906 ; R. Soc. Biol.  60:359-361.
13. Podolsky S.H. Metchnikoff and the microbiome. Lancet. 2012;380(9856):1810-1811.
    CrossRef
14. Lactobacillus casei strain Shirota., Yakult Honsha Co. Ltd., Yakult Central Institute for Microbiological Research, Tokyo, Japan 1998.
15. Lilly D.M., Stillwell R.H. Probiotics: Growth-promoting factors produced by microorganisms. Science. 1965;147(3659):747-748.
    CrossRef
16. Parker R.B. Probiotics: the other half of the antibiotic story. Anim Nutr. Health. 1974: 29: 4-8.
17. Fuller R. Probiotics in human medicine. Gut. 1991;32(4):439-442.
    CrossRef
18. Salminen S., von Wright A. Current probiotics-safety assured?. Microbial Ecology in Health Dis. 1998;10(2):68-77.
    CrossRef
19. Salminen S., Ouwehand A., Benno Y., Lee Y.K. Probiotics: how should they be defined? Trends in Food Science and Technology. 1999;10(3):107–110.
    CrossRef
20. FAO/WHO. Report on Joint FAO/WHO Expert Consultation on Evaluation of Health and Nutritional Properties of Probiotics in Food Including Powder Milk with Live Lactic Acid Bacteria. 2001
21. Arslan S., Erbas M. Probiotic cereal-based fermented functional foods. Fermented foods, part I. 2015:211-27.
22. Ramos C.L., Thorsen L., Schwan R.F., Jespersen L. Strain-specific probiotics properties of Lactobacillus fermentum, Lactobacillus plantarum and Lactobacillus brevis isolates from Brazillian food products. Food Miocrobiology.2013;36:22-29
    CrossRef
23. Kechagia M., Basoulis D., Konstantopoulou S., et al. Health benefits of probiotics: a review. ISRN Nutr. 2013;2013:481651.
    CrossRef
24. de Magalhães J.T., Uetanabaro A.P., de Moraes C.A. Identification of Lactobacillus UFV H2B20 (probiotic strain) using DNA-DNA hybridization. Braz J Microbiol. 2008;39(3):542-546.
    CrossRef
25. Isolauri E., Salminen S., Ouwehand A.C. Microbial-gut interactions in health and disease. Probiotics. Best Pract Res Clin Gastroenterol. 2004;18(2):299-313.
    CrossRef
26. Pandey K.R., Naik S.R., Vakil B.V. Probiotics, prebiotics and synbiotics- a review. J Food Sci Technol. 2015;52(12):7577-7587.
    CrossRef
27. Isolauri E., Salminen S., Ouwehand A.C. Microbial-gut interactions in health and disease. Probiotics. Best Pract Res Clin Gastroenterol. 2004;18(2):299-313.
    CrossRef
28. Fijan S. Microorganisms with claimed probiotic properties: an overview of recent literature. Int J Environ Res Public Health. 2014;11(5):4745-4767.
    CrossRef
29. Kechagia M., Basoulis D., Konstantopoulou S., et al. Health benefits of probiotics: a ISRN Nutr. 2013;2013:481651.
    CrossRef
30. Dionisio D., Valassina M., Uberti M., Fabbri C., Parri F., Saffi E.G. Mycoplasma pneumoniae non-pulmonary infection presenting with pharyngitis, polyarthritis and localized exanthem. Scandinavian J infect dis. 2001 Jan 1;33(10):782-3.
    CrossRef
31. Havenaar R., Ten Brink B., Huis J.H. Selection of strains for probiotic use. In Probiotics , Dordrecht.1992 (pp. 209-224).
    CrossRef
32. Messina M. Western soy intake is too low to produce health effects. Am J Clin Nutr. 2004;80(2):528-530.
    CrossRef
33. Soccol C.R., Vandenberghe L.P., Spier M.R., Medeiros A.B., Yamaguishi C.T., Lindner J.D., Pandey A., Thomaz-Soccol V. The potential of probiotics: a review. Food Technology and Biotechnology. 2010 Dec 15;48(4):413-34.
34. Kothari D., Patel S., Kim S. Probiotic supplements might not be universally effective and safe: A review. Biomedicine and Pharmacotherapy. 2019;111:537-547
    CrossRef
35. Borriello S.P., Hammes W.P., Holzapfel W., et al. Safety of probiotics that contain lactobacilli or bifidobacteria. Clin Infect Dis. 2003;36(6):775-780.
    CrossRef
36. Donohue D.C., Salminen S. Safety of probiotic bacteria. Asia Pac J Clin Nutr. 1996;5(1):25-28.
37. Ansari J.M., Colasacco C., Emmanouil E., Kohlhepp S., Harriot O. Strain-level diversity of commercial probiotic isolates of Bacillus, Lactobacillus, and Saccharomyces species illustrated by molecular identification and phenotypic profiling. PLoS One. 2019;14(3):e021384
    CrossRef
38. Hill C., Guarner F., Reid G., Gibson G.R., Merenstein D.J., Pot B., Morelli L., Canani R.B., Flint H.J., Salminen S., Calder P.C. Expert consensus document: The International Scientific Association for Probiotics and Prebiotics consensus statement on the scope and appropriate use of the term probiotic. Nature Rev Gastro Hep. 2014 Aug;11(8):506-14.
    CrossRef
39. Kechagia M., Basoulis D., Konstantopoulou S., et al. Health benefits of probiotics: a review. ISRN Nutr. 2013;2013:481651.
    CrossRef
40. Lenoir-Wijnkoop I., Gerlier L., Bresson J.L., Le Pen C., Berdeaux G. Public health and budget impact of probiotics on common respiratory tract infections: a modelling study. PLoS One. 2015;10(4):e0122765.
    CrossRef
41. Gueimonde M., Sanchez B., Margolleas A. Antibiotic resisatance in probiotic bacteria. Front Microbiol. 2013;4:202
    CrossRef
42. Sanders M. E., Akkermans L. M., Haller D., Hammerman C., Heimbach J., Hörmannsperger G., Huys G., Levy D. D., Lutgendorff F., Mack D., Phothirath P., Solano-Aguilar G., & Vaughan E. Safety assessment of probiotics for human use. Gut microbes. 2010;1(3): 164–185.
    CrossRef
43. Corcoran B.M., Stanton C., Fitzgerald G.F., Ross R.P. Survival of probiotic lactobacilli in acidic environments is enhanced in the presence of metabolizable sugars. Appl Environ Microbiol. 2005;71(6):3060-3067.
    CrossRef
44. Patel A.K, Singhania R.P., Pandey A., Chincholkar S.B. Probiotic bile salt hydrolase : current development and perspectives. Appl Biochem Biotechnol. 2010;162(1):166-88
    CrossRef
45. Pavlović N., Stankov K., Mikov M. Probiotics-interactions with bile acids and impact on cholesterol metabolism. Appl Biochem Biotechnol. 2012;168(7):1880-1895.
    CrossRef
46. Woo J., Ahn J. Probiotic-mediated competition, exclusion and displacement in biofilm formation by food-borne pathogens. Lett Appl Microbiol. 2013;56(4):307-313.
    CrossRef
47. Monteagudo-Mera A., Rastall R.A., Gibson G.R., Charalampopoulos D. et al. Adhesion mechanisms mediated by probiotics and prebiotics an d the Appl Microbiol Biotechnol. 2019;103(16):6463-6472.
    CrossRef
48. Hill C., Guarner F., Reid G., Gibson G.R., Merenstein DJ., Pot B., Morelli L., Canani R.B., Flint H.., Salminen S., Calder P.C. The International Scientific Association for Probiotics and Prebiotics consensus statement on the scope and appropriate use of the term probiotic. Nature Rev Gastro Hep. 2014;11(8):506-14.
    CrossRef
49. Reid G., Gadir A.A., Dhir R. Probiotics: Reiterating What They Are and What They Are Not. Front Microbiol. 2019;10:424.
    CrossRef
50. Harty D.W., Patrikakis M., Hume E.B., Oakey H.J., Knox K.W. The aggregation of human platelets by Lactobacillus species. J Gen Microbiol. 1993;139(12):2945-2951.
    CrossRef
51. Oakey H.J., Harty D.W., Knox K.W. Enzyme production by lactobacilli and the potential link with infective endocarditis. J Appl Bacteriol. 1995;78(2):142-148.
    CrossRef
52. Ruseler-van Embden J.G., van Lieshout L.M., Gosselink M.J., Marteau P. Inability of Lactobacillus casei strain G.G, acidophilus, and Bifidobacterium bifidum to degrade intestinal mucus glycoproteins. Scand J Gastroenterol. 1995;30(7):675-680.
    CrossRef
53. Didari T., Solki S., Mozaffari S., Nikfar S., Abdollahi M. A systematic review of the safety of probiotics. Expert Opin Drug Saf. 2014;13(2):227-239.
    CrossRef
54. Hempel S., Newberry S.J., Maher A.R., et al. Probiotics for the prevention and treatment of antibiotic-associated diarrhoea: a systematic review and meta-analysis. JAMA. 2012;307(18):1959-1969.
    CrossRef
55. Plaza-Díaz J., Ruiz-Ojeda F.J., Vilchez-Padial L.M., Gil A. Evidence of the Anti-Inflammatory Effects of Probiotics and Symbiotics in Intestinal Chronic Diseases. Nutrients. 2017;9(6):555.
    CrossRef
56. Oelschlaeger T.A. Mechanisms of probiotic actions – A review. Int J Med Microbiol. 2010;300(1):57-62.
57. Yang I., Corwin E.J., Brennan P.A., Jordan S., Murphy J.R., Dunlop A. The Infant Microbiome: Implications for Infant Health and Neurocognitive Development. Nurs Res. 2016;65(1):76-88.
    CrossRef
58. Zoumpopoulou G., Tsakalidou E., Thomas L.V. An Overview of Probiotic Research: Human and Mechanistic Studies1. Probiotic Dairy Products. 2017 Oct 31:293-357.
    CrossRef
59. Plaza-Diaz J., Ruiz-Ojeda F.J., Gil-Campos M., Gil A. Mechanisms of Action of Probiotics. Adv Nutr. 2019;10(suppl_1):S49-S66.
    CrossRef
60. Mayrhofer S., van Hoek A.H., Mair C., et al. Antibiotic susceptibility of members of the Lactobacillus acidophilus group using broth microdilution and molecular identification of their resistance determinants. Int J Food Microbiol. 2010;144(1):81-87.
    CrossRef
61. Ribet D., Cossart P. How bacterial pathogens colonize their hosts and invade deeper tissues. Microbes Infect. 2015;17(3):173-183.
    CrossRef
62. Hevia A., Delgado S., Sánchez B., Margolles A. Molecular Players Involved in the Interaction Between Beneficial Bacteria and the Immune System. Front Microbiol. 2015;6:1285.
    CrossRef
63. Vuong H.E., Yano J.M., Fung T.C., Hsiao E.Y. The Microbiome and Host Behavior. Annu Rev Neurosci. 2017;40:21-49.
    CrossRef
64. Tillisch K., Labus J., Kilpatrick L., et al. Consumption of fermented milk product with probiotic modulates brain activity. Gastroenterology. 2013;144(7):1394-1401.
    CrossRef
65. Bonaz B.L., Bernstein CN. Brain-gut interactions in inflammatory bowel disease. Gastroenterology. 2013;144(1):36-49.
    CrossRef
66. Zamora N., Elvin E. Personalized gut mucosal colonization resistance to Empiric Probiotics Is associated with Unique host and Microbiome features. Cell. 2018;174:1388-1405
    CrossRef
67. Papadimitriou K., Zoumpopoulou G., Foligné B., et al. Discovering probiotic microorganisms: in vitro, in vivo, genetic and omics approaches. Front Microbiol. 2015;6:58.
    CrossRef
68. Figueroa-González I., Quijano G., Ramírez G., Cruz-Guerrero A. Probiotics and prebiotics–perspectives and challenges. J Sci Food Agric. 2011;91(8):1341-1348.
    CrossRef
69. Kumar M., Nagpal R., Verma V., et al. Probiotic metabolites as epigenetic targets in the prevention of colon cancer. Nutr Rev. 2013;71(1):23-34.
    CrossRef
70. Hendler R., Zhang Y. Probiotics in the Treatment of Colorectal Cancer. Medicines (Basel). 2018;5(3):101.
    CrossRef
71. Gismondo M.R., Drago L., Lombardi A. Review of probiotics available to modify gastrointestinal flora. Int J Antimicrob Agents. 1999;12(4):287-292.
    CrossRef
72. Ugboko H.U., Oyewale J. Childhood diarrhoeal disease in developing countries. Heliyon.2020;e03690
    CrossRef
73. Xiong T., Maheshwari A., Neu J., El-Saie A. et al. An overview of systematic reviews of Randomised controlled trials for preventing Necrotizing Enterocolitis in preterm infants. Neonatology. 2020;117:46-56
    CrossRef
74. HP van den Akker C., B van Goudoever J., Shamir R., Domellof M., Embleton N.D.,Hojsak I. et al. Probiotic and preterm infants: A position paper by the European society for paediatric gastroenterology Hepatology and nutrition committee on nutrition and European society for paediatric gastroenterology Hepatology and Nutrition working group for probiotics and prebiotics. J Pediatr Gastroenterol Nutr. 2020;70(5):664-680
    CrossRef
75. Nanthakumar N.N., Fusunyan R.D., Sanderson I., Walker W.A. Inflammation in the developing human intestine: A possible pathophysiologic contribution to necrotizing enterocolitis. Proc Natl Acad Sci U S A. 2000;97(11):6043-6048.
    CrossRef
76. Allen S.J., Martinez E.G., Gregorio G.V., Dans L.F. Probiotics for treating acute infectious diarrhoea. Cochrane Database Syst Rev. 2010;2010(11):CD003048.
    CrossRef
77. Guo Q., Goldenberg J.Z., El Dib R. Probiotic for prevention of pediatric antibiotic associated diarrhoea. Cochrane Database syst Rev. 2019;4(4):CD004827
    CrossRef
78. McFarland L.V. Meta-analysis of probiotics for the prevention of traveler’s diarrhoea. Travel Med Infect Dis. 2007;5(2):97-105.
    CrossRef
79. Hickson M., D’Souza A.L., Muthu N., et al. Use of probiotic Lactobacillus preparation to prevent diarrhoea associated with antibiotics: randomised double blind placebo controlled trial. BMJ. 2007;335(7610):80.
    CrossRef
80. Pillai A., Nelson R. Probiotics for treatment of Clostridium difficile-associated colitis in adults. Cochrane Database Syst Rev. 2008;(1):CD004611.
    CrossRef
81. Ouwehand A.C., Salminen S., Isolauri E. Probiotics: an overview of beneficial effects. Antonie Van Leeuwenhoek. 2002;82(1-4):279-289.
    CrossRef
82. Gonzalez-Ochoa G., Flores-Mendoza L.K., Tamez-Guerra P. Modulation of rotavirus severe gastroenteritis by the combination of probiotics and prebiotics. Archives of Microbiology. 2017;199:953-961
    CrossRef
83. Ahmadi E., Alizadeh-Navaei R., Rezai M.S. Efficacy of probiotic use in acute rotavirus diarrhoea in children: A ayastematic review and meta-analysis. Caspian J Intern Med. 2015;6(4):187-195
84. Allen S.J., Martinez E.G., Gregoria G.V., Dans L.F. POrobiotics for treating acute infectious diarrhoea. Sao Paulo Medical Journal. 2011;129(3)185
    CrossRef
85. Hempel S., Newberry S.J., Maher A.R., et al. Probiotics for the prevention and treatment of antibiotic-associated diarrhoea: a systematic review and meta-analysis. JAMA. 2012;307(18):1959-1969.
    CrossRef
86. Bae J.M. Prophylactic efficacy of probiotics on traveller’s diarrhoea: an adaptive meta-analysis of randomised controlled trials. Epidemiol Health. 2018;40:e2018043
    CrossRef
87. Briand V., Buffet P., Genty S., Lacombe K. et al. Absence of efficacy of nonviable Lactbacillus acidophilus for the prevention of travelle’s diarrhea:a randomised, double blinded controlled study. Clin Infect Dis. 2006;43:1170-75
    CrossRef
88. Katelaris P.H., Salam I., Farthing M.J. Lactobacilli to prevent traveler’s diarrhoea?. N Engl J Med. 1995;333(20):1360-1361.
    CrossRef
89. Sazawal S., Hiremath G., Dhingra U., Malik P., Deb S., Black R.E. Efficacy of probiotics in prevention of acute diarrhoea: a meta-analysis of masked, randomised, placebo-controlled trials. Lancet Infect Dis. 2006;6(6):374-382.
    CrossRef
90. Marteau P., Seksik P., Jian R. Probiotics and intestinal health effects: a clinical perspective. Br J Nutr. 2002;88 Suppl 1:S51-S57.
    CrossRef
91. Khor B., Gardet A., Xavier R.J. Genetics and pathogenesis of inflammatory bowel disease. Nature. 2011;474(7351):307-317.
    CrossRef
92. Ng S.C., Hart A.L., Kamm M.A., Stagg A.J., Knight S.C. Mechanisms of action of probiotics: Recent Advances. Inflamm Bowel Dis. 2009;15(2):300-310.
    CrossRef
93. Derwa Y., Gracie D.J., Hamlin P.J., Ford A.C. Systematic review with meta analysis: the efficacy of probiotics in inflammatory bowel disease. Alimentary pharmacology and therapeutics. 2017;46:4.
    CrossRef
94. Shi L.H., Balakrishnan K., Thiagarajah K., Mohd Ismail N.I, Yin O.S. Beneficial Properties of Probiotics. Trop Life Sci Res. 2016;27(2):73-90.
    CrossRef
95. Gionchetti P., Rizzello F., Venturi A., et al. Oral bacteriotherapy as maintenance treatment in patients with chronic pouchitis: a double-blind, placebo-controlled trial. Gastroenterology. 2000;119(2):305-309.
    CrossRef
96. Butterworth A.D., Thomas A.G., Akobeng A.K. Probiotics for induction of remission in Crohn’s disease. Cochrane Database Syst Rev. 2008;2008(3):CD006634.
    CrossRef
97. Duary R.K., Rajput Y.S., Batish V.K., Grover S. Assessing the adhesion of putative indigenous probiotic lactobacilli to human colonic epithelial cells. Indian J Med Res. 2011;134(5):664-671.
    CrossRef
98. Chen Y.P., Hsiao P.J., Hong W.S., Dai T.Y., Chen M.J. Lactobacillus kefiranofaciens M1 isolated from milk kefir grains ameliorates experimental colitis in vitro and in vivo. J Dairy Sci. 2012;95(1):63-74.
    CrossRef
99. Zocco M.A., dal Verme L.Z., Cremonini F., et al. Efficacy of LactobacillusG in maintaining remission of ulcerative colitis. Aliment Pharmacol Ther. 2006;23(11):1567-1574.
    CrossRef
100. Huang C.C., Nam M.K., Tsai Y.T., Tsai C.C. Safety evaluation for multispecies probiotics in a 28-day feeding study in Sprague-Dawley rats. African J Biochem Res. 2014 Sep 30;8(7):127-36.
     CrossRef
101. Ahn Y.T., Kim G.B., Lim K.S., Baek Y.J., Kim H.U. Deconjugation of bile salts by Lactobacillus acidophilus International Dairy J. 2003;13:303-311
     CrossRef
102. Kimoto H., Ohmomo S., Okamoto T. Cholesterol removal from media by lactococci. J Dairy Sci. 2002;85(12):3182-3188.
     CrossRef
103. Park J.W., Jeong J.S., Lee S.I., Kim I.H. Effect of dietary supplementation with a probiotic (Enterococcus faecium) on production performance, excreta microflora, ammonia emission, and nutrient utilization in ISA brown laying hens. Poult Sci. 2016;95(12):2829-2835.
     CrossRef
104. Cavallini D.C., Abdalla D.S., Vendramini R.C., et al. Effects of isoflavone-supplemented soy yogurt on lipid parameters and atherosclerosis development in hypercholesterolemic rabbits: a randomized double-blind study. Lipids Health Dis. 2009;8:40.
     CrossRef
105. Jones M.L., Tomaro-Duchesneau C., Martoni C.J., Prakash S. Cholesterol lowering with bile salt hydrolase-active probiotic bacteria, mechanism of action, clinical evidence, and future direction for heart health applications. Expert Opin Biol Ther. 2013;13(5):631-642.
     CrossRef
106. Lye H.S., Rusul G., Liong M.T. Removal of cholesterol by lactobacilli via incorporation and conversion to coprostanol. J Dairy Sci. 2010;93(4):1383-1392.
     CrossRef
107. Wong J.M., de Souza R., Kendall C.W., Emam A., Jenkins D.J. Colonic health: fermentation and short chain fatty acids. J Clin Gastroenterol. 2006;40(3):235-243.
     CrossRef
108. Commane D., Hughes R., Shortt C., Rowland I. The potential mechanisms involved in the anti-carcinogenic action of probiotics. Mutat Res. 2005;591(1-2):276-289.
     CrossRef
109. Geier M.S., Butler R.N., Giffard P.M., Howarth G.S. Lactobacillus fermentum B.R11, a potential new probiotic, alleviates symptoms of colitis induced by dextran sulfate sodium (DSS) in rats. Int J Food Microbiol. 2007;114(3):267-274.
     CrossRef
110. Roller M., Pietro Femia A., Caderni G., Rechkemmer G., Watzl B. Intestinal immunity of rats with colon cancer is modulated by oligofructose-enriched inulin combined with Lactobacillus rhamnosus and Bifidobacterium lactis. Br J Nutr. 2004;92(6):931-938.
     CrossRef
111. Hirayama K., Rafter J. The role of lactic acid bacteria in colon cancer prevention: mechanistic consideration . Antonie Van Leeuwenhoek. 1999;76(1-4):391-394.
     CrossRef
112. Isolauri E., Sütas Y., Kankaanpää P., Arvilommi H., Salminen S. Probiotics: effects on immunity. The American journal of clinical nutrition. 2001 Feb 1;73(2):444s-50s.
     CrossRef
113. Erdman S.E., Poutahidis T. Probiotic ‘glow of health’: it’s more than skin deep. Benef Microbes. 2014;5(2):109-119.
     CrossRef
114. Guéniche A., Bastien P., Ovigne J.M., et al. Bifidobacterium longum lysate, a new ingredient for reactive skin. Exp Dermatol. 2010;19(8):e1-e8.
     CrossRef
115. Lew L.C., Liong M.T. Bioactives from probiotics for dermal health: functions and benefits. J Appl Microbiol. 2013;114(5):1241-1253.
     CrossRef
116. Tanida M., Shen J., Maeda K., et al. High-fat diet-induced obesity is attenuated by probiotic strain Lactobacillus paracaseiT11 (NCC2461) in rats. Obes Res Clin Pract. 2008;2(3):1-11
     CrossRef
117. Levri K.M, Ketvertis K, Deramo M, Merenstein J.H, D’Amico F. Do probiotics reduce adult lactose intolerance? A systematic review. J Fam Pract. 2005;54(7):613-620.
118. Cildir S.K., Germec D., Sandalli N., et al. Reduction of salivary mutants streptococci in orthodontic patients during daily consumption of yoghurt containing probiotic bacteria. Eur J Orthod. 2009;31(4):407-411.
     CrossRef
119. Masdea L., Kulik E.M., Hauser-Gerspach I., Ramseier A.M., Filippi A., Waltimo T. Antimicrobial activity of Streptococcus salivarius K12 on bacteria involved in oral malodour. Arch Oral Biol. 2012;57(8):1041-1047.
     CrossRef
120. Reid G., Bruce A.W., Fraser N., Heinemann C., Owen J., Henning B. Oral probiotics can resolve urogenital infections. FEMS Immunol Med Microbiol. 2001;30(1):49-52.
     CrossRef
121. Reid G., Jass J., Sebulsky M.T., McCormick J.K. Potential uses of probiotics in clinical practice. Clin Microbiol Rev. 2003;16(4):658-672.
     CrossRef
122. Grenham S., Clarke G., Cryan J.F., Dinan T.G. Brain-gut-microbe communication in health and disease. Front Physiol. 2011;2:94.
     CrossRef
123. Neufeld K.M., Kang N., Bienenstock J., Foster J.A. Reduced anxiety-like behavior and central neurochemical change in germ-free mice. Neurogastroenterol Motil. 2011;23(3):255-e119.
     CrossRef
124. Lazar V., Ditu L., Pir-calabioru G.G., Gheorghe I., Curutiu C., Holban A.M., Picu A. et al. Aspects of Gut Microbiota and Immune system Interactions in infectious diseases, Immunopathology, and Cancer. Front Immunol. 2018. https://doi.org/10.3389/ fimmu.2018.01830
     CrossRef
125. Lerner A., Shoenfeld Y., Matthias T. Probiotics: If It Does Not Help It Does Not Do Any Harm. Really?. Microorganisms. 2019;7(4):104.
     CrossRef
126. Wang Y., Jiang Y., Deng Y. et al. Probiotic Supplements: Hope or Hype?. Front Microbiol. 2020;11:160. Published 2020 Feb 28.
     CrossRef
127. Imperial I.C., Ibana J.,A. Addressing the Antibiotic Resistance Problem with Probiotics: Reducing the Risk of Its Double-Edged Sword Effect. Front Microbiol. 2016;7:1983.
     CrossRef

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