Probiotics: An Update to Past Researches

Probiotics are beneficial bacteria living in the microbiota ecosystem of the human body playing particular important roles in human health. The increasing rate of various diseases and the studies about the balance of gut microbiome made scientists trying to find novel therapies in this regard and hypothesize the relationships between the imbalance of gut microbiome and spread of various diseases especially in the immune system. Previous studies have indicated that when administrated in specific amounts, probiotics exert beneficial properties for human health such as antibacterial effects, cytotoxic effects, Hypocholesterolemic effects, immunomodulatory effects, wound healing effects etc. Probiotics also are known to produce nourishing healthy supplements for the human body such as vitamin K and B as well as healthy fatty acids. In this regard summarization of scientific evidence may help to familiarize the scientists with this novel area of research helping to find effective therapies for various disease. In this study, we used published literature in scientific databases such as Web of Science, Cochrane Library, Medline, PubMed, Science Direct, Scopus, as well as Google Scholar for data collection. So, the present review describes scientific-based evidence about probiotics and some of their beneficial effects to highlight the path for further researches about these beneficial bacteria.


Introduction
The word 'probiotic' derived from a Greek background means "for life" which is attributed to the non-pathogenic microorganisms associated with the beneficial effects for mankind and animals. If we want to introduce the term probiotics, we can say probiotics are some live strains of bacteria that when administrated in adequate amounts exert beneficial effects on the host. Prebiotics are substances that promote the growth of probiotic bacteria playing a vital role in the modulation of gut microbiome. Synbiotic is a combination of probiotics and prebiotics. 1,2 The term probiotic was first introduced by Vergin when he was studying the effects of microbial substances on the intestine microbial population and also first was used by Lilley and Stillwell to introduce some kinds of microorganisms based products, stimulating the growth of another. 3,4 At present, the most used definition for probiotics is that of Fuller: living microbial feed supplements beneficially affecting the host by contribution to intestinal microbial community balance playing a vital role in health maintenance. 5, 6 Probiotics consist mostly strains of the genera Bifidobacterium and Lactobacillus, additionally, strains of Pediococcus, Bacillus and some yeasts can be introduced as suitable candidates. These strains together play important roles in the protection of the host against pathogen microorganisms, the host's immune system strength, and the persistence of the intestinal microbial balance. 5 Recently remarkable research efforts confirm the significant importance of the microbial population of the gastrointestinal tract (GIT) revealing the great importance of probiotics. 7 Recent pieces of research have expressed some kinds of beneficial effects for probiotics including antibacterial effects, modulation of the immune system, wound healing,

Lactobacilli
First isolated from a human source, L. acidophilus a grampositive and homofermentative, microorganism with the bacteriocins belonging to class II a. This is the most widely considered organism for dietary use. L. acidophilus inhabit in a wide variety of environments from dairy products to GIT. [27][28][29] This microorganism ferments the sugar and produces lactic acid using the Embden Meyerhof-Parnas pathway. 30 The word homofermentative refers that L. acidophilus utilizes glycolysis pathway to ferment hexoses leading to the production of D and L-lactic acids while heterofermentatives follow the phosphoketolase pathway to ferment hexoses and pentoses. 31 L. acidophilus can ferment various carbohydrates such as fructose, galactose, lactose cellobiose, amygdalin, maltose, glucose, stachyose, but mellibiose, raffinose, melezitose, mannitol, and arabinose are the kinds of carbohydrates that can't be fermented by this microorganism. Some strains of L. acidophilus have the ability to ferment mannitol, fructooligosaccharides, and inulin. 32 L. acidophilus has a desirable rate of survival after even 21 days of storage in dairy products including milk and acidified milk which propose this microorganism as a favorable option for the production of dairy probiotic supplements. 33 L. acidophilus is isolated from many fermented foods such as yoghurt and can produce high amounts of lactic acid. 30 One of the important aspects about L. acidophilus is its antimicrobial resistance. Some studies have demonstrated that L. acidophilus has the genes associated with antimicrobial resistance and the ability to spread among other species and bacteria colonized in the GIT. 34 So far, many studies have indicated the desirable and promising effects of Lactobacillus for the treatment of the diseases associated with diarrhea. 35 The published data and other pieces of evidence revealed the effectiveness of Lactobacillus on health. 36 Drinking yoghurt fortified with L. acidophilus reduced the cholesterol up to 7 percent in comparison to the ordinary yoghurts. [37][38][39] It has been expressed that a combination therapy containing L. acidophilus and other probiotics reduce the diarrhea induced by radiotherapy in cancer patients. 40 The data obtained about the Lactobacillus as a probiotic is making promising evidence for beneficial properties of this bacteria, but obviously, more investigations are needed.

Bifidobacterium
Bifidobacteria are anaerobe bacteria possessing strains that most of them cannot grow at the conditions containing 90% air and 10% CO 2 . Bifidobacterium forms convex, creamy or white, smooth, glossy, neat edged, sticky and soft colonies in agar plates; these bacteria comprise the dominant population in the human gastrointestinal microbiome as well as a range of about 90% of the total population in breastfeed infants microbiome. 41 These bacteria were first isolated from infant feces and attracted attention due to significant beneficial properties in the human microbiome. So far, bifidobacteria are isolated from six different niches including the human gut and oral cavity as well as animals' intestine (bovine, rabbit, murine, chicken and insect) while other contaminations (sewage, blood, and food) may be due to the contamination by GIT. 42 Important species are isolated from the GIT are B. longum, B. infantis, B. adolescentis and from the oral cavity: B. dentium, B. breve, B. inopinatum, and B. denticolenu. 43 The studies demonstrated to date that about 31 species have been isolated form the genus Bifidobacterium with nine of them (adolescentis, angulatum, bifidum, breve, catenulatum, dentium, gallicum, longum, and pseudocatenulatum) isolated from human feces and oral cavity. 44 Some species and subspecies including animalis spp. animalis, lactis, breve, longum spp. Longum, and longum spp. Infantis are considered as probiotics. 45 Bifidobacteria are widely used in food products, for instance, infant formulas, milk, cheese, yoghurt and dietary supplements, 46 and possess a wide range of beneficial effects including hypocholesteric effects, improvement of gut microbiome especially in preterm infants, treatment of lactose intolerance, protection against infectious diseases like diarrhea, cancer prevention, modulation of mucosal barrier function and stimulation of calcium uptake by enterocytes. 44 It must be emphasized that when a strain is called probiotic, this fact is only referred to the same strain and not for other genus or the other members of the family. 45 There are various data about the significance of the effect of bifidobacteria on gastrointestinal health and some evidence on the Bifidobacterium association with various diseases. 47-50 Some strains of Bifidobacterium have shown beneficial effects in the healing of pain and bowel movement difficulties as bloating versus placebo and a Lactobacillus species. 51 The role of bifidobacteria for the production of beneficial substances including B vitamins and healthy fatty acids has been proven. 52,53 In a huge follow-up study, the Bifidobacterium consumption significantly reduced the pain and other complication associated with IBS. 54 As mentioned before, the beneficial properties of probiotics for the human being health are under investigation and need more and more researches, but obviously, there are promising reasonable pieces of evidence for pharmacologic and beneficial properties of probiotics, especially bifidobacteria and Lactobacillus probiotic strains, in promoting the human health.

Balance of the Gut Microbiome
Brown et al in their study conducted for evaluation the beneficial effects of probiotics declared the fact that probiotics can restore the natural balance of the gut microbiome. 55 As mentioned before, the imbalance in probiotics results in various pathologic conditions such as celiac disease, gastric cancer, autism, obesity, anorexia, inflammatory bowel diseases (IBD, Crohn's disease), IBD (General), and type 2 diabetes. 56 It is also clarified that gut microbiome can produce desirable substances such as vitamin B. The role of probiotics to improve digestion and promote the nerve function and angiogenesis has been proven too. 57 Effect of composition and activity of microbiome on the health status of various systems of the body including neural, cardiovascular, metabolic, and immune systems is expressed also. The altered balance of the microbiome is associated with various pathologic conditions for instance type 2 diabetes mellitus, cancer, cardiovascular diseases, malignancy, colitis, obesity, psychiatric and gut-brain axis related diseases as well as numerous immunological disorders. [58][59][60][61][62][63] Modulation and changes in the gut microbiome are involved in various health problems. in a research conducted by Liang et al, the results showed that oral administration of probiotics ameliorated the dysbiosis partly due to the modulation of the gut microbiome in addition to short-chain fatty acid and their receptor, GPR 43, in rats with non-alcoholic fatty liver leading to the inhibition of lipid deposition and chronic metabolic inflammation. 64 Chen et al showed that supplementation with L. rhamnosus (hsryfm1301) in hyperlipidemic rat model improved lipid metabolism due to regulation and modulation of rat microbiome balance. 65 So, these shreds of evidence reveal that probiotics play very important roles in the balance of gut microbiota ecosystem in humans and animals.

Diarrhea
Sazawal et al performed a study and expressed that probiotics reduced the risk of acute diarrhea of diverse causes by 34% as well as administration of probiotics caused the reduced risk of acute diarrhea among adults by 26% and among children by 57%. 35 Phavichitr et al also exhibited that the consumption of probiotics was associated with reduced duration of diarrhea by an average of one day. 66 The effects of probiotics on diarrhea after three days were assessed too, and 55% of people who received probiotics improved after 3 days. 67 In a metaanalysis performed by McFarland, several probiotics including a mixture of B. bifidum and L. acidophilus in addition to Saccharomyces boulardii had significant efficacy for prevention of traveler's diarrhea. 68 The role of probiotics for amelioration and treatment of acute pediatric diarrhea has been proven too. 69 S. boulardii, a probiotic that is routinely used, was shown to exhibit convincing efficacy in the treatment of various chronic and acute gastrointestinal disorders including Clostridium difficile (CD) infection, acute or persistent diarrhea as well as human immunodeficiency virus (HIV) related diarrhea enteral nutrition-related diarrhea and Traveler's diarrhea.  Mego et al designed a study in which between January 2011 and December 2013, patients suffering from colorectal cancer were randomized to receive placebo or probiotics. The results revealed that consumption of probiotics in the patients suffering from colorectal cancer and experiencing gastrointestinal toxicity due to irinotecan-based chemotherapy was safe and could reduce the symptoms of chemotherapy. 105 Lactobacillus strains are safe to be used as a cure in infectious diarrhea in children, but as said before more investigations are needed to prove the claim. 106 Huang et al performed a meta-analysis research to evaluate the efficacy of probiotics for treatment of diarrhea, and the results showed that probiotics reduced the diarrhea duration by about one day in children. 107 A study showed the promising effects of probiotics for the treatment of diarrhea in children and infants, declaring L. rhamnosus GG as the most strain of probiotics with the confirmed effects in diarrhea. 108,109 However, there were no demonstrable effects followed by administration of some strains of probiotics such as L. casei subspecies rhamnosus (LGG) and L. paracasei strain ST11 (ST11) in the treatment of children suffering from severe diarrhea. 110,111 Although the second study confirmed the effect of L. paracasei ST11 (ST11) for the treatment of nonrotavirus-induced diarrhea. 111 Despite the promising properties of probiotics in various diseases, the data about the diarrhea induced by nosocomial infections are contradicting, for example, Szajewska et al performed a study in which 89 children aged 1 to 36 months were enrolled in a double-blind trial receiving either L. rhamnosus GG or placebo orally twice a day. The data suggested beneficial effects of probiotics especially L. rhamnosus GG in the treatment of nosocomial infections in infants, particularly nosocomial rotavirus gastroenteritis. 112 Moreover, a double-blinded randomized study containing 220 children evaluating the same strain of probiotics failed to show promising effects against nosocomial rotaviral infection while breastfeeding was effective. 113 A randomized trial study including 55 infants showed a lower prevalence of nosocomial diarrhea in the infants consuming probiotic-containing formula. 114 In study enrolling malnourished children in Peru, the number of episodes of diarrhea was reduced after using probiotics. 115 Meanwhile, another study in Finland failed to show significant differences among the experimental groups. 116 Children fed with a formula containing L. reuteri and B. lactis showed lesser and shorter episodes of diarrhea. 117 Growth inhibitory effects of probiotics in the treatment and prevention of vibrio cholera induced acute diarrhea has been proved too, suggesting probiotics as new sources to develop new pharmaceutical preparations for public health promotion. 118 A study performed by Saavedra et al. on infants aged 5-24 months showed that an infant formula containing probiotics could reduce the incidence of acute diarrhea in infants. 119 Previous studies showed that infant formulas containing either B. lactis or a combination of B. breve and S. thermophilus showed protective effects against acute diarrhea in children. 120,121 Other published studies also showed that L. reuteri had significant effects in the reduction of the episodes of diarrhea and respiratory tract infections. 23,122,123 Another impact of probiotics is in the improvement of the complications due to gastroenteritis especially when combined with rehydration. 124 In another study performed by Salazar-Lindo et al for evaluation of the effects of probiotics for the treatment of watery diarrhea, they failed to show any kind of beneficial effects in this regard. 125

Prevention of Antibiotic Associated Diarrhea
Diarrhea is one of the most important side effects of antibiotics as a result of an imbalance in good and bad microbiome populations. 126 Consumption of antibiotics is said that can be associated with overgrowth of pathogens in some cases of CD, leading to life-threatening antibiotic associated diarrhea (AAD). 127 This fact also has been proven in other studies too. [128][129][130] Hempel et al in a meta-analysis revealed that consumption of probiotics is associated with the reduction of AAD. 129 Many of studies conducted to evaluate the impacts of probiotics on antibiotics associated diarrhea are performed on small sample sizes and possess methodological biases. Studies based on the meta-analysis approaches declared reduction of AAD by about 60%. 131 effective probiotics in this condition are S. boulardii in adults and L. rhamnosus GG in children. 132 Another meta-analysis for evaluating the effectiveness of S. boulardii for prevention of AAD in different ages showed the moderate efficacy of this probiotic in the prevention of antibiotic-associated diarrhea. 133 Another meta-analysis conducted by McFarland et al showed that a combination of various probiotics showed their desirable effects in treating AAD and CD. Additionally, three types of probiotics (probiotic mixtures, L. rhamnosus GG, and S. boulardii) significantly reduced antibiotic-associated diarrhea. 100 Another meta-analysis based study indicated that probiotics reduced the risk of AAD by 52%. 35 Johnston et al showed that Children treated with probiotics showed a lower risk of AAD. 134 Goldenberg et al in another metaanalysis revealed a protective effect induced by probiotics against AAD with no mentionable side effects. 135 In a study performed on the hospitalized children under antibiotics treatments, diarrhea was less likely to develop in the probiotic consuming group in comparison with oral rehydration and the risk of AAD, CD associated diarrhea as well as mean duration of diarrhea reduced too. It is noteworthy that a higher recovery rate was observed in children receiving probiotics. 124,136 Pattani et al stated that probiotics reduce the risk of CD infection and AAD. 137,138 Another systematic review and meta-analysis showed that the people who used probiotics significantly were in lower risk of CD. 128 Moderate quality shreds of evidence exhibit that probiotics significantly reduce the CDD without any kinds of important side effects. Pediatric AAD is also prevented using probiotics, the data also exhibit an insignificant rate of side effect. 139 Previous studies have indicated that S. boulardii and lactobacilli are the most used strains of probiotics for the treatment of AAD as well as L. rhamnosus GG and Bacillus coagulans. 132,140 Cai et al tried to find the effects of probiotics for the management of AAD. The result of this study expressed L. rhamnosus GG as the best option in the treatment of AAD. 141 Patients treated with probiotics for 3 days showed a significantly (P = 0.009) lower frequency of AAD while cephalosporins, clindamycin or broad-spectrum penicillin were associated with the increased risk of pathologic conditions such as AAD. 142 Another meta-analysis conducted by Szajewska et al shows that probiotics are effective in the prevention of AAD in participants of different ages under treatment of antibiotics. 143 Probiotics are effective in the prevention of AAD in different ages and may be used during antibiotic therapy as well as 14 days after the antibiotic therapy discontinuance. 144,145 L. reuteri consumption reduces the duration of diarrhea while increases the chance of treatment in this disease. This probiotic strain potentially reduces the risk of acquired diarrhea in children as well as the frequency and intensity of antibiotics induced side effects during treatment for H. pylori. 146,147 This is mentionable that yogurt containing L. acidophilus, L. rhamnosus GG and B. lactis, was effective for reducing the incidence of antibiotic-associated gastrointestinal disturbance in children. 148 Despite all beneficial effects of probiotics, L. plantarum DSM 9843 compared to placebo was not effective in the incidence of diarrhea and abdominal symptoms. 149 Another study to confirm the beneficial effects of drinking probiotics failed to confirm a beneficial effect on the prevention of AAD. 150 Ruszczyński et al showed that consumption of L. rhamnosus by children receiving antibiotics based treatments reduced the risk of any diarrhea. 151 A systematic review stated that the administration of probiotics closer to the first dose of antibiotic reduced the risk of CD infection by about more than 50% in patients. 152 In another report, the risk of AAD reduced due to the administration of probiotics. 153 Probiotics especially specific strains for example: L. rhamnosus GG had beneficial effects in preventing AAD, but more investigations are still needed in this area. 154,155 Cancer A research by Ostad et al revealed some anticancer effects of probiotics in different cancer cell lines such as HT-29, Caco-2 and T47D in a dose-dependent manner. 11 Rafter et al. performed a randomized trial aimed on the evaluation of the effects of a synbiotic for on cancer risk biomarkers in 80 patients who received either placebo or synbiotic. The results showed that synbiotic intervention could modulate cancer biomarkers in these patients. 156 Thirabunyanon et al isolated various strains of probiotics from fermented dairy milks; two of which including Enterococcus faecium and L. fermentum exhibited antiproliferation effects against colon cancer cells. 157 In another study, heat killed L. acidophilus 606 and L. casei ATCC 393 also showed antiproliferative effects in various cell lines, and soluble polysaccharide constituents isolated from L. acidophilus 606 showed potent antioxidant properties. 158 Moreno et al in their study tried to explore anticancer effects of probiotics and stated that L. helveticus R389 could delay breast cancer tumor growth through inducing decrement of IL-6 as well as increment of IL-10. 159 Another study trying to find more reliable shreds of evidence about the role of probiotics in cancer found that mice pre-inoculation with L. acidophilus significantly reduced tumor growth by 50.3%. Moreover, administration of L. acidophilus NCFM significantly downregulated the CXCR4 mRNA expressions in the extra-intestinal tissue, mesenteric lymph nodes and colon, highlighting the role of this strain of probiotics in triggering the molecular and cellular mechanisms involved in cancer pathogenesis. 160 Another study stated that through the intervention in inflammatory processes, the probiotic VSL#3 can prevent dysplasia and cancer. 161 Also, it has been noted that the administration of E. faecium CRL 183 was associated with a 50% reduction in the average number of tumors when compared to other groups in 4-week old male Wistar rats as animal models of cancer. 162 Bacillus polyfermenticus a probiotic bacterium inhibited tumor growth partly due to the inhibition of the ErbB receptors. This study showed that ErbB2 and ErbB3, as receptors that are involved in the cancer pathogenesis, are suppressed by this probiotic. 163 Nami et al evaluated the effects of L. acidophilus 36YL on four cancer cell lines (HeLa, AGS, HT-29, and MCF-7) and a normal cell line that was HUVEC cell line. The results revealed apoptotic effects of this probiotic on cancer cell lines and negligible toxicity against normal cells. 164 A bunch of studies also show the probiotics effectiveness in various extraintestinal and gastrointestinal cancers especially colon and colorectal cancers, but there is a great need for more clinical trial-based shreds of evidence highlighting a direct effect for probiotics in the treatment of cancer.  Antibacterial Effects Traditional yoghurts containing some strains of lactobacillus showed antimicrobial effects against Escherichia coli and Salmonella typhi. The most antimicrobial effects were observed by L. casei. 9 Some other studies showed the antibacterial and antioxidant effects of probiotics too. 191 A study on kefir, another probiotic product, showed desirable anti-pseudomonal effects as well as a significant improvement of wound healing. 10

Irritable Bowel Syndrome
Another kind of abnormalities whose response to probiotics is tested is IBS. Various data suggests the beneficial effects of probiotics, but data is hard to compare partly due to differences in the dose of probiotics, duration of therapy, and the study design. A double-blinded randomized clinical trial showed that probiotics are not likely to heal IBS but the symptoms were reduced. 192 Francavilla et al performed a randomized double-blind trial in which children received either L. rhamnosus GG or placebo for the duration of 8 weeks and the results showed that this probiotic was significantly effective to reduce the severity in addition to the frequency of abdominal pain in children with IBS. 193 Horvath et al. in a study to evaluate the effects of L. rhamnosus GG for treating abdominal painful disorders in children observed that supplementation with this probiotic strain leads to a significantly increase in the rate of treatment responders when Compared with placebo. Moreover a randomized cross-over trial among 59 patients conducted for the duration of six weeks to compare VSL#3 and placebo showed a significant effect for VSL#3 in symptom relief and abdominal pain/ discomfort as well as abdominal bloating/gassiness. 194 There is no data on prevention of IBS by prebiotics, but consumption of a prebiotic-containing whey-based formula in a controlled trial including 224 infants showed lesser gastrointestinal discomforts. 195 Korterink et al in a meta-analysis based study showed that probiotics reduce abdominal pain in related disorders, especially in patients with IBS. 196

Helicobacter pylori
The use of probiotics in the treatment of HP is a controversial topic, but the beneficial characteristics of probiotics for the treatment of HP have been exhibited in various animal models. Bifidobacterium and Lactobacillus are specific bacteria with desirable effects in the treatment of HP in vitro through the production of bacteriocins or organic acids in addition to the inhibition of its adhesion to epithelial cells and reducing the load of HP. 197,198 It is noteworthy that Some studies exhibit higher eradication rate of HP due to consumption of probiotics in association with antibiotics and proton pump inhibitors that are normal drugs for treating HP. 199 Using in association with the normal therapy of HP, probiotics can reduce the side effects of antibiotic treatments especially diarrhea in children. [200][201][202][203] A study conducted to evaluate the effects of probiotics in the treatment of HP showed the desirable effects that may be partly due to the eradication of the risk of disorders associated with gastric inflammation. 204 In concordance with the above studies, Losurdo stated that probiotics in the treatment of HP showed a direct effect in its clearance and eradication. 205 This is noteworthy that in HP infection, combined therapy with probiotics can protect and restore the microbiome of the intestine. 206 So probiotics both alone and in combination with antibiotics and other HP treatments may alleviate the infection's symptoms as well as reduce drug side effects. 207

Constipation
Constipation is a disorder in GIT associated with infrequent stools, difficult stool passage as well as pain and stiffness. 208 Children 3-16 years of age experiencing constipation were randomized in a pilot study and consumed one sachet containing 10 8 -10 10 CFU B. breve daily. The data of this study showed the positive effect of this strain of probiotic. 209 Another study conducted by Zhao et al to evaluate the effect of probiotics on constipation showed the positive effects of a mixture containing, B. longum, B. bifidum, B. infantis, L. plantarum, L. casei, and L. rhamnosus on the constipation. 210 Administration of L. rhamnosus (Lcr35) to children with chronic constipation showed desirable effects of this probiotic. 211 There are pieces of evidence for some strains stating failure of showing efficacy in the treatment of constipation, for example, L. rhamnosus failed to show desirable effects. 212,213 Due to the consumption of L. reuteri, bowel frequency improved in infants with functional constipation. 214 Improvement of defecation frequency and abdominal pain was accomplished due to the consumption of yogurt supplemented with B. longum. 215 A dairy product containing B. animalis increased stool frequency in children experiencing constipation. 216 Santhosh Jose evaluated the effects of probiotics consumption on the treatment of constipation and exhibited the desirable effects of probiotics in this condition. 217 In another study reported by Choi et al, significant reduction of Bifidobacterium and Bacteroides species in the feces of the patients suffering from functional constipation was observed. 218 Dimidi et al exhibited that probiotics, particularly B. lactis, improved stool consistency, stool frequency and whole gut transit time. 219 It is well understood that altered microbiome precisely contributes to the pathogenesis of constipation, but the specific mechanism of probiotics in the constipation is still unclear, and this effect may be partly due to their impact on the fermentation and gut microbiome, as well as effects on the central and enteric nervous systems and the immune system. 220

Atopic Dermatitis and Dermal Health
There is a bunch of studies indicating the beneficial role of probiotics in various conditions of the skin such as atopic eczema, wound, and scar healing as well as a help to skin-rejuvenation. 8 Consumption of probiotics containing L. acidophilus, L. casei, L. salivarius, and B. bifidum was effective to reduce Scoring Atopic Dermatitis (SCORAD) index as well as total serum immunoglobulin E (IgE) and cytokines such as interleukin (IL)-5, IL-6, and interferon (IFN)-γ in pediatric patients. 221 Weise et al showed that E. coli Nissle 1917 modulated immune responses through the increment of Foxp3 (+) cells and immunoregulatory cytokine patterns. 222 In a study by Kukkonen et al, pregnant women carrying infants with a high risk of allergy received a mixture of 4 species of probiotics or placebo for about 4 weeks before delivery and their children received the same probiotics or a placebo daily for 6 months after birth. The data showed that feeding probiotics to newborn infants increased the resistance to respiratory infections during the first 2 years of life as well as a significant reduction in (atopic) eczema. 223 Another study expressed that a great reduction was observed in clinical eczema among children whose mother received probiotic. 224 A meta-analysis based study conducted by Doege et al revealed the fact that administration of probiotics during pregnancy prevented atopic eczema in children with the ages ranging from 2 to 7 years. 225 It has been declared that when applied on the skin, B. longum lysate had beneficial effects on the symptoms of sensitive and reactive skin. 226 Lew and Liong in their study reported that some bioactive compounds from probiotics such as hyaluronic acid, sphingomyelinase, peptidoglycans and lipoteichoic acid exert beneficial dermal effects, but the exact mechanism remains unclear. 227 Lactobacillus fermentum is another strain with beneficial effects in children experiencing moderate or severe atopic dermatitis. 228 Probiotics, particularly L. rhamnosus GG is effective either for the prevention of atopic dermatitis or healing of the related symptoms. 229 However, there are various studies in which there was no convincing data about the efficacy of some strains of probiotics in the treatment of atopic dermatitis. 230 A meta-analysis conducted by Pelucchi et al exhibited the role of probiotics for some kinds of dermal conditions such as atopic dermatitis. 231 Consumption of B. lactis and L. rhamnosus relieved the symptoms of atopic dermatitis only in food sensitized children. 232 Yeşilova et al reported that probiotics are effective in reducing an indicator of atopic dermatitis that is SCORAD index in the patients as well as serum IFN-γ, IL-6, and IL-5 as well as total serum IgE levels. 233 Another meta-analysis also consisted of about ten studies showed the moderate role of probiotics in the treatment of atopic dermatitis. 234 Based on the data such as reduction of the clinical symptoms as well as local and systemic inflammation, probiotics can be used to alleviate allergic inflammations such as atopic dermatitis. 235 Probiotics are announced as a new strategy in the treatment of atopic dermatitis, their beneficial effects may be partly due to the balance of the gut microbiome, improvement of immunological defense barrier (IgA) in the intestine, modulation of inflammatory responses in addition to the production of inflammatory cytokines. 236 L. gasseri is another strain of probiotics assumed to reduce the immune responses induced by inflammatory cytokines for instance IL-17 that is another kind of evidence confirming the desirable effects of probiotics in atopic dermatitis. 237 Meneghin et al studied the effect of probiotics in the atopic dermatitis of children, and the data suggested about the effectiveness of probiotics; moreover, most of the studies about this matter were conducted on a single strain of probiotics other than a mixture, but the effectiveness of the mixture was more. 238 Foolad et al declared the usefulness of probiotics in the treatment of atopic dermatitis. Probiotics induced a long term reduction in the symptoms of atopic dermatitis, and the severity of the symptoms was reduced. 239 In a study in which 88 children were enrolled to evaluate the effectiveness of a single strain of probiotics called L. sakei, the results confirmed a significant reduction of symptoms and severity of dermatitis in the intervention group. 240 L. plantarum CJLP133 is another strain of probiotics with promising effects in the treatment of atopic dermatitis in children. 241 In a study a combination of Lactobacillus strains including L. reuteri and L. rhamnosus were given to atopic dermatitis experiencing children. the results at the end of the intervention, showed that about 56% of the patients declared the improvement of eczema symptoms. 242 Niccoli et al also reported the effectiveness of L. salivarius LS01 in children with atopic dermatitis. 243 A meta-analysis on the data published during February 1997 and May 2007 provided more convincing evidence about the effectiveness of probiotics in the treatment of some kinds of dermal disorders such as atopic dermatitis. 244 Consumption of probiotics has shown promising effects in adults too. For instance, in a study conducted on 38 patients suffering from atopic dermatitis, the results showed that L. salivarius LS01 significantly improved the clinical manifestation and quality of life that may be partly due to the modulation of Th1/Th2 cytokine profiles. 245 A combination of B. lactis, L. acidophilus and fructooligosaccharides administrated to preschool children experiencing atopic dermatitis showed significant improvement of clinical symptoms in the intervention groups. 246 Improvement and stabilization of intestinal mucosal barrier is associated with the pathogenesis of atopic dermatitis, and probiotics may stabilize this barrier in the intestine. 247 Gøbel et al expressed that the consumption of probiotics decreased the levels of IFN-γ and IL-10 leading to the beneficial effects of probiotics in young children experiencing atopic dermatitis. 248 A metaanalysis suggests that probiotics may be an option for the treatment of atopic dermatitis including moderate to severe atopic dermatitis in the children and adults. 249 Another meta-analysis also exhibits that probiotics have a protective role in the pre and postnatal period in all risky population. 250 Iemoli et al conducted another study in which a combination of L. salivarius LS01 and B. breve BR03 exhibited beneficial effects in the treatment of atopic dermatitis in adults. 251 Likewise, 53 children enrolled in an eight week supplementation period during which a probiotic (L. fermentum) (n=26) or a placebo (n=27) was administrated, and improvement in atopic dermatitis severity with probiotic treatment was observed. 228 Grüber et al declared that there are not enough shreds of evidence on the beneficial effects of probiotics in the treatment of atopic dermatitis in children. 252 Atopic eczema/dermatitis syndrome was alleviated after the administration of L. rhamnosus GG for 4 weeks; the observed data also exhibited the beneficial effects of this probiotic in IgE-sensitized infants but not in non-IgEsensitized infants (Figure 1). 253

Conclusion
This review aimed to briefly introduce probiotics as well as some of their beneficial effects including antibacterial effects, balance of the gut microbiome, prevention of AAD, and treatment of some pathologic conditions such as diarrhea, cancer, IBS, HP infection, constipation and atopic dermatitis. In our review, the most known health properties of probiotics are found to be the prevention of diarrhea due to the balance of the gut microbiome. Despite these beneficial effects, some strains of probiotics failed to show efficacy in various pathologic conditions that highlight this fact that the beneficial effects exerted by probiotics are limited to precise strains of theses bacterial communities. Regarding the vast developments in this area of research, there is more and more requirements for investigations on this interesting area of research to find biological products with more efficacy and less side effects.

Conflict of interests
The authors declare no conflict of interests.

Ethical Approval
This review was based on the previously published articles and no ethical approval is provided.
Authors' contribution AAG designed the study and scientifically revised the manuscript. RS drafted and wrote the manuscript and performed the searching of databases. APM drafted the manuscript and performed the searching of databases. MRF scientifically revised the manuscript.