Head, Department of Obstetrics and Gynecology, GNS Multispeciality Hospital, Chattarpur, New Delhi, India

^*Corresponding author: Tania SG, Head, Department of Obstetrics and Gynecology, GNS Multispeciality Hospital, Chattarpur, New Delhi, India; Tel: 9625930047; Email: taniasingh.ts@gmail.com

Article Information: Submission: 22/04/2021; Accepted: 28/05/2021; Published 31/05/2021

Copyright: © 2021 Tania SG. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Probiotics are live microorganisms (in most cases bacteria) that are similar to beneficial microorganisms found naturally in the human gut. They are available mainly in the form of dietary supplements and foods, and when administered in adequate amounts confer a health benefit on the host. They are a safe and effective way of enhancing the diversity and health of the microbiome in pregnant women. Probiotics given prenatally are an important way for mothers to safeguard their health during pregnancy as well as the health of their babies.

Colonization of the neonatal gut by beneficial bacteria is important in protecting the neonate from enteric pathogens and local as well as systemic inflammation. Maternal microbiome in pregnancy together with infant diet impacts neonatal microbiome.

Microbiota; Dysbiosis; Synbiotics; Bifidobacterium; FODMAP; Lactobacillus; Prebiotics; Pregnancy; Urogenital infections; Infant colic

Gut microbiota is a heterogeneous microbial community that includes 10¹⁴ [1,2] microorganisms comprising predominantly bacteria, along with viruses, archaeans, and protozoa. The gastrointestinal microbiota can be considered as an organ within an organ contributing to host nutrition, developmental regulation of intestinal angiogenesis, protection from pathogens and development of the immune response [3]. Three dominant phyla comprise almost 80% of gut flora [4]: Bacteroidetes, Firmicutes, and Actinobacteria [5].

The neonatal microbiota is highly different compared to the adult one, since the former is characterized by rapid changes especially in the first year of life [6]. Colonization of the neonatal gut by beneficial bacteria is important in protecting the neonate from enteric pathogens and local as well as systemic inflammation. Maternal microbiome in pregnancy together with infant diet impacts neonatal microbiome. Dysbiosis in pregnancy increases the risk of preeclampsia, diabetes, infection, preterm labour, and later childhood atopy. It can also lead to postnatal maternal depression and infant colic. It also plays an important role in necrotizing enterocolitis and sepsis, both of which can occur as a result of prematurity affecting the long term outcomes in neonates. Administration of enteral prebiotics, probiotics, and synbiotics during pregnancy, lactation, and postnatal life appears to be a safe and feasible method to alter the maternal and neonatal microbiome, thus improving pregnancy and neonatal outcomes [7].

Synbiotics refers to a product which has an appropriate combination of both probiotic and prebiotic components. Synbiotics ensures that it has a superior effect when compared to the activity of probiotic or prebiotic alone. It was developed in order to overcome some possible difficulties in the survival of probiotics in the gastrointestinal tract.

Prebiotics generally refers to a substrate (non-digestible food ingredient) which, when added to the dietary intake, is selectively used by host microorganisms conferring a health benefit [8] by selectively stimulating the growth and/or activity of one or a limited number of bacteria in the colon, especially Bifidobacterium species [9]. Prebiotics evade digestion in the small intestine and must be selectively fermented in the colon.

Prebiotics are typically comprised of nondigestible carbohydrates but can also include non-carbohydrates such as fatty acids, phenolics, and phytochemicals [8].

The most widely accepted prebiotics are together referred to as FODMAPs (Fermentable Oligosaccharides Disaccharides Monosaccharides and Polyols). The types of FODMAPs which hold prebiotic effects are mainly fructans, galacto-oligosaccharides (GOS), and inulin. Foods high in fructans include wheat products, rye products, onion and garlic. Foods high in GOS include legumes, such as chickpeas and baked beans. Inulin is found in some yoghurts (even some lactose-free), asparagus, garlic/onion, and some confectionary. The reason fructans and GOS are able to act like prebiotics is because our gut doesn’t have enzymes to break them down, so they remain undigested like prebiotics [10,11].The down side to a low FODMAP diet is that it often limits the intake of prebiotics (Table 1).

Prebiotic carbohydrates are a major substrate for bacterial growth, selectively stimulating the growth and/or activity of beneficial members of the gut microbiota, particularly bifidobacteria [12,13].

Short-chain prebiotics are mainly fermented in the cecum and colon ascendens. Long chain oligosaccharides are fermented along the entire colon [14].Thus, prebiotics could, at least in theory, have more global effects on colonization than adding a single probiotic strain. A second, more direct immune effect appears to be mediated by the fermentation products of prebiotics. Gut microorganisms ferment prebiotics to produce short-chain fatty acids (SCFAs) that have direct anti-inflammatory effects [15]. SCFAs also promote intestinal integrity through effects on epithelial cell proliferation and differentiation [16]. Animal and human studies suggest that prebiotics may directly affect both mucosal and systemic immunity [17-19]. However, more studies are needed to confirm that these are clinically relevant effects.

The gastrointestinal microbiota of breastfed babies differ from classic standard formula fed infants. While mother’s milk is rich in prebiotic oligosaccharides and contains small amounts of probiotics, standard infant formula doesn’t [14]. Different prebiotic oligosaccharides are added to infant formula: galactooligosaccharides, fructo-oligosaccharide, polydextrose, and mixtures of these which brings infant formula one step closer to breastmilk.

Prebiotics are present as supplements also, and they’re sometimes added to probiotic supplements or yoghurts.

The United Nations Food and Agriculture Organization (FAO) and World Health Organization (WHO) have defined probiotics as “live micro-organisms, which when administered in adequate amounts confer a health benefit on the host” with a wide and varying range of clinical and immunologic capacities [20].The term probiotic means “for life” and it is currently used to name bacteria associated with beneficial effects for humans and animals [21].

The concept of probiotics was introduced in the early 20^thcentury by Elie Metschnikoff, the Russian born Nobel Prize winner working at the Pasteur Institute, who suggested that “The dependence of the intestinal microbes on food makes it possible to adopt measures to modify the flora in our bodies and to replace the harmful microbes by useful microbes” [22]. At the same time, Henry Tissier, a French paediatrician, observed that children with diarrhea had in their stools a low number of bacteria characterized by a peculiar, Yshaped morphology. These “bifid” bacteria were, on the contrary, abundant in healthy children [23]. He suggested that these bacteria could be administered to patients with diarrhea to help restore a healthy gut flora.

Probiotics, however, have gained momentum in recent past after almost a century, with considerable growth in functional food market.

The concept of probiotic food came from the fact that bacteria are normal inhabitants of humans (as well as the bodies of upper animals and insects) including the gastrointestinal tract, where more than 400 bacterial species are found [24]: half of the wet weight of colonic material is due to bacterial cells whose numbers exceed by 10-fold the number of tissue cells forming the human body. Normally the stomach contains few bacteria (10³colony forming units per mL of gastric juice) whereas the bacterial concentration increases throughout the gut resulting in a final concentration in the colon of 1012 bacteria/g. Bacterial colonization of the gut begins at birth, as newborns are maintained in a sterile status until the delivery begins, and continues throughout life, with notable age-specific changes [25]. Bacteria, forming the so-called resident intestinal microflora, do not normally have any acute adverse effects and some of them have been shown to be necessary for maintaining the wellbeing of their host.

The term probiotic was introduced in 1953 by the German bacteriologist Werner Kollath to mean “active substances essential for a healthy life” [26]. In the last 30 years or so, however, research in the probiotic area has progressed considerably and significant advances have been made in the selection and characterization of specific probiotic cultures and substantiation of health claims relating to their consumption. For use in foods, the probiotic microorganisms should not only be capable of surviving passage through the digestive tract but also have the capability to proliferate in the gut. This means they must be resistant to gastric juices and be able to grow in the presence of bile under conditions in the intestines, or be consumed in a food vehicle that allows them to survive passage through the stomach and exposure to bile. The most commonly used probiotics are lactobacilli and bifido bacteria strains [27-28], but not exclusively, as other micro-organisms have also been used as probiotics, including the yeast Saccharomyces boulardii.

Probiotic microorganisms are generally LAB belonging to the species Lactobacillus acidophilus, L. gasseri, L. helveticus, L. johnsonii, L. (para)casei, L. reuteri, L. plantarum, L. rhamnosus, and L. fermentum, while members of the genus Bifidobacterium are also used, e.g., Bifidobacterium bifidum, B. longum, B. animalis, and B. breve [29-31]. On the basis of the currently available literature, probiotics can balance intestinal microbiota, and thereby regulate proper intestinal function and be effective in the prevention or treatment of several gastrointestinal disorders such as infectious diarrhea, antibiotic-related diarrhea, irritable bowel syndrome or Crohn’s disease [32]. Other examples of health benefits promoted by probiotics supplied via dairy products are immunomodulatory effects (L. casei CRL431), reduction of serum cholesterol level (L. reuteri NCIMB 30242) and antihypertensive effects (L. plantarum TENSIATM) [33-35]. Of late, probiotics seems to be quite helpful in the management of rheumatoid arthritis.

Some foods naturally contain probiotics, while others have probiotics added during preparation. Foods containing probiotics include:
Live yoghurt
Live yoghurt drinks
Fermented and unfermented milk
Miso and tempeh, which are made from fermented soya beans
Some juices and soya drinks
Probiotics are available as supplements also.

Bifidobacteria are the most important constituent of the dominant active flora [36]. Lactobacilli are part of the sub-dominant flora and are under control by the dominant flora. Dietary and environmental changes constitute the transient flora, which is exogenous and does not colonize the GI tract.

Since probiotics normally exist in our digestive system, their intake is generally considered safe. But effectiveness in treating specific symptoms or conditions is strain specific. Before starting a regimen of probiotics, it is wise to look for the right strain in that particular health condition.

Constipation is one of the most common conditions that can cause discomfort in pregnancy. Hormones of pregnancy often result in relaxation of smooth muscle in the gastrointestinal (GI) tract, therefore, dietary manipulation that includes increasing fibre and fluids can help reduce constipation [37]. Over years, several studies have found that yogurt can treat constipation, of these few studies have been done in pregnant population. In one such randomized controlled trial of 60 women, researchers found that 300 g of probiotic-enriched yogurt (Bifidobacterium and Lactobacillus 4.8 × 10¹⁰ [CFU]) per day alleviated constipation better than conventional yogurt among pregnant women [38].

Few researchers have recommended including probiotic foods such as fermented dairy products like yogurt and kefir every day over probiotic supplements. They also mention the need for prebiotics in the form of fibre, recommending at least 30 g of fibre each day from whole foods such as whole grains, fruits and vegetables (including legumes), and nuts and seeds in the diet during pregnancy.

The proposed mechanisms by which probiotics can help in constipation are:

First, probiotics modify the gastrointestinal microbiota, which is known to be altered in constipation [39-40].

Second, probiotic metabolites may alter gut function, including sensation [41-42] and motility [43-44].

Third, some probiotics increase the production of lactate and short-chain fatty acids, reducing luminal pH, which some researchers have proposed will enhance colonic peristalsis and shorten whole gut transit time (GTT) [45-46].

A meta-analysis by Dimidi et al [47] indicated that overall probiotics positively affected and significantly improved the cardinal symptoms of constipation such as bloating, sensation of incomplete evacuation, occurrence of hard stools, ease of stool expulsion. There was a decrease in GTT by half a day. This latter finding was consistent with a meta-analysis by Miller et al [48] who had earlier shown that gut transit time is significantly decreased with probiotics.

B.lactis plays a significant role in increasing the stool frequency and improving stool consistency [49]. Normal stool frequency ranges from 3 to 21 bowel movements per week [50-51] and an increase of 1.3 bowel movements per week through probiotic consumption could normalize bowel frequency in adults with functional constipation.

Probiotics can potentially provide an important means to reduce the problems associated with acute diarrhea, which is a major health problem globally, especially among children. The strongest evidence of a beneficial effect of defined strains of probiotics had been established using Lactobacillus rhamnosus GG and Bifidobacterium lactis BB- 12 for prevention [52-53] and treatment [54-58] of acute diarrhea mainly caused by rotaviruses in children. A systematic review that included 12 randomized, controlled trials in the Cochrane database (the majority from affluent countries) concluded that probiotics reduced the mean duration of acute diarrhea in children by 29.2 hours in a fixed-effects model and by 30.48 hours in a random-effects model [59]. Two meta-analyses that evaluated similar studies found statistically significant but modest reductions of diarrhea duration [60]. Two RCTs evaluated probiotics for children with persistent diarrhea and reported dramatic reductions in diarrhea duration—4.8 and 3.9 days in Argentina [61] and India [62] respectively. Two trials evaluated probiotics for diarrhea prevention; children in Peru had 13% fewer diarrheal episodes after 15 months of Lactobacillus rhamnosus [63], whereas diarrhea frequency was reduced by 14% among children in India who received daily doses of Lactobacillus casei for 12 weeks, with a 12-week follow-up period [64].

In the prevention of antibiotic-associated diarrhea (AAD), meta-analyses of published results of RCTs provide evidence for efficacy of a number of probiotic strains, such as S. boulardii [65-69]. Approximately one in seven cases of AAD was prevented by the use of a probiotic [65]. According to another review, administration of lactobacilli reduces AAD in adults, but not in children [66].

Diarrhea occurs in up to 34% of pregnant women, and its’ causes in pregnancy mirror those of the non pregnant state, with the most common being infectious agents (e.g, Salmonella, Shigella, and Campylobacter species; Escherichia coli; protozoans; viruses). Food poisoning, medications, and irritable bowel syndrome are other common causes. Exacerbations of inflammatory bowel disease can also occur in pregnancy. Gastroenteritis symptoms, when severe, can cause dehydration and even preterm labour in cases that go untreated. Therefore, addition of probiotics would definitely make a difference.

Another development for probiotic applications is activity against Helicobacterpylori (H. pylori), a Gram negative pathogen responsible for type B gastritis, peptic ulcers and gastric cancer. Epidemiological studies show a close association between the prevalence of H. pylori and dyspeptic symptoms. Data from various studies suggests that most of the Lactobacillus and Bifidobacterium strains possess properties of acid tolerance and antimicrobial activity [70-72].

A study by Chen et al reported that probiotics, L. rhamnosus (GMNL-74) and L. acidophilus (GMNL-185), possess potent activity to inhibit H. pylori adhesion to epithelia, thereby inhibiting the release of inflammatory cytokines, and alleviating gastric inflammation [73]. The results are consistent with study done by Martinez et al [74]. A persistent stomach infection with H. pylori induces secretion of proinflammatory cytokines, including IL-1β, IL-6, IL-8, and TNF-α, which are closely linked to MALT-lymphoma and gastric adenocarcinoma [75]. In addition, H. pylori infection alters gastric microbiota, leading to dysbiosis that favours H. pylori colonization and development of gastric cancer [76].

It has been further reported that probiotics exhibit anti-obesity effects by lowering serum cholesterol [77-78]. High serum cholesterol levels in humans leads to an increased risk of being infected with H. pylori and induction of pathogenesis [79-80].

Gestational diabetes mellitus (GDM) is defined as carbohydrate intolerance first diagnosed during pregnancy [81]. Maternal pregnancy complications in GDM include preeclampsia and instrumental or operative delivery. Fetal complications include macrosomia, polyhydramnios, preterm birth, shoulder dystocia and neonatal complications of admission to neonatal ICU, respiratory distress, hypoglycaemia, and jaundice. Both women with GDM and their infants are at increased risk of diabetes mellitus and metabolic dysfunction later in life [82-83]. A study examining probiotics in pregnancy suggested a benefit in reducing the incidence of gestational diabetes [84]. Supplementation with probiotics has been shown to improve glycaemic control in men and women with type 2 diabetes [85-86]. The gut microbiome is thought to influence obesity and type 2 diabetes through modification of energy extraction, inflammation, hunger and satiety, as well as lipid and glucose metabolism [87-89]. Probiotics may regulate glucose metabolism and metabolic syndrome [90-92], and the regulation of glucose metabolism is associated with improvement in type 2 diabetes and hyperglycemia. Probiotic supplementation during pregnancy may help maintain the density of the intestinal flora, thereby reducing the metabolic imbalance in pregnant women [93-94]. They are helpful in preventing worsening of insulin resistance in late pregnancy [95].

A recent Cochrane review studying the role of probiotics in GDM involving 256 women showed a 60% decrease in the rate of diagnosis of gestational diabetes mellitus in women taking probiotics from early pregnancy [96]. A systematic review and meta‐analysis looking at the effect of treatment of GDM on pregnancy outcomes showed that treatment significantly reduced the risks of fetal macrosomia, large‐for‐gestational‐age births, shoulder dystocia and gestational hypertension, as well as a tendency to reduction of perinatal/neonatal mortality and birth trauma [97].

In a randomized controlled trial, published in January 2017, subjects either took Lactobacillus rhamnosus HN001 or a placebo. Those who took the probiotic had a significantly lower incidence of GDM than those who didn’t (2.1% vs 6.5%) [98]. A previously published randomized controlled trial found no protection against gestational diabetes with the use of Lactobacillus salivarius UCC118, perhaps indicating the difference in efficacy of the strain [99]. Other factors could be dosage, duration of treatment, timing of delivery (early vs later in pregnancy), or other genetic or environmental differences between the study groups.

A very recent study by Callaway et al [100] studied the role of probiotics in the prevention of GDM in overweight and obese women, in a total of 411 participants fulfilling the criteria. Probiotics containing strains Lactobacillus rhamnosus and Bifidobacterium animalis subspecies lactis were administered from the second trimester in these women. Assessment by OGTT (oral glucose tolerance test) was done at 28 weeks’ gestation. The probiotics used in this study did not prevent GDM in overweight and obese pregnant women.

The diet therapy (including specific fat and fibre intake recommendations) was given to all patients enrolled. Diet together with probiotic group had a significantly reduced rate of gestational diabetes mellitus when compared to controls in a study conducted by Baral M including 256 women [101]. Probiotic treatment included Lactobacillus rhamnosus GG and Bifidobacterium lactis. Each probiotic was taken at 10 billion CFU per day. Specific bacterial ratios will either encourage or discourage obesity later in life and even predict obesity development [102]. High numbers of bifidobacteria and low numbers of Staphylococcus aureus in infancy can help protect against overweight and obesity in children, possibly revealing a key reason that breastfed infants enjoy a healthier metabolic outcome.

Probiotics help modulate the immune system and therefore inflammation [103]. Obesity can lead to a state of low-grade systemic inflammation, possibly explaining the increased incidence of asthma in obese patients [104]. Since obesity and inflammation are related, it can be postulated that the probiotic control of inflammation plays a role in obesity prevention.

The microbial species that inhabit the vaginal tract play an important role in the maintenance of health, and prevention of infection. Over 50 microbial species have been recovered from the vaginal tract [105-107]. These species do not exist independently, and studies in vitro and in humans have shown that a multispecies microbiota, usually associated with bacterial vaginosis (BV), are present in dense biofilms [108-111], while a lactobacilli dominant microbiota can be sparsely distributed on the epithelium [108,109,112]. Despite the close proximity of the vagina to the anus, the diversity of microbes present in the vagina is much lower than in the gut. The reason for this lower diversity is still unclear. Some species found in the gut, such as E. coli and Streptococcus, can also be found in the vagina, indicating that proper receptors, nutrients, and oxygen tension, are present for them to grow.

Factors such as hormonal changes (particularly estrogen), vaginal pH, and glycogen content can all affect the ability of lactobacilli to adhere to epithelial cells and colonize the vagina [113]. The menstrual cycle can also cause changes in the vaginal microbiota, with high concentrations of estrogen increasing adherence of lactobacilli to vaginal epithelial cells [114]. With the decrease in estrogen levels, there is also a decrease in lactobacilli present in the vaginal tract as seen in postmenopausal women [109,115-117].

While a vaginal tract dominated by lactobacilli appears to protect the host against some vaginal infections, it does not fully prevent colonization by other species. Pathogens are still able to coexist with these commensal organisms, as shown by Burton and Reid [118], where G. vaginalis, a pathogen associated with BV, was detected in a vaginal sample which also contained a species of Lactobacillus. Interestingly, G.vaginalis was displaced beyond detectable limits for 21 days, following a single intravaginal instillation of probiotic lactobacilli [115].

Pathogenic organisms are able to infect the vagina, with BV, yeast vaginitis, and UTI (urinary tract infections) causing an estimated one billion or more cases per year [119-122]. Lactobacilli are often found in patients with yeast vaginitis, therefore, the induction of infection does not appear to require the yeast displacing or killing off the lactobacilli. Urinary tract infections occur when pathogenic bacteria ascend from the vagina and replicate on, and sometimes within, the bladder urothelium [119,123.124]. In women with no history of UTI, vagina and perineum are most commonly colonized by lactobacilli [125], while in women with recurrent UTI there is an inverse association between lactobacilli and E. coli [126], suggesting that lactobacilli play a role in preventing infection.

The most common urogenital disorder in women of reproductive age is BV. Aerobic vaginitis has also been described in which the vagina is colonized by organisms such as E. coli and enterococci [127]. During pregnancy, BV can increase the risk of preterm labour and low birth weight [128-129]. Other problems associated with BV include pelvic inflammatory disease, UTI, and increased susceptibility to sexually transmitted diseases, including HIV [130-133].The organisms associated with BV form dense biofilms on the vaginal epithelium, and these are associated with increased resistance to lactobacilli-produced lactic acid and hydrogen peroxide (H₂O₂) which are normally antagonistic to planktonic organisms [126]. The bio films are also able to induce host expression of certain inflammatory factors, such as IL-1 and IL-8 [135]. It is not currently known whether the production of H₂O₂ by lactobacilli has a clinically protective role against BV.

As antimicrobial treatment of urogenital infections is not always effective, and problems remain due to bacterial and yeast resistance, recurrent infections [136-137], as well as side effects, it is no surprise that alternative remedies are of interest to patients and their caregivers. It is assumed that recurrences are due to antimicrobials failing to eradicate the pathogens, perhaps because of biofilm resistance, or that the virulent organisms come back from their source (the person’s gut, or a sex partner) and attack a host whose defenses are suboptimal. Young girls who suffer from UTI are more likely to have repeated episodes in adulthood, and overall many UTI, BV, and yeast vaginitis patients will have a recurrence [138-139].

Recurrent infection may also be due to the elimination of the commensal organisms in the vagina by the antimicrobial, thereby increasing susceptibility to recolonization by pathogens [140-141]. This is one of the main reasons for considering the use of probiotics, to replenish the commensal microbes as a way to lower the risk of reinfection. The concept of delivering lactobacilli orally to repopulate the vagina was first reported in 2001 [142], and based upon the question “If urogenital pathogens can do this, why cannot lactobacilli”? The organisms were delivered in a milk base and shown to be recovered from the rectum [143]; therefore supporting the concept that ingested strains could pass through the intestine, reach the rectum, and potentially ascend to the vagina. This was confirmed independently by others [144].

The mechanisms whereby lactobacilli function as anti infective defenses are still not fully understood. As discussed above, this may involve production of antimicrobial factors [145], and maintenance of a vaginal pH of ≤4.5. It could also be due to bio surfactants which alter the surrounding surface tension and reduce the ability of a wide range of pathogens to adhere [146-147]. This might explain the relatively sparse coverage of epithelial cells noted in healthy women [112]. In addition, lactobacilli have been shown to bind (coaggregate) some pathogens and this may be a means to block their adhesion, kill them through production of antimicrobials, and prevent their spread to other areas of the vagina and bladder [108]. Among 10 strains of lactobacilli being evaluated for use in a probiotics tablet, Mastromarino et al. [148] found, in vitro, that Lactobacillus gasseri 335 and Lactobacillus salivarius FV2 were able to coaggregate with G.vaginalis. When these strains of lactobacilli were combined with Lactobacillus brevis CD2 in a vaginal tablet, adhesion of G. vaginalis was reduced by 57.7%, and 60.8% of adherent cells were displaced. Boris et al. found that the adherent properties of G. vaginalis were similarly affected by Lactobacillus acidophilus [149]. It has been known for some time that Lactobacillus produce bacteriocins that can inhibit the growth of pathogens, including some associated with BV, such as G. vaginalis [150]. Only relatively recently has a study shown in animals that bacteriocin production might have an effect in vivo. Neri et al. [140-151] studied 84 women in the first trimester of pregnancy to observe the effects of probiotic-containing yoghurt on BV. The subjects were randomized to one of three treatment groups: inserting a tampon containing 5% acetic acid, a 10 to 15 mL vaginal douche containing > 1.0 × 10⁸ colony-forming units/mL of L. acidophilus, or no treatment. Both active treatments were administered twice a day for one week. Amsel criteria were absent in 88%, 38%, and 15% of subjects who received intra vaginal lactobacilli, acetic acid tampons, and placebo, respectively, after 30 days. There was a significant difference in the cure rate between probiotic and control groups, and lactobacilli and acetic acid groups.

The efficacy of combining probiotics or placebo with oral metronidazole was assessed in 125 women aged 18 to 44 [152]. Oral metronidazole was administered at 500 mg twice daily to all patients for 7 days, and they were randomized to receive twice-daily oral capsules containing either a placebo or L. rhamnosus GR-1 and L. reuteri RC-14 at 1.0×10⁹ colony-forming units for a total treatment duration of 30 days. At the end of 30 days, BV was considered absent if the patient had a negative sialidase test and a Nugent score of <3. This was the case in 40% of placebo and 88% of probiotic subjects. If an intermediate Nugent score was regarded as “cure of BV”, the cure rate was 100% with metronidazole and probiotics versus 70% with metronidazole and placebo. This study is important as it implies that probiotics can augment the effects of antibiotics in treatment of disease.

Group B Streptococcus (GBS) is the leading cause of neonatal morbidity and mortality [153]. It may be passed from the mother colonized in the genital tract by GBS to their baby during vaginal birth, or by being spread to the amniotic fluid. This vertical transmission can lead to early-onset GBS disease of the newborn (EOGBSD), which manifests in the first 7 days of life, and can be fatal. While approximately 10 to 30% of pregnant people harbour GBS in the vagina or rectum, the incidence of neonatal GBS disease is 1 to 2 infants per 1000 births. The use of intrapartum antibiotics to treat colonized individuals with or without risk factors has led to a 70% decline in the incidence of early-onset GBS sepsis in the past decade [154]. Despite this impressive decline, antibiotic resistance has become a major public health concern. Association between intrapartum antibiotic use and ampicillin resistance in E. coli isolated from neonates has previously been documented [155]. Furthermore, while GBS has remained sensitive to penicillin, 20% are resistant to erythromycin and clindamycin, which are alternate drugs for patients allergic to penicillin. Alternative approaches are therefore needed to reduce the risk of GBS infection.

Earlier researches have been done which include the use of Lactobacillus rhamnosus GR-1 and Lactobacillus reuteri RC-14 (Lactobacillus fermentum RC-14) in the colonization status of GBS in pregnant people [152]. Lactobacilli are part of normal gut and vaginal flora and have been widely used as probiotics to treat various conditions. In particular, these two strains have shown to be beneficial in the treatment of urinary tract infections and bacterial vaginosis [156]. As lactobacilli are part of the human gut flora and have low pathogenicity, no adverse reaction to lactobacilli is usually anticipated, though some patients may experience flatulence.

Bacteria of the lactobacillus sp. are the most common in probiotic capsule preparations. The natural vaginal flora play an important role in dislodging and inhibiting pathogens. The rationale for the use of probiotics then, is the return of the vaginal flora to their healthy, natural state [157]. Indeed, probiotics have been shown to alter the vaginal flora being an effective supplement in the treatment and cure of bacterial vaginosis, and vulvovaginal yeast infections. Probiotic capsules are considered safe for use in pregnancy [158].

The ongoing researches are using 2 capsules (together) of oral Lactobacillus GR-1 and RC-14 once daily for 12 weeks from 24 weeks of pregnancy until their GBS swab test is taken at 35-37 weeks of pregnancy. The studies tend to provide evidence that probiotic prophylaxis is an effective, low-risk strategy that can be offered to patients to reduce their risk of GBS colonization and thus, the need for intrapartum antibiotic prophylaxis and the risks and inconvenience associated with it.

The raised estrogen and growth hormone during pregnancy may increase the activity of HPV molecule and human papilloma virus (HPV) infection. Short-time HPV persistence has been associated with higher risk for cervical intra-epithelial neoplasia and a higher risk of High-Grade Squamous Intraepithelial Lesion (HSIL). Clinical data showed GR-1 and RC-14 can improve the cervical malignancy diagnostics quality for non-pregnant women. The influence of oral probiotics on postpartum diagnosis of cervical pathology remains unknown.

In a study by Hanson et al [159], participants in the probiotic group reported no adverse events or minor side effects; one half reported improved gastrointestinal symptoms. Although two women in each group had positive qualitative prenatal GBS cultures at 36 weeks, the probiotic group participants had lower quantitative GBS colony counts. The eight GBS negative averaged 90% probiotic adherence compared with two GBS positive women who averaged 68%. Yogurt ingestion was inversely related to GBS colonization. It was concluded that prenatal probiotic therapy has the potential to reduce GBS colonization which appears to be linked to its daily adherence.

Timely intake of probiotics during pregnancy might help lower the risks of preeclampsia and premature birth, suggests observational research. Probiotics may have an anti-inflammatory effect on lipopoly saccharide inflammatory response in human placental trophoblast cells [160,161]. The anti-inflammatory effect of orally ingested probiotics has also been shown in vivo [162-163].

In a study by Nordqvist et al [164], it was revealed that probiotic milk intake during late pregnancy (but not before or in early pregnancy) was associated with reduced risk of preeclampsia, and that intake during early pregnancy (but not before or in late pregnancy) was associated with reduced risk of preterm delivery.

Two previous studies in the Norwegian Mother and Child Cohort Study (MoBa) showed associations between intake of milk containing probiotics during the first half of pregnancy and reduced risk of preeclampsia and spontaneous preterm delivery [165-166].

The gastrointestinal tract represents the largest immune interface with the environment, probiotics are known to modulate gastrointestinal health through suppression of pathogenic bacteria as stated earlier. Steinborn et al showed that preeclampsia and preterm delivery are characterised by changes in the composition of regulatory T cell, decreasing their suppressive activity [167]. In vitro studies have shown that probiotics (Lactobacillus rhamnosus GR-1 and LGG) may have an anti-inflammatory effect on LPS inflammatory response in human placental trophoblast cells [160,161], potentially a key cell type in preeclampsia. In another large observational study by Brantsaeter et al, it was concluded that there is an independent protective association between intake of probiotic milk products and preeclampsia, especially severe preeclampsia, suggesting that probiotics might specifically “target” and modify the type of inflammation underlying severe preeclampsia [165].

In a randomised, double-blind, placebo-controlled trial which was completed by 29 mother-infant pairs, it was shown that bacterial DNA was detected in all placental samples. Microbial DNA in amniotic fluid and placenta was associated with changes in TLRrelated gene expression in the fetal intestine. Maternal probiotic supplementation (10⁹ Bifidobacterium lactis alone or in combination with 10⁹Lactobacillus rhamnosus GG) significantly modulated the expression of TLR-related genes both in the placenta and in the fetal gut. These findings suggest a link between the maternal gut and that of the developing fetus and that microbial contact at the feto-placental interface may be considered a physiological phenomenon [168].

Probiotics appear not only to modulate T-cells and cytokine profile, but also to help accelerate recovery of barrier function. There is increasing evidence that disturbances in gut microbial composition play a role in the pathophysiology of immune-mediated disorders, such as allergic disease [169]. Gut microbiota are key players in the early development of both local immune maturation and systemic immune programming.

Gut microbiota confer specific immune-protective effects that are probably mediated through complex pathways within (and potentially even beyond) the gut-associated lymphoid tissue (GALT), the largest immune “organ” in humans. These effects include altered local immunoglobulin A (IgA) production and induction of tolerogenic dendritic cells and regulatory T cell populations, with production of immunomodulatory cytokines, such as interleukin (IL) 10 and transforming growth factor (TGF) beta [170]. These mechanisms appear to collectively inhibit local inflammation, improve gut barrier mechanisms, and consequently reduce the risk of inappropriate systemic immune responses.

Early studies reported that low levels of Bifidobacterium and early colonization with potentially pathogenic bacteria, such as Clostridioides (formerly Clostridium) difficile [171,172] and Staphylococcus aureus [171], were more prevalent in children who subsequently developed allergy. Consequently, it has been suggested that a high gut microbial diversity might be more important than the absence or presence of specific genera or species in the context of immune system maturation and subsequent development of immune-mediated disorders. This view is supported by prospective studies that demonstrated reduced gut microbial diversity early in life in infants who later developed allergic manifestations [173-175].

In a double-blind, randomized, placebo-controlled trial, L. rhamnosus GG was given to pregnant women for four weeks prior to delivery, then to newborns at high risk of allergy for six months with the result that there was a significant reduction in early atopic disease [176].The precise mechanisms have not been elucidated, but the premise is based upon the ability of lactobacilli to reverse increased intestinal permeability, enhance gut-specific IgA responses, promote gut barrier function through restoration of normal microbes, and enhance transforming growth factor beta and interleukin 10 production as well as cytokines that promote production of IgE antibodies [176,177].

Folates represent an essential nutrition component in the human diet, being involved in many metabolic pathways. The daily recommended intake of folate is 400 μg/day for adults [178,179] (Table 2).

The gut microbiota has been recognized as a source of vitamins. The microbiota of the human colon is known to produce vitamin K (menaquinones) and most of the water-soluble vitamins of group B, including biotin, nicotinic acid, folates, riboflavin, thiamine, pyridoxine, panthotenic acid, and cobalamin [184]. Unlike dietary vitamins, which are mainly absorbed in the proximal part of the small intestine, the uptake of microbial vitamins predominantly occurs in the colon [185]. Colonocytes appear to be able to absorb biotin, thiamin, folates, riboflavin, panthotenic acid, and menaquinones, indicating that the microbiota-produced vitamins may contribute to the systemic vitamin levels and especially to the homeostasis of the vitamins in the localized epithelial cells [185,186].

Bifidobacterium are one of the most important health-promoting groups of the colonic microbiota and one of the most important microorganisms to be used as probiotics [187]. Bifidobacterium is a genus of high G + C Gram-positive eubacteria within the phylum of Actinobacteria (Table 3). Among nearly fifty species of bifidobacteria recognized so far [190], the most represented in the gastrointestinal tract of human adults or infants, are Bifidobacterium pseudocatenulatum, B. catenulatum, B. adolescentis, B. longum, B. infantis, B. breve, B. angulatum and B. dentium [191]. In a human trial, the administration of the few strains of bifidobacteria resulted in a significant increase of folate concentration in feces. Even though the effect on plasmatic levels needs further investigation, folateproducing bifidobacteria provide a complementary endogenous source of the vitamin and may contribute to prevent folate deficiency, which is often associated with premalignant changes in the colonic epithelia.

Prevalence of folate deficiency - especially among women of childbearing age- is a growing concern and thereby folate fortification programs should be implemented [192]. Foods can be naturally fortified with folate synthesized by LAB and bifidobacteria during manufacture of fermented foods [193,194].

B. adolescentis and B. dentium are capable of de novo folate production, while B. longum needs to be provided with pABA (paraaminobenzoic acid), and B. animalis requires folate. Several strains of bifidobacteria have been screened for their ability to produce folate in low-folate or folate-free media. Twenty-four strains of B. bifidum, B. infantis, B. breve, B. longum, and B. adolescentis were cultured in a low - folate semi synthetic medium and significant differences in vitamin accumulation were found among the species tested [195]. All B. bifidum and B. infantis strains were classified as high folate accumulators, while B. breve, B. longum, and B. adolescentis produced lower amounts of the vitamin. For all the strains, extracellular folate accounted for most of the accumulated vitamin [196]. In other studies, the highest folate accumulation in reconstituted skim-milk was obtained after incubation with B. breve and B. infantis or B. longum strains [193].

Ability to produce the vitamin in the folate-free medium was found only in 17 strains belonging to nine different species (B. adolescentis, B. breve, B. pseudocatenulatum, B. animalis, B. bifidum, B. catenulatum, B. dentium, B. infantis, and B. longum) [195]. The highest extracellular folate levels (between 41 and 82 ng mL⁻¹) were produced by four strains of B. adolescentis and two of B. pseudocatenulatum. Only one out of 15 B. longum strains grew in folate free-medium. The highest extracellular folate levels (between 41 and 82 ng mL⁻¹) were produced by four strains of B. adolescentis and two of B. pseudocatenulatum. Only one out of 15 B. longum strains grew in folate free-medium. These same strains of B. adolescentis and B. pseudocatenulatum, when given to 23 healthy volunteers in a pilot human study, significantly increased folate concentration in the feces of the subjects [197]. These results corroborate the assumption that the increase of folate levels was markedly due to the effective growth of the folate-producing bifidobacteria. The results from various studies support the evidence that folate-producing probiotic strains may represent an endogenous source of vitamin, preventing its’ deficiency in the colon. Localized folate production in the large intestine may provide the proliferating enterocytes with this essential vitamin with potential effects in reducing colonic carcinogenesis [198].

The strains Streptococcus thermophilus CRL803/CRL415 and L. bulgaricus CRL871 were reported to be suitable for the elaboration of yogurt naturally bio-enriched in this vitamin [199]. High folate concentration (up to 150 μg/l) can be reached in yogurt as a result of the ability of S. thermophilus to produce this vitamin [200]. Among bifidobacteria, B. catenulatum ATCC 27539 was shown to produce high levels of folate in vitro [201], and B. lactis CSCC5127, B. infantis CSCC5187, and B. breve CSCC5181 strains increased folate concentration during fermentation of reconstituted skim milk [202]. Similarly, L. amylovorus CRL887 can be used for natural folate bioenrichment of fermented milk [203].

Depression and anxiety in pregnancy and after birth affects 10-15 per cent of women, although many are not recognised or treated. There is mounting evidence from animal studies that, the ‘microbiomegut- brain axis’ - the biochemical signalling that takes place between the gastrointestinal tract and the central nervous system - may be important for mental health. Maternal depression can produce longlasting effects on children’s cognitive, social-emotional and health outcomes [204,205]. Anxiety often coexists with depression. Despite this, most women with post natal depression are either not recognised as being depressed, are unable to access psychological therapy or are reluctant to take antidepressant medication in pregnancy or while breastfeeding [206]. Furthermore it takes several weeks for the therapeutic effect of antidepressants to appear and there is a 15– 30% discontinuation rate [207]. Furthermore, it has been suggested that fermented foods (prebiotics) alter dietary items before they are ingested, resulting in phytochemical transformation into bioactive chemicals which reduce oxidative stress and inflammation [208].

In 2005 it was first suggested that probiotics might be an adjuvant therapy for major depression [209]. The study suggests that in depression and similar conditions where depression is a common symptom, lactobacilli levels may be low owing to migration of bacteria from the colon into the small intestine resulting in small intestinal bacterial overgrowth (SIBO). In patients with MDD (major depressive disorder), SIBO is likely to occur because it is often the result of intestinal stasis or low stomach acid secretion. Patients with depression are known to have low levels of stomach acid production and intestinal stasis. Cytokines linked to depressive symptoms, particularly interleukin1-beta (Il-1b) and tumor necrosis factor alpha(TNFa), are capable of inhibiting gastric acid secretion. In addition, physical inactivity, common to depression, is associated with SIBO [209]. Others have also suggested that probiotic enhancement of gut microbiota may improve mood outcomes [210].

The significance of small intestine bacterial overgrowth in cases of depression can lead to functional abdominal complaints, it can cause malabsorption of fat, carbohydrate, protein, B vitamins and other micronutrients, in turn leading to weakening of host defence against SIBO. Patients with depression are known to have low levels of folic acid, vitamins B₁₂, B₆ and zinc [211-214]. Low levels of vitamin B₆ is associated with diminished conversion of alpha linolenic acid into mood regulating eicosapentaenoic acid (EPA). Non-digestible oligosaccharides can increase the availability of nutrients including zinc, effects that are attributed to increased bifidobacterium. It is interesting to note that treatment of SIBO has led to improvements in depression, memory and concentration among CFS patients [215].

A recent systematic review identified 10 clinical trials of the effect of probiotics on symptoms of depression [216]. Seven studies were in healthy subjects, 2 in chronic fatigue syndrome and one in depression. Three of 5 studies reported improved mood with probiotics, and 5 of 7 studies reported improvements in stress and anxiety. A recent study that was published after these reviews reported that obese women treated with a weight-reduction programme and probiotic had reduced symptoms of depression compared with the comparison group, but this effect was not seen in men [217]. There was no effect on anxiety.

In a very recent, first double-blind RCT of probiotics that has evaluated symptoms of depression and anxiety in the postpartum period [206], a significantly lower prevalence of symptoms of depression and anxiety was seen postpartum in women supplemented with the probiotic HN001 during and after pregnancy than in those given a placebo. Furthermore, the number of women reporting clinically significant levels of anxiety on screening was significantly lower in the probiotic group. In this study infant colic was associated with higher depression and anxiety scores. There has been a suggestion in the literature that probiotic supplementation may benefit maternal mood by reducing infant colic. One study reported that direct probiotic supplementation of infants reduced infant colic and this in turn was associated with lower rates of maternal depression [218].

RCT of 40 people with major depressive disorder treated with a combination of three probiotics (Lactobacillus acidophilus, Lactobacillus casei, and Bifidobacterium bifidum) or placebo, also found a significant reduction in symptoms of depression on the Beck Depression Inventory (BDI) in the treatment group [219].

Many Lactobacillus and Bifidobacterium strains have been studied with respect to mental health and these genera seem to show the most beneficial effects [220]. Maternal stress during pregnancy can result in a reduction of both lactobacilli and bifidobacterium in offspring, relative to controls [221].

There is also evidence from human studies indicating that stress can negatively affect microflora [222,223]. Emotional stress can lead to acute and long term reductions in lactobacilli and Bifidobacterium [224]. Bifidobacterium appear to be extremely sensitive to emotional stress. Restraint stress and excess physical demands can also lead to decreases in lactobacilli and bifidobacterium in humans [221].

The gut contains over 100 million neurons; the GI tract is ultimately a meeting place of nerves, microorganisms and immune cells. Microorganisms are responsive to the host’s neuroendocrine environment and, conversely, bacteria can influence the neuroendocrine environment by the production of neurochemicals such as gamma amino butyric acid (GABA), serotonin, and various biologically active peptides. Animal studies indicate that GI microorganisms can directly activate neural pathways, even in the absence of an immune response [226,227]. Probiotic bacteria may influence mood by their effect on cytokine production.

The intestinal microflora in atopic dermatitis has been shown to contain significantly lower levels of bifidobacterium and higher levels of staphylococcus. Percentages of bifidobacteria are significantly lower in patients with severe atopy versus those with mild symptoms [209]. Probiotics should be consumed by pregnant and lactating women and their breastfed infants to prevent the development of atopic dermatitis [228].

A probiotic extract being developed from the human microbiome could offer drug-free topical therapy for patients with atopic dermatitis, and could protect against pathogenic biofilms [229]. The extract has anti-inflammatory effects as well. Staphylococcus aureus biofilms — both methicillin-resistant (MRSA) and methicillinsusceptible (MSSA) — play an important role in patients with moderate and severe atopic dermatitis. The topical extract can disrupt these biofilms and has tremendous potential to not only decrease infection risk, but to improve other aspects of the disease as well, since the bacterial colonization likely contributes to inflammation and skin barrier disruption. The effects are similar to dexamethasone.

In other clinical studies with infants allergic to cow’s milk, atopic dermatitis was alleviated by ingestion of probiotic strains L. rhamnosus GG and B. lactis BB-12 [230-232].

The development of the infant microbiome is a key area of study, and its known that there are a variety of contributing factors and situations that impact differences in microbial colonization among infants. Differences in the microbiome have been linked to increased allergy risk. Presently, there is support for the use of probiotics to prevent eczema. Since eczema is a precursor to a variety of atopic conditions (eg, food allergies and asthma), and because it causes a great deal of suffering, reducing or preventing it, is important. About 10.7% of children younger than 18 have eczema, and about 37% of those with moderate to severe eczema go on to develop food allergies, according to the American College of Allergy, Asthma and Immunology [233,234].While researchers continue to learn about the connection, controlling eczema may be one way to reduce the development of food allergies.

Two separate systematic meta-analyses found a reduction in eczema risk among the offspring of mothers who took probiotic supplements during pregnancy [235,236]. However, these two reviews had some limitations, so they were considered low quality and were not according to the current research [237]. According to the World Allergy Organization-McMaster University Guidelines for Allergic Disease Prevention (GLAD-P): Probiotics, clinicians should recommend probiotics to women at high risk of having an allergic child, those who breast-feed infants who are at high risk, and to infants who are predisposed to the development of allergy [238]. According to the guidelines, “High risk for allergy in a child is defined as biological parent or sibling with existing or history of allergic rhinitis, asthma, eczema, or food allergy.” In addition, the guidelines say that although the quality of the evidence may be low, the possible net effect is worth supplementation, since the risk of negative impact is low.

Babies who cry and fuss for more than 3 h daily have colic. The condition generally starts at 3 weeks of age, occurs on more than 3 days/week, and resolves after 3 months of age (hence the “rule of threes” . The most common description of colic is intense, “paroxysmal” crying that is markedly different from normal fussing and crying. It can also occur as prolonged, unpredictable crying, and the infant is restless and inconsolable. Crying may occur any time of the day without obvious cause but is most common after the evening feeding. The colicky episode is often accompanied by distention of the abdomen and cold feet. Often the baby seems to feel better after passing gas or a stool.

The neonatal microbiota is highly different compared to the adult one, since the first is characterized by rapid changes as mentioned earlier [239]. At birth, the newborn is exposed to a set of bacteria including staphylococci, enterobacteria, and enterococci that immediately colonize the gastrointestinal tract. In the first days of life, the gut is inhabited mainly by Bifidobacterium, Lactobacillus, Clostridium, and Bacteroides. From one to five months of life, the population of the gastrointestinal tract consists of Bifidobacteriales, Lactobacillales, and Clostridiales. At one year of age, the microbiota is similar to the adult one [240,241].

Infant colic previously was felt to be unresponsive to any treatment. Microbial dysbiosis began to be linked to this condition and was confirmed by several groups [242-244], and it was linked to gut inflammation [245]. Therefore, colic might represent a condition for which probiotic treatment would be useful. Several meta-analyses have shown that the probiotic L. reuteri, isolated from a Peruvian mother’s breast milk, reduces crying time and irritability in this condition [246-248].

Very recently, dysbiosis have been included in the list of triggers leading to rheumatoid arthritis (RA). Rheumatoid arthritis is a systemic autoimmune disease characterized by autoantibody formation leading to the chronic inflammation of multiple joints. RA is also known to affect other internal organs, including the lungs, heart, and kidneys [249].

People with inflammatory arthritis have been shown to have inflammation of the intestinal tract, which results in increased intestinal permeability. This enables certain bacteria to cross the intestinal barrier, get into the bloodstream and trigger an inflammatory response. Probiotics may be able to help decrease the inflammation associated with increased intestinal permeability. Probiotics appear to have an impact on inflammation, reducing common biomarkers of inflammation, including C-reactive protein. They help to decrease the inflammation associated with increased intestinal permeability.

In a recent study by Zamini et al [250], daily probiotic capsules containing Lactobacillus acidophilus, Lactobacillus casei and Bifidobacterium bifidum were given for 8 weeks. Probiotic supplementation group resulted in improved Disease Activity Score of 28 joints (DAS-28). There was a significant decrease in serum insulin levels, homeostatic model assessment-B cell function (HOMA-B) and serum high-sensitivity C-reactive protein (hs-CRP) concentrations.

In a study by Mohammed et al [251], the efficacy of probiotics as an adjuvant therapy for rheumatoid arthritis was studied. The meta-analyses indicated that pro-inflammatory cytokine IL-6 was significantly lower in the probiotics compared with the placebo group but disease activity score could not find any difference.

A study by Chen et al. evaluated the gut microbiota profile in 40 patients with RA and 32 healthy controls. They found decreased gut microbial diversity in RA compared to controls, which additionally correlated with disease duration and with levels of serum rheumatoid factor [252].

Alipour et al. showed that L. casei 01 supplementation decreased serum high-sensitivity C-reactive protein (hs-CRP) levels, reduced tender and swollen joint counts, and improved global health (GH) score. A significant difference was also observed between the two groups with respect to circulating levels of interleukin (IL)-10, IL-12, and tumour necrosis factor (TNF)-α, in favour of the probiotic group [253].

Many probiotic products are used on the simple assumption that probiotics can retain health and well being, and potentially reduce long-term risk of diseases of the bowel, kidney, respiratory tract and heart. Multicentre large randomised controlled trials are needed to authenticate such an assumption before making it a regular practice. Study by Tannock et al. [253] mentions an important observation that the ingestion of probiotic strains has not led to measurable long-term colonization and survival in the host. Invariably, the microorganisms are retained for days or weeks, but no longer. Thus, use of probiotics likely confers more transient than long-term effects, and so continued intake appears to be required. However, in newborn children where a commensally flora has not yet been established, it is assumed that probiotic microorganisms could become primary colonizers that remain long-term, perhaps even for life.

When ingested orally or used vaginally, probiotics are generally considered safe and are well tolerated. One theoretical concern associated with probiotics is the potential for these organisms to cause systemic infections. Although rare, probiotic-related bacteremia and fungemia have been reported [255]. It is estimated that the risk of developing bacteremia from ingested Lactobacillus probiotics is less than 1 per 1 million users [256], and the risk of developing fungemia from Saccharomyces boulardii estimated at 1 per 5.6 million users, and is estimated to be lower in healthy individuals [257]. There have been no reports of bifidobacterium sepsis associated with the use of probiotics in healthy individuals [258]. Risk factors for systemic infections include immune suppression, critical illness, central venous catheters, and impairment of the intestinal epithelial barrier. Probiotics administered orally to combat urogenital infections are not systemically absorbed but rather get to the site of action by passage through the gastrointestinal system and ascending into the vagina [142].

Annually, over one billion doses of probiotics are administered worldwide, and those administered for urogenital health have been well tolerated [115,152,256,259-261]. In addition, the mouth, gastrointestinal tract, and female genitourinary tract are inhabited by Lactobacillus [256]. Yet, endocarditis and bacteremia caused by lactobacilli are extremely rare. Most cases occur in patients with chronic diseases or debilitating conditions that provide direct access to the bloodstream from a leaky gut. Only 1.7% of 241 cases of bacteremia, endocarditis, and localized infections associated with Lactobacillus that were investigated by Cannon et al. were considered to have a possible link with heavy consumption of dairy products [262]. Only one case had a Lactobacillus isolate that was indistinguishable from a probiotic strain. There was no connection between the species of Lactobacillus isolated and the type of infection or mortality. A recent study that directly instilled a six-strain bacterial product into the intestine of patients with severe, potentially fatal pancreatitis portrayed probiotics as being dangerous [262]. However, the product had never been proven to be probiotic, it was administered as a drug unlike 99.9% of probiotics, the randomization process led to patients with multiorgan failure being given large doses of live bacteria, and the authors failed to provide a rationale for the study in an appropriate animal model. All this led to warranted adverse publicity for the field of probiotics [263].

Probiotics do not appear to pose any safety concerns for pregnant and lactating women. Systemic absorption is rare when probiotics are used by healthy individuals [264].

One of the studies to watch for is the Probiotics in Pregnancy (PiP) Study, a multicentre, multinational study that has recruited pregnant women to research the effect of L rhamnosus HN001 in early pregnancy through breast-feeding. Researchers expect administration to reduce the rate of infant eczema and atopic sensitization at 12 months. Researchers also are studying the impact of supplementation on GDM, bacterial vaginosis, and group B streptococcal vaginal colonization before birth, and depression and anxiety postpartum [265].

Another study to keep an eye on is The Environmental Determinants of Diabetes in the Young (TEDDY), also a multicentre, multinational study. The TEDDY study is exploring the causes of type 1 diabetes mellitus to understand what interventions could help reduce the risk of it’s development. These researchers are exploring the interaction between genes and environmental contributors. The study is ongoing, but in 2015, researchers presented early data that showed a reduction of 33% in autoimmunity, based on the development of auto antibodies after infant supplementation with probiotics starting in the first month of life. Although promising, more research is needed to confirm these findings [266].

Probiotic foods are a safe way for pregnant women to introduce and consume healthful microbes during pregnancy and may provide other positive nutritional benefits. These may include foods such as fermented sauerkraut (a source of fibre), and yogurt and kefir (providing calcium and vitamin D). Pregnant patients should avoid unpasteurized milk and juice products because of the risk of foodborne illness. Pregnant women who fall into the high-risk category are good candidates for probiotic supplements. In fact, regular consumption of safe, whole, fermented, and probiotic foods may benefit all patients. Finally, research on the benefits of probiotics is growing and dietitians should continue to follow the research in this area to provide the best evidence-based guidelines to use in practice.