CLINICALLY PROVEN;

• Supports infant secretory immunoglobulin A (sIgA) to encourage a healthy intestinal microbiota

• Displaces gut pathogens

• Supports a more robust immune response 

• Increase the immunoprotective potential of breast milk

• Significant reduces the risk of eczema for the first 7 years of life

• Increases anti-body levels to Polio and RotaVirus 

• Mitigates some of the immune-related effects of not breastfeeding and caesarean delivery

• Supports allergy reduction to cows milk

• Reduces Risk of Respiratory Tract Infections 

• Reduce Risk of Behavioural Complaints

• Reduces risk of ADHD and Autism Spectrum Disorders

• Regulates emotional behaviour, supports emotional stability

• Reduced Risk of Elevated Glucose Levels During Pregnancy

MODULATES IMMUNE RESPONSES 

Lactobacillus rhamnosus (LGG®) has been shown to increase the secretion of interleukin-10 (IL-10), which up-regulates the growth of B cells and down-regulates immunoglobulin (Ig) E synthesis.[15] This demonstrates an immunomodulation response sufficient to counter the excessive inflammation associated with up-regulated T helper 2 (Th2) activation. 

The administration of LGG® and Bifidobacterium animalis ssp lactis (BB-12®) has been shown to result in increased transforming growth factor-beta 2 (TGF-β2) in breast milk. TGF-β2 is an immunomodulatory compound that has been shown to have a protective effect on the infant by reducing allergic inflammation. 

Allergic mothers have lower concentrations of this compound in their breast milk. TGF-β2 is a key factor for increasing secretory immunoglobulin A (sIgA) production in the mucosa, thereby inducing oral tolerance.[16]

A study on infants observed that Bifidobacterium longum (BB536) can help to establish a healthy intestinal microbiota in early life and improve Th1 immune response, through enhancement of interferon gamma (IFN-γ) secretion.[17] Similarly, an animal study showed that oral administration of Bifidobacterium breve (M-16v) suppressed Th-2 type immune response and IgE production, along with modulating systemic Th1/Th2 balance.[18]

LGG® and BB-12® have been shown to result in increased TGF-β2 in breast milk

In addition to tempering immune system responses, probiotics can support a more robust immune response. Lactobacillus spp help to promote immune regulation by interacting with dendritic cells within the gut-associated lymphoid tissue, stimulating the production of regulatory T cells, and increasing production of regulatory cytokines.[19] Specific strains such as LGG® may exert such effects via modulation of the intestinal microbiota, and the restoration of the mucosal barrier.[20]

ECZEMA PREVENTION IN INFANTS

LGG® has been shown to provide protection from atopic eczema for the infant when administered to the mother before delivery and during breastfeeding. 

A randomised controlled trial[32]  was conducted in 159 mothers who had at least one first-degree relative or partner with atopic eczema, allergic rhinitis, or asthma. LGG® (20 billion CFU/daily) or placebo was given to expectant mothers in the last month prior to expected delivery and for six months postnatally, either to breastfeeding mothers or directly to the infants. 

The frequency of atopic eczema in the probiotic group was half that of the placebo group, 23% versus 46%, (Figure 2), with the preventive effect not dependant on the mode of delivery. Infants with an elevated cord blood IgE concentration (considered to reflect atopic sensitisation in utero), were most likely to benefit.

The preventive effect of LGG® on atopic eczema also extends beyond infancy. The above primary study was followed up at four years and again at seven years. At four years, there was a reduced incidence of atopic eczema in the probiotic group.[34]  These effects continued through to the final follow-up visit at seven years of age, with 116 children completing the study. 

Overall, the risk of eczema during the first seven years of life was significantly reduced in the LGG® group compared with the placebo group.[35]

In a separate double-blinded, placebo-controlled study[37] of 62 mother-infant pairs, LGG® was given for four weeks before birth and during breastfeeding. Administration of probiotics to the pregnant and lactating mother increased TGF-β2 levels in mothers receiving probiotics compared with those receiving placebo. 

The risk of developing atopic eczema during the first two years of life was significantly reduced in infants of the mothers who received probiotics compared to infants whose mothers received placebo (15% vs. 47%). 

INFANT IMMUNE DEVELOPEMENT

The first months of life represent a critical period for the maturation of an infant’s immune system. 

Supplementation with LGG® pre- and postnatally has been shown to enhance the immune benefits of breastfeeding. 

Breastfeeding is known to promote the growth of bifidobacterium and reduces the risk of infection and allergic diseases. Breastfed children whose mothers received 10 billion LGG® daily for four weeks prior to delivery (and who were then supplemented directly with the same dose during infancy) had significantly greater numbers of serum Ig-secreting cells at 12 months compared to those receiving the placebo.[42] 

At three months, the total number of IgG-secreting cells in breastfed infants supplemented with probiotics significantly exceeded those in breastfed infants receiving placebo. The numbers of IgG-secreting cells also correlated with the sCD14 antigen in colostrum. Total numbers of IgM-, IgA-, and IgG-secreting cells at 12 months were higher in infants breastfed exclusively for at least three months and supplemented with probiotics as compared with placebo. 

Similarly to the three month result, sCD14 in colostrum significantly correlated with numbers of both IgM and IgA cells. Interestingly, faecal bifidobacterium and Lactobacillus/Enterococcus spp counts were higher in breastfed, compared to formula-fed infants at six months, indicating the importance of breastfeeding for gastrointestinal microbiota establishment. The results of the above study indicate that both probiotic supplementation and breastfeeding can influence gut immunity positively in infants.

The influence of probiotic supplementation on immunity was also demonstrated in a double-blinded, placebo-controlled study of 62 mother-infant pairs from atopic families. Administering LGG® to pregnant and lactating mothers, for four weeks before birth and then during breastfeeding, was shown to significantly increase the immunoprotective potential of breast milk. 

This was assessed by the amount of anti-inflammatory TGF-β2 in the milk in mothers receiving probiotics versus mothers receiving placebo.[43]  As discussed previously, this factor contributes to the development of oral tolerance.

Breast milk is also a source of IgA, as well as bacteria, which enhance both passive and active infant immunity. 

A trial[44] investigated the effect of an infant starter formula containing the probiotic BB-12® on intestinal immunity and inflammation. Healthy full-term infants (n=172) aged six-weeks were enrolled in a prospective, randomised, double-blind, controlled clinical trial with two groups studied in parallel to a breastfed comparison group. Formula-fed infants were randomised to partially hydrolysed whey formula (control) or the same formula containing BB-12® for six weeks (average intake 100-110 million CFU/day).[45] 

Faecal sIgA, calprotectin, lactate, and stool pH were assessed at baseline, two weeks, and six weeks. Anti-poliovirus-specific IgA and anti-rotavirus specific IgA were assessed at two and six weeks. Among vaginally delivered infants, BB-12® supplementation significantly increased faecal sIgA, compared to the control infant group. 

Anti-poliovirus-specific IgA concentration also significantly increased in all infants consuming the probiotic. Further, there was also a non-significant trend for an increase in antirotavirus-specific IgA in the BB-12® group in cases of caesarean-delivered infants. 

Interestingly, breastfed infants that were observed had significantly higher concentrations of faecal sIgA in stool samples compared to the formula-fed infants at each time point. Yet, infants consuming formula containing BB-12® did display augmented sIgA concentration in faeces. Caesarean-delivered infants consuming BB-12® had a heightened immune response, as evidenced by increased anti-rotavirus- and anti-poliovirus-specific IgA following immunisation. These results demonstrate that some of the negative immune-related effects of not breastfeeding and caesarean delivery can be mitigated by including BB-12® in infant formula.

Negative immune-related effects of not breastfeeding and caesarean delivery can be mitigated by including BB-12® in infant formula.

The studies described above have demonstrated that the first months of life represent a critical period for the maturation of an infant’s immune system, and this is relevant to the development of allergy. The number of cow’s milk–specific and total IgA-secreting cells were measured at three, seven and 12 months of age in a double-blind placebo-controlled study[46] of 72 infants with early artificial feeding. 

The infants consumed infant formula supplemented with either a combination of LGG® and BB-12® (10 billion CFU/day, of each strain) or placebo formula during the first year of life. Analyses of the serum concentrations of the IgA-inducing cytokine, but also TGF-β2 and the soluble innate microbial receptor sCD14 were conducted. The numbers of cow’s milk–specific IgA secreting cells were significantly higher in infants receiving probiotics compared with those receiving placebo. 

At 12 months of age, the serum concentrations of sCD14 were also significantly increased in infants receiving the probiotics compared to those receiving placebo. Interestingly there was also a trend towards cow’s milk allergy reduction, with 0/32 (0%) of the infants receiving probiotics and 3/40 (8%) infants receiving placebo. 

This study therefore showed that administration of LGG® and BB-12® at the time of cow’s milk introduction in the infant’s diet resulted in cow’s milk specific IgA antibody responsiveness that may be the result of increased production of sCD14, with a coinciding trend in allergy reduction.

The establishment of a balanced Th1/Th2 immune response is another key aspect of immune development in early life. A double-blind, randomised, placebo-controlled intervention trial[47] attempted to determine if infant formula supplementation with BB536 could provide beneficial effects on the immune balance of the Th1/Th2 response. 

Three-hundred healthy newborns were recruited, randomised and fed formula either supplemented with BB536 or without, from enrolment (day zero to seven days after birth) until six months of age. The Th1/Th2 balance was examined at four and seven months of age by measuring IFN-γ and IL-4 secretion cells and the ratio between them. It was found that the number of IFN-γ secretion cells and the ratio of IFN-γ:IL-4 increased significantly at seven months of age in the BB536 supplemented group compared to those in the control group. It was also observed that BB536 can improve Th1 immune response through enhancing the secretion of cytokine IFN-γ.

The establishment of a balanced Th1/Th2 immune response is another key aspect of immune development in early life.

REDUCES RISK OF RESPIRATORY TRACT INFECTIONS

It has already been shown that probiotic supplementation can influence immune system responses, so it follows that supplementation also appears to provide protection against infection. 

A randomised, double-blind, placebo-controlled study[48] was conducted to determine whether probiotics might be effective in reducing the risk of infections in infancy. 

Infants requiring formula before the age of two months were recruited and given an infant formula supplemented with a combination of LGG® and BB-12® 10 billion CFU/day, or placebo. The formula was administered daily until the age of 12 months. Incidence of early infections (before the age of seven months) and incidence of recurrent (three or more) infections during the first year of life were recorded as the main outcome measures of the study.

The administration of BB-12® in early childhood may reduce respiratory tract infections.

During the first seven months of life, 7/32 (22%) infants receiving probiotics and 20/40 (50%) infants receiving placebo experienced acute otitis media, which was a significant reduction. 

Recurrent respiratory infections were also significantly reduced, with 9/32 (28%) infants receiving probiotics and 22/40 (55%) infants receiving placebo experiencing these. Not surprisingly, the number of antibiotics prescribed between the two groups was also significantly different, with 10/32 (31 %) infants in the probiotic group receiving antibiotics, compared to 24/40 (60 %) infants in the placebo group. 

These results suggest that probiotics may offer a safe means of reducing the risk of early acute otitis media, recurrent respiratory infections and antibiotic use during the first year of life.

A separate double-blind, placebo-controlled study[49] also looked at the impact of single strain probiotic administration (BB-12®) on the risk of acute infectious diseases in healthy infants. The study included one-month old infants (n=109) who were assigned randomly to a probiotic group receiving a pacifier containing 10 billion CFU/day of BB-12® (n=55) or a placebo pacifier (n=54). Infants continued this treatment until two years of age.

The infants receiving BB-12® were reported to have experienced significantly fewer respiratory tract infections than the control group. There was also a trend towards a lower frequency of recurrent respiratory tract infections in children receiving the probiotic (39%), as compared with placebo (61%). The authors concluded that the administration of BB-12® in early childhood may reduce respiratory tract infections.

REDUCE RISK OF BEHAVIOURAL COMPLAINTS

Human studies have shown that gut problems in early childhood may contribute to the development of autism. 

Various disorders, such as ADHD and ASD share behavioural abnormalities in sociability, communication, and/or compulsive activity.[50] 

There is evidence of deficiencies in early Bifidobacteria spp composition in those with ADHD or ASD, with links to a lack of breastfeeding which, as discussed above, is a potent inducer of bifidobacterium in the gut microbiota. Providing adequate levels of bifidobacterium has been shown to be associated with lower levels of conduct disorder symptoms in middle childhood.[51]

There is evidence of deficiencies in early Bifidobacteria spp composition in those with ADHD or ASD

In an ongoing, randomised, double-blind, placebo-controlled prospective follow up study[52] of 159 mother-infant pairs, LGG® (10 billion CFU/day) was given to pregnant mothers four weeks before expected delivery and for six months after delivery (if not breastfeeding, LGG® was given directly to the infant). 

At 13 years of age, ADHD or Asperger’s Syndrome (AS) was diagnosed in 6/35 (17.1%) children in the placebo and none in the probiotic group, which was a statistically significant difference. This trial highlights the potential for tailored probiotic supplementation to reduce the risk of certain behavioural complaints in children as they develop.

REGULATES ADULT AND INFANT EMOTIONAL BEHAVIOUR 

Early bacterial exposure and colonisation patterns are critical for immune system development, and may also play a role in nervous system development. Increased production of serotonin (5-HT) and γ-aminobutyric acid (GABA), along with the expression of various cytokines, has been shown to proceed bacterial colonisation. 

This highlights the physiological changes that occur as result of bacterial exposures in the gut. These changes are integral to gut homeostasis and to programming of the hypothalamic–pituitary–adrenal (HPA) axis, which plays an important role in the stress response.[21]

An experimental study has shown that LGG® regulates emotional behaviour and the central GABAergic system via the vagus nerve. Another study demonstrated that the consumption of a mixture of probiotic bacteria had significant effects on brain regions that control the processing of emotions,[22] indicating the potential use of probiotics for emotional stability and regularity, both in adults and children. Such studies highlight the influence of GIT physiology on neuronal networks, and how probiotics can exert beneficial effects on these systems.

REGULATES GLUCOSE METABOLISM

Pregnancy is accompanied by metabolically adaptive processes that both maintain the pregnancy and help the baby grow and develop. An example of this is in late pregnancy, where increased insulin concentration is accompanied by insulin resistance. 

This deviation in normal homeostatic regulation helps to ensure the developing foetus gets an adequate supply of energy for growth and development. Exaggerations in this adaptive process can lead some women to develop gestational diabetes, along with associated clinical complications for both mother and foetus. 

Low grade inflammation, and accompanying immune activation, may also negatively contribute to conditions where glucose metabolism issues are involved. Probiotic organisms such as LGG® and BB-12® may be able to influence glucose metabolism through their immunoregulatory properties. Probiotics elicit powerful anti-inflammatory capabilities by inhibiting the nuclear factor kappa-B (NFкB) pathway, which mediates microbial activation of the immune system through TLRs.[23]

LGG® and BB-12® may be able to influence glucose metabolism through their immunoregulatory properties

Another  randomised, double-blind, placebo controlled trial[53] included 256 normoglycaemic pregnant women in their first trimester. They were randomised into three groups (group one received nutritional counselling with probiotics; group two received nutritional counselling and a placebo; group three received no nutritional counselling or placebo). The probiotic group received LGG® and BB-12® (10 billion CFU/day of each strain). The women were followed clinically and their glucose metabolism repeatedly evaluated from early pregnancy up until 12 months postpartum. 

Blood glucose concentrations were lowest in the nutritional counselling plus probiotic group during pregnancy and over the 12 months postpartum period, when compared to their baseline levels (Figure 4). 

Better glucose tolerance in the nutritional counselling with probiotics group was confirmed by a reduced risk insulin concentration and homeostasis model assessment, and the highest quantitative insulin sensitivity checking index during the last trimester of pregnancy. These changes were considered to be significant, and demonstrate the metabolic benefits of probiotic supplementation in pregnancy.

MODIFICATION OF INTESTINAL MICROBIOTA

Probiotics support the intestinal microbiota in various ways. For example, probiotics may manipulate both immune and nervous system responses. In turn, these mechanisms indirectly influence intestinal microbial community balance and function. 

Probiotics may also influence the gastrointestinal microbiota via more direct mechanisms. Strains such as LGG®[24] and BB-12®[25] have demonstrated the ability to displace pathogens via direct competition and through the secretion of antimicrobial substances,[26] to influence indigenous microbiota populations and manipulate their activities.[27]

The probiotic strains BB536 and M-16v have also demonstrated a modulating action on the gastrointestinal microbiota, specifically of pregnant women and their infants.[28],[29] 

The vaginal microbiota is thought to be transferred to the infant and to influence early microbiota development. A clinical study has shown that Bifidobacteria breve (the species to which M-16v belongs) was the most prevalent species in both the faeces of babies and the vaginal swabs of mothers.[30] A study on infants observed that BB536 can also help to establish a healthy intestinal microbiota in early life.[31]