Review of Pro-and / or Prebiotics in Extensively Hydrolyzed or Amino Acid-Based Infant Formula for Food Allergy

Received: January 27, 2017 Revised: March 30, 2017 Accepted: April 12, 2017 Abstract: Background: The incidence of food allergy is a growing health concern in the United States. Research suggests that there is a link between the gut microbiota and the development of allergy. As a result, researchers propose that gut microbial populations could affect the development and management of immunological disease.


INTRODUCTION
The incidence of food allergy has increased worldwide and is a growing health concern in the United States, where an estimated 6% of children under 3 years of age and approximately 4% of adults are affected [1].The risk of developing food allergies varies based on age, race, gender, and genetic factors.The National Health and Nutrition Examination (NHANES) survey found that non-Hispanic blacks, males, and children exhibit increased risk for the development of food allergies [2].
Food allergy is defined as adverse reactions to food involving specific Immunoglobulin E (IgE)-mediated, cellmediated, or both IgE-and cell-mediated immunologic mechanisms [3].IgE-mediated reactions include anaphylaxis, angiodemia, urticaria, wheezing, vomiting, rhinitis, and eczema.Non-IgE-mediated reactions include villous atrophy, eosinophilic proctocolitis, enterocolitis, and esophagitis and are associated with the consumption of cow's milk, soy, and other dietary proteins.In addition, affected infants may display symptoms of food allergy such as irritability and colic [4].
The clinical management of food allergy should involve both short-term interventions as well as long-term management to decrease the risk of future reactions.The primary strategy for long-term management is the adoption of an elimination diet.Specialized hypoallergenic formulas such as extensively hydrolyzed protein formulas (EHF) and amino acid-based formulas (AAF) are recommended for young patients including infants and children.
In infants diagnosed with food allergies, elimination diets (restriction in the offending protein) are generally followed for at least 9-12 months from diagnosis.Extensively hydrolyzed protein formula and AAF are utilized for infants who are unable to tolerate breastmilk, cow's milk or soy protein.Extensively hydrolyzed protein formulas have been safely consumed by infants with conditions such as severe inflammatory bowel disease and cow's milk allergy for more than 50 years, and is the first choice for allergic infants who cannot be breast fed.Amino acid-based formulas are recommended in the event when EHF is not tolerated.Both formulas in the U.S. are required to undergo extensive clinical testing in order to prove their compliance with established standards for hypoallergenicity [4].
Research suggests that there is a link between the gut microbiota and the development of allergy.The gut microbiota consists of more than 1000 bacterial species, and developments in sequencing technology have allowed researchers to better understand the diversity of all bacterial species within the gut microbiota [5].As a result, researchers have proposed that the bacterial populations making up the gut microbiota impact systemic immunity and metabolism, and could therefore affect the development of immunological disease [6].
A recent study following 33 subjects diagnosed with food allergy from infancy to 5 years of age found that 84.8% of subjects experienced resolution of food allergy by 5 years of age.The research also indicated that high rates of breastfeeding in addition to early introduction of supplementary foods rich in prebiotics may impact the development of food allergy [7].
Mouse models have been utilized to understand the effects of gut microbiota on the development of food allergy.In a study focused on oral tolerance, gnotobiotic mice were transplanted with gut microbiota composed mainly of Bifidobacterium and Bacteroides, and as a result exhibited low sensitization to cow's milk [8].These results suggest that the transplanted bacteria have a protective effect on food allergy development.Another study showed that the gut microbiota in a food allergy model displayed increased levels of Lachnospiraceae, Lactobacillaceae, Rikenellacease, and Porphyromonadaceae, indicating their possible role in the development of sensitization [9].
Studies focused on human models have indicated similar results.A recent study found that among infants displaying food allergen sensitization, Enterobacteriaceae were overrepresented and Bacteroidaceae were underrepresented at 3 months and 1 year.The risk of allergen development increased with higher Enterobacteriaceae/Bacteroidaceae ratio but decreased with microbiota diversity [10].Two additional studies exist comparing the gut microbiota of the healthy infant versus the gut microbiota of infants exhibiting food allergy.Both studies found that infants with food allergy displayed different strains of microbiota as well as different levels of microbiota diversity than that of healthy infants [11,12].The development of atopic disease is also shown to be affected by composition of gut microbiota.A study by Nylund et al. found that the microbiota composition among infants with eczema did not differ from the controls at 6 months of age, but was more diverse and at 18 months of age, more similar to adult gut microbiota composition than control subjects [13].
Probiotics and prebiotics may alter the gut flora in a way that confers health benefits.Probiotics are live microorganisms that have demonstrated, in animal and in vitro studies, to have numerous beneficial impacts on overall health.Among these benefits are the improved protection from infection, development of innate immunity, improvement of gut barrier function, and the inhibition of gut colonization of pathogenic bacteria while allowing for the enhanced colonization of healthy bacteria [14 -20].One study found a link between the addition of prebiotics to infant formula and higher fecal levels of secretory immunoglobulin A, an antibody that plays a role in the defense of the gastrointestinal tract [21].Prebiotics are non-digestible substances that provide a beneficial health impact by stimulating the growth or activity of advantageous bacteria in the gut.The term synbiotic refers to a combination of probiotics and prebiotics.
The evidence indicating the impact of gut microbiota composition on immune development and function presents an opportunity to re-evaluate the preventative and therapeutic strategies in response to food allergy.A recent study demonstrated that daily Lactobacillus GG supplementation resulted in a shift in intestinal microbial population to one with increased taxa associated with a decreased risk of allergy and atopy [22].Altering the composition of an allergic patient's microbiota to one that has higher levels of bacteria associated with tolerance may be possible by the use of probiotics and/or prebiotics.However, reviews focused on the effect of probiotic and/or prebiotic supplementations as part of treatment for food allergy have been inconclusive.The purpose of this review is to present current evidence on the efficacy of probiotic, prebiotic, and synbiotic addition to EHF and AAF for the management of food allergy.

Types of Studies
Randomized clinical trials are the only studies included in this review.Case reports, observational studies, systematic and narrative reviews, letters, editorials, and commentaries were excluded.

Types of Participants
Studies included were limited to those with infant and child participants less than 12 years of age who were consuming EHF or AAF supplemented with probiotics and/or prebiotics and had a confirmed diagnosis of food allergy.

Search Strategy
The databases PubMed (www.ncbi.nlm.nih.gov),Embase (Excerpta Medica database), FSTA (Food Science and Technology Abstracts), and MEDLINE were searched for articles published from January 1, 1946 to June 28, 2016.Google Scholar was searched to identify any literature not found in other databases All databases were searched using the following terms: (prebiotic* OR probiotic* OR synbiotic*) AND (infants OR children OR child OR baby OR babies) AND ("amino acid" OR "extensively hydrolyzed").

RESULTS
The Embase, FSTA, and MEDLINE searches yielded 139 results total.After application of inclusion and exclusion criteria Table (1), seven studies were included for review.The Pubmed search yielded 54 results.After application of inclusion and exclusion criteria, four additional studies were included for review.No additional studies were included from Google Scholar searches.Out of the 11 studies included, five measured the effects of probiotic addition, one measured the effects of prebiotic addition, and five measured the effects of synbiotic addition to EHF and AAF.All five probiotic studies focused on the addition of probiotics to EHF for the management of cow's milk allergy.The outcomes for these studies included changes in fecal characteristics, development of tolerance, changes in SCORAD index (SCORing Atopic Dermatitis), changes in immunological and inflammatory factors, microbial cell counts in feces, and effects on wheezing and hospital admissions.Lactobacillus was included as part of the treatment in all five studies, and Bifidobacterium was part of the treatment in two of the studies.
Only one study involving prebiotic addition met inclusion and exclusion criteria.The primary outcome for the study was the effect on SCORAD index of infants with atopic dermatitis after prebiotic galacto-oligosaccharide (GOS) addition to EHF.Among five of the studies focusing on synbiotic addition to EHF or AAF, three studies measured the effects of synbiotic addition to AAF in response to cow's milk allergy.The remaining two studies measured the effects of synbiotic addition to EHF in response to atopic dermatitis.The outcomes for these studies included anthropometric changes, formula tolerance, hypoallergenicity, changes in SCORAD index, fecal characteristics and bacterial composition of feces, changes in immunological factors, and incidence of infection.Out of the five studies, three studies used a synbiotic blend of Bifidobacterium breve M-16V + oligofructose, long-chain inulin, and acidic oligosaccharides.The remaining two studies used a synbiotic blend of Bifidobacterium breve M-16V + a mixture of short chain galacto-/long chain fructooligosaccharides.

SCORAD Index
Out of the 11 studies, eight listed change in SCORAD index as an outcome.SCORAD index reportedly improved in all eight studies in which probiotics and/or prebiotics were added to EHF or AAF.However, only three studies demonstrated statistically significant improvement in SCORAD index in the treatment group than in the control group [23,24,29].One study found that SCORAD index was only significantly improved among patients who exhibited elevated total or specific IgE levels [25].

Inflammatory and Immunological Factors
Inflammation is a significant factor in the manifestation of atopic disease, and certain strains of microflora have been shown in vitro to impact the immune system as well as the production of pro-inflammatory and anti-inflammatory cytokines [26 -28].Four of the included studies found that Lactobacillus GG, Bifdobacterium lactis, or a mix of Bifidobacterium breve with short chain galacto-/long chain fructooligosaccharides, when added to EHF, significantly led to moderate immunologic and/or inflammatory responses [23 -25, 29].These results provide further possible evidence of probiotic and synbiotic effectiveness in the reduction of atopic disease in food allergic individuals.

Stool Characteristics
In patients exhibiting hematochezia, probiotic addition to EHF was beneficial.One study found that the consumption of EHF with the addition of Lactobacillus GG resulted in decreased fecal calprotectin levels, and it was also found that after 4 weeks, none of the patients in the treatment group had blood in their stool compared to 5 out of 14 in the control group that still had blood in their stool [30].
Results varied among studies with outcomes including fecal consistency and frequency.One study did not report any significant difference in stool consistency and frequency, whereas two other studies reported softer stools and higher stool frequency among treatment groups [31 -33].When outcomes included stool bacterial populations, the results varied.One study measuring the effects of Lactobacillus GG supplementation found that fecal bacterial counts were unaffected [32]; while another study measuring the effects of Bifidobacterium breve supplementation found that the treatment group demonstrated a significantly higher detection rate of B. breve in stools [33].

Infection Incidence
Three of the included studies measured incidence of infection after probiotic and synbiotic supplementation to EHF and AAF.One study found that Lactobacillus casei and Bifidobacterium lactis, when added to EHF, did not have any effect on hospital admissions [29].The remaining two studies found that Bifidobacterium breve and a mixture of prebiotics resulted in a lower incidence of infection and antibiotic use [31,34].

Growth
Changes in weight, length, and head circumference were outcomes included in two studies.Both studies found that synbiotic-supplemented AAF supported normal growth and both control and treatment groups experienced increases in weight, length, and head circumference, with no significant differences between the two groups [31,34].

Adverse Effects
There were very few adverse effects reported in the studies included.One study found that heat-inactivated Lactobacillus GG resulted in adverse gastrointestinal effects and was discontinued.However, the use of viable Lactobacillus GG in the same study did not have any adverse effects [32].In a second study, diarrhea was reported in 4% of subjects in the control group and in 22% of subjects in the treatment group receiving AAF supplemented with Bifidobacterium breve and a prebiotic mixture of oligofructose, long-chain inulin, and acidic oligosaccharides [34].

DISCUSSION
In summary, while the results of this review suggest that the advantages associated with probiotic and/or prebiotic addition to hypoallergenic formulas improved skin conditions and SCORAD index, decreased incidence of hematochezia and infection, improved inflammatory and immunological factors, improved fecal characteristics, and supported normal growth, very few studies reported a statistically significant effect of feeding prebiotics or probiotics.
The modulation of immunological and inflammatory factors as a result of probiotic addition to EHF is supported by a recent meta-analysis showing that probiotic supplementation was effective in reducing total IgE as well as the risk of atopic sensitization among patients [35].Reduced IgE levels are one of the hallmarks in the development of allergen tolerance, and the results of this review as well as the meta-analysis suggests that probiotics may play a role in this process [36].Probiotics affect IFN-γ secretion in patients with cow's milk allergy and IgE-associated atopic dermatitis.Decreased IFN-γ response is associated with the development of cow's milk allergy, and probiotic supplementation resulted in increased IFN-γ secretion and therefore likely contributes to the management of the condition [37].This review found that in every instance that SCORAD index was an outcome for probiotic and/or prebiotic addition to hypoallergenic formula, SCORAD index improved.Despite the general improvements in SCORAD, only three out of eight studies with this outcome found the results to be significant.A Cochrane Review also reported mixed results of infant eczema outcomes in patients consuming probiotic supplements; however, the author noted that the varying outcomes may be attributed to heterogeneity among the studies [38].This review shows that a possible driving factor for the effectiveness of probiotic and/or prebiotic supplementation in hypoallergenic formula on SCORAD index is the level of total or specific IgE in subjects in the treatment group.Not all studies reported the baseline IgE levels for their subjects, which may account for differing results.
In addition, research has shown that probiotic and/or prebiotic addition to hypoallergenic formula does not affect the formula's hypoallergenicity.One study measured the hypoallergenicity of an extensively hydrolyzed protein formula containing Bifidobacterium lactis and compared its hypoallergenicity to that of an EHF containing Lactobacillus GG.The study found that out of 66 participants, none had a reaction to EHF + Bifidobacterium lactis and only one had a reaction to EHF + Lactobacillus GG.Both formulas met hypoallergenicity criteria set by the American Academy of Pediatrics (AAP) [39].Three studies included in this review found that AAF with synbiotics resulted in normal tolerance and either normal or increased growth in patients [31,34,40].There were two cases of adverse gastrointestinal effects in this review; an increase in the incidence of diarrhea [34] and gastrointestinal intolerance due to heat-inactivated Lactobacillus GG [32].The literature review did not report any serious contraindications to adding probiotic and/or prebiotic to hypoallergenic formula.