The Open Nutrition Journal




(Discontinued)

ISSN: 1874-2882 ― Volume 15, 2021
REVIEW ARTICLE

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



Nichole Giardina1, Barbara Marriage2, *
1 Abbott Nutrition, Research Park at University of Illinois at Urbana-Champaign, Champaign, Illinois
2 Abbott Nutrition, Columbus, Ohio

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.

Objectives:

The purpose of this review is to present current evidence of the advantages and disadvantages of probiotic and/or prebiotic addition to extensively hydrolyzed protein (EHF) and amino acid-based infant formulas (AAF) for the management of food allergy.

Method:

Only randomized controlled trials were included for review. The randomized controlled trials were limited to human subjects less than 12 years of age with a confirmed case of food allergy who were consuming EHF or AAF supplemented with probiotics and/or prebiotics.

Results:

Eleven studies were included for review. Probiotic and synbiotic addition was associated with an improvement in SCORAD index in EHF and AAF, and EHF significantly moderated immunologic and/or inflammatory responses. Probiotic addition to EHF benefited patients exhibiting hematochezia, and synbiotic addition resulted in softer stool, higher stool frequency, and decreased incidence of infection in some studies.

Conclusion:

Although few studies report statistically significant effects upon feeding prebiotics or probiotics with EHF and AAF on food allergy, this review sheds light on evidence that such inclusion may have positive impacts on SCORAD index, stool quality, immunologic and inflammatory factors, and incidence of infection.

Keywords: Food allergy, Infant formula, Microbiota, Probiotics, Prebiotics, Synbiotics.


Article Information


Identifiers and Pagination:

Year: 2017
Volume: 11
First Page: 27
Last Page: 38
Publisher Id: TONUTRJ-11-27
DOI: 10.2174/1874288201711010027

Article History:

Received Date: 27/01/2017
Revision Received Date: 30/03/2017
Acceptance Date: 12/04/2017
Electronic publication date: 30/05/2017
Collection year: 2017

© 2017 Giardina and Marriage.

open-access license: This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International Public License (CC-BY 4.0), a copy of which is available at: https://creativecommons.org/licenses/by/4.0/legalcode. This license permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


* Address correspondence to this author at the Abbott Nutrition, Regulatory Science and Innovation, 3300 Stelzer Road, Columbus, Ohio 43219, Tel: +1 614-624-4416, Fax: +1 614-727-4417; Email: barbara.marriage@abbott.com





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 [1Sicherer SH, Sampson HA. Food allergy. J Allergy Clin Immunol 2010; 125(2)(Suppl. 2): S116-25.
[http://dx.doi.org/10.1016/j.jaci.2009.08.028] [PMID: 20042231]
]. 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 [2Liu AH, Jaramillo R, Sicherer SH, et al. National prevalence and risk factors for food allergy and relationship to asthma: results from the National Health and Nutrition Examination Survey 2005-2006. J Allergy Clin Immunol 2010; 126(4): 798-806.e13.
[http://dx.doi.org/10.1016/j.jaci.2010.07.026] [PMID: 20920770]
].

Food allergy is defined as adverse reactions to food involving specific Immunoglobulin E (IgE)-mediated, cell-mediated, or both IgE- and cell-mediated immunologic mechanisms [3Muraro A, Werfel T, Hoffmann-Sommergruber K, et al. EAACI food allergy and anaphylaxis guidelines: Diagnosis and management of food allergy. Allergy 2014; 69(8): 1008-25.
[http://dx.doi.org/10.1111/all.12429] [PMID: 24909706]
]. 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 [4American Academy of Pediatrics. Committee on Nutrition. Hypoallergenic infant formulas. Pediatrics 2000; 106(2 Pt 1): 346-9.
[PMID: 10920165]
].

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 [4American Academy of Pediatrics. Committee on Nutrition. Hypoallergenic infant formulas. Pediatrics 2000; 106(2 Pt 1): 346-9.
[PMID: 10920165]
].

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 [5Human Microbiome Project Consortium. Structure, function and diversity of the healthy human microbiome. Nature 2012; 486(7402): 207-14.
[http://dx.doi.org/10.1038/nature11234] [PMID: 22699609]
]. 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 [6Hooper LV, Littman DR, Macpherson AJ. Interactions between the microbiota and the immune system. Science 2012; 336(6086): 1268-73.
[http://dx.doi.org/10.1126/science.1223490] [PMID: 22674334]
].

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 [7Doğruel D, Bingöl G, Yılmaz M, Altıntaş DU. The ADAPAR birth cohort study: Food allergy results at five years and new insights. Int Arch Allergy Immunol 2016; 169(1): 57-61.
[http://dx.doi.org/10.1159/000443831] [PMID: 26954777]
].

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 [8Rodriguez B, Prioult G, Hacini-Rachinel F, et al. Infant gut microbiota is protective against cows milk allergy in mice despite immature ileal T-cell response. FEMS Microbiol Ecol 2012; 79(1): 192-202.
[http://dx.doi.org/10.1111/j.1574-6941.2011.01207.x] [PMID: 22029421]
]. 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 [9Noval Rivas M, Burton OT, Wise P, et al. A microbiota signature associated with experimental food allergy promotes allergic sensitization and anaphylaxis. J Allergy Clin Immunol 2013; 131(1): 201-12.
[http://dx.doi.org/10.1016/j.jaci.2012.10.026] [PMID: 23201093]
].

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 [10Azad MB, Konya T, Guttman DS, et al. Infant gut microbiota and food sensitization: Associations in the first year of life. Clin Exp Allergy 2015; 45(3): 632-43.
[http://dx.doi.org/10.1111/cea.12487] [PMID: 25599982]
]. 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 [11Björkstén B, Sepp E, Julge K, Voor T, Mikelsaar M. Allergy development and the intestinal microflora during the first year of life. J Allergy Clin Immunol 2001; 108(4): 516-20.
[http://dx.doi.org/10.1067/mai.2001.118130] [PMID: 11590374]
, 12Ling Z, Li Z, Liu X, et al. Altered fecal microbiota composition associated with food allergy in infants. Appl Environ Microbiol 2014; 80(8): 2546-54.
[http://dx.doi.org/10.1128/AEM.00003-14] [PMID: 24532064]
]. 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 [13Nylund L, Satokari R, Nikkilä J, et al. Microarray analysis reveals marked intestinal microbiota aberrancy in infants having eczema compared to healthy children in at-risk for atopic disease. BMC Microbiol 2013; 13(1): 12.
[http://dx.doi.org/10.1186/1471-2180-13-12] [PMID: 23339708]
].

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 [14Fukuda S, Toh H, Hase K, et al. Bifidobacteria can protect from enteropathogenic infection through production of acetate. Nature 2011; 469(7331): 543-7.
[http://dx.doi.org/10.1038/nature09646] [PMID: 21270894]
-20Ewaschuk JB, Diaz H, Meddings L, et al. Secreted bioactive factors from bifidobacterium infantis enhance epithelial cell barrier function. Am J Physiol Gastrointest Liver Physiol 2008; 295(5): G1025-34.
[http://dx.doi.org/10.1152/ajpgi.90227.2008] [PMID: 18787064]
]. 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 [21Bakker-Zierikzee AM, Tol EA, Kroes H, Alles MS, Kok FJ, Bindels JG. Faecal SIgA secretion in infants fed on pre- or probiotic infant formula. Pediatr Allergy Immunol 2006; 17(2): 134-40.
[http://dx.doi.org/10.1111/j.1399-3038.2005.00370.x] [PMID: 16618363]
]. 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 [22Cox MJ, Huang YJ, Fujimura KE, et al. Lactobacillus casei abundance is associated with profound shifts in the infant gut microbiome. PLoS One 2010; 5(1): e8745.
[http://dx.doi.org/10.1371/journal.pone.0008745] [PMID: 20090909]
]. 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.

MATERIALS AND METHODS

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.

Table 1
Inclusion and Exclusion Criteria.


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.

Table 2
Detailed Characteristics of Included Studies.


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 [23Isolauri E, Arvola T, Sütas Y, Moilanen E, Salminen S. Probiotics in the management of atopic eczema. Clin Exp Allergy 2000; 30(11): 1604-10.
[http://dx.doi.org/10.1046/j.1365-2222.2000.00943.x] [PMID: 11069570]
, 24Majamaa H, Isolauri E. Probiotics: a novel approach in the management of food allergy. J Allergy Clin Immunol 1997; 99(2): 179-85.
[http://dx.doi.org/10.1016/S0091-6749(97)70093-9] [PMID: 9042042]
, 29Hol J, van Leer EH, Elink Schuurman BE, et al. The acquisition of tolerance toward cows milk through probiotic supplementation: a randomized, controlled trial. J Allergy Clin Immunol 2008; 121(6): 1448-54.
[http://dx.doi.org/10.1016/j.jaci.2008.03.018] [PMID: 18436293]
]. One study found that SCORAD index was only significantly improved among patients who exhibited elevated total or specific IgE levels [25van der Aa LB, Heymans HS, van Aalderen WM, et al. Effect of a new synbiotic mixture on atopic dermatitis in infants: A randomized-controlled trial. Clin Exp Allergy 2010; 40(5): 795-804.
[PMID: 20184604]
].

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 [26Pessi T, Sütas Y, Saxelin M, Kallioinen H, Isolauri E. Antiproliferative effects of homogenates derived from five strains of candidate probiotic bacteria. Appl Environ Microbiol 1999; 65(11): 4725-8.
[PMID: 10543777]
-28Sütas Y, Soppi E, Korhonen H, et al. Suppression of lymphocyte proliferation in vitro by bovine caseins hydrolyzed with Lactobacillus casei GG-derived enzymes. J Allergy Clin Immunol 1996; 98(1): 216-24.
[http://dx.doi.org/10.1016/S0091-6749(96)70245-2] [PMID: 8765837]
]. 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 [23Isolauri E, Arvola T, Sütas Y, Moilanen E, Salminen S. Probiotics in the management of atopic eczema. Clin Exp Allergy 2000; 30(11): 1604-10.
[http://dx.doi.org/10.1046/j.1365-2222.2000.00943.x] [PMID: 11069570]
-25van der Aa LB, Heymans HS, van Aalderen WM, et al. Effect of a new synbiotic mixture on atopic dermatitis in infants: A randomized-controlled trial. Clin Exp Allergy 2010; 40(5): 795-804.
[PMID: 20184604]
, 29Hol J, van Leer EH, Elink Schuurman BE, et al. The acquisition of tolerance toward cows milk through probiotic supplementation: a randomized, controlled trial. J Allergy Clin Immunol 2008; 121(6): 1448-54.
[http://dx.doi.org/10.1016/j.jaci.2008.03.018] [PMID: 18436293]
]. 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 [30Baldassarre ME, Laforgia N, Fanelli M, Laneve A, Grosso R, Lifschitz C. Lactobacillus GG improves recovery in infants with blood in the stools and presumptive allergic colitis compared with extensively hydrolyzed formula alone. J Pediatr 2010; 156(3): 397-401.
[http://dx.doi.org/10.1016/j.jpeds.2009.09.012] [PMID: 19880141]
].

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 [31Burks WA, Harthoorn LF, Langford JE, et al. Functional effects of an amino-acid based formula with synbiotics in cows milk allergic infants. Clin Transl Allergy 2014; 4(1): 1.
[PMID: 24393277]
-33Van Der Aa LB, Heymans HS, Van Aalderen WM, et al. Beneficial effects of a synbiotic mixture on the intestinal microbiota of infants with atopic dermatitis. Allergy 2009; 64: 277-8.]. 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 [32Kirjavainen PV, Salminen SJ, Isolauri E. Probiotic bacteria in the management of atopic disease: Underscoring the importance of viability. J Pediatr Gastroenterol Nutr 2003; 36(2): 223-7.
[http://dx.doi.org/10.1097/00005176-200302000-00012] [PMID: 12548058]
]; 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 [33Van Der Aa LB, Heymans HS, Van Aalderen WM, et al. Beneficial effects of a synbiotic mixture on the intestinal microbiota of infants with atopic dermatitis. Allergy 2009; 64: 277-8.].

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 [29Hol J, van Leer EH, Elink Schuurman BE, et al. The acquisition of tolerance toward cows milk through probiotic supplementation: a randomized, controlled trial. J Allergy Clin Immunol 2008; 121(6): 1448-54.
[http://dx.doi.org/10.1016/j.jaci.2008.03.018] [PMID: 18436293]
]. The remaining two studies found that Bifidobacterium breve and a mixture of prebiotics resulted in a lower incidence of infection and antibiotic use [31Burks WA, Harthoorn LF, Langford JE, et al. Functional effects of an amino-acid based formula with synbiotics in cows milk allergic infants. Clin Transl Allergy 2014; 4(1): 1.
[PMID: 24393277]
, 34Burks AW, Harthoorn LF, Van Ampting MT, et al. Synbiotics-supplemented amino acid-based formula supports adequate growth in cows milk allergic infants. Pediatr Allergy Immunol 2015; 26(4): 316-22.
[http://dx.doi.org/10.1111/pai.12390] [PMID: 25845680]
].

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 [31Burks WA, Harthoorn LF, Langford JE, et al. Functional effects of an amino-acid based formula with synbiotics in cows milk allergic infants. Clin Transl Allergy 2014; 4(1): 1.
[PMID: 24393277]
, 34Burks AW, Harthoorn LF, Van Ampting MT, et al. Synbiotics-supplemented amino acid-based formula supports adequate growth in cows milk allergic infants. Pediatr Allergy Immunol 2015; 26(4): 316-22.
[http://dx.doi.org/10.1111/pai.12390] [PMID: 25845680]
].

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 [32Kirjavainen PV, Salminen SJ, Isolauri E. Probiotic bacteria in the management of atopic disease: Underscoring the importance of viability. J Pediatr Gastroenterol Nutr 2003; 36(2): 223-7.
[http://dx.doi.org/10.1097/00005176-200302000-00012] [PMID: 12548058]
]. 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 [34Burks AW, Harthoorn LF, Van Ampting MT, et al. Synbiotics-supplemented amino acid-based formula supports adequate growth in cows milk allergic infants. Pediatr Allergy Immunol 2015; 26(4): 316-22.
[http://dx.doi.org/10.1111/pai.12390] [PMID: 25845680]
].

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 [35Elazab N, Mendy A, Gasana J, Vieira ER, Quizon A, Forno E. Probiotic administration in early life, atopy, and asthma: A meta-analysis of clinical trials. Pediatrics 2013; 132(3): e666-76.
[http://dx.doi.org/10.1542/peds.2013-0246] [PMID: 23958764]
]. 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 [36Wisniewski J, Agrawal R, Woodfolk JA. Mechanisms of tolerance induction in allergic disease: Integrating current and emerging concepts. Clinical and experimental allergy. J British Soc Allergy Clin Immunol 2013; 43(2): 164-76.
[http://dx.doi.org/10.1111/cea.12016]
]. 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 [37Pohjavuori E, Viljanen M, Korpela R, et al. Lactobacillus GG effect in increasing IFN-gamma production in infants with cows milk allergy. J Allergy Clin Immunol 2004; 114(1): 131-6.
[http://dx.doi.org/10.1016/j.jaci.2004.03.036] [PMID: 15241356]
].

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 [38Osborn DA, Sinn JKH. Probiotics in infants for prevention of allergic disease and food hypersensitivity. Cochrane Database of Systematic Reviews 2007; 4: 5.
[http://dx.doi.org/10.1002/14651858.CD006475.pub2]
]. 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) [39Czerkies L, Collins B, Nowak-Wegrzyn AH, Saavedra J. Hypoallergenicity of a new extensively hydrolyzed 100% Whey-Based formula containing probiotics. J Allergy Clin Immunol 2015; 135(2): AB35.
[http://dx.doi.org/10.1016/j.jaci.2014.12.1045]
]. Three studies included in this review found that AAF with synbiotics resulted in normal tolerance and either normal or increased growth in patients [31Burks WA, Harthoorn LF, Langford JE, et al. Functional effects of an amino-acid based formula with synbiotics in cows milk allergic infants. Clin Transl Allergy 2014; 4(1): 1.
[PMID: 24393277]
, 34Burks AW, Harthoorn LF, Van Ampting MT, et al. Synbiotics-supplemented amino acid-based formula supports adequate growth in cows milk allergic infants. Pediatr Allergy Immunol 2015; 26(4): 316-22.
[http://dx.doi.org/10.1111/pai.12390] [PMID: 25845680]
, 40Harvey BM, Langford JE, Harthoorn LF, et al. Effects on growth and tolerance and hypoallergenicity of an amino acid-based formula with synbiotics. Pediatr Res 2014; 75(2): 343-51.
[http://dx.doi.org/10.1038/pr.2013.211] [PMID: 24216543]
]. There were two cases of adverse gastrointestinal effects in this review; an increase in the incidence of diarrhea [34Burks AW, Harthoorn LF, Van Ampting MT, et al. Synbiotics-supplemented amino acid-based formula supports adequate growth in cows milk allergic infants. Pediatr Allergy Immunol 2015; 26(4): 316-22.
[http://dx.doi.org/10.1111/pai.12390] [PMID: 25845680]
] and gastrointestinal intolerance due to heat-inactivated Lactobacillus GG [32Kirjavainen PV, Salminen SJ, Isolauri E. Probiotic bacteria in the management of atopic disease: Underscoring the importance of viability. J Pediatr Gastroenterol Nutr 2003; 36(2): 223-7.
[http://dx.doi.org/10.1097/00005176-200302000-00012] [PMID: 12548058]
]. The literature review did not report any serious contraindications to adding probiotic and/or prebiotic to hypoallergenic formula.

CONCLUSION

The purpose of this paper was to review the use of probiotics and/or prebiotics in extensively hydrolyzed protein or amino acid-based formula and their impact on food allergy.

The strength of evidence in this review is limited by heterogeneity among the studies reviewed and the limited number of studies included. There are vast differences in factors such as sample size, age range, intervention, dose, and duration in the studies included in this review. In addition, the scientific community strongly lacks studies measuring the effects of probiotic and/or prebiotic addition to hypoallergenic formulas.

At present, there is not enough evidence to make any recommendation for inclusion of prebiotics or probiotics to EHF or AAF. Moving forward, future research should ensure adequate sample size and focus on using similar age groups, outcomes measures, and measuring techniques. The results of this review cannot be generalized and extrapolated to other prebiotic mixtures and probiotic strains. Different probiotic strains and prebiotic mixtures may yield different results.

Although there is insufficient evidence to draw a conclusion, the results of this review suggest that there may be benefits associated with hypoallergenic formulas supplemented with probiotics and prebiotics, and that further research in this area is warranted. It is also of note that both prebiotics and probiotics in the doses studied appear to be safe and well tolerated.

CONFLICT OF INTEREST

The authors confirm that this article content has no conflict of interest.

ACKNOWLEDGEMENTS

Declared none.

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