First, a little background: Soy is one of the eight foods thought to be responsible for 90% of food-allergic reactions among Americans.1 Even so, only about three out of every 1,000 adults are allergic to soy, averaging the results of North American surveys published over the past decade or so. However, about twice as many people believe they have food allergies than studies indicate is the case.2 Therefore, a finding that fermented soyfoods do not elicit reactions in soy-sensitive individuals would be good news to lots of consumers. But are fermented soyfoods hypoallergenic?
There is no question that processing affects the allergenicity of foods.3 But why might fermenting soyfoods lower allergenicity? To understand why requires some basic knowledge of how foods elicit allergic reactions.
Food allergy is an abnormal immunological reaction, usually immunoglobulin E (IgE)-related. It results from the exposure (ingestion, skin contact, or inhalation) to exogenous food macromolecules (generally proteins) known as allergens or antigens. The allergen generates an initial IgE antibody response followed by a secondary IgE antibody response, which triggers an allergic reaction.4 Food proteins bind to the allergen-specific IgE molecules residing in the mast cells and basophils, causing them to release inflammatory mediators.
As many as 28 soy proteins bind to IgE from soy-allergic patients.5,6 Soybean seeds contain approximately 37% of protein, of which eight allergenic proteins (Gly m 1 to Gly m 8) have so far been registered by the International Union of Immunological Societies Allergen Nomenclature Sub-Committee.3,7 The major storage proteins β-conglycinin (Gly m 5) and glycinin (Gly m 6) represent 70% of the whole soybean protein and have been related to severe allergic reactions in European soy allergic subjects.8 The soybean protein Gly m Bd 30 K, also known as P34, is also thought to be one of the more allergenic soy proteins. IgE binding assays using immunoglobulin from soybean sensitive individuals shows that 65% of the total allergenic response was accounted for by P34.9
Fermentation is one of oldest methods of processing; fermentation can be traced back to the Neolithic period between 7000 and 6600 BC.10 Fermented foods account for about one-third of the food consumed in the world.11 In theory, fermented soyfoods could be less allergenic than unfermented soyfoods because during fermentation, microbial proteases are able to partially degrade food proteins, that is, to hydrolyze proteins into smaller peptides.12 If a protein is sufficiently degraded, it may lose its ability to bind to IgE and therefore also lose its ability to elicit an allergic reaction. In vitro work consistently shows fermentation reduces allergen content and allergenicity.
In 1993, Herian et al.13 determined the allergenicity of soy products using RAST inhibition. RAST is a radioimmunoassay test to detect specific IgE antibodies to suspected or known allergens. The suspected allergen is bound to an insoluble material and the patient’s serum is added. If the serum contains antibodies to the allergen, those antibodies will bind to the allergen. Radiolabeled anti-human IgE antibody is added where it binds to those IgE antibodies already bound to the insoluble material. The unbound anti-human IgE antibodies are washed away. The amount of radioactivity is proportional to the serum IgE for the allergen.
Based on the RAST inhibition curves, Herian et al.13 concluded that fermentation destroyed many of the allergens present in soybeans. Two years later, Bondo et al.14 were able to detect one of the major allergens in soybeans in tofu, but not in the fermented soyfoods natto and miso. In agreement with this finding is work by Mittag et al.,15 who analyzed 10 soyfoods and soybeans heated for between 0.5 and 4 hours for Gly m 4 (a major allergen in soybeans16). In miso, no Gly m 4 could be detected whereas textured soy protein contained 2 ppm Gly m 4, and tofu and soy flakes contained 9 and 11 ppm, respectively.
Several other studies also suggest fermented soy products are less likely to cause allergic reactions than their unfermented counterparts.17-21 For example, Tsuji et al.18 found that soybean-koji miso showed no P34 immunoreactivity in the sera of soybean-sensitive patients. Also, Yamanashi et al.19 simulated natto fermentation with autoclaved soybeans soaked in water overnight and inoculated with Bacillus natto (0.8 mg/g soybean). After 24 hours of fermentation, the product obtained did not bind with the monoclonal antibody against P34 or with soy-allergic patients’ sera. All proteins were hydrolyzed (molecular weight <10 kD), and the subsequent peptides showed no immunoreactivity. This study suggests that proteases particular to Bacillus natto digested the soy proteins into peptides that could not be recognized by antibodies. Song et al.22 also found fermented soybean meal, tempeh, and miso showed reduced immunoreactivity to human plasma, particularly if proteins were <20 kDa. In some cases, IgE immunoreactivity was reduced by almost 90%.
More recently, fermentation of soymilk by Lactobacillus helveticus and Enterococcus feacalis strains reduced the IgE immunoreactivity of patients allergic to the two main soy allergens: Gly m 5 and Gly m 6.23,24 Also, Yang et al.25 showed that fermentation of a soybean meal by a starter culture containing Lacticaseibacillus casei, yeast, and Bacillus subtilis impacted allergenicity when studied by in vitro and in vivo methods. Soy proteins were degraded into low-molecular-weight polypeptides, in which allergenic epitopic sequences of b-conglycinin and glycinin were destroyed, and a decrease in the in vitro human IgE-binding capacity of the fermented soybean proteins was observed.
Finally, sensitization experiments in a mouse model revealed that fermented soybean products induced lower levels of mucosal mast cell protease-1 (mMCP-1, a marker of intestinal immunopathology in food allergy models) and specific IgE25 and the fermented product soymilk kefir decreased serum ovalbumin-specific IgE levels in mice.26
In summary, considerable evidence indicates that fermentation reduces in vitro soy allergenicity and limited data indicate this is also the case in animal models. However, no study was identified that showed soy-sensitive individuals can consume fermented soy without experiencing an allergic reaction. Thus, the evidence does not appear to support statements in the literature that most people with a soybean allergy can safely consume fermented soybean products.27
Additional preclinical and clinical studies are required to assess the allergy risk of fermented soy products. Fermentation likely reduces allergenicity because allergen content is reduced. Therefore, in theory, in comparison to unfermented soyfoods, larger amounts of fermented soyfoods could be consumed without eliciting an allergic reaction. However, the dose of soy protein accepted as eliciting an allergic reaction is no more than 1.0 mg.7 Therefore, this threshold will be exceeded via the consumption of soyfoods regardless of whether they are fermented. Finally, it would be remiss not to mention that several cases have been reported of natto-induced late-onset anaphylaxis in adults due to formation of poly-γ-glutamic acid (a polymer of the amino acid glutamic acid) during fermentation.27
- Messina M, Venter C. Recent surveys on food allergy prevalence. Nutr Today. 2020;55:22-9.
- Gupta RS, Warren CM, Smith BM, et al. Prevalence and severity of food allergies among US adults. JAMA Netw Open. 2019;2:e185630.
- Verhoeckx KCM, Vissers YM, Baumert JL, et al. Food processing and allergenicity. Food Chem Toxicol. 2015;80:223-40.
- Babu KS, Arshad SH, Holgate ST. Anti-IgE treatment: an update. Allergy. 2001;56:1121-
- Awazuhara H, Kawai H, Maruchi N. Major allergens in soybean and clinical significance of IgG4 antibodies investigated by IgE- and IgG4-immunoblotting with sera from soybean-sensitive patients. Clin Exp Allergy. 1997;27:325-32.
- Wilson S, Blaschek K, de Mejia E. Allergenic proteins in soybean: processing and reduction of P34 allergenicity. Nutr Rev. 2005;63:47-58.
- Taylor SL, Houben GF, Blom WM, et al. The population threshold for soy as an allergenic food – Why did the reference dose decrease in VITAL 3.0? Trend Food Sci Technol. 2021;112:99-1-8.
- Holzhauser T, Wackermann O, Ballmer-Weber BK, et al. Soybean (Glycine max) allergy in Europe: Gly m 5 (beta-conglycinin) and Gly m 6 (glycinin) are potential diagnostic markers for severe allergic reactions to soy. J Allergy Clin Immunol. 2009;123:452-8.
- L’Hocine L, Boye JI. Allergenicity of soybean: new developments in identification of allergenic proteins, cross-reactivities and hypoallergenization technologies. Crit Rev Food Sci Nutr. 2007;47:127-43.
- McGovern PE, Zhang J, Tang J, et al. Fermented beverages of pre- and proto-historic China. Proc Natl Acad Sci U S A. 2004;101:17593-8.
- El Mecherfi KE, Todorov SD, Cavalcanti de Albuquerque MA, et al. Allergenicity of fermented foods: Emphasis on seeds protein-based products. Foods. 2020;9.
- Cabuk B, Nosworthy MG, Stone AK, et al. Effect of fermentation on the protein digestibility and levels of non-nutritive compounds of pea protein concentrate. Food Technol Biotechnol. 2018;56:257-64.
- Herian AM, Taylor SL, Bush RK. Allergenic reactivity of various soybean products as determined by RAST inhibition. J Food Sci. 1993;58:385-8.
- Bando N, Tsuji H, Heimori M, et al. Quantitative analysis of Gly m Bd 28K in soybean products by a sandwich enzyme-linked immunosorbent assay. J Nutr Sci Vitaminol. 1998;44:655-64.
- Mittag D, Vieths S, Vogel L, et al. Soybean allergy in patients allergic to birch pollen: clinical investigation and molecular characterization of allergens. J Allergy Clin Immunol. 2004;113:148-54.
- Julka S, Kuppannan K, Karnoup A, et al. Quantification of Gly m 4 protein, a major soybean allergen, by two-dimensional liquid chromatography with ultraviolet and mass spectrometry detection. Anal Chem. 2012;84:10019-30.
- Frias J, Song YS, Martinez-Villaluenga C, et al. Immunoreactivity and amino acid content of fermented soybean products. J Agric Food Chem. 2008;56:99-105.
- Tsuji H, Okada N, Yamanashi R, et al. Fate of a major soybean allergen, Gly m Bd 30K, in rice-, barley-, and soybean-koji miso (fermented soybean paste) during fermentation. Food Sci Technol Int (Tokyo). 1997;3:145-9.
- Yamanashi R, Huang T, Tsuji H. Reduction of the soybean allergenicity by the fermentation with Bacillus natto. Food Sci Technol Int (Tokyo). 1995;1:14-7.
- Liu B, Teng D, Wang X, et al. Detection of the soybean allergenic protein Gly m Bd 28K by an indirect enzyme-linked immunosorbent assay. J Agric Food Chemistry. 2013;61:822-8.
- Huang L, Wang C, Zhang Y, et al. Degradation of anti-nutritional factors and reduction of immunoreactivity of tempeh by co-fermentation with Rhizopus oligosporus and Actinomucor elegans. Int J Food Science Technol. 2019;54:1836–48.
- Song YS, Frias J, Martinez-Villaluenga C, et al. Immunoreactivity reduction of soybean meal by fermentation, effect on amino acid composition and antigenicity of commercial soy products. Food Chem. 2008;108:571-81.
- Meinlschmidt P, Schweiggert-Weisz U, Eisner P. Soy protein hydrolysates fermentation: Effect of debittering and degradation of major soy allergens. LWT Food Sci Technol. 2016;71:202-12.
- Biscola V, de Olmos AR, Choiset Y, et al. Soymilk fermentation by Enterococcus faecalis VB43 leads to reduction in the immunoreactivity of allergenic proteins beta-conglycinin (7S) and glycinin (11S). Beneficial microbes. 2017;8:635-43.
- Yang A, Zuo L, Cheng Y, et al. Degradation of major allergens and allergenicity reduction of soybean meal through solid-state fermentation with microorganisms. Food & function. 2018;9:1899-909.
- Liu J-R, Wang S-Y, Chen M-J, et al. The anti-allergenic properties of milk kefir and soymilk kefir and their beneficial effects on the intestinal microflora. J Sci Food Agric. 2006;86:2527–33.
- Mori S, Tsumagari S, Kurihara K. A case of a 7-year-old girl with late-onset anaphylaxis to fermented soybeans. Pediatr Allergy Immunol. 2017;28:501-2.
This blog sponsored by the Soy Nutrition Institute and the United Soybean Board.