Re: 식이 피트산 부작용 phytase 보충제로 생체이용율 높이기.

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Dietary Phytic Acid, Dephytinization, and Phytase Supplementation Alter Trace Element Bioavailability—A Narrative Review of Human Interventions

by 

Thiresia Chondrou

 1,†,

Nikoleta Adamidi

 1,†,

Dimosthenis Lygouras

 2,3,

Simon A. Hirota

 4

,

Odysseas Androutsos

 1

 and

Vaios Svolos

 1,5,*

1

Laboratory of Clinical Nutrition and Dietetics, Department of Nutrition and Dietetics, School of Physical Education, Sport Science and Dietetics, University of Thessaly, 42100 Trikala, Greece

2

Computer Science Department, Democritus University of Thrace, 65404 Kavala, Greece

3

Larisa Day Care Center of People with Alzheimer’s Disease, Association for Regional Development and Mental Health (EPAPSY), 15124 Marousi, Greece

4

Snyder Institute for Chronic Diseases, Alberta Children’s Hospital Research Institute, Department of Physiology & Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 1N4, Canada

5

Human Nutrition, School of Medicine Dentistry & Nursing, College of Medical Veterinary and Life Sciences, Glasgow G12 8QQ, UK

*

Author to whom correspondence should be addressed.

†

These authors contributed equally to this work.

Nutrients 2024, 16(23), 4069; https://doi.org/10.3390/nu16234069

Submission received: 10 November 2024 / Revised: 21 November 2024 / Accepted: 24 November 2024 / Published: 27 November 2024

(This article belongs to the Special Issue Trace Minerals in Human Health: Hot Topics and Information Update)

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Abstract

Background: Phytic acid is abundant in plant-based diets and acts as a micronutrient inhibitor for humans and non-ruminant animals. Phytases are enzymes that break down phytic acid, releasing micronutrients and enhancing their bioavailability, particularly iron and zinc. Deficiencies in iron and zinc are significant public health problems, especially among populations with disease-associated malnutrition or those in developing countries consuming phytic acid-rich diets. This narrative review aimed to summarize findings from human intervention studies on the interactions between phytic acid, phytase, and micronutrient bioavailability. Methods: An extensive PubMed search (1 January 1990 to 8 February 2024) was conducted using MeSH terms (phytic acid, phytase, IP6, “inositol hexaphosphate,” micronutrient, magnesium, calcium, iron, zinc). Eligible studies included human intervention trials investigating the bioavailability of micronutrients following (a) phytase supplementation, (b) consumption of phytic acid-rich foods, or (c) consumption of dephytinized foods. In vitro, animal, cross-sectional, and non-English studies were excluded. Results: 3055 articles were identified. After the title and full-text review, 40 articles were eligible. Another 2 were identified after cross-checking reference lists from included papers, resulting in 42 included articles. Most studies exploring the efficacy of exogenous phytase (9 of 11, 82%) or the efficacy of food dephytinization (11 of 14, 79%) demonstrated augmented iron and zinc bioavailability. Most phytic acid-rich food-feeding studies (13 of 17, 77%) showed compromised iron and zinc bioavailability. Conclusions: Strong evidence supports decreased iron and zinc bioavailability in phytic acid-rich diets and significant improvements with phytase interventions. Studies of longer periods and within larger populations are needed.

초록

배경:

피트산은 식물성 식단에 풍부하게 함유되어 있으며,

인간과 반추동물이 아닌 동물에게

미량 영양소 억제제 역할을 합니다.

피타제는

피트산을 분해하여 미량 영양소를 방출하고,

특히 철분과 아연의 생체 이용률을 높이는 효소입니다.

철분과 아연의 결핍은

특히 질병과 관련된 영양실조 인구 집단이나

피트산이 풍부한 식단을 섭취하는 개발도상국 인구 집단에서

중요한 공중 보건 문제입니다.

이 서술적 검토는

피트산, 피타제, 미량영양소 생체이용률 간의 상호작용에 대한

인간 대상 중재 연구 결과를 요약하는 것을 목표로 합니다.

방법: 메쉬 용어(피트산, 피타제, IP6, “이노시톨 헥사포스페이트,” 미량영양소, 마그네슘, 칼슘, 철, 아연)를 사용하여 광범위한 PubMed 검색(1990년 1월 1일부터 2024년 2월 8일까지)을 실시했습니다.

연구 대상은

(a) 피타제 보충, (b) 피틴산이 풍부한 식품 섭취, 또는

(c) 피틴이 제거된 식품 섭취 후 미량영양소의 생체이용률을 조사하는 인체 개입 시험이었습니다.

시험관 내, 동물, 단면, 비영어권 연구는 제외되었습니다. 결과: 3,055건의 논문이 확인되었습니다.

제목과 전문을 검토한 결과, 40개의 논문이 선정되었습니다. 포함된 논문들의 참고 문헌 목록을 교차 확인한 결과, 2개의 논문이 추가로 확인되어, 최종적으로 42개의 논문이 선정되었습니다.

외인성 피타제의 효능(11개 중 9개, 82%) 또는

식품의 탈피틴화(14개 중 11개, 79%)의 효능을 조사한 대부분의 연구에서

철분과 아연의 생체 이용률이 증가하는 것으로 나타났습니다.

피틴산이 풍부한 식품에 대한 대부분의 연구(17개 중 13개, 77%)에서

철분과 아연의 생체 이용률이 저하되는 것으로 나타났습니다.

결론:

피틴산이

풍부한 식단에서 철분과 아연의 생체 이용률이 감소한다는 강력한 증거가 있으며,

피타아제 개입으로 상당한 개선이 이루어집니다.

더 긴 기간 동안 더 많은 인구를 대상으로 한 연구가 필요합니다.

Keywords: 

phytase; phytate; phytic acid; iron; zinc; micronutrient; dephytinization; bioavailability; trace element

Graphical Abstract

1. Introduction

Inositol hexaphosphate (IP6), commonly known as phytic acid, is a natural compound predominantly present in cereals, legumes, oilseeds, and nuts, with the richest foods from each category being maize germ, kidney beans, soybean oil, and peanuts, respectively [1]. Its main function is to serve as one of the main forms of phosphorus storage in plant tissues [2]. Despite its importance in plant metabolism, phytic acid is considered an anti-nutrient for both humans and non-ruminant animals [1].

Phytic acid is a potent chelating agent, capable of binding to essential micronutrients such as zinc, iron, calcium, manganese, and magnesium [3]. This results in the formation of insoluble plant salt complexes that significantly reduce the bioavailability of bound minerals, inhibiting their absorption in the gastrointestinal tract [4] and thus leading to potential deficiencies, particularly in populations whose diets are based on foods high in phytic acid [5].

Phytases, also known as myo-inositol hexakisphosphate phosphohydrolase, are enzymes classified under E.C. 3.1.3.8 (the 3-phytase originating from microbe) as well as E.C. 3.1.2.26 (the 6-phytase derived from plants). They catalyze the sequential release of phosphate from phytic acid (IP6), resulting in lower inositol phosphate esters (IP5 to IP1) and free inorganic phosphate (PI) [5]. This process releases orthophosphate groups from the inositol ring of phytic acid, producing intermediate myo-inositol phosphates and free inorganic phosphorus. By breaking down phytic acid, phytase not only makes phosphorus available for bone growth but also releases calcium, magnesium, protein, and lipids, thus enhancing nutrient availability from plant-based diets [6].

Most diets in developing countries mainly consist of plant-based dishes, which have low bioavailability of minerals such as zinc, iron, calcium, and manganese. This is caused by the high deposits of phytic acid contained in these types of diets, which acts as an anti-nutrient and inhibits the absorption of these micronutrients. For example, a cross-sectional study in China found that there was a significant range in phytic acid consumption among residents in six different regions, with intake varying from 648 to 1433 mg per day. Urban residents consumed less phytic acid compared to rural residents, with an intake of 781 mg per day versus 1342 mg per day, respectively [7].

The daily intake of phytic acid varies depending on the country, food culture, food availability, and purchasing habits. It differs significantly between more industrialized nations and low-income regions like South and Southeast Asia, as well as Central Africa. Additionally, there is a distinction between urban areas (large cities) and rural communities in China, where many low-income families live [3]. Furthermore, deficiencies caused by this phenomenon are one of the most important health concerns in many developing countries. For example, children in sub-Saharan Africa who have high needs for iron are often iron deficient, either anemic or not [8]. The local plant-based nutritional habits are phytic acid dense and low on micronutrients, as well as energy-poor foods. As a result of the prominent food insecurity issue, children struggle to meet their energy goals [9]. Also, malnutrition prevention is of high importance, especially in disease-associated malnutrition. For instance, patients with multiple sclerosis are often malnourished and have lost weight unintentionally. Malnutrition has been demonstrated to weaken the immune system, reduce strength, cause fatigue, and impair muscle function, which affects mental function and respiratory muscle strength and increases the risk of infections. Preventing malnutrition is crucial for patients with multiple sclerosis because it can exacerbate existing symptoms like muscle dysfunction, fatigue, and muscle spasms [10]. Another research team investigated the impact of micronutrient deficiencies in people with inflammatory bowel disease (IBD). It seems like there is a notable link between zinc deficiency and the time to subsequent disease relapse in patients with Crohn’s disease (CD). However, it must be further investigated [11]. Acknowledging the significant challenges posed by phytate-induced micronutrient deficiencies to vulnerable populations, one promising approach is the use of exogenous phytase, particularly that derived from Aspergillus niger [12].

Given these challenges, there is a pressing need to explore effective strategies to manage phytic acid and enhance micronutrient absorption. This includes eval‎uating the role of exogenous phytase and other dietary interventions in mitigating the adverse effects of phytic acid. Considering the above-mentioned points, we aimed to review the literature on phytic acid and micronutrient deficiencies, including studies of human trials.

1. 소개

일반적으로 피틱산으로 알려진

이노시톨 헥사포스페이트(IP6)는

곡물, 콩류, 유지 종자, 견과류에 주로 존재하는 천연 화합물입니다.

각 카테고리에서 가장 풍부한 식품은

옥수수 배아, 강낭콩, 콩기름, 땅콩입니다[1].

이노시톨 헥사포스페이트의 주요 기능은

식물 조직에

인을 저장하는 주요 형태 중 하나입니다[2].

식물 대사에 중요한 역할을 하지만,

피트산은 인간과 반추동물을 제외한 동물에게 영양을 공급하지 못하는 영양소입니다 [1].

피트산은

강력한 킬레이트제로서,

아연, 철, 칼슘, 망간, 마그네슘과 같은 필수 미량 영양소를 결합할 수 있습니다 [3].

그 결과,

결합된 미네랄의 생체 이용률을 현저하게 감소시키는

불용성 식물성 소금 복합체가 형성되어 위장관에서 흡수를 억제합니다 [4]

따라서,

특히 피틴산이 풍부한 식품을 주로 섭취하는 인구 집단에서

잠재적인 결핍을 초래할 수 있습니다 [5].

미오이노시톨 헥사키스포스페이트 포스포하이드롤라제(myo-inositol hexakisphosphate phosphohydrolase)로도 알려진 피타제는 EC 분류에 따라 효소로 분류됩니다. 3.1.3.8(미생물에서 유래한 3-피타제)과 E.C. 3.1.2.26(식물에서 유래한 6-피타제)도 있습니다. 이들은 피트산(IP6)에서 인산염을 순차적으로 방출하는 촉매 작용을 통해 이노시톨 인산염 에스테르(IP5~IP1)와 유리 무기산염(PI)을 생성합니다[5]. 이 과정은 피틱산의 이노시톨 고리에서 오르토인산염 그룹을 분리하여 중간체인 미오이노시톨 인산염과 유리 무기 인을 생성합니다.

피틱산을 분해함으로써 피타제는

뼈의 성장을 위해 인을 사용할 수 있게 할 뿐만 아니라

칼슘, 마그네슘, 단백질, 지질을 방출하여

식물성 식단에서 영양소의 가용성을 향상시킵니다 [6].

개발도상국의 대부분의 식단은

식물성 식품을 주로 사용하는데,

이 식단에는 아연, 철, 칼슘, 망간과 같은 미네랄의 생체이용률이 낮은 식품이 많습니다.

이러한 식단에는

피트산이 많이 함유되어 있기 때문에

생체이용률이 낮은 미네랄의 흡수를 방해하는

항영양소 역할을 하기 때문입니다.

예를 들어, 중국의 단면 연구에 따르면 6개 지역 주민들의 피트산 섭취량에 상당한 차이가 있는 것으로 나타났습니다. 섭취량은 하루 648mg에서 1433mg까지 다양했습니다. 도시 거주자들은 농촌 거주자에 비해 피트산을 적게 섭취했는데, 하루 섭취량은 각각 781mg과 1342mg이었습니다 [7].

피틴산의 일일 섭취량은 국가, 식문화, 식량 가용성, 구매 습관에 따라 다릅니다. 선진국과 남아시아, 동남아시아, 중앙아프리카 등 저소득 지역 간에 상당한 차이가 있습니다. 또한, 중국의 도시 지역(대도시)과 저소득층 가정이 많은 농촌 지역[3] 간에도 차이가 있습니다. 더욱이, 이러한 현상으로 인한 결핍은 많은 개발도상국에서 가장 중요한 건강 문제 중 하나입니다.

예를 들어, 철분 섭취가 부족한 사하라 사막 이남 아프리카의 어린이들은 빈혈이나 철분 결핍에 시달리는 경우가 많습니다 [8].

현지 식물성 영양 습관은

피트산이 풍부하고 미량 영양소가 부족하며,

에너지가 부족한 음식입니다.

심각한 식량 불안의 결과로, 어린이들은 에너지 목표를 달성하는 데 어려움을 겪습니다 [9]. 또한, 특히 질병과 관련된 영양실조 예방이 매우 중요합니다. 예를 들어, 다발성 경화증 환자는 종종 영양실조 상태에 있고, 의도치 않게 체중이 감소합니다. 영양실조는 면역 체계를 약화시키고, 체력을 감소시키며, 피로를 유발하고, 근육 기능을 손상시켜 정신 기능과 호흡기 근육의 힘에 영향을 미치고 감염 위험을 증가시키는 것으로 입증되었습니다. 다발성 경화증 환자에게 영양실조는 근육 기능 장애, 피로, 근육 경련과 같은 기존 증상을 악화시킬 수 있으므로 예방하는 것이 중요합니다 [10]. 또 다른 연구팀은 염증성 장 질환(IBD) 환자의 미량 영양소 결핍이 미치는 영향을 조사했습니다. 크론병(CD) 환자의 경우, 아연 결핍과 후속 질병 재발 사이의 연관성이 뚜렷한 것으로 보입니다. 그러나 이에 대해서는 추가 조사가 필요합니다 [11]. 피테이트로 인한 미량 영양소 결핍이 취약한 인구 집단에 미치는 심각한 영향을 고려할 때, 특히 아스페르질루스 니제르에서 추출한 외인성 피타아제를 사용하는 것이 유망한 접근법입니다 [12].

이러한 문제들을 고려할 때, 피트산을 관리하고 미량 영양소 흡수를 향상시키는 효과적인 전략을 모색해야 할 시급한 필요성이 있습니다. 여기에는 피트산의 부작용을 완화하는 데 있어 외인성 피타아제와 기타 식이 중재의 역할을 평가하는 것이 포함됩니다. 위에서 언급한 점을 고려하여, 우리는 인간 대상 실험 연구를 포함하여 피트산과 미량 영양소 결핍에 관한 문헌을 검토하는 것을 목표로 삼았습니다.

2. Materials and Methods

We performed a narrative review searching in the PubMed database (from 1 January 1990 to 8 February 2024), including the terms “Phytic acid” OR phytate OR phytase OR phytin OR IP6 OR “inositol hexaphosphate” OR “inositol hexakisphosphate” or “inositol polyphosphate”) AND (micronutrient OR magnesium OR calcium OR iron OR zinc. The selection process is shown in the PRISMA flow diagram (Figure 1).

Figure 1. PRISMA 2020 flow diagram for new systematic reviews, which included searches of databases and registers only; * all records were identified through PubMed database.

A total of 3113 records were identified, and after filtering for the English language, 3055 articles were yielded. Eligible studies included original articles describing interventions that investigated the absorption of micronutrients following (a) the supplementation of exogenous phytase, (b) the consumption of phytic acid, and (c) the consumption of phytase-treated foods. Animal, in vitro, and cross-sectional studies were excluded. We also excluded studies with double or multiple interventions. A total of 2993 studies were excluded, and 2 others were not available in full text.

3. Results

After a full-text review of 60 articles, 40 studies fulfilled the eligibility criteria. In addition, 2 studies were identified by hand-searching, resulting in a final inclusion of 42 studies. Three comprehensive evidence tables were made to present the included studies (Supplementary Materials Tables S1–S3). Phytase units are abbreviated in the current review as FTU, though other abbreviations, including PTU, PU, or U, have also been used in the literature with interchangeable meanings.

The first evidence table presents 11 eligible studies investigating the efficacy of exogenous phytase on micronutrient absorption. Subsequently, the second evidence table presents 17 eligible studies examining the effect of phytic acid presence on micronutrient absorption. Finally, the third evidence table presents 14 studies investigating the consumption of phytase-treated foods on micronutrient absorption. The data from these evidence tables are summarized in Table 1, Table 2, Table 3, which are presented below.

Table 1. Intervention studies exploring the impact of phytase on micronutrient absorption.

Table 2. Intervention studies exploring the impact of phytic acid on micronutrient absorption.

Table 3. Intervention studies exploring the impact of food dephytinization on micronutrient absorption.

3.1. Phytase Interventions

The studies reviewed took place in various locations that featured different geographical and socio-economic contexts. In Europe, studies were conducted in Switzerland, specifically Zurich and other university settings [13,15,17,20], as well as in Denmark [21] and Sweden [23], providing insights into phytase’s effects in developed countries high-income settings with access to well-controlled research environments. In Africa, research was conducted in Gambia [14], Burkina Faso [16], and Benin [18], which presented data from developing countries with a focus on improving micronutrient absorption among young children through dietary interventions. Additionally, a study in South Africa explored the impact of phytase on school-aged children’s micronutrient status, highlighting regional differences in dietary challenges and intervention strategies [19]. The study conducted in Venezuela provided data on phytase’s impact on iron absorption from a controlled experimental setting, contributing insights from a Latin American context [22]. These diverse locations underscore the broad applicability of phytase in enhancing micronutrient absorption across different populations and dietary environments.

The majority (82%, 9 out of 11) of the reviewed studies consistently reported that phytase supplementation enhanced micronutrient absorption, namely for zinc and iron [14,15,16,17,18,19,20,22,23]. Notably, studies by Bach Kristensen et al., 2005 and Herter-Aeberli et al., 2020, reported no effect of phytase supplementation [13,21], while the remaining nine studies strongly support the hypothesis of micronutrient bioavailability enhancement during phytase supplementation [14,15,16,17,18,19,20,22,23]. For instance, two studies observed significant increases in fractional zinc absorption with phytase supplementation (p < 0.001 and p < 0.0001), respectively [14,16]. Similarly, another study reported that phytase nearly doubled iron absorption from FeSO4-fortified millet porridge (p < 0.001) [18], and Brnić et al. (2014) found that consuming the active phytase enzyme together with a cereal meal increased zinc absorption to the same extent as when the meal was completely dephytinized before consumption [17]. Studies that combined phytase with ascorbic acid showed synergistic effects in improving iron absorption. For example, the authors of one study demonstrated that adding phytase and ascorbic acid to meals significantly increased iron absorption from both FeSO4 and NaFeEDTA (p < 0.001) [20], which is reflected in the fact that the combination of phytase and ascorbic acid led to greater iron absorption [18]. Despite the overall positive impact of phytase, there were discrepancies in iron absorption results. Herter-Aeberli et al., 2020, found no significant increase in iron absorption from tef injera with added phytase compared to control meals (p > 0.05) [13], contrasting with the significant improvements observed in other studies [15,18]. This inconsistency may arise from differences in food matrices, phytase types, and intervention durations, highlighting the need for context-specific adjustments in phytase application. Bach Kristensen et al. (2005) found that adding phytase to fiber-rich wheat bread did not prevent a decline in iron status, which contrasts with findings from other studies where phytase effectively improved iron absorption [21].

The duration of interventions across the reviewed studies varied significantly, offering a diverse perspective on the effectiveness of phytase on micronutrient absorption. Short-term studies focused on single-day interventions to assess immediate effects on zinc and iron absorption revealed significant short-term increases in nutrient absorption [14,16,18]. In contrast, other studies extended their observations over a few days, offering a slightly broader view of short-term effects [13,15,23]. Longer-duration studies spanned several weeks to months, providing insights into the sustained impact of phytase on iron and zinc status, highlighting the potential for long-term nutritional benefits and the necessity to monitor for any prolonged consumption issues [19,21]. Also, two studies used crossover designs and controlled settings over several weeks to months, offering robust evidence by incorporating repeated measures and washout periods [17,22]. Finally, a study employed a two-day design for each segment to eval‎uate various combinations of enhancers, emphasizing the flexibility and adaptability of phytase interventions [20].

The type of phytase used across studies was predominantly Aspergillus niger, indicating a common preference for this microbial source due to its effectiveness in degrading phytic acid [13,14,15,16,17,18,19,20]. Also, in the study of Sandberg et al., 1996, the authors utilized Aspergillus niger, consistent with the previous studies but with a notably high enzyme activity dose. Bach Kristensen et al. (2005) used a phytase produced from Aspergillus Oryzae NOVO-L, showing some variation in phytase source but still within the Aspergillus genus [21]. Interestingly, Layrisse et al. (2000) diverged by using phytase from wheat, suggesting potential differences in enzymatic activity or stability [22].

The dosage of phytase varied across the studies, reflecting different experimental designs and objectives. Studies by Herter-Aeberli et al., 2020 and Troesch et al., 2011 both used a dose of 380 FTU [13,19], whereas Zyba et al., 2019 used a higher dose of 588 × 2 FTUs [14] and the study by Brnić et al., 2016 used a lower dose of 20.5 FTUs [16]. Notably, three studies had consistent doses, each using 190 FTU [15,17,20]. Cercamondi et al. (2013) used a similar approach with 200 mg/portion, approximately 400 FTU [18], while Bach Kristensen et al. (2005) administered a significantly higher dose of 2500 FTU/100 g [21]. In contrast, Layrisse et al. (2000) used a more moderate dose of 304 U/100 g [22], and Sandberg et al., 1996, applied an exceptionally high activity dose of 4 × 107 FTU/L [23]. These variations highlight the lack of a standardized dosing protocol and suggest that further research is needed to determine optimal dosing for different populations and settings.

The test meals and supplements across the 11 studies demonstrated considerable diversity, reflecting the different research goals and contexts. However, there were notable correlations among studies that used similar or different approaches. Several studies utilized maize-based meals, either as porridge or in combination with other ingredients [13,15,17,20]. These studies consistently investigated the effect of phytase on iron or zinc absorption, demonstrating the relevance of maize as a common dietary staple and the potential benefits of phytase in enhancing nutrient absorption from maize-based foods. Others focused on millet-based porridges, exploring the impact of phytase on zinc and iron absorption in young children [14,16,18]. These studies consistently found that the addition of phytase significantly improved micronutrient absorption, highlighting millet as another key staple where phytase can be beneficial. One study provided a sweetened maize porridge with a micronutrient powder containing iron and zinc [19], while another focused on wheat bread with or without phytase [21]. The differences in these test meals underscore the versatility of phytase across various food forms, although the outcomes varied, with Bach Kristensen et al., 2005, not showing a significant improvement in iron status despite phytase addition [21]. Layrisse et al., 2000, used a basal breakfast with ferrous sulfate or ferrochel [22], and Sandberg et al., 1996, tested white wheat rolls with wheat bran, comparing phytase-active and phytase-deactivated conditions [23].

Finally, the methodological quality and study designs of the 11 studies varied, encompassing randomized controlled trials (RCTs), crossover designs, and controlled experimental studies. Most studies were RCTs [14,16,18,19,21,23], providing robust evidence through randomization and control groups. Other studies employed crossover designs [13,15,17,20], allowing each participant to serve as their own control, thereby reducing inter-individual variability and increasing the reliability of the findings. Layrisse et al. (2000) utilized a controlled, but not randomized, experimental design to test iron absorption under various conditions, adding valuable comparative data [22].

3.2. Dietary Phytic Acid Interventions

The 17 included studies encompass a wide range of geographical and socio-economic contexts. Research was conducted in developed countries such as Switzerland [26,30], Sweden [27,35], and the USA [29,33], as well as in low-resource settings such as Guatemala [32,38] and Rwanda [39]. Further, these studies also range in settings, from controlled laboratory environments [34,37] to real-world settings, such as community feeding programs [38] and home-based interventions [32]. Such geographical and socio-economic diversity highlights the widespread applicability of the findings and underscores the global importance of understanding the impact of phytic acid on micronutrient absorption.

Out of the 17 studies, eight studies specifically examined the absorption of iron. More specifically, four of these studies confirmed that phytic acid inhibits iron absorption [26,27,39,40]. For example, high phytic acid content was consistently associated with reduced fractional iron absorption [39,40]. However, other studies, such as Lind et al., 2003 and Hoppe et al., 2018, showed less pronounced effects or mixed results [35,37]. Also, six other studies examined zinc absorption. Half of these studies confirmed that phytic acid inhibits zinc absorption [26,31,32]. For example, diets rich in phytic acid were associated with lower fractional zinc absorption [36]. However, a few studies found no significant difference in zinc absorption with low-phytic acid maize or beans when compared to controls [38,39]. Furthermore, three other studies examined calcium absorption. Most of these studies showed that high-phytic acid content results in reduced calcium absorption [31,33]. For example, calcium absorption was significantly greater from low-phytic acid maize tortillas when compared to control ones [33]. Out of the 17 studies, only 1 study examined the effect of phytic acid on manganese absorption, stating that high phytic acid content inhibits its absorption [26]. Also, a single study assessed the absorption of copper and found no significant impact of phytic acid on copper absorption [30]. These contradictory findings imply that while phytic acid generally affects micronutrient absorption, its effect may be influenced by the dietary context and food matrix.

The duration of the studies’ interventions differed considerably, with intervention periods ranging from one day [26,34] to six months [37]. The studies of Heaney et al. (1991) and Bohn et al. (2004) involved single-day interventions, focusing on the acute effects of phytic acid on micronutrient absorption [26,34]. On the contrary, more longitudinal studies, such as those conducted by Lind et al. (2003) and Hoppe et al. (2018), were conducted over several weeks to months, investigating the effect of phytic acid over greater periods [35,37]. For example, Lind et al. (2003) conducted an intervention period of 6 months [37], while Hoppe et al. (2018) ran interventions for 12 weeks [35]. This diversity reflects different research objectives, from acute to chronic effects, offering a comprehensive insight into the effects of phytic acid on various time scales.

Across all 17 studies, interventions were primarily concerned with controlling the phytic acid content of the test meals. In most cases, this was achieved either by using low-phytic acid bean, maize, or cereal variants [37,38,40] or by adding phytic acid to the meals to test its effects [27,31,34]. A few studies used dehydrated foods to eval‎uate changes in nutrient absorption [27,30]. These interventions aimed to isolate the effect of phytic acid by comparing low and high phytic acid foods or by adding measured levels of phytic acid to test meals, thus providing evidence of how phytic acid affects micronutrient bioavailability.

There was a wide variety of test meals and diets used in the interventions. Examples include bread made from different types of flour [26], bread prepared with different phytic acid content [27], and maize tortillas with different levels of phytic acid [33]. While some studies used complete meals that included different types of foods, such as beans, maize, and cereals [39,40], other studies focused on specific ingredients, such as iron-fortified infant formulas or cereals with reduced phytic acid [35,37]. This diversity of test meals underlines the adaptability of the research designs to different dietary contexts and provides a broad scope for assessing the effects of phytic acid in different food matrices.

The methodological quality and study design of the 17 studies differed substantially. Almost half of the studies (9 out of 17) used randomized controlled trials (RCTs) [27,31,32,34,35,37,38,39], which are perceived to be robust for assessing causal effects. However, other studies used less stringent designs, such as community-based interventions [38] or non-randomized trials [34]. Designs also differed in terms of blinding and control measures, with some using double blinding [35,37], while others did not specify blinding methods. Such variability in study design both reflects the different technical and organizational challenges faced by the researchers in diverse settings and adds to a well-rounded understanding of the impact of phytic acid on micronutrient absorption.

3.3. Dephytinization Interventions

The 14 included studies cover a broad spectrum of geographical and socio-economic settings. Study settings spanned multiple continents, including Europe (France, Switzerland) [43,45], Africa (Malawi, Benin, Rwanda) [46,53,54], Asia (Republic of Korea, Singapore) [49,52], and North America (USA) [42]. These studies involved populations with varying socio-economic backgrounds, from research universities and urban health centers to rural communities with limited access to advanced healthcare. For instance, Manary et al. (2000) and Petry et al. (2014) focused on communities in Malawi and Rwanda, where high levels of dietary phytic acid are preval‎ent due to staple food sources [53,54]. In contrast, studies like Davidsson et al., 1997 and Zhang et al., 2007 were conducted in more developed settings, such as France and Sweden, with controlled dietary conditions and higher resources for research infrastructure [43,47]. This diversity highlights the global relevance of studying food dephytinization’s impact on micronutrient absorption and the varying challenges faced by different populations.

The studies collectively demonstrate that phytase effectively dephytinizes foods, enhancing micronutrient absorption, albeit the results are mixed. For iron absorption, half of the studies (7 out of 14) consistently show that dephytinization increases iron bioavailability [43,45,46,47,51,54]. Notably, Petry et al. (2014) found that removing up to 95% of phytic acid significantly improved iron absorption from biofortified beans [54], while Hurrell et al. (2003) observed increased iron absorption from cereal porridges with reduced phytic acid content [45]. On the other hand, Davidsson et al., 1997, 1995, reported that, while dephytinization generally improved iron bioavailability, the effect was not always pronounced, and the presence of ascorbic acid further enhanced absorption in some cases [43,44]. For zinc absorption, five studies investigated the impact of phytase treatment [49,50,52,53,54]. More than half of these studies found that phytase treatment improved zinc absorption [52,53,54], with Manary et al. (2000) showing greater fractional absorption in children on a diet with low phytic acid content [53]. However, Petry et al. (2010) and Couzy et al. (1998) reported mixed results, indicating that while phytase treatment enhanced the absorption, the impact varied depending on the presence of polyphenols and the baseline phytic acid levels [49,50]. For manganese absorption, only one study specifically addressed this, showing that dephytinization significantly increased manganese absorption, doubling the fractional absorption compared to non-dephytinized soy formula [44]. This highlights the potential of phytase to enhance the bioavailability of multiple micronutrients, although the effects can vary based on the specific nutrient and context of the diet.

The types, doses, and durations of phytase interventions varied significantly across the studies. Most studies used Aspergillus niger phytase, but dosages ranged widely. The doses of phytase used in the studies ranged from as low as 40 FTU/L [51] to as high as 5000 FTU/g [52,53]. For instance, Manary et al. (2000) used 5000 FTU/g of phytase for a short duration of 3–7 days [53], while Davidsson et al. (1995) did not specify the dose but utilized a 1-day intervention [44]. Kim et al. (2007) administered 5000 FTU/g of Aspergillus niger phytase over 9 days for high and low phytic acid diets [52]. Some studies, like Hurrell et al., 2003, also did not specify doses but ensured effective phytic acid degradation [45]. The intervention durations overall varied from 1 day [43,44,46,52] to 42 days [53], reflecting different study designs and objectives. This variation underscores the need for standardization in phytase treatment research to better compare outcomes.

The test meals or diets across the studies were diverse and tailored to the specific dietary patterns and research aims of each study. Davidsson et al. (1997) used iron-fortified cereals with native and dephytinized phytic acid content [43], while Petry et al. (2014) employed beans with varying phytic acid levels [54]. Manary et al. (2000) provided corn-plus-soy porridge, with and without phytase, to assess zinc absorption [53]. Zhang et al. (2007) tested oat-based beverages supplemented with different iron compounds and phytase [47]. Other studies included soy formulas [51], fonio porridges [46], and roller-dried cereal porridges [45]. This variety reflects the adaptation of interventions to local dietary habits and nutritional challenges, highlighting the importance of context-specific solutions.

The methodological quality and study designs varied considerably across the 14 studies. Most studies (8 out of 14) employed randomized controlled trials [43,46,47,49,51,52,53,54], which are robust methods for assessing the effects of dietary interventions. For instance, Petry et al. (2014), Kim et al. (2007), and Davidsson et al. (1994) used RCT and crossover designs to eval‎uate the impact of phytase on iron and zinc absorption [51,52,54]. Other studies used interventional designs with a focus on community-based approaches [48,53]. Despite this, variations in study quality were evident, with some studies lacking detailed information on phytase dosages [43,44,45,46,47,50].

4. Discussion

The current narrative review indicates that supplementation with exogenous phytase significantly improves micronutrient absorption, namely for iron and zinc, with most of the reviewed articles confirm‎ing this beneficial effect. In contrast, the presence of phytic acid in the diet was associated with reduced absorption of micronutrients, with evidence suggesting that it mainly affects iron and zinc. In addition, dephytinization of foods improves the bioavailability of micronutrients, with most studies showing increased absorption of iron and zinc after removing phytic acid. These findings are especially important in phytic acid-rich diets, where reducing its content can enhance micronutrient absorption and improve overall nutritional status.

Phytic acid consumption varies considerably around the world and is influenced by the dietary habits of each country. In the United Kingdom, phytic acid intake has increased over the decades, from 504–844 mg/day in 1986 [55] to 1436 ± 755 mg/day in 2005 [56]. The average estimated intake in Italy is lower, at 219 mg/day [57]. In India, intake varies widely, with children aged 4–9 years consuming 720–1160 mg/day, while adolescents (10–19 years) consume 1350–1780 mg/day [58]. In Sweden and Finland, intakes for adults following a Western-style diet range from 180 to 370 mg/day [57], while Swedish vegetarians consume significantly higher levels, reaching 1146 mg/day [28]. These data suggest that phytic acid intake varies widely, with the highest intakes being observed in populations with diets rich in plant foods, such as vegetarians and populations in developing countries. Also, the reviewed studies in this paper, while employing different food bases, consistently found that the addition of phytase significantly enhanced iron absorption, reinforcing the effectiveness of phytase in improving iron bioavailability across different meal types.

According to animal studies, microbial phytases appear to improve iron bioavailability by enhancing iron markers, such as plasma transferrin and hemoglobin levels, in rats [59] and pigs [60]. Phytase also significantly increases zinc bioavailability, improving plasma zinc concentration and zinc digestibility in rats [61,62] and pigs [63]. There is also evidence that phytase improves copper absorption, as shown by increased digestibility and urinary excretion of copper in pigs [64]. However, the effect of phytase on manganese absorption is less clear, with a study showing no significant changes in rats [65], while another study reports increased bone manganese concentrations, particularly in pigs [66].

The use of phytase is not only applicable to developing countries but is also of particular importance for the vegetarian and vegan diets that dominate the Western world, as well as for disease-related malnutrition. The presence of phytic acid significantly limits the absorption of minerals such as iron, which can contribute to problems such as iron deficiency anemia. Today, about 25% of the world’s population suffers from anemia, with the largest proportion due to iron deficiency, affecting about 1 billion people [67]. Especially for patients with malnutrition associated with diseases, such as IBD or multiple sclerosis, intake of phytic acid can exacerbate already limited micronutrient absorption [10,11]. Phytase interventions may be an effective strategy to prevent or treat iron deficiency anemia in these populations by improving iron absorption from plant-based foods.

Our review provides insights for addressing micronutrient deficiencies, especially in developing countries where diets are often high in phytic acid and poor in bioavailable micronutrients [68]. The potential of phytase use is emerging as a sustainable and cost-effective strategy to improve the nutritional value of staple foods, which can help improve overall health outcomes in vulnerable communities [69]. In addition, the results of this study can be used in public health programs to inform communities about the effect of phytic acid on nutrient absorption and to promote food preparation methods that reduce phytic acid, such as soaking, fermentation, and sprouting [6]. At the same time, these findings may also be useful in patients with chronic diseases because adequate intake of micronutrients is critical for managing chronic diseases and supporting patients’ quality of life. Iron deficiency, often seen in chronic kidney disease, heart failure, and IBD, can worsen these conditions [70]. At the same time, zinc deficiency, which occurs in malabsorption and liver and kidney disease, negatively affects the immune response and overall recovery [71]. Finally, our study highlights the importance of developing low-phytic acid foods to improve nutrient bioavailability on a global scale.

This narrative review offers significant advantages, extensively covering phytase supplementation, the effect of phytic acid, and food dephytinization on micronutrient absorption. The focus exclusively on intervention studies enhances the validity of the conclusions. Furthermore, the review follows a multifaceted approach, combining three different research directions: investigating the effect of phytase on micronutrient absorption, analyzing the effect of phytic acid as an absorption inhibitor, and eval‎uating studies using phytase for food dephytinization. This comprehensive approach provides a complete understanding of the effects of each of these factors, helping to identify gaps in the literature and confirm‎ing previously known data.

The present narrative review, although extensive, has some weaknesses. First, it was performed using a single search database, and it is not a systematic review, as it does not formulate a clear research question to guide the study selection process. This may limit the generalizability of the results. In addition, the review does not include an assessment of the quality of the studies included, which may reduce the reliability of the overall findings, as it does not consider any methodological weaknesses or limitations of the studies included. While the diversity in study designs enriches the understanding of the dephytinization impact, it also emphasizes the need for consistent reporting and methodological rigor to enhance the comparability and generalizability of findings.

However, despite the widespread acceptance of the safety of phytase, a gap remains regarding the defined optimal dose of phytase that should be used to dephytinize foods with high phytic acid content, such as cereals and legumes. Also, the lack of long-term studies conducted to eval‎uate the actual benefit of phytase on micronutrient levels in different populations, especially in vulnerable groups such as children and people facing nutritional deficiencies in developing countries, is a shortcoming of this field of research.

Leading organizations, such as the World Health Organization (WHO) and the European Food Safety Authority (EFSA), have addressed the use of phytase in food, guiding safety and dosage. EFSA has approved the safety of 3-phytase produced by Aspergillus niger for use in the food industry for dephytinization of cereal products, products of plant origin, and dairy substitutes. The eval‎uated study showed that there are no safety concerns regarding the genetic modification of the production organism, and the enzyme does not contain any residues from the production organism [72].

EFSA also considered the dietary exposure to the phytase preparation and estimated that exposure levels in children may reach 3.5 mg Total Organic Solids (TOSs) per kilogram body weight per day and in adults 1.2 mg TOS per kilogram body weight, under conservative assumptions WHO [73]. Despite this conservative estimate, the committee found that the safety margin is high (approximately 250), as the no observed adverse effect level from 13-week toxicity studies in rats was 833 mg TOS/kg body weight. Thus, phytase is considered safe in its intended uses, such as in processed foods and food supplements [72].

5. Conclusions

This literature review discusses the increased focus on the exogenous phytase as an enhancer of the bioavailability of essential micronutrients, especially iron and zinc, by reducing the phytic acid present in plant foods, which is a common problem. Phytase supplementation has demonstrated high efficacy for nutrient bioavailability, especially in populations of developing countries that predominantly consume diets that are rich in phytic acid and among the vegetarian/vegan populations of the Western world. The present review supports the potential of phytase as a safe option for the prevention of deficiencies in micronutrients—or how to avoid this—while outlining major weaknesses in the current body of data, such as the absence of studies of longer duration and whether there is an optimum dose of phytase. While the results are favorable, it will be necessary to conduct additional studies to verify these outcomes, especially in at-risk populations, such as children and nutritionally deficient individuals in developing countries. There is great potential for phytase use as a low-cost measure for improving public health, but the immediate cornerstone towards its wider use includes guaranteeing the safety of its use, determining the right amounts, and eval‎uating long-term effects.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/nu16234069/s1, Table S1: Intervention studies exploring the impact of phytase on micronutrient absorption; Table S2: Intervention studies exploring the impact of phytic acid on micronutrient absorption; Table S3: Intervention studies exploring the impact of food dephytinization on micronutrient absorption.

Author Contributions

V.S. contributed to the conception and methodology of the review, performed the literature search, analyzed and interpreted the results, prepared the first draft of the manuscript and edited it, and was responsible for the overall supervision of this research work. T.C. and N.A. performed the literature search, analyzed and interpreted the results, prepared the first draft of the manuscript, and edited it. D.L., S.A.H. and O.A. contributed to the conception and methodology of the review and data interpretation and provided critical feedback, including review and editing of the manuscript at all stages. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Conflicts of Interest

S.A.H. and V.S. are scientific consultants for Access Nutrients, a company that markets a phytase-based supplement. Access Nutrients had no role in the design of the study, in the collection, analysis, or interpretation of data, in the writing of the manuscript, or in the decision to publish the results. T.C., N.A., D.L. and O.A. declare no conflicts of interest.

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