CPQ Nutrition (2021) 4:2
Review Article

Impact of Soy Isoflavones on Gut Microbiota Dysbiosis


Cíntia Rabelo e Paiva Caria* & Gabriela Alves Macedo

Department of Food and Nutrition, Faculty of Food Engineering, University of Campinas, Brazil

*Correspondence to: Dr. Cíntia Rabelo e Paiva Caria, Department of Food and Nutrition, Faculty of Food Engineering, University of Campinas, Brazil.

Copyright © 2021 Dr. Cíntia Rabelo e Paiva Caria, et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Received: 11 December 2021
Published: 21 December 2021

Keywords: Soy Isoflavones; Gut Microbiota and Dysbiosis


Abstract

The impact of soy isoflavones on the intestinal microbiota has been investigated in different situations of dysbiosis, such as the type of diet adopted, medications taken, intestinal mucosa, immune system and the microbiota itself. Thus, we aim to describe, through a literature review, the modulation of the intestinal microbiota after consumption and/or treatment with soy isoflavones in situations of dysbiosis. Through the studies selected in this review, we could observe that soy isoflavones are able to modulate the intestinal microbiota, but the effects observed in dysbiosis are not fully understood.

Abbreviations

FSBM: fermented soybean meal
FSM: fermented soymilk
HFD: high-fat diet
LcS: Lactobacillus casei Shirota
LPS: lipopolysarides
NAFLD: non-alcoholic fatty liver disease
NOD: non-obese diabetic mouse model
O-DMA: O-desmethylangolensin
SBM: soybean meal

Introduction
Isoflavones are mostly found in soybeans, characterizing them as soy isoflavones [1]. When consumed they can be rapidly hydrolyzed by gut bacteria into aglycones that are partially absorbed by the gut epithelium [2]. Epidemiological studies show that a proper level of isoflavones consumed in the diet can prevent diseases like cancer or diabetes type II [3], although there are some controversies along these findings [1]. Moreover, isoflavones bioavailability is important to reach the benefits and food processing can change isoflavones profile interfering in their absorption [4]. Also, the quantity and quality of gut microbiota can result in a dysbiosis state and it is not known how and how much dysbiosis participate in the xenobiosis in the presence of soy isoflavones [5].

Materials and Methods
This study has a descriptive character and was carried out through a literature review, which aims to describe the modulation of intestinal microbiota after treatment and/or consumption of soy isoflavones in different situations of dysbiosis. A search was performed in the National Library of Medicine using the descriptors “soy isoflavones” and “gut microbiota”. All articles considered relevant to the topic discussed were selected for discussion in this review.

Results and Discussion
Isoflavones Metabolism and Bioavailability

It is known that the human gut microbiota is involved in the degradation of several polyphenolic compounds that are consumed in the diet, including flavonoids, flavanones, flavan-3-ools, anthocyanidins, isoflavones, flavones, tannins, lignans and chlorogenic acids. The level of biotransformation of these compounds depends on their structural specificity, as well as on the interindividual richness of the gut microbiota [6]. Flavonoids and their derivatives, for example, are most absorbed by the intestine [6], while conversion of isoflavones, which have large hydrophilic structures, are not easily absorbed by intestinal absorptive cells [7].

For this (Figure 1), the primary metabolites of isoflavones are metabolized by the liver, while the unabsorbed portion is hydrogenated by glucosidases, hydrolytic enzymes produced by the colonic gut microbiota. Then, the complex isoflavone molecules, that are glycosidic forms (daidzine, genistin and glycite) are broke down into aglycone forms (daidzein, genistein and glycitein), that is, in smaller molecules that can be absorbed in the intestine and, finally, metabolized into their final active metabolites [2,8]. Then, these products are absorbed through the portal vein and travel to other tissues and organs, providing several metabolic actions, such as, for example, the estrogenic [9,10], anti-androgenic and hypolipidemic activity of aglycone equol [7].


Figure 1: Metabolism of isoflavones

It is estimated that there are trillions of microorganisms inhabiting the human body [11], with approximately one thousand different species found in the human large intestine [12]. Through fermentation of the gut microbiota, the relationship between beneficial bacteria (Bifidobacterium spp. and Lactobacillus spp. for example) and harmful bacteria (Clostridium for example) produces a variety of products that can have positive or negative effects on the intestine, as well as to influence various systemic responses [8]. Beneficial effects for health promotion can be observed as a result of a symbiotic relationship between the intestinal microbiota and its host, while a dysbiotic relationship can result in the development of inflammatory diseases and even cancers [11].

Regarding aglycones isoflavone’s metabolism, several microorganisms have been implicated, such as lactic acid bacteria and Bifidobacterium, due to strong β-glucosidase activity. However, other species also are able to improve the bioavailability and conversion rate of isoflavones by the action of the β-glucosidase, including Lactobacillus acidophilus, Lactobacillus casei, Lactobacillus fermentum, Lactobacillus rhamnosus, Lactobacillus plantarum, Lactobacillus bulgaricus, Bifidobacterium breve, and Bifidobacterium bifidum [2].

Impact of Soy Isoflavones on Gut Microbiota
The gut microbiota maintains a symbiotic relationship with its host, interfering in the function of the metabolism of nutrients, xenobiotics and drugs, maintaining the structural integrity of the intestinal mucosa barrier, immunomodulation and protection against pathogens [7]. For the best performance of the gut microbiota functions, a stable cellular composition is required, consisting mainly of bacteria from the phyla Bacteroidetes, Firmicutes, Actinobacteria and to a lesser extent, Proteobacteria [13].

However, many factors can interfere negatively in bacterial population presents in the gut, as example, stress conditions, type of diet adopted, ingested drugs, the intestinal mucosa, the immune system, and the microbiota itself. The combination of these factors, in addition to the presence of some diseases, such as inflammatory bowel diseases and metabolic disorders, are associated with intestinal dysbiosis [13]. Dysbiosis of gut microbiota is characterized by the reduction of microbial diversity and beneficial bacteria, beyond the growth of harmful bacteria [5], leading to a disease-promoting imbalance [13]. Thus, identifying the bacterial profile in different situations can contribute to a better understanding of the impact of the intestinal microbiota on health and disease.

Regarding soy isoflavones, the gut microbiota is important in the bioavailabity and biological activities of isoflavones and influences the host’s metabolic profile after consumption [6]. In healthy volunteers, a single-dose of soybean meal (SBM) and fermented soybean meal (FSBM) biscuits, containing isoflavones (0.44mg/kg of body weight), increased aglycones metabolites in urine in both treatments, being FSBM 54% higher than SBM biscuits. The FSBM biscuits were also able to excret all metabolites more rapidly than SBM and urinary recovery of isoflavones was 67% higher after FSBM biscuits consumption. From an improvement in the bioavailability of isoflavones, it was possible to suggest a reduction in the impact of the intestinal microbiota on the metabolism of isoflavones [14], (Table 1). Additionaly, healthy young volunteers that received a single dose of 30 mg of genistein in tablet, containing low fat milk and soy milk, resulted in presence of free genistein in the plasma, 7 more of its phase-II metabolites, 15 gut-derived metabolites, and a new metabolite, genistein-4 glucuronide-7-sulfate (G-4 G-7S). Despite the lower bioavailability of genistein tablet used in this study, after intake of genistein or genistin formats, it was observed the presence of dihydrogenistein and 2 (4-hydroxy phenyl) propionic acid, both considered the major phase II metabolite and gut-derived metabolite [15], (Table 1). The dihydrogenistein is an intermediate compound in the production of 5-hydroxy-equol from genistein by certain intestinal bacteria, which was not demonstrated in the Smith and collaborators` study. On the other hand, 2-(4-hydroxyphenyl) propionic has been described as a degradation compound of genistein metabolism by Eubacterium ramulus, through the transformation of 6-hydroxy-O-DMA into floroglucinol and 2-(4-hydroxyphenyl) propionic acid [16].

Table 1: Findings summary from metabolism isoflavones and microbiota changes


As previously mentioned, the positive effects of isoflavones consumption on health are highly dependent on isoflavones bioavailability, which is influenced by several factors, including dose and frequency of consumption, isoflavone food source, sex, age, intestinal microbiota composition, and gut transit time [14].

Soy isoflavones act as compounds of phytoestrogens, as they are structurally and functionally similar to estradiol, and thus bind to estrogen receptors and perform various biological activities, including the relief of symptoms associated with menopause and associated diseases [9]. In this context, as soy isoflavones interact with the signaling pathways of estrogen, the main female sex hormone, there is concern that these compounds feminize men. A recent meta-analysis examined clinical data published over the past two decades on the effects of soy intake on estrogen levels in men, demonstrating that soy intake or its isoflavones do not affect the levels of total testosterone, free testosterone, estradiol or estrone, even when exposure occurs in the long term and exceeds the amount of isoflavones ingested by Asian populations. Despite the lack of effect of soy intake and exposure to isoflavone in these reproductive hormones in men, it cannot be concluded that its ingestion has no hormonal effect, but isoflavones can also have independent biological effects on hormone levels [42].

However, the effectiveness of isoflavones is related to an individual’s ability to convert their glycosylate forms into equol [8,9]. Equol is a metabolite of daidzein produced exclusively by the intestinal microbiota of only a few individuals, resulting in a wide range of beneficial health effects due to its superior nutraceutical effect compared to soy isoflavones [9,43].

A randomized clinical trial with 60 postmenopausal women showing symptoms of genitourinary syndrome, was administrated isoflavones (150mg of dry glycine extract max) in association with the use of probiotics (Lactobacillus acidophilus, L. casei, Lactococcus lactis, Bifidobacterium bifidum and B. lactis) for 16 weeks, resulted in an increase in daidzein, glycitein, equol intermediate and O-dimethylangolensin content. However, the increased content of isoflavones and their metabolites did not alleviate vulvovaginal symptoms [21], Table 1. The relationship between the gut microbiota and lifestyle habits in postmenopausal Japanese women were investigated from self-administered questionnaires, fecal microbiome analysis and urinary equol concentration. This study showed that 97% of women had equol-producing bacteria, but only 22% had equol-producers, while more than 50% of subjects with equol-producers were constant consumers of soybased foods among other foods and showed significantly higher microbiota diversity compared with nonequol producers women, with higher percentage of Firmicutes and lower of Proteobacteria [19], (Table 1). In another study with postmenopausal women, a daily soy diet-supplementation (containing 160mg of soy isoflavones and 1g saponin) for one week, resulted in changes of fecal bacteria composition, increasing Bifidobacterium and decreasing Lactobacillus and unclassified Clostridiaceae. For equol producers women there was an increase of Bifidobacterium, Rothia, other Bifidobacteriaceae and Actinobacteria, and reduction of Roseburia, supporting the hypothesis that equol production is dependent on gut microbiota composition [25], (Table 1).

In order to detect and quantify equol-producing bacteria, a study used two sets of targeted primers involved in equol synthesis, the dihydrodaidzein reductase (ddr) and tetrahydrodaidzein reductase (tdr) genes. Both primers showed high specificity when used in the DNA of control bacteria, such as Slackia isoflavoniconvertens, Slackia equolifaciens, Asaccharobacter celatus, Adlercreutzia equolifaciens and Enterorhabdus mucosicola. In fecal samples from menopausal women treated with soy isoflavone concentrate (80mg genistin / daidzine) for 6 months, the tdr gene was detected in the feces of all women producing equol, while the ddr gene was detected only in two of the three women considered to be previously detected equol producers of the molecule in urine. However, no significant increase in the number of copies of equol-related genes was observed during treatment with soy isoflavone concentrate and, moreover, in fecal samples from women, tdr and ddr genes not producing equol, suggesting that the genes used may be non-functional or possibly daidzein has been metabolized to other compounds in samples from these two women producing equol [24], (Table 1). Although this work did not relate the genes used to the treatment with the soy isoflavone concentrate, the species of bacteria Adlercreutzia equolifaciens, Slakia isoflavoniconvertens and Slakia equolifaciens, used as control of the PCR assays, as well as other species Streptococcus intermedius, B. ovatus , Ruminococcus products, Eggerthella sp. Julong732 are known for the conversion of dadzein to equol by the minority of individuals, while the conversion of dadzein to O-DMA occurs from the involvement of a species of Clostridium by the majority of individuals [44].

In order to assess the impact of isoflavone supplementation on intestinal bacterial composition and its associated transformations, fecal samples from menopausal women with an equol-producing phenotype treated with an isoflavone concentrate (80mg/day) for 6 months were added to a model of anaerobic culture in vitro, resulting in the bioconversion of isoflavones into equol, as well as in the enrichment of some bacterial strains, such as Collinsella, Faecalibacterium and members of Clostridium clusters IV and XIVa [8], Table 1.

In another study involving faecal samples from three women producing equol, several bacterial strains capable of producing dihydrodaidzein and O-DMA from daidzein and dihydrogenistein from genistein were detected. However, none of the strains tested produced equol from daidzein, although the isolate W18.34a was identified as A. equolifaciens, a well-described equol-producing species. In this study, the authors suggested deletions within the operon equol for the strain W18.34a, among other strains that could produce equol, contributing to the argument of the coexistence of bacterial strains that produce and do not produce equol in the human intestine [17], Table 1. On the other hand, a study used 37 strains of dominant and representative bacterial populations of isoflavone glycosides from the human intestine (daidzine and genistin), their aglycone derivatives (daidzein and genistein) and equol, against bacterial strains, resulting in the modulation of the number of species essential bacterial in the intestine, such as reduction of Bacteroides fragilis, Lactococcus lactis subsp. lactis and Slackia equolifaciens from genistein, in addition to the increase in Lactobacillus rhamnosus and Faecalibacterium prausnitzii from genistein and equol [18], Table 1.

Some dietary strategies have been used in order to modulate the gut microbiota, bringing improvements to health. Probiotics, defined as bacterial food supplements, are known to modify the composition of intestinal bacterial populations and their products, maintaining, or improving health or even for therapeutic purposes [45].

The combination of probiotics to any substrate that is capable of resisting the upper gastrointestinal environment and being made available to the intestinal microbiota, stimulating the fermentation of beneficial bacteria [45], act synergistically, stimulating proliferation and/or activating the metabolism of health-promoting bacteria [46]. The consecutive association of fermented soy milk (FSM) with Lactobacillus casei Shirota (LcS), a known probiotic, resulted in increased levels of isoflavones in the urine and the levels of Lactobacillaceae increased significantly and those of Bifidobacteriaceae tended to increase in healthy Japanese women in pre- menopause. In contrast, the levels of Enterobacteriaceae and Porphyromonadaceae decreased significantly during the period of ingestion in the FSM group. From these results, it was suggested that only the FSM beneficially modifies the intestinal microbiota in healthy pre-menopausal women [23], (Table 1).

On the other hand, some drugs may adversely affect the intestinal microbiota. Oral ciprofloxacin for example, commonly used to treat acute cystitis among postmenopausal women. In this context, a study investigated the effect of short-acting oral ciprofloxacin (250mg twice a day for three consecutive days) on the pharmacokinetics of isoflavone (single oral - 375mL of UHT soybeans) in healthy postmenopausal Thai women, resulting a significant decrease of dadzein and genistein. In this study, the reduction in the bioavailability of isoflavones after the use of ciprofloxacin, was associated with a presumed decrease in the amount of intestinal microbiota. However, a direct quantification of the fecal microbiota has not been performed, which could determine the impact of oral ciprofloxacin on the intestinal microbiota [20], Table 1.

The consumption of a high-fat diet or Western diet is also considered responsible for changing the intestinal microbiota generating dysbiosis, which triggers local inflammation and causes an increase in intestinal permeability, thus allowing the absorption of lipopolysarides (LPS) [47], and mucosal immune responses, contributing to the development of obesity and chronic inflammation [31]. The increase in intestinal permeability is also associated with a reduction in Bifidobacteria spp, bacteria known to reduce LPS levels and also improve intestinal barrier function. In addition, the high-fat diet is able to induce the proliferation of gram-negative bacteria, such as Enterobacteriaceae, which is also associated with an increase in plasma LPS [47].

A cross-sectional study with peri- and post-menopausal women, consuming at least three or more servings of soy per week, related O-DMA non-producer phenotype with obesity, however equol non-producer phenotype was not associated with obesity [32], Table 1. In Chinese adults, equol producers showed lower prevalences of dyslipidemia, which was associated with presence of 32 species of bacteria, including Adlercreutzia equolifaciens and Bifdobacterium bifidum. However, equol production was not determined by intake of soy isoflavones, suggesting that gut microbiota is critical in the equol production process [26], Table 1. ODMA-producer phenotype was also related with obesity, even after ingestion commercial soy bar for three days [29]. In addition, soy isoflavones (80mg aglycone equivalents) daily ingestion over three consecutive days, was able to reduce arterial stiffness, reducing risk of cardiovascular disease in healthy men [28]. In contrast, adults with cardiometabolic risk factors that received soy nuts for four weeks did not present any healthy benefit, but equol+ODMA producers were associated with gut microbiota profiles through of composite of biochemical markers, intermediary metabolism and secondary metabolites [27].

From animal studies, non-alcoholic fatty liver disease (NAFLD) in high-fat diet (HFD) obese male Sprague Dawley rats, 2% of fermented soy paste for 9 weeks improved HFD-induced lipid accumulation in the liver by activating fatty acid oxidation and modulating gut microbiota, increasing Bacteroidetes and Proteobacteria, and reducing Firmicutes [30], Table 1. Another study with HFD obese male Sprague Dawley rats, the treatment with soy isoflavone extract (150 or 450mg/kg) for 4 weeks also resulted in an increase of Bacteroidetes and Proteobacteria and reduction of Firmicutes and Firmicutes/Bacteroidetes ratio [31], Table 1. Besides that, the treatment with cooked soybean (40mg/kg body weight/day) or probiotic fermented tempeh (40mg/kg body weight/day) for 14 weeks promoted lipolysis, inhibiting cholesterol synthesis and modulated gut microbiota, increasing Bacteroides and changed to Prevotella [32]. In adult non-obese diabetic (NOD) mouse model (male and female), genistein (20mg/kg body weight) daily for 5 months reduced blood glucose levels, improved glucose tolerance, produced anti-inflammatory responses and also perturbed gut microbiota in both males and females, increasing Prevotella and reducing Alistipes and Blautia. In NOD females also increased Erysipelotrichaceae and reduced Escherichia, Lachnospira, Firmicutes and Enterococcus [33]. Another study with NOD model treat with genistein (20mg/kg body weight) during embryonic day 7 to postnatal day 21, gut microbiota was perturbed toward a pro-inflammatory response among female offspring, increasing Enterobacteriales and reducing Bacteroides/Firmicutes ratio, but toward anti-inflammatory response among male offspring [34].

In an in vitro study, biotransformed soymilk with tannase and β-glycosidase enzymes showed antioxidant and anti-inflammatory activity in RAW 264.7 murine macrophages and 3T3-L1 murine preadipocytes. Although no reduction in lipid accumulation was observed by the 3T3-L1 adipocyte assay, biotransformed soymilk was able to reduce the expression of inflammatory cytokines, such as TNFα and IL-6, protecting cells from oxidative damage and helping to maintain health under stress inflammatory conditions [35].

In another in vitro study using the Caco-2 cell line, biotransformed soy milk with tanase in association with probiotic strains, resulted in an improvement in aglycones content, reduced intracellular reactive oxygen species production, as well as anti-inflammatory responses, demonstrating a positive impact of soy isoflavones present in biotransformed soy extract on antioxidant defense systems and modulation of intestinal inflammation [36].

The microorganisms present in the host can be permanent or transient residents, as well as their by-products, including toxic metabolites that can contribute to the appearance or progression of cancer in places far from where a specific microorganism resides, but can also migrate to other parts of the organism and become associated with the development of tumors. Therefore, an organism’s resident microbiota plays an essential role in activating, training and modulating the host’s immune response [11].

In this context, some studies have shown an association between different types of cancers being influenced by soy isoflavones consumption and gut microbiota composition. Subjects of both sexes with or without precancerous lesions, undergoing colonoscopy received four capsules of soy extract containing 11mg of daidzein and 4.38mg genistein per capsule. Seventeen bacterial species were present in the fecal samples, while ten species belong to the Bacteroides genus. Parabacteroides distasonis, Clostridium clostridioforme and Pediococcus pentasaceus were identified only in control group, while Bacteroides fragilis and Prevotella melaningenica were identified only in colorectal adenomas group. Regarding the daidzein and genistein levels, no significant differences were observed between the groups, however, urinary equol were lower in colorectal adenomas subjects compared to controls [37], Table 1. The results obtained in this study suggest that the presence of Bacteroides genus in the fecal samples of control subjects seems to be involved in the daidzein transformation to equol, an antioxidative, anti-carcinogenic molecule, which shows the most active estrogenic properties of soy isoflavones. In the transgenic adenocarcinoma of mouse prostate model fed with control or HFD and treat with 3mg of daidzein for the first three days and 6 mg of dadzein on the fouth day, resulted in the increase of 21 microbial phylotypes and reduction of 11 phylotypes, including decreased of equol-producing bacterium Adlercreutzia. This study, also revealed lower levels of equol in HFD group, suggesting that HFD may promote prostate carcinogenesis through adversely affecting equol-producing bacterium [38], Table 1. In another experimental study, the humanization of germ-free RAG2-/- athymic female mice were carried out by transplanting fecal samples from breast cancer patients before and after chemotherapy in order to investigate whether the intestinal microbiota of breast cancer patients could be modulated by genistein. For that, humanized mice were treat with genistein supplemented (special corn oil customized diet) for four weeks, resulting in the increase of Lactococcus and Eubacterium genus, confirming the hypothesis that genistein modulates the gut microbiota and may contribute on increasing the latency of breast tumor and reducing tumor growth [48], Table 1.

The use of antibiotics also dramatically affects bacterial composition and consequently isoflavone absorption and metabolism [4]. A fermented soymilk from Lactobacillus rhamnosus strain diet with antibiotic treatment improved fecal enzyme activity and kept the balance of the gut microbiota, increasing isoflavone metabolites in urine, besides increasing Bacteroides and Lactobacillus, and reducing in bacterial taxa in germ-free in male BALB/c mice [39], Table 1. In another study using dinitro- fluorobenzene-induced contact hypersensitivity in female BALB/c mice, dietary with soy isoflavones associated with antibiotics treatments resulted in the increase of Proteobacteria and Firmicutes/Bacteroidetes ratio, and reduction of Bacteroidetes and Actinobacteria [40], Table 1. In the early study, the same researchers investigaded changes in the gut microbiota caused by dinitro- fluorobenzene-induced contact hypersensitivity in female BALB/c mice in association of soymilk, improving contact hypersensitivity and changing the gut microbiota caused by contact hypersensitivity, increasing mainly Lactobacillaceae [41], Table 1.

Conclusions
It was possible to confirm that isoflavones can modulate the intestinal microbiota, but the effects seen on dysbiosis are not fully understood, because the amount of species that are found according both to a preexistent diet and/or after a supplementation with soy isoflavones and its subproducts. We could observe that many studies concerning the Asian diet, which is notably rich in soy products, may call our attention to the importance of isoflavones, but they are not a good parameter for studies regarding the difficulties in keeping studies patterns beyond isoflavones. A clinical randomized trial was not able to measure microbiota changes and more studies with equol producers are needed in order to characterize the responsible populations in microbiota. Experimental studies show a better controlled diet and soy isoflavones intake, thus an increase in Prevotella and a decrease in Firmicutes populations were observed in studies which verified changes in microbiota due to obesity and NAFLD. Further studies are necessary regarding cancer and inflammatory bowel disease. The use of antibiotics has a drastic effect on microbiota with or without isoflavones intake, however the presence of isoflavones decreases contact hipersensivity and keeps the balance of gut microbiota during antibiotics use.

Acknowledgements
This work was supported by Fundação de Amparo à Pesquisa do Estado de São Paulo - FAPESP, Brazil, (2019/10325-0).

Conflicts of Interests
The authors declare that there is no conflict of interest.

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