**1. Introduction**

The human gastrointestinal tract has various microorganisms, and "gut microbiota" has received attentions recently because the microbe population living in human intestine has significant effects to human health. Gut microbiota plays important roles in human, involving in many activities in a host body, for example, metabolism of xenobiotic compounds, immune system, nutrition, inflammation, and behavior. The delivery of prebiotics and probiotics to the human gastrointestinal tract, via dietary products or supplements, is one of the tools for management of microbiota in order to improve host health [1]. Moreover, gut microbiome has interactions with drugs and natural products, producing metabolites, which give

effects on efficacy, metabolism, and toxicity of drugs. Gut microbiota plays a role in the metabolism of drugs and natural products, as well as nutrients in diet or food. The conversion of a dietary soybean isoflavone, daidzein (**1**) or genistein (**2**), to a bioactive compound, *S*-equol (**3**) (**Figure 1**) [2, 3], is a good example for the role of gut bacteria in the production of pharmacologically active agent in human because *S*-equol (**3**) is a potent ligand for estrogen receptor *β* [4]. Daidzein (**1**) is also derived from its corresponding isoflavone glycoside, daidzin (**4**), by *Bifidobacterium*, a representative of major bacterial species of human origin; this bacterium could transform daidzin (**4**) to daidzein (**1**) by cell-associated *β*-glucosidases (**Figure 1**) [5]. Moreover, *O*-desmethylangolensin (**5**) is also found as an intestinal bacterial metabolite of daidzein (**1**) [6, 7].

The transformation of achiral molecule daidzein (**1**) to a chiral molecule equol, which has one chiral center in its molecule, should provide two possible enantiomers of *S*-equol (**3**) and *R*-equol (**3R**) (**Figure 2**). However, gut bacteria selectively gives only *S*-equol (**3**), not *R*-equol (**3R**); this is interesting because only *S*-equol (**3**) has a high affinity to bind with estrogen receptor *β*, while *R*-equol (**3R**) has much less activity [4]. Therefore, *S*-equol (**3**), but not *R*-equol (**3R**), has high affinity for estrogen receptor *β* in human, and *S*-equol (**3**) has more potent estrogenic activity than estradiol [4]. In animal model, although a mixture of the two enantiomers of equol have the ability to inhibit bone loss in ovariectomized mice [8], *S*-equol (**3**) has better inhibitory effects on bone fragility than the racemic mixture containing both *S*-equol (**3**) and *R*-equol (**3R**) [9].

The ability of gut bacteria to selectively produce the correct bioactive isomer of *S*-equol (**3**) needed for human is intriguing. Shimada and co-workers identified enzymes involved in the bioconversion of daidzein (**1**) to *S*-equol (**3**) by the bacterium *Lactococcus* sp. strain 20–92, which was isolated from feces of healthy human [10]. The enzyme daidzein reductase catalyzes the transformation of daidzein (**1**) to (*R*)-dihydrodaidzein (**6**), which is in turn converted to (*S*)-dihydrodaidzein (**7**) by the enzyme dihydrodaidzein racemase (**Figure 2**). The enzyme dihydrodaidzein reductase catalyzes the conversion of (*S*)-dihydrodaidzein (**7**) to *trans*-tetrahydrodaidzein (**8**), which is converted to *S*-equol (**3**) by the enzyme tetrahydrodaidzein reductase [10]. The bioconversion of daidzein (**1**) selectively to *S*-equol (**3**), not *R*-equol (**3R**), by gut bacteria provides human the correct enantiomer for binding with estrogen receptor *β*; this may be host-bacterial mutualism in human intestine. An isoflavone daidzein (**1**) is found in leguminous plants such as soybeans and other

#### **Figure 1.**

*Bioconversion of soybean isoflavones, daidzein (1), genistein (2), and daidzin (4), to* S*-equol (3) and*  O*-desmethylangolensin (5) by intestinal bacteria.*

**89**

**health and diseases**

diabetes [11].

**Figure 2.**

*Contribution of Gut Microbiome to Human Health and the Metabolism or Toxicity of Drugs…*

legumes, which have been used as food for human since ancient times. Therefore, it is possible that gut bacteria have experienced with daidzein (**1**) long time ago, and their enzymatic evolutions lead to the selective bioconversion of daidzein (**1**) to *S*-equol (**3**), which has biological activity for human. Interestingly, many studies revealed that there is the intestinal microbiota-to-host relationship, i.e., a cross talk, between gut microbiota and human host and interactions between gene products from the microbiome with metabolic systems of human diseases such as obesity and

*Structures of two enantiomers of* S*-equol (3) and* R*-equol (3R) and the bioconversion of daidzein (1) to*  S*-equol (3) by the bacterium* Lactococcus *sp. through the metabolites (*R*)-dihydrodaidzein (6),* 

The conversion of a dietary soybean isoflavone, daidzein (**1**) or genistein (**2**), to *S*-equol (**3**), by gut bacteria has been known for many years; however, scientists might not be aware of the importance of gut microorganisms in the past. Recently, a number of studies have revealed many essential roles of gut microbiota in human health and diseases. Gut microbiome can transform nutrients and dietary fibers to produce bioactive metabolites, for example, short-chain fatty acids (SCFAs) and nicotinamide, which have a significant impact on human health and diseases. There have been reports on interactions of gut microbiome and compounds, e.g., drugs and natural products, after humans take these compounds as drugs for the treatment of diseases. The metabolites obtained from the metabolism of drugs/natural products by the activities of gut microbiome have either positive or negative effects on therapeutic efficiency. This chapter provides the information of recent studies on the influence of the metabolites produced by gut microbiome on human health and diseases and on the interactions of microbiome and drugs/natural products.

**2. Contributions of metabolites produced by gut microbiome to human** 

The human gastrointestinal tract has trillions of microorganisms with a complex and diverse community. Gut microbiome is recognized as an "organ" because gut

*DOI: http://dx.doi.org/10.5772/intechopen.92840*

*(*S*)-dihydrodaidzein (7), and* trans*-tetrahydrodaidzein (8).*

*Contribution of Gut Microbiome to Human Health and the Metabolism or Toxicity of Drugs… DOI: http://dx.doi.org/10.5772/intechopen.92840*

**Figure 2.**

*Human Microbiome*

effects on efficacy, metabolism, and toxicity of drugs. Gut microbiota plays a role in the metabolism of drugs and natural products, as well as nutrients in diet or food. The conversion of a dietary soybean isoflavone, daidzein (**1**) or genistein (**2**), to a bioactive compound, *S*-equol (**3**) (**Figure 1**) [2, 3], is a good example for the role of gut bacteria in the production of pharmacologically active agent in human because *S*-equol (**3**) is a potent ligand for estrogen receptor *β* [4]. Daidzein (**1**) is also derived from its corresponding isoflavone glycoside, daidzin (**4**), by *Bifidobacterium*, a representative of major bacterial species of human origin; this bacterium could transform daidzin (**4**) to daidzein (**1**) by cell-associated *β*-glucosidases (**Figure 1**) [5]. Moreover, *O*-desmethylangolensin (**5**) is also found as

The transformation of achiral molecule daidzein (**1**) to a chiral molecule equol, which has one chiral center in its molecule, should provide two possible enantiomers of *S*-equol (**3**) and *R*-equol (**3R**) (**Figure 2**). However, gut bacteria selectively gives only *S*-equol (**3**), not *R*-equol (**3R**); this is interesting because only *S*-equol (**3**) has a high affinity to bind with estrogen receptor *β*, while *R*-equol (**3R**) has much less activity [4]. Therefore, *S*-equol (**3**), but not *R*-equol (**3R**), has high affinity for estrogen receptor *β* in human, and *S*-equol (**3**) has more potent estrogenic activity than estradiol [4]. In animal model, although a mixture of the two enantiomers of equol have the ability to inhibit bone loss in ovariectomized mice [8], *S*-equol (**3**) has better inhibitory effects on bone fragility than the racemic mixture containing

The ability of gut bacteria to selectively produce the correct bioactive isomer of *S*-equol (**3**) needed for human is intriguing. Shimada and co-workers identified enzymes involved in the bioconversion of daidzein (**1**) to *S*-equol (**3**) by the bacterium *Lactococcus* sp. strain 20–92, which was isolated from feces of healthy human [10]. The enzyme daidzein reductase catalyzes the transformation of daidzein (**1**) to (*R*)-dihydrodaidzein (**6**), which is in turn converted to (*S*)-dihydrodaidzein (**7**) by the enzyme dihydrodaidzein racemase (**Figure 2**). The enzyme dihydrodaidzein reductase catalyzes the conversion of (*S*)-dihydrodaidzein (**7**) to *trans*-tetrahydrodaidzein (**8**), which is converted to *S*-equol (**3**) by the enzyme tetrahydrodaidzein reductase [10]. The bioconversion of daidzein (**1**) selectively to *S*-equol (**3**), not *R*-equol (**3R**), by gut bacteria provides human the correct enantiomer for binding with estrogen receptor *β*; this may be host-bacterial mutualism in human intestine. An isoflavone daidzein (**1**) is found in leguminous plants such as soybeans and other

*Bioconversion of soybean isoflavones, daidzein (1), genistein (2), and daidzin (4), to* S*-equol (3) and* 

an intestinal bacterial metabolite of daidzein (**1**) [6, 7].

both *S*-equol (**3**) and *R*-equol (**3R**) [9].

**88**

**Figure 1.**

O*-desmethylangolensin (5) by intestinal bacteria.*

*Structures of two enantiomers of* S*-equol (3) and* R*-equol (3R) and the bioconversion of daidzein (1) to*  S*-equol (3) by the bacterium* Lactococcus *sp. through the metabolites (*R*)-dihydrodaidzein (6), (*S*)-dihydrodaidzein (7), and* trans*-tetrahydrodaidzein (8).*

legumes, which have been used as food for human since ancient times. Therefore, it is possible that gut bacteria have experienced with daidzein (**1**) long time ago, and their enzymatic evolutions lead to the selective bioconversion of daidzein (**1**) to *S*-equol (**3**), which has biological activity for human. Interestingly, many studies revealed that there is the intestinal microbiota-to-host relationship, i.e., a cross talk, between gut microbiota and human host and interactions between gene products from the microbiome with metabolic systems of human diseases such as obesity and diabetes [11].

The conversion of a dietary soybean isoflavone, daidzein (**1**) or genistein (**2**), to *S*-equol (**3**), by gut bacteria has been known for many years; however, scientists might not be aware of the importance of gut microorganisms in the past. Recently, a number of studies have revealed many essential roles of gut microbiota in human health and diseases. Gut microbiome can transform nutrients and dietary fibers to produce bioactive metabolites, for example, short-chain fatty acids (SCFAs) and nicotinamide, which have a significant impact on human health and diseases. There have been reports on interactions of gut microbiome and compounds, e.g., drugs and natural products, after humans take these compounds as drugs for the treatment of diseases. The metabolites obtained from the metabolism of drugs/natural products by the activities of gut microbiome have either positive or negative effects on therapeutic efficiency. This chapter provides the information of recent studies on the influence of the metabolites produced by gut microbiome on human health and diseases and on the interactions of microbiome and drugs/natural products.
