**2. Toxicokinetics and heavy metal toxicodynamics**

Of the most important aspects to consider in heavy metal poisoning is toxicokinetics and toxicodynamics. In this regard, the term toxicokinetics refers to the way through which toxins from the source of exposure enter the body, are distributed, biotransformed and eliminated [27]. On the other hand, toxicodynamics studies the mechanisms at the cellular or molecular level by which toxins cause damage [27]. These branches of toxicology are important to know because through toxicokinetics it is possible to prevent the metal from entering the bloodstream, its distribution can be modified and therapeutic measures can be taken to eliminate and reduce the toxic effects caused in the organism [28].

In this context, there are different sources of exposure to heavy metals, these sources can be natural such as water for human consumption or food of animal and plant origin mainly contaminated with arsenic, mercury or lead [29]. On the other hand, there are other sources of exposure such as the use of clay utensils or glazed earthenware that are used in Mexico to prepare food, industrial activities for the manufacture of accumulators, paints, cosmetics, medicines, thermometer manufacturing, etc., which also contribute to heavy metals being available in the environment so that they can enter the body of those exposed to them [27, 30, 31]. Of these sources of exposure, the most worrisome are natural sources such as water and food contaminated with these metals, because the population is unaware that their natural resources are contaminated and use them daily so they have a high risk of these metals that can damage your health, whether in the short, medium and/ or long term [32]. In the case of the sources generated by man as a work practice, it is easier to prevent exposure by taking various hygiene and safety measures in the work environment.

From the sources of exposure, heavy metals enter the body through different routes such as oral, topical and inhalation [27]. However, the main route of entry is the oral and sometimes in the same individual heavy metals can enter through different routes; such as mercury, the most common case is when a glass thermometer containing this metal is broken and the user tries to pick it up with their hands, it will be absorbed through the skin, in addition to room temperature the mercury evaporates in its elementary form so that in this same individual mercury vapors enter by inhalation. But if, in addition, he did not wash his hands after collecting the mercury and immediately consumes food, he can contaminate them by taking them by hand and the mercury will enter orally, although by this route practically the elemental mercury is absorbed very little [33]. In this example, it is clear how the metal can enter via different ways, which increases the amount of metal that enters the body. However, in general, for all metals it is important to consider jointly and not in isolation: the source of exposure, the amount of toxic present, the route of entry of the toxic and the time of exposure to the toxic, since these aspects influence the magnitude of the damage that metals can cause in the organism [27, 28].

From these routes of entry, the four toxicokinetic processes of absorption, distribution, biotransformation and elimination are initiated. The absorption process refers to the passage of the toxic through the route of entry into the blood, for this to happen, it is important to consider whether it is exposed to organic and inorganic

**153**

*Role of the Microbiome as the First Metal Detoxification Mechanism*

redistributed and deposited in bone and teeth [27].

enterohepatic circulation of bile acids and lead [40].

In another study in rodents with a probiotic strain (*Lactobacillus plantarum CCFM8610*) administered orally, significantly improved hepatic synthesis of bile

compounds or to the elemental form of the metal that is contaminating either water or the food. In the case of organic compounds, they enter the bloodstream more easily because they are fat soluble and diffuse biological membranes faster and therefore their absorption rate may be higher than that of inorganic species. The species in elementary state evaporate so that when they are inhaled, they diffuse through the alveoli [34]. As for the distribution of heavy metals, it is observed that the organic forms are rapidly distributed to the central nervous system since they can easily cross the blood-brain barrier due to their liposolubility, they are also distributed to adipose tissue and other organs with higher fat content such as liver, heart and kidneys [27]. In contrast, inorganic compounds do not pass blood-brain barrier [28]. In general, metals pass placenta, and are attached to the disulfide bonds present in the keratin of the skin, hair and nails. On the other hand, lead is

In the biotransformation process of some heavy metals such as mercury and arsenic mainly, methylation reactions occur [27]. These occur in the liver and kidney, but various biotransformation reactions in the intestine can also be carried out through the microbiota. In this context, there is evidence at the preclinical level in cell cultures and in animal models that the microbiota performs various chemical reactions that can modify the toxicity of heavy metals; since heavy metals when distributed in the body can be concentrated in the bile and subsequently enter the enterohepatic circuit, or during their journey through the gastrointestinal system they may be susceptible to being biotransformed by the microbiota enzymes to less or more compounds toxic to the individual and even to the microbiota itself [35, 36]. This is a new issue that is changing the approach to toxicokinetics and toxicodynamics of heavy metals and other environmental toxins. For example, it has been described in murine models that the intestinal microbiota specifically the presence of bacteria such as *Faecalibacterium* can protect against acute arsenic toxicity [37]. At the preclinical level, there is a very interesting study on the intestinal microbiome of conventionally raised mice (with normal microbiomes) and of mice with mammalian microbiomes altered with antibiotics and both groups exposed to sodium arsenite. In this regard, the authors found high levels of As in urine of mice with altered mammalian microbiomes, but the levels of As in the total feces were lower in this group, compared with conventionally raised mice. They also observed that the interruption of the intestinal microbiome with antibiotics significantly modified the biotransformation of arsenic and the urinary ratio of *monomethylarsonic acid/dimethylarsinic acid* increased. Regarding the expression of carbon metabolism genes (folr2, bhmt and mthfr), they observed a downward regulation, and the levels of S-adenosyl methionine (SAM) in the liver of mice with mammalian microbiome altered with antibiotics and treated with arsenic they also decreased significantly. Finally, they concluded that altering the microbiome with antibiotics also increases the toxic effects of arsenic in mice [38]. In another study, it was observed that dietary supplementation with a galactooligosaccharide produced an increase in fecal excretion of lead, a decrease in plasma and tissue concentration of the metal in mice. This effect was not observed when the microbiota of the mice was modified with antibiotics [39]. On the other hand, the probiotic strain *Lactobacillus plantarum* CCFM8661, prevented the absorption of lead in mice by intestinal sequestration, also significantly induced bile acid synthesis, improved bile flow and bile glutathione excretion, and increased bile acid excretion in feces of mice, the outflow of bile lead and improved fecal excretion of lead. Previous antibiotic treatment eliminated the effects induced by *L. plantarum* CCFM8661 on

*DOI: http://dx.doi.org/10.5772/intechopen.89232*

#### *Role of the Microbiome as the First Metal Detoxification Mechanism DOI: http://dx.doi.org/10.5772/intechopen.89232*

*Prebiotics and Probiotics - Potential Benefits in Nutrition and Health*

**2. Toxicokinetics and heavy metal toxicodynamics**

toxic effects caused in the organism [28].

work environment.

could contribute to their elimination, because these kinds of bacteria have a high affinity for heavy metals [26]. Therefore, a diet that favors the proliferation of LAB could be used as the natural detoxification of the organism in populations exposed to environmental pollutants. In this chapter, we review the role of diet in the gut microbiota and its possible use for the natural detoxification of the organism.

Of the most important aspects to consider in heavy metal poisoning is toxicokinetics and toxicodynamics. In this regard, the term toxicokinetics refers to the way through which toxins from the source of exposure enter the body, are distributed, biotransformed and eliminated [27]. On the other hand, toxicodynamics studies the mechanisms at the cellular or molecular level by which toxins cause damage [27]. These branches of toxicology are important to know because through toxicokinetics it is possible to prevent the metal from entering the bloodstream, its distribution can be modified and therapeutic measures can be taken to eliminate and reduce the

In this context, there are different sources of exposure to heavy metals, these sources can be natural such as water for human consumption or food of animal and plant origin mainly contaminated with arsenic, mercury or lead [29]. On the other hand, there are other sources of exposure such as the use of clay utensils or glazed earthenware that are used in Mexico to prepare food, industrial activities for the manufacture of accumulators, paints, cosmetics, medicines, thermometer manufacturing, etc., which also contribute to heavy metals being available in the environment so that they can enter the body of those exposed to them [27, 30, 31]. Of these sources of exposure, the most worrisome are natural sources such as water and food contaminated with these metals, because the population is unaware that their natural resources are contaminated and use them daily so they have a high risk of these metals that can damage your health, whether in the short, medium and/ or long term [32]. In the case of the sources generated by man as a work practice, it is easier to prevent exposure by taking various hygiene and safety measures in the

From the sources of exposure, heavy metals enter the body through different routes such as oral, topical and inhalation [27]. However, the main route of entry is the oral and sometimes in the same individual heavy metals can enter through different routes; such as mercury, the most common case is when a glass thermometer containing this metal is broken and the user tries to pick it up with their hands, it will be absorbed through the skin, in addition to room temperature the mercury evaporates in its elementary form so that in this same individual mercury vapors enter by inhalation. But if, in addition, he did not wash his hands after collecting the mercury and immediately consumes food, he can contaminate them by taking them by hand and the mercury will enter orally, although by this route practically the elemental mercury is absorbed very little [33]. In this example, it is clear how the metal can enter via different ways, which increases the amount of metal that enters the body. However, in general, for all metals it is important to consider jointly and not in isolation: the source of exposure, the amount of toxic present, the route of entry of the toxic and the time of exposure to the toxic, since these aspects influence the magnitude of the damage that metals can cause in the organism [27, 28]. From these routes of entry, the four toxicokinetic processes of absorption, distribution, biotransformation and elimination are initiated. The absorption process refers to the passage of the toxic through the route of entry into the blood, for this to happen, it is important to consider whether it is exposed to organic and inorganic

**152**

compounds or to the elemental form of the metal that is contaminating either water or the food. In the case of organic compounds, they enter the bloodstream more easily because they are fat soluble and diffuse biological membranes faster and therefore their absorption rate may be higher than that of inorganic species. The species in elementary state evaporate so that when they are inhaled, they diffuse through the alveoli [34]. As for the distribution of heavy metals, it is observed that the organic forms are rapidly distributed to the central nervous system since they can easily cross the blood-brain barrier due to their liposolubility, they are also distributed to adipose tissue and other organs with higher fat content such as liver, heart and kidneys [27]. In contrast, inorganic compounds do not pass blood-brain barrier [28]. In general, metals pass placenta, and are attached to the disulfide bonds present in the keratin of the skin, hair and nails. On the other hand, lead is redistributed and deposited in bone and teeth [27].

In the biotransformation process of some heavy metals such as mercury and arsenic mainly, methylation reactions occur [27]. These occur in the liver and kidney, but various biotransformation reactions in the intestine can also be carried out through the microbiota. In this context, there is evidence at the preclinical level in cell cultures and in animal models that the microbiota performs various chemical reactions that can modify the toxicity of heavy metals; since heavy metals when distributed in the body can be concentrated in the bile and subsequently enter the enterohepatic circuit, or during their journey through the gastrointestinal system they may be susceptible to being biotransformed by the microbiota enzymes to less or more compounds toxic to the individual and even to the microbiota itself [35, 36]. This is a new issue that is changing the approach to toxicokinetics and toxicodynamics of heavy metals and other environmental toxins. For example, it has been described in murine models that the intestinal microbiota specifically the presence of bacteria such as *Faecalibacterium* can protect against acute arsenic toxicity [37]. At the preclinical level, there is a very interesting study on the intestinal microbiome of conventionally raised mice (with normal microbiomes) and of mice with mammalian microbiomes altered with antibiotics and both groups exposed to sodium arsenite. In this regard, the authors found high levels of As in urine of mice with altered mammalian microbiomes, but the levels of As in the total feces were lower in this group, compared with conventionally raised mice. They also observed that the interruption of the intestinal microbiome with antibiotics significantly modified the biotransformation of arsenic and the urinary ratio of *monomethylarsonic acid/dimethylarsinic acid* increased. Regarding the expression of carbon metabolism genes (folr2, bhmt and mthfr), they observed a downward regulation, and the levels of S-adenosyl methionine (SAM) in the liver of mice with mammalian microbiome altered with antibiotics and treated with arsenic they also decreased significantly. Finally, they concluded that altering the microbiome with antibiotics also increases the toxic effects of arsenic in mice [38]. In another study, it was observed that dietary supplementation with a galactooligosaccharide produced an increase in fecal excretion of lead, a decrease in plasma and tissue concentration of the metal in mice. This effect was not observed when the microbiota of the mice was modified with antibiotics [39]. On the other hand, the probiotic strain *Lactobacillus plantarum* CCFM8661, prevented the absorption of lead in mice by intestinal sequestration, also significantly induced bile acid synthesis, improved bile flow and bile glutathione excretion, and increased bile acid excretion in feces of mice, the outflow of bile lead and improved fecal excretion of lead. Previous antibiotic treatment eliminated the effects induced by *L. plantarum* CCFM8661 on enterohepatic circulation of bile acids and lead [40].

In another study in rodents with a probiotic strain (*Lactobacillus plantarum CCFM8610*) administered orally, significantly improved hepatic synthesis of bile acids, bile glutathione release and fecal excretion of bile acids. The biliary and fecal excretion of cadmium increased markedly after the administration of *L. plantarum CCFM8610*, which resulted in a marked reduction in Cd levels in tissues. These effects were related to the intestinal microbiota, since prior antibiotic treatment reversed the effects induced by *L. plantarum CCFM8610* on the metabolism of bile acids and cadmium [41].

Finally, heavy metals and some demethylated metabolites are eliminated primarily by urine, but they can also be eliminated by bile, feces, breast milk, skin, nails and hair [27, 28]. Once the processes of absorption, distribution, metabolism and elimination of heavy metals are analyzed, it is very important to consider the pharmacokinetic changes that can occur in the most vulnerable populations who suffer from toxic effects such as children and pregnant women (**Table 1**) [27].

Regarding the toxicodynamics of heavy metals, various toxicity mechanisms have been described, however the most important are:


These cell targets are primarily responsible for alterations and damage in various organs and systems [42]. Currently, the treatment for heavy metal poisoning is based on the administration of chelating drugs, which form a coordination link with heavy metal, favoring its elimination mainly by urine [27, 43]. However, when analyzing toxicodynamics, an important aspect to consider during treatment is to block the free radicals that are formed to prevent damage caused by the oxidation


**155**

*Role of the Microbiome as the First Metal Detoxification Mechanism*

of lipids and proteins of the membranes and thus avoid oxidative cell stress, so that phytochemical compounds present in various foods can be effective in preventing oxidative cell damage. It has been described in the literature that heavy metals readily bind to groups -SH-, -SS-, -NH2-, -OH and -COO-, these groups are present in some endogenous antioxidants such as glutathione and exogenous acids such as acid ascorbic, so many antioxidant compounds such as flavonoids present in food can be an alternative to block the oxidative effect of heavy metals and thereby minimize or prevent oxidative damage in the population that has exposure to heavy

In recent years, the study of intestinal microbiota has increased significantly,

In this regards, intestinal microbiota compete for nutrients, space and receptors with pathogenic microorganisms, as well as stimulating the production of antimicrobial peptides and IgA antibodies; whereas in metabolic functions, the microbiota converts many complex substances such as starches, cellulose, pectins and gums into metabolites that are easily absorbed and used by the host, it also ferments another non-digestible residues from the diet, synthesizes some vitamins and is also involved in the absorption of ions (such as calcium, magnesium and iron) and

because important protective and metabolic functions have been associated.

The intestinal microbiota comprised about 35,000 species of microbes and includes at least six bacteria phyla, among them *Firmicutes*, *Bacteroidetes, Fusobacteria, Proteobacteria, Actinomycetes and Verrucomicrobia*; the predominant bacteria populations constituting about 90% of the total being Firmicutes and Bacteroidetes [45]. In gastrointestinal tract, there is a wide variety of bacteria that survive and have adapted to different pH conditions. In the esophagus, pH <4 is inhabited by bacterial strains from phyla *Bacteroides, Gemella, Megasphaera, Pseudomonas, Prevotella, Rothia sps., Streptococcus and Veillonella*. The phylas such as *Streptococcus, Lactobacillus, Prevotella, Enterococcus* and *Helicobacter* reside mainly in stomach (pH = 2). In small intestine (pH = 5–7), the phylas such as *Bacteroides, Clostridium, Streptococcus, Lactobacillus, g-Proteobacteria* and *Enterococcus* are found mainly (**Figure 1**). In colon (pH = 5–5.7), *Bacteroides, Clostridium, Prevotella, Porphyromonas, Eubacterium, Ruminococcus, Streptococcus, Enterobacterium, Enterococcus, Lactobacillus, Peptostreptococcus* and *Fusobacteria* are the resident phylas and finally in cecum (pH = 5–7) the phylas such as *Lachnospira, Roseburia, Butyrivibrio, Ruminococcus, Fecalibacterium* and *Fusobacteria* are found [46]. The intestinal microbiota has both a symbiotic and mutualism relationship, and also it has an important influence on the health and physiology of host. In this way, intestinal dysbiosis has been associated with a large array of human diseases such as, irritable bowel syndrome, inflammatory bowel disease, metabolic diseases (obesity

and diabetes), as well as allergic and neurological diseases [47–49].

There are several factors affecting variations on intestinal microbiota, including age and diet [46, 50, 51]. It has been suggested that intestinal microbiota in healthy individuals is relatively stable when the diet remains without major changes, but with a subtle change in diet, the intestinal bacterial composition may also change and produces important alterations on the protective barrier function of the intestine. It is well known that not only the intestinal microbiota supports the protective functions of host. In addition, there is a complex cellular barrier where a variety of cells with different functions are housed, such as enterocytes, goblet cells, enteroendocrine cells, Paneth cells and intraepithelial lymphocytes; together with the mucus

*DOI: http://dx.doi.org/10.5772/intechopen.89232*

**3. Microbiota and its composition**

metals [28, 44].

energy recovery [13, 14].

#### **Table 1.**

*Most important aspects to consider in the toxicokinetics of vulnerable populations.*

*Role of the Microbiome as the First Metal Detoxification Mechanism DOI: http://dx.doi.org/10.5772/intechopen.89232*

of lipids and proteins of the membranes and thus avoid oxidative cell stress, so that phytochemical compounds present in various foods can be effective in preventing oxidative cell damage. It has been described in the literature that heavy metals readily bind to groups -SH-, -SS-, -NH2-, -OH and -COO-, these groups are present in some endogenous antioxidants such as glutathione and exogenous acids such as acid ascorbic, so many antioxidant compounds such as flavonoids present in food can be an alternative to block the oxidative effect of heavy metals and thereby minimize or prevent oxidative damage in the population that has exposure to heavy metals [28, 44].
