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Functional Foods and Antioxidant Effects: Emphasizing the Role of Probiotics

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Arezu Heydari, Farshid Parvini and Najaf Allahyari Fard

Submitted: February 27th, 2022Reviewed: March 7th, 2022Published: April 11th, 2022

DOI: 10.5772/intechopen.104322

IntechOpen
Functional FoodEdited by Naofumi Shiomi

From the Edited Volume

Functional Food [Working Title]

Dr. Naofumi Shiomi and Ph.D. Anna Savitskaya

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Abstract

Probiotics are host-compatible microorganisms that can optimally alter the balance of intestinal microflora, inhibit the growth of harmful bacteria, improve digestion, and increase the body\'s resistance by strengthening the immune system. Studies show that probiotics have antioxidant properties. Antioxidants are compounds that reduce the risk of various cancers and diseases. These compounds, in fact, inhibit the activity of free radicals and prevent their oxidation. By inactivation of free radicals, the body cells are protected from the destructive effects of these compounds. Oxidative stress is a condition that occurs as a result of disturbing the antioxidant-prooxidant balance in the cell, which eventually leads to apoptosis and cell death. Consumption of probiotic strains with antioxidant activity can benefit human health by reducing oxidative damage. Since the use of probiotics helps hemostasis, improves immune responses, and prevents many disorders caused by oxidation in the host, in this chapter, we discuss the antioxidant effects of probiotics as functional foods.

Keywords

  • functional foods
  • antioxidant effects
  • probiotics

1. Introduction

Oxidative stressis a process that leads to an increase in the level of oxygen radicals within the cell, which in turn causes damage to vital macromolecules (such as lipids, proteins, and nucleic acids) in the body [1]. Reactive oxygen species (ROS) are reactive molecules that contain superoxide anion radicals, hydroxyl radicals, and hydrogen peroxide. By contrast, natural antioxidants contain enzymatic antioxidants, such as superoxide dismutase (SOD), glutathione reductase (GR), and glutathione peroxidase (GPx), as well as non-enzymatic antioxidants, such as various types of vitamins, glutathione, and carotenoids, which have been formed during the evolution of organisms to prevent damage caused by oxidative stress [2]. Synthetic antioxidant additives can be used to prevent the oxidation of cellular compounds and thus prevent damage due to oxidative stress. The use of synthetic antioxidants has been questioned due to some reported side effects. Therefore, the preparation and use of natural antioxidants instead of synthetic antioxidants have attracted much attention [3, 4]. Probiotics are non-pathogenic microorganisms so sufficient consumption of them is beneficial for gastrointestinal health [4]. They also show antioxidant properties in various ways [5, 6, 7, 8].

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2. Reactive oxygen species

In all animals and plants, maintaining a normal oxygen concentration is essential. In contrast, an imbalance in oxygen concentration will lead to consequences, such as hypoxia (low oxygen) and oxidative stress (high oxygen), which can lead to tissue damage and even cell death. Cigarettes, herbicides, nitrogen oxide, ozone, radiation, and some metals affect oxygen concentration and oxidative stress conditions [9].

ROS originates from the metabolic process of oxygen used to induce oxidative stress [10]. The sources of ROS production are divided into exogenous and endogenous. Vital molecule changes due to reaction with ROS can be associated with various chronic diseases, such as atherosclerosis, osteoarthritis, diabetes, Alzheimer's disease, degenerative neurological diseases, and cardiovascular disease (Figure 1) [11, 12, 13, 14, 15, 16]. ROS concentration determines their role; so that in equilibrium, they can play a role as the second cellular messenger and regulator of biological processes, but an excessive increase of ROS concentration causes oxidative stress [17, 18].

Figure 1.

Reactive oxygen species (ROS) and associated diseases.

In 1991, the relationship between the induction of oxidants (ionizing radiation) and the activation of transcription factors was identified [19]. ROS affects the redox-sensitive elements of some transcription factors, such as hypoxia-inducible factors (HIFs) and kinases like phosphatidylinositol 3-kinase (PI3K); thus, it is possible to regulate these factors by oxygen free radicals [1, 20]. It is not easy to use antioxidants, because the body needs a sufficient concentration of ROS for specific purposes, but antioxidants alter the redox biology and interfere with the body's normal functioning.

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3. Probiotics and antioxidant properties

According to researches, in metabolic diseases (such as obesity and diabetes), there is an imbalance in the intestinal microbiota, so people's health is associated with the intestinal microbiota. As a result, by balancing the altered microbial flora by consuming some cloning probiotics, the health status of individuals can be improved [21, 22, 23]. In addition, reducing undesirable metabolites and precancerous enzymes and stimulating the immune system (cellular and humoral) are other beneficial effects of probiotics to improve the gastrointestinal status and prevent colorectal cancer [2].

In the pharmaceutical and food industries, lactic acid bacteria (LAB) strains are widely used probiotics [24]. One of the beneficial effects of these probiotics on the body of patients is the improvement of the condition in metabolic diseases [22, 25] and ulcerative colitis (UC) [26, 27, 28]. Also, based on research on fish, improvement of oxidative status and promotion of immunity with probiotics, such as Lactobacillus lactisand Lactobacillus rhamnosus, are observed [29, 30].

Bifidobacteriaare an example of another common bacterial probiotic. The beneficial effects of these probiotics include improving women with irritable bowel syndrome [31] and strengthening the immune system against tumors [32]. The presence of characteristics in Bacillusspecies has made them one of the most widely used probiotics in the food industry. One of these characteristics is the ability to produce protease, amylase, and lipase enzymes [33].

Based on the evidence, LAB strains are resistant to various types of ROS, such as superoxide anions, peroxide radicals, and hydroxyl radicals [34, 35]. Studies in recent decades show the antioxidant potential of probiotics; for example, the probiotic Bifidobacterium animalis 01eliminates free radicals (such as hydroxyl and anion peroxide) in vitroand increases antioxidant activity in mice [6]. In addition, improving the state of oxidative stress by multivitamin probiotics in people with type 2 diabetes [36] and increasing the level of antioxidants and neutralizing the effects of ROS by Lactobacillus rhamnosusin athletes who expose their bodies to oxidative stress [37]. Some of the studies on the relationship between probiotics and various diseases are listed in Table 1.

ProbioticsResultsReferences
Lactobacillus plantarumPBS067, Lactobacillus reuteriPBS072 and Lactobacillus rhamnosusLRH020Improving levels of inflammatory markers in patients with atopic dermatitis.[38]
Lactobacillus acidophilusLa-14, Lactobacillus caseiLc-11, Lactococcus lactisLl-23, Bifidobacterium lactisBl-04, and B. bifidumBb-06Reducing inflammatory biomarkers and improving the oxidative/nitrosative profile in people with rheumatoid arthritis.[39]
Lactobacillus casei ShirotaImproving cytokine profile toward an anti-inflammatory phenotype in stable cirrhotic patients.[40]
Lactobacillus acidophilusLA-5, BifidobacteriumBB-12, Streptococcus ThermophilusSTY-31, and Lactobacillus delbrueckii bulgaricusLBY-27Improving several inflammations and oxidative stress biomarkers in women with gestational diabetes mellitus.[41]
Lactobacillus acidophilus, Lactobacillus caseiand Bifidobacterium bifidumReducing inflammatory biomarkers in patients with major depressive disorder.[42]
Lactobacillus plantarumDR7Improving upper respiratory tract infections via enhancing immune and inflammatory parameters.[43]
Streptococcus thermophilusReducing biomarkers of oxidative stress and cardiovascular disease.[44]

Table 1.

Relationship between probiotic consumption and treatment of various diseases.

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4. The mechanisms of action of probiotics in antioxidation

There are different types of probiotics, so a variety of resistance mechanisms in different probiotic strains to cope with oxidative stress can be expected (Figure 2).

Figure 2.

The action modes of probiotic bacteria in antioxidation.

4.1 Metal chelating ability

Some probiotics exert their antioxidant potential by preventing metal ions from oxidizing. They use chelators to trap metal ions. These chelators include bathophenanthroline disulfonic acid (BPS), desferrioxamine, and ethylene diamine tetraacetic acid (EDTA) [45].

Different strains of probiotic bacteria were studied for this antioxidant mechanism; for example, among the various strains capable of chelating iron (II) or copper (II), the strains of Lactobacillus caseiKCTC 3260 and Streptococcus thermophilus821 have a much higher ability to chelate iron (II) and copper (II) [46]. Also, the high potency of Lactobacillus helveticusCD6 intracellular cell-free extraction in chelating iron (II) ions can be mentioned [47].

These chelating agents are not fully understood in probiotic bacteria. However, studies have shown their role in inhibiting phosphate ester displacement enzymatic reactions, as well as the production of radicals (such as peroxyl radical and alkoxyl radical) due to the decomposition of hydroperoxide compounds [48].

4.2 Antioxidant enzymes system

Mitochondria are sources of superoxide production. Superoxide is one of the most prevalent ROS. To reduce the risk of this compound, an enzyme called superoxide dismutase (SOD), as one of the essential enzymes in antioxidant enzyme systems, is needed. This enzyme breaks down the high-risk compound superoxide and converts it into less dangerous compounds, such as hydrogen peroxide and water. Therefore, it can be said that SOD in animals and also in prokaryotes plays an important role in regulating ROS [49].

Types of SOD enzymes have been identified in mammals and bacteria, which are used against oxidative stress. Fe-SOD and Mn-SOD have been observed in bacteria [50]; for example, the Mn-SOD in Lactobacillus fermentumE-3 and E-18 was reported by Kalisar et al. [35]. While cytoplasmic and extracellular Zn-SOD and mitochondrial Mn-SOD have been observed in mammals [50].

SOD enzymes need suitable transporters, that can be used in the local delivery of these enzymes [51] because despite its antioxidant activity [52, 53, 54], the limited bioavailability of SOD (due to its short half-life in the circulating) has questioned its therapeutic application. The use of probiotic bacteria for this purpose led to successful results; for example, the use of probiotic bacteria as a transporter for topical delivery of SOD was effective in counteracting the oxidative stress induced by ROS in people with intestinal diseases. Also, according to a study, engineered strains of Lactobacillus caseiBL23 (capable of producing SOD) improved the inflammatory status and increased enzymatic activity of mice with Crohn's disease, which shows the beneficial effect of using probiotic bacteria as a carrier [51].

Another enzyme that can be found in probiotic bacteria (except LAB) is called catalase (CAT), Which acts as an antioxidant under oxidative stress. CAT is involved in a reaction known as Fenton. In this reaction, CAT inhibits the production of hydroxyl radicals by the decomposition of hydrogen peroxide, in this way, exerts its antioxidant role [55]. To determine the antioxidant effect of the enzyme CAT, studies have been performed on bacteria that contain this enzyme. CAT-producing probiotic bacteria include Lactococcus lactisand the engineered strains of Lactobacillus caseiBL23 [56].

Another action of probiotics inside the host is to enhance antioxidant activity by increasing the levels and activity of several enzymes. For example, according to studies, the probiotic Lactobacillus fermentumincreases the levels of SOD, GPx, CAT and Cu, and Zn-SOD enzymes [57], yeast probiotics increase the activity of GPx enzyme [58], and Bacillus amyloliquefaciensSC06 probiotic increases the expression of genes such as CATand glutathione S-transferase (GST) in the studied animals [7]. In addition, people with type 2 diabetes show increased antioxidant activity by taking the probiotics Lactobacillus acidophilusLa5 and Bifidobacterium lactisBb12, which is due to increased activity of antioxidant enzymes such as SOD and GPx in red blood cells [59].

4.3 Antioxidant metabolites

Probiotics can exert their antioxidant power in other ways, for example, theyproduce various metabolites with antioxidant properties. These metabolites include glutathione (GSH), butyrate, and folate.

The properties of folate include the acceptance of mono carbon units, its use in various metabolic pathways, and its necessity in DNA synthesis and regeneration, DNA methylation, and cell division [60].

Studies showed an increase in folate levels in the body of rats and humans after treatment with bifidobacteria[61, 62] and an increase in the level of this metabolite and vitamin B12 in people treated with the probiotic Lactobacillus acidophilusLa1 [63]. Evidence also showed that patients with type 2 diabetes experience oxidative stress, and in the absence of metabolites, such as folate and vitamin B12, this condition is exacerbated. Therefore, host treatment with these types of probiotics can increase the levels of these antioxidant metabolites in patients [64]. In addition, according to the study, intact cells of Lactobacillus helveticusCD6 producing folate and intracellular cell-free extract of this probiotic have similar antioxidant power [47]. Vitamins, such as vitamin B1, can make cells more resistant to oxidative stress. According to research, consumption of some probiotics can lead to increased absorption of this vitamin in individuals, which helps protect cells against oxidative stress [65, 66, 67].

GSH is another example of a non-enzymatic antioxidant, which is involved in the removal of radicals (such as hydrogen peroxides, hydroxyl radicals, and peroxynitrite). GSH works in conjunction with the selenium-dependent enzyme glutathione peroxidase [68]. Probiotics may contain GSH, and have antioxidant properties under oxidative stress. According to studies, Lactobacillus fermentumE-3, E-18, and ME-3 are among the probiotics with large amounts of GSH [35, 69].

During the fermentation of a series of indigestible substances, the microbiota makes a short-chain fatty acid (SCFA) called butyrate [70]. Butyrate has an antioxidant role under oxidative stress by inducing antioxidants. Some probiotics can produce butyrate; for example, based on evidence, MIYAIRI 588 strain of Clostridium butyricumwith the production of butyrate has been able to improve rats with non-alcoholic fatty liver and exposed to oxidative stress [71].

4.4 Antioxidant signaling pathway mediated by probiotic bacteria

4.4.1 Nrf2-Keap1-ARE

Under oxidative stress, the expression of genes involved in the detoxification of ROS can be mediated through a pathway called Nrf2-Keap1-ARE (Figure 3) [72, 73]. In this pathway, the binding of Nrf2 to the antioxidant response element (ARE) sequences in the nucleus leads to the expression of factors related to the detoxification of ROS [74, 75, 76]. The activation or inhibition of Nrf2 depends on the amount of ROS. When the amount of ROS is low, the cytoplasmic inhibitor Keap1 binds to Nrf2, causing its proteasome degradation by polyubiquitination [77]; however, under oxidative stress, the functional structure of Keap1 changes due to the influence of the amino acid cysteine, which leads to the activation of Nrf2 and its entry into the nucleus and binding to the ARE sequences [74, 75, 76, 78].

Figure 3.

Nrf2-keap1-ARE pathway mediated by probiotics.

Probiotics can exert their antioxidant effects by regulating the Nrf2-Keap1-ARE pathway. According to research, probiotics such as Lactobacillus PlantarumFC225, Lactobacillus PlantarumCA16, and Lactobacillus PlantarumSC4 can increase the level of Nrf2 in the liver cells of hypertensive mice [79, 80]. The effect of Clostridium butyriciumMIYAIRI 588 [71] and Bacillus amyloliquefaciensSC06 on increasing the level and regulation of Nrf2 expression in the studied animals has been shown [7].

4.4.2 NFκB

In inflammatory conditions, the expression of inflammatory cytokines is mediated by the transcription factor NFκB. This factor is activated by ROS. It can be said that NFκB is the first transcription factor that responds to oxidative stress [19]. Evidence suggests that probiotics may inhibit NFκB by their antioxidant power, and thus play a role in preventing inflammation. Inhibition of NFκB and stimulation of heat shock proteins (Hsps) in colon epithelial cells by probiotic mixture VSL # 3 and also the effect of Bacillussp. strain LBP32 in the prevention of inflammation in RAW 264.7 macrophages are examples of the antioxidant effect of probiotics by inhibiting NFκB [81, 82].

4.4.3 MAPK

Among the four subfamilies of mitogen-activated protein kinases (MAPKs), c-jun N-terminal kinase (JNKs) and p38-MAPK are key enzymes involved in response to various stresses (UV irradiation and osmotic shock), and extracellular regulated protein kinases (ERKs) have an important role in anabolic metabolisms [83, 84]. These are the best-known mitogen-activated protein kinases [85].

Based on studies, some probiotics, such as LactobacillusGG, can activate MAPK in the young adult mouse colon (YAMC) cells. Soluble agents in the conditioned media from the probiotic LactobacillusGG (LactobacillusGG-CM) in these cells stimulate Hsp25 and Hsp72. MAPK signaling pathways are involved in the expression and stimulation of Hsps in treated cells, so inhibition of p38 and JNK in the YAMC and then treatment with the probiotic LactobacillusGG-CM stops the expression of Hsp72 [86]. In addition, the soluble proteins p40 and p75 produced by the probiotic Lactobacillus rhamnosusGG via the MAPK pathway can correct the dysfunction of epithelial cell barriers caused by a potent oxidant [85].

4.4.4 PKC

The control of the phosphorylation function of hydroxyl groups of serine and threonine residues in proteins is associated with Protein kinase C (PKC). PKC is also cellular messenger molecule that plays a role in various pathways, including regulation of cell growth and death and response to stresses. This molecule is very sensitive to redox modification, as well [87, 88, 89]. On the other hand, some probiotics can affect PKC activity. Corresponding to the previous report (Seth et al., 2008), inhibition of Ro-32-0432 (PKC inhibitor) by soluble proteins p40 and p75 produced by L. rhamnosusGG improves H2O2-induced epithelial barrier disorder [85].

4.5 Regulation of the ROS producing enzymes

Production of ROS through enzymatic reactions and various chemical processes in the host body is essential [90]; because they play an important role in defense and messaging functions [91]. The human NADPH oxidase (NOX) complex, as the main source of reactive oxygen species [92, 93, 94], has seven homologs (NOX1–5, dual oxidase 1 (DUOX1), and DUOX2) [91]. Membrane-bound NOX2 catalytic subunits and p22phox in combination with cytosolic agents (e.g., p40phox, p47phox, p67phox, and small GTPase RAC1, called by neutrophils) cause a respiratory burst (Figure 4) [95, 96]. However, oxidative stress occurs if there is an imbalance in the production of ROS or a decrease in the level of oxygen-scavenging proteins, which leads to tissue damage and cell death [93].

Figure 4.

NADPH oxidase (NOX) complex regulated by probiotics.

Probiotics are able to affect the production of ROS by the NOX complex. Based on researches, the probiotic Bacillus amyloliquefaciensSC06 reduces the activity of NOX and expression of p47phox (H2O2-induced IPEC-1) and the probiotics Lactobacillus fermentumCECT5716, Lactobacillus coryniformisCECT5711 (K8) and Lactobacillus gasseriCECT5714 (LC9) reduce NOX activity and decrease the mRNA expression of NOX-1 and NOX-4 enzymes (in hypertensive rats), as a result, they reduce the production level of ROS [7, 97].

On the other hand, ROS can be produced during prostaglandin biosynthesis. For example, cyclo-oxygenase (COX) participates in process of prostaglandin biosynthesis [98]. In some diseases, such as atherosclerosis, COX-2 expression is increased [99]. Therefore, it can be said that the production of vascular prostanoids is caused by overexpression of the COX-2 enzyme [100]. Studies have shown that some probiotics can reduce the expression of COX-2 in the host; for example, the commercial probiotic Lacidofil, when used in mice infected with Helicobacter pylori [101]. Furthermore, it has been established that the expression of COX-2 is reduced by Lactobacillus acidophilusin Catla thymus macrophages [102].

Improper functioning of cytochrome P450 (CYP) enzymes is associated with overproduction of ROS and oxidative stress conditions [103]; because they are involved in the metabolism of xenobiotic substances [104]. Some probiotics reduce the expression of these enzymes. Matuskova et al. reported Lactobacillus caseiis involved in reducing the expression of CYP1A1 enzyme in the intestines of male rats [105].

4.6 Modulation of the intestinal microbiota

Studies have shown that some probiotics can be used to treat intestinal diseases [106, 107] because they have the ability to improve the oxidative stress created by changing the composition of the microbiota. In fact, probiotics show their antioxidant properties by settling in the gastrointestinal tract [108, 109] to regulate the altered microbiota composition and prevent the proliferation of harmful bacteria. Based on researches, Lactobacillusand Bifidobacteriumare among the probiotics that prevent the growth of pathogenic bacteria by lowering the pH of the intestine; as a result, a balance is established in the composition of the microbiota [110, 111]. In addition, some probiotics produce toxic compounds (such as organic acids, bactericides, and biosurfactants) against pathogenic microorganisms [112]. For example, Lactobacillus rhamnosusGG, suppresses different bacteria by producing antimicrobial compounds [113]. As previously mentioned, the use of probiotics leads to improving oxidative stress by modulating the composition of gut microbiota and reducing the abundance of harmful bacteria.

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5. Conclusion

Probiotics are microorganisms, when consumed in appropriate doses, can be beneficial to humans in a variety of biological manners. In the last few years, probiotics with antioxidant potential that have the ability to cope with oxidative stress have received much attention. Therefore, extensive studies have shown that the use of these probiotics can improve health in patients who experience different oxidative stress conditions. Known mechanisms that probiotics use to counteract with reactive oxygen species include chelating metal ions, affecting enzymes, metabolites, antioxidant signaling pathways, and modulating intestinal microbial composition. However, more research is required on the type of probiotics and their dosage. Ultimately, probiotics can regard as the therapeutic potential for inflammatory disease.

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Acknowledgments

The authors thank the National Institute of Genetic Engineering and Biotechnology (NIGEB) and Semnan University for their facilities and cooperation.

This section of your manuscript may also include funding information.

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Conflict of interest

The authors declare no conflict of interest.

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Written By

Arezu Heydari, Farshid Parvini and Najaf Allahyari Fard

Submitted: February 27th, 2022Reviewed: March 7th, 2022Published: April 11th, 2022