Probiotics Beverages: An Alternative Treatment for Metabolic Syndrome

PROBIOTICS BEVERAGES: AN ALTERNATIVE TREATMENT FOR METABOLIC SYNDROME

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Edwin E. Martínez Leo*,†, Armando M. Martín Ortega†, Abigail Meza Peñafiel*, Maira R. Segura Campos† *

Unidad de Posgrado e Investigación, Universidad Latino, Mérida, Mexico, Facultad de Ingeniería Química, Universidad Autónoma de Yucatán, Mérida, Mexico †

14.1 Introduction Metabolic syndrome (MS) refers to the set of metabolic disorders framed in the context of chronic inflammation and insulin ­resistance (IR). This process is characterized by a disorder that results in the chronic progression of visceral adipose tissue, the decrease in high-density lipoprotein concentrations (c-HDL), the elevation of triglycerides and low-density lipoprotein levels (c-LDL), endothelial dysfunction with sustained increase in blood pressure, and chronic hyperglycemia (Rani et al., 2016). The term MS was released in the early 1980s. It was till then known as the syndrome X, later it was also called IR syndrome, cardiovascular dysmetabolic syndrome, death quartet, and finally MS or cardiometabolic, which is well known and is studied by the World Health Organization (WHO) since 1999 (Leslie, 2005; Parikh and Mohan, 2012). The MS is considered the 21st-century pandemic, associated with a fivefold increase in the prevalence of type 2 diabetes and 2–3 times increase in cardiovascular disease (CVD). Premature morbidity and mortality due to MS increases health risks and completely unbalances the health budgets of many developed and developing countries. According to WHO statistics, in 2016 > 1900 million adults, aged over 18 years, were overweight, of which 650 million were obese. Between 1975 and 2016 the global prevalence of obesity had tripled, representing a public health problem and important social and economic consequences. On the other hand, in 2014, 422 million people aged over 18 years had diabetes. Between 1980 and 2014 the number of people with diabetes was 108 million, that is, the figure has doubled in Functional and Medicinal Beverages. https://doi.org/10.1016/B978-0-12-816397-9.00014-5 © 2019 Elsevier Inc. All rights reserved.

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34 years, this growth is also believed to be due to aging and increased prevalence of different age groups. Until July 2017, the mortality rate from CVD was 17.7 million, representing 31% of all deaths worldwide, while due to alterations in total cholesterol (TC) levels, alterations in total cholesterol levels is estimated to cause 2.6 million deaths, which represents a global percentage of 4.5% (WHO, 2017).

14.2  MS in the Context of a Complex Disease Since the culmination of the human genome project in 2003, a scientific and technological advancement has been presented worldwide, which has given rise to the generation of research on the role of genetics in the development of the disease (Hunter, 2005). The scientific knowledge of multiple organisms and the human being at the genomic level allowed us to suggest better diagnostic methods, novel drugs, and a greater impulse to research in biomedicine, bionanotechnology, and in general biosciences. One of the sciences that recovered great strength is molecular nutrition, which already had advanced in epigenetics and nutrigenetics (De Lorenzo, 2012). The idea of personalized nutrition as a key to maintaining health is one of the few ideas that have not changed for thousands of years. Referred by the father of medicine, Hippocrates in 400 BCE: “If we could give each individual the right amount of food and exercise, not too little or too much, we would have found the safest path to health.” Currently this statement is important given the nature of complex diseases resulting from poor diet and unhealthy lifestyles (De Lorenzo, 2012). Complex diseases, also known as chronic noncommunicable ­diseases (CNCDs), are those that have a multigenic genetic component and an environmental component. These types of diseases are determined by a complex system of interactions between specific genetic changes in more than one gene (Hunter, 2005). In recent years, the association between environment, epigenetic changes, and some of the most common complex diseases such as cancer, CVDs, type 2 diabetes, and chronic adipose-based disease has been studied. In the framework of the environment–gene relationship, nutrition plays a key role in the development of living beings, and its importance has acquired a new dimension as a result of recent advances in the knowledge of the molecular bases of human pathophysiology. In this sense, the identification of genes on which certain nutrients act allows a better understanding of the role of food in the suffering of certain diseases, and provides the molecular basis for the implementation of measures that affect the development and adaptation to the environment of the healthy and sick individual (Sales et al., 2014).

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The study of metabolic hereditary diseases has allowed to know the modifications of certain genes during different stages of development of the individual and their interaction with the environment. It has been shown that there is considerable variation and plasticity of metabolic systems in terms of environmental factors, which makes possible an accommodation to the environment through changes that can be temporary or permanent (Bennett et al., 2015). In specific for MS, there are several criteria used for its diagnosis. However, the most widely used and recognized are those of the WHO and the Adult Treatment Panel III (ATP III). The WHO defines MS with the presence of glucose intolerance, diabetes mellitus (DM), or IR and at least two of the following components, indicated in Table 14.1. For its part, the ATP III diagnostic criteria for MS required the presence of three or more of the factors indicated in Table  14.2 (Rodríguez et al., 2016). The etiology of MS is usually linked to central or visceral obesity as a determinant of IR. However, other factors such as genetic and environmental factors are important for the development of this syndrome, being one of the main ones, the feeding habits, as it is the case of a high ingestion of simple carbohydrates and saturated fatty acids and the low consumption of fruits and vegetables (Daskalopoulou et al., 2004). Malnutrition and genetic factors are the cornerstones of the development of obesity, IR, and therefore MS. Hypertrophy of adipose tissue, excessive consumption of saturated and/or trans fats, and excessive consumption of simple carbohydrates generate a state of cellular and systemic glycolipotoxicity, responsible for the production of reactive oxygen species (ROS) and mediator’s inflammatory diseases (Srinivasan et  al., 2012). The above is defined by a saturation of the

Table 14.1  WHO diagnostic criteria for metabolic syndrome Component

Criterion

Arterial hypertension

Blood pressure > 140 mmHg and/or medication with antihypertensive agents High plasma triglycerides (>1.7 mmol/L); low HDL (men > 0.9 mmol/L, women > 1.0 mmol/L) Waist/hip ratio in men > 0.9 and women > 0.85 Urinary albumin excretion ≥20 μg/min or albumin: creatinine ≥30 mg/g

Dyslipidemia Central obesity Microalbuminuria

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Table 14.2  Diagnostic criteria of ATP III for the diagnosis of metabolic syndrome Risk Factor

Criterion

Abdominal obesity Triglycerides HDL Blood pressure Fasting blood glucose

Waist circumference in men > 102 cm and women > 88 cm >150 mg/dL or pharmacological treatment for hypertriglyceridemia Men > 40 mg/dL and women > 50 mg/dL >130/85 mmHg or pharmacological treatment for hypertension >100 mg/dL or pharmacological treatment for glucose elevation

­ xidative pathways in mitochondria, due to a high intake of simple caro bohydrates in a chronic manner, leading to an increase in free oxygen, responsible for the nonenzymatic production of ROS and decrease in the production of ATP, given the oxidative alterations generated in the mitochondria, this state of toxicity is termed as mitochondrial dysfunction. The collapse of the mitochondria due to the establishment of oxidative stress causes disturbances in the level of subcellular organelles and cellular lesions that ends with the rupture of the plasma membrane and cell necrosis (Hernández et al., 2013). The necrosis comprises an irreversible state of the cell, where the integrity of the plasma membrane cannot be maintained and there is an escape of cytoplasmic elements, denaturation of the proteins by autolysis or coming from lytic enzymes of neighboring leukocytes, since the necrosis attracts the components of inflammation. The severity of the above is exacerbated when the damage is in cells that do not have regenerative capacity, such as neurons, nephrons, and retinocytes, associated with the microvascular complications of DM: neuropathy, nephropathy, and retinopathy, respectively, that within the framework of MS patients usually show signs of alterations and dysfunction in the neurological and renal system. On the other hand, the excessive circulation of free fatty acids, mainly saturated ones, as part of the lipotoxicity contributes to the metabolic activation of cells of the immune system mediated by tolllike receptors (TLRs) which induces the activation of the nuclear factor Kappa beta (NF-kB) and with it the synthesis of proinflammatory cytokines such as tumor necrosis factor alpha (TNF-α), interleukin-1 (IL-1), interleukin-6 (IL-6), and the chemoattractant protein of ­macrophages-1 (MCP)-1) as well as the reduction or inhibition of the expression of anti-inflammatory cytokines (Hirai et  al., 2010), generating a low-grade pro-inflammatory state. The chronic inflammatory state, generated by obesity and glycolipotoxicity, is the main

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triggers of IR. Inflammatory cytokines and lipotoxicity bring about the activation of intracellular kinases such as C-Jun N-Terminal kinase (JNK) and nuclear factor-κB (IκB) kinase (IKK) β, activating enzymes of the inflammatory pathways and catalysts of phosphorylation of the insulin receptor substrate (IRS-1) in specific serine residues. The phosphorylation of IRS-1 inhibits the signal transduction mediated by this substrate and catalyzes its proteosomal degradation, causing partial inhibition of insulin signaling (Nieto-Vazquez et al., 2008). On the other hand, the increased circulation of free fatty acids increases the synthesis rate of triacylglycerides in the liver, thus increasing the concentration of plasma lipoproteins and contributing to the dyslipidemia characteristic of MS (Ebbert and Jensen, 2013). Likewise, the increase in plasma concentrations of proinflammatory cytokines activates the vascular endothelium (VE), which will express adhesion molecules (ICAM/VACM) and the alteration of its metabolism in its apical membranes. The activation of the VE induces the adhesion of leukocytes and with it induces the ROS generation; this act favors the endothelial dysfunction, the atherosclerosis, and the increase in the arterial pressure. In the VE, cell signaling mediated by IRS-1 is necessary for the production of nitric oxide synthase (NOS) stimulated by insulin. Therefore, the phosphorylation of IRS-1 brings about the inhibition of synthesis of NOS, the main enzyme producing nitric oxide (NO), regulator of vasodilation. In turn, other vasoconstrictor molecules such as endothelin-1 (ET-1) and angiotensin-II maintain the VE stimulation, promoting alterations in the regulation of vascular diameter and thus blood pressure (Arce-Esquivel et al., 2013). Inflammatory cytokines regulate a large number of cell signaling processes. Part of the effect of these cytokines is the increase in the hepatic synthesis of acute phase proteins and coagulation factors. Other tissues and systems regulate other signaling pathways involved in proteolysis, at the muscle level, appetite regulation and modification of nervous tone in the central nervous system; increased secretion of ­catecholamines and cortisol, in the endocrine system; and modification in the leukocyte profile, at hematological and immune level (Gruys et al., 2005; Lumeng and Saltiel, 2011). The pathophysiology of MS is really complex since a large number of cell signaling pathways are altered, in the response to insulin being essential for clinical manifestations. However, the chronic inflammatory state and oxidative stress play a major role in the degenerative process and in the exacerbation of the signs and symptoms of MS. Currently, the role of various environmental factors in the development of the disease as well as nutrition is recognized, such as the level of physical activity, drug use, and access to health services, among others. One of the environmental factors that has become

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more ­important in recent years is the microbiome, whose dysbiosis has been widely related to the development of diseases that present a degree of chronic inflammation (Slingerland et al., 2017).

14.3  Role of the Microbiota in the Development of the MS The term microbiota refers to the community of microorganisms living in a certain ecological niche. Among the main functions of the microbiota are: (a) supply of essential nutrients; (b) development and modulation of the immune system; and (c) microbial antagonism (Young, 2017). The microorganisms that make up the microbiota are determined by the types of nutritional sources, the profiles of omnivores, carnivores, and herbivores being different. The characteristics of the diet, together with the genetic factors, influence the predominance of some microorganisms over others. The initial microbiota generates metabolites that can have a beneficial effect on the carrier such as anti-inflammatory and antioxidant actions, regulation of the intestine barrier function, as well as the production of vitamins and energy sources (HMPC, 2012). The microbial ecosystem of the intestine (intestinal microbiota) includes many native species that permanently colonize the gastrointestinal tract, and a variable series of microorganisms that only do so transiently. To the set formed by the microorganisms, their genes and their metabolites are called microbiome. The human being has 100 trillion microorganisms in the intestine, a figure that is calculated to be 10 times higher than the number of cells in the human body, so the commensal bacteria and the fungi that inhabit the body greatly outnumber the cells in human beings (Icaza, 2013). The number and variety of bacteria increase exponentially from the proximal end of the gastrointestinal tract to the distal end, with the colon harboring most of the intestinal microbiota. The anatomical, histological, chemical, and biochemical conditions of the digestive system are a determining factor for the development of microorganisms, thus generating specific niches in different portions of said apparatus (Icaza, 2013). Intestinal colonization is a dynamic process influenced by factors such as the nutritional status and microbiota of the mother, the gestational age of the newborn, the type of delivery, breastfeeding and its microbiological quality, the complementary feeding of the infant, and the use of antibiotic therapy in the mother or child (Browne et al., 2017). The colonization begins at birth when the newborn, practically sterile, meets its environment and the first microbial biofilms.

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The newborn acquires bacteria such as bifidobacteria and lactobacilli from the birth canal. Children born by caesarean section are initially colonized by bacteria from the hospital environment and the skin, exhibiting a lower pattern of protective bacteria (Sánchez et al., 2017). The intestinal microbiota of newborns fed only breast milk has a predominance of bifidobacteria, while children who receive artificial lactation have a more complex and diverse microbiota, with members of the families Enterobacteriaceae and Enterococcus. It is speculated that this differential colonization has a protective effect against the inflammatory microenvironment induced by the immunogens transferred through artificial lactation, important in sensitivity or resistance to the development of chronic diseases of inflammatory origin (Gritz and Bhandari, 2015). Microbiota plays an important role in maintaining the homeostasis of the individual. Competes for nutrients, receptors, and displaces pathogens, produces antimicrobial factors, regulates the turnover rate of enterocytes, promotes the development and differentiation of epithelial cells, fortifies the intestinal barrier, and maintains the proper functioning of mucosal immune system by inducing IgA secretion (Gritz and Bhandari, 2015). The physical, chemical, and immune union of the intestinal barrier are pillars in the maintenance of the number and location of the microbial population and of the beneficial effects on health that this entails. The intestinal epithelial cells are constantly subjected to cytotoxic, metabolic, and pathogenic stress, situations that can produce a break in the intestinal barrier causing the passage of microbial components into the bloodstream resulting in a pro-inflammatory response (Sommer et al., 2017). The dysbiosis (changes in the intestinal microbiota and the adverse host response) has been associated with important conditions for the development of the characteristic alterations of the MS. In people with MS an increase in the Firmicutes/Bacteroidetes ratio is exhibited. The Bifidobacteria and the Bacteroides spp. seem to be protective against the development of chronic inflammation characteristic of the MS. This could have a microbial component, with probable therapeutic implications (Sommer et al., 2017). The MS has been associated with an increase in the relative abundance of Firmicutes and proportional reductions in Bacteroidetes, by comparing the composition of the intestinal microbiota of genetically obese (leptin-deficient mice ob/ob) and skinny mice (Ley et al., 2005). This was confirmed by Waldram et  al. (2009) who stated that there is also a decrease in Bifidobacterium and an increase in Halomonas and Sphingomonas in the intestinal microbiota of genetically obese Zucker rats (fa/fa), in comparison with control rats. Changes in the relative proportions between Firmicutes and Bacteroidetes of the gut

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­ icrobiota have also been associated with obesity in humans. In m addition, obese humans, following a hypocaloric diet (low in carbohydrates or fats), showed significant increases in the proportions of Bacteroidetes parallel to weight loss during a 1-year intervention period (Ley et al., 2006). Mice genetically modified for the development of obesity (ob/ob), present 50% less Bacteroidetes and more Firmicutes than their slender brothers. On the other hand, the colonization of mice with the microbiota of normal mice produces a decrease in fat in 10–14 days, independent of a variation of the intake of simple carbohydrates and saturated fatty acids (Ley et al., 2005). By supplying normal-weight mice with a typical western diet high in simple carbohydrates for 8 weeks, a marked reduction in Bacteroidetes and a marked increase in Firmicutes were observed. Jumpertz et  al. (2011) administered 12 thin people and 9 people with obesity, variable diets in caloric content and compared the calories ingested with the fecal calories. The modification of the secondary microbiota to the diet showed a 20% increase in Firmicutes and corresponding decrease in Bacteroidetes, accompanied by an increase in energy recovery of approximately 150 kcal. Findings such as those described above have led to the hypothesis that the microbiota of people with obesity may be more efficient in extracting energy than the microbiota of thin individuals. By virtue of the above, situations that occur around birth and modify the composition of the intestinal microbiota, increase the risk of developing obesity, diabetes, and CVD in adulthood (Martínez et al., 2017). The intestinal microbiota, although beneficial, must be maintained within specific limits. It has been argued that modifications in the intestinal microbiota lead to a chronic state of endotoxemia having as a consequence a process of chronic inflammation, which is a key factor associated with the increase in adiposity. In Table  14.3, some mechanisms are described where dysbiosis is related to the development of MS. The main association between the development of a proinflammatory response and the intestinal microbiota lies in the recognition of bacterial recognition receptors. Currently, two types of receptors have been studied, the so-called TLRs and NOD-type receptors (NLRs). Most TLRs are surface receptors whereas NODs (NOD1 and NOD2) are cytoplasmic (Yiu et al., 2017). Cell recognition receptors of cells of the innate immune system, such as TLR receptors, constitute a starting point for immunity, which is activated in response to microbial- or dietary-derived stimuli (proteins or lipids) and informs cells of the immune system so that they respond appropriately to these. After activation by a ligand, the TLRs interact with different proteins that activate the transcription of different factors (such as MAPKs and NF-kB), and

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Table 14.3  Mechanisms of dysbiosis related to the development of metabolic syndrome Mechanism

Description

Bacterial fermentation

Alterations in the bacterial fermentation of the carbohydrates of the diet, which cannot be digested by the host, with the consequent decrease in the production of monosaccharides and short-chain fatty acids (SCFA). The SCFA are substrates of the colonocytes that bind to specific receptors of endocrine intestinal cells (GRP43 and GRP41) which increases the YY peptide, leading to the delay of intestinal transit, increasing the absorption of nutrients and leptin levels. The decrease in SCFA in people with metabolic syndrome is related to a lower satiety response The dysbiosis in metabolic syndrome is associated with greater gene expression that promotes lipogenesis and fat deposition in adipocytes. The decrease in intestinal expression of the adipose factor induced by fasting (FIAF) favors the capture of fatty acids and the expansion of adipose tissue The microbiota increases the vascularization induced by inflammation and mucosal blood flow, which increases the absorption of nutrients. The intestinal microbiota is able to promote a state of low-grade systemic inflammation, insulin resistance, and increase cardiovascular risk through mechanisms that include exposure to bacterial products, in particular, LPS derived from Gram negative bacteria. This is called metabolic endotoxemia

Microbial regulation

Increase of vascularization

the synthesis of different cytokines and immunological mediators of inflammation (Caricilli et al., 2011). In this regard, it has been shown that lipopolysaccharide (LPS) of the cell membrane of Gram-negative bacteria, such as Firmicutes, can act as a receptor ligand TLR4 and TRL2, which have the function of stimulating the release of endogenous inflammatory cytokines such as TNF-α, IL-6, and other pro-inflammatory cytokines related to the induction of IR. Therefore, the increase in Firmicutes implies an important factor in the development of inflammation (Ghoshal et al., 2017). Histochemical studies show that in people with MS there is an increase in LPS in the colonocytes. The LPS from the death of Gramnegative bacteria is transported to the bloodstream by chylomicrons (synthesized in greater quantities as a result of a high-fat diet). In the bloodstream, LPS is recognized by the CD14/TLR4 receptor of macrophages, activating a signaling pathway that ends with the activation of NF-κB and subsequent synthesis and release of cytokines TNF-α, IL-1, and IL-6, leading to a state of chronic inflammation, ABCD, and IR. The blood LPS increases when there is a rupture in the integrity of

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the intestinal barrier, a high permeability and less degradation of LPS by intestinal alkaline phosphatase (Ghoshal et al., 2017; Ubeda et al., 2012). Based on the foregoing, a restoration of Firmicutes/Bacteroidetes relationship, through the administration of probiotics, is suggested as an alternative in the treatment of diseases of inflammatory origin. The use of probiotics, as food or nutraceutical, is a viable therapeutic option, which should be considered within the framework of the diet therapy treatment of people with MS.

14.4  Characteristics of Probiotics The WHO defines probiotics as “live microorganisms that, when administered in adequate amounts, confer a benefit to the consumer’s health” (FAO, 2001). In principle, any component of the occupation microbiota could be a candidate to become a probiotic, since all of them potentially participate in the benefits granted by the group. However, in practice they mainly belong to two microbial groups: the lactobacilli and the bifidobacteria. The reason for this is that they are probably the only ones, among those that colonize the mucous membranes, that are innocuous under almost any circumstance and that, therefore, have been recognized as GRAS (generally regarded as safe) organisms and QPS (qualified presumption of safety) by the Food and Drug Administration of the United States and the European Food Safety Authority, respectively (Szajewska et al., 2014). Among the desirable characteristics of a probiotic are: (1) adaptation to the conditions of the target cavity and a good adherence to the epithelium that covers it (that is why organisms with the same origin are preferred), (2) generation of antimicrobial substances; (3) absence of resistance transmissible to antibiotics; and (4) existence of clinical trials that certify the beneficial effect on health. Probiotics include a large number of genera of microorganisms, such as Lactobacillus, Bifidobacterium, Saccharomyces, Streptococcus, and Enterococcus. In turn, the genus Lactobacillus comprises >90 species, the most commonly used include Lactobacillus acidophilus, Lactobacillus rhamnosus, Lactobacillus casei, Lactobacillus bulgaricus, Lactobacillus plantarum and Lactobacillus reuteri. Most of the clinical trials reported to date have used mixtures of different probiotics mainly Lactobacillus spp. in combination with another probiotic (Hill et al., 2014). The dose of probiotics needed for a biological effect varies enormously depending on the strain and the product. Although many over-the-counter products provide between 1 and 10 billion CFU/ dose, some products have been shown to be effective at lower ­levels, while others require larger amounts, so it is not possible to ­establish

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a general dose for probiotics. The minimum criteria required for ­probiotic products are that the probiotic must: (1) be specified by ­gender and strain, research on specific probiotic strains cannot be applied to any product marketed as probiotics; (2) contain live bacteria; (3) be administered in adequate dose until the end of its useful life (with minimum variability from one batch to another); and (4) have been shown to be effective in controlled studies in humans (ILSI, 1999). Since standards for content and label declarations on products are not universally established and/or not universally applied, industry must maintain integrity in formulation and labeling so that consumers can rely on this category of products.

14.5  Mechanisms of Action of Probiotics The intestinal microbiota is responsible for producing metabolites that function as signaling molecules at the systemic level, affecting the host’s metabolism. These metabolites directly affect the function of different organs, including the intestine, liver, brain, adipose tissue, and muscle (Tremaroli, 2012). Likewise, the microbiota contributes to the enzymatic digestion in the digestive tract, through the production of enzymes capable of degrading polysaccharides and bile acids (Tremaroli, 2012), and capable of modifying the phytochemicals consumed in the diet (Laparra and Sanz, 2010). Thus, the mechanisms by which they offer a health benefit are several, and will be discussed more thoroughly in this section.

14.5.1 Fermentation of Polysaccharides Foods of vegetable origin provide nondigestible carbohydrates for human enzymes. However, these carbohydrates are susceptible to enzymatic degradation and fermentation by the intestinal microbiota. Some species of microorganisms such as bacteroides ovatus have double the enzymes glucosidases and liases encoded in their genome, compared to humans (Tremaroli, 2012). The nondigestible poly-oligosaccharides are considered prebiotics, which have a favorable effect on the growth of the commensal intestinal microbiota. Likewise, some microorganisms such as lactobacilli and bifidobacteria are able to ferment the said prebiotics and produce short-chain fatty acids (SCFAs) (Laparra and Sanz, 2010). The SCFAs are composed of acetic, butyric, and propionic acids. These compounds have a wide variety of biological effects, such as the regulation of immune function, liver metabolism, and as an energy substrate of intestinal epithelial cells (Laparra and Sanz, 2010). The GPR41/FFAR3 and GPR43/FFAR2 receptors are two G-protein-coupled receptors that have affinity for SCFA, found in

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e­ nteroendocrine, immunological, and adipocyte cells. At the intestinal level, SCFA binds to the GPR41 receptor in enteroendocrine cells, stimulating the secretion of peptide YY, an intestinal hormone that induces satiety and reduces food consumption (Samuel et  al., 2008; Cani et al., 2009). On the other hand, the binding of SCFA to intestinal receptors GPR43 promotes the secretion of incretins, increasing the sensitivity and secretion of the host’s insulin (Tolhurst et al., 2012; Ezcurra et al., 2013). In adipose tissue, adipocytes express both receptors, GPR41 and GPR43. The stimulation of the first by SCFA stimulates the synthesis and secretion of leptin, generating a feeling of satiety mediated by the arquato nucleus of the hypothalamus. On the other hand, the binding of SCFA with GPR43 suppresses insulin signaling, reducing adipogenesis and lipogenesis (Li et al., 2017). Also, butyrate is a potent inhibitor of the enzymes histone acyltransferase and deacetylase, thus regulating epigenetically the proliferation and differentiation of the immune system (Chang et al., 2013), and the biogenesis of the mitochondria of different cells and increasing their capacity for beta oxidation. In turn, it directly stimulates pancreatic beta cells to increase insulin secretion (Li et al., 2017). On the other hand, SCFAs have a regulatory effect on the metabolism of fatty acids. Through the activation of AMP-activated protein kinase (AMPK) in liver and muscle tissue cells (Hu et al., 2010), SCFA increases the expression of the peroxisome proliferator-activated receptor gamma coactivator (PGC)-1α, which controls the transcriptional activity of diverse transcription factors, including the peroxisome ­proliferator-activated receptor (PPAR) α, PPARγ, and PPARδ, among the main ones, which regulate the metabolism of cholesterol, glucose, and lipids. As a result of the regulation of transcription factors, it is possible to reduce the de novo fatty acid synthesis in the liver, and increase the oxidation of fatty acids at muscular and hepatic levels, as well as reduce the synthesis of cholesterol (Den Besten et al., 2013; Hu et al., 2010). Likewise, the synthesis of SCFA by probiotic strains reduces the colon pH, which favors the growth of beneficial bacteria, among them are lactobacillus and bifidobacterium. In turn, the latter increases the production of SCFA, favors a healthy immune response, and reduces the growth of pathogenic microorganisms, thus reducing inflammation and the frequency of gastrointestinal disorders (McLoughlin et al., 2017). The consumption of probiotics with microorganisms that favor the fermentation of nondigestible carbohydrates or prebiotics, promotes the generation of SCFA which in turn provides a variety of biological effects. Likewise, it is important to highlight the need to consume an adequate amount of fiber in order to encourage the synthesis of SCFA, and not the consumption of probiotics alone. Thus, it is possible to

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f­avor the metabolic control of the patient with MS by means of the wide variety of biological effects exerted by the SCFA (McLoughlin et al., 2017).

14.5.2 Regulation of Bile Acid Metabolism As mentioned, the composition of the gut microbiota is altered by different factors, with bile acids being one of the main regulators. Studies on patients with liver cirrhosis, whose bile acid production has reduced with the advancement of the disease, have shown bacterial dysbiosis and a significant reduction in biological acids in feces (Ridlon et al., 2014). On the other hand, the intestinal microbiota plays a bilateral role in the synthesis and degradation of bile fatty acids. Through the expression of hydrolases of bile salts, intestinal microorganisms promote deconjugation of bile acids, thus preventing their enterohepatic resorption. The reduction in bile acids, due to its degradation, stimulates feedback mechanisms at the hepatic and intestinal level, increasing the expression of the nuclear receptor farnesoid x receptor (FXR). This receptor regulates the expression of the hepatic enzyme 7α-hydroxylase (CYP7A1), which is the limiting enzyme in the synthesis of bile acids (Ridlon et al., 2014). As a result, the synthesis of bile acids increases, while maintaining a reduction in the pool of bile acids from the gallbladder, which increases the excretion of cholesterol by fecal route and reduces the risk of vesicular lithiasis. Likewise, the degradation and conversion of bile acids by bacteria in the microbiota reduces the absorption of lipids and intestinal cholesterol. However, Bacteroides intestinalis, Bacteroides fragilis, and Escherichia coli are potent generators of enzymes that convert bile acids into possible carcinogens. Therefore, the restoration of a healthy microbiota, through the use of probiotics, can reduce the absorption of lipids and the production of metabolites with carcinogenic activities (Laparra and Sanz, 2010).

14.5.3 Choline Microbial Metabolism Choline is a component of various biomolecules, but fundamental in the phospholipids of cell membranes and play an important role as a methyl-group donor in methionine metabolism, it also participates in the synthesis of the neurotransmitter acetylcholine (Michel et  al., 2006). This nutrient is obtained mainly from dietary sources, since in spite of existing endogenous production, this appears to be insufficient in some cases. Also, choline is essential for lipid metabolism and the synthesis of very low-density lipoproteins in the liver, so a consumption, absorption, or poor production is associated with

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alterations of the intestinal microbiota and development of hepatic steatosis (Tremaroli, 2012). The alteration of the gut microbiota in obesity and/or MS may be accompanied by an increase in the microorganism involved in the transformation of choline to toxic metabolites such as trimethylamine and reduce nutrient absorption. The decrease in the bioavailability of choline suggests a triggering factor for nonalcoholic fatty liver, which is also related to IR and alteration in the blood lipid profile (Tremaroli, 2012).

14.5.4 Regulation of Permeability and Inflammation The intestinal permeability refers to the capacity of this organ to allow the passage of substances from the epithelium or mucosal layer to the submucosa or enter the systemic circulation. In recent years, it has been discovered that obesity and other diseases with a background of chronic inflammation have an alteration (increase) in intestinal permeability. Thus, allowing the passage of unwanted substances, such as LPS, which trigger an inflammatory response that can become systemic. Likewise, some enteropathogenic microorganisms obtain access to the body through the alteration in intestinal permeability (Bischoff et al., 2014; Boulangé et al., 2016). The intestinal permeability depends on the tight junctions, which seal the paracellular space, regulating the passage of water, ions, and small molecules. The adherence junctions are another type of junction that is found in this space, and these in turn are important in cell– cell signaling processes (Bischoff et al., 2014). Some probiotics, such as the bacterium E. coli Nissle 1917, have been shown to reduce alterations in intestinal permeability due to pathogenic microorganism species. Said probiotic increases the expression of ZO−2 proteins, which play an important role in tight junction. On the other hand, said probiotic also increases the expression of other proteins related to tight junction, such as claudin−14. Therefore, the increase in the expression of said proteins reduces intestinal permeability (Bischoff et al., 2014). The reduction in intestinal permeability is an important protection mechanism to prevent translocation of bacteria or bacterial products (e.g., LPS) to the submucosa or circulation. Thus, contributing to the reduction in the activation of the immune system, mediated by TLR, and reduction in the consequent inflammatory response (Bischoff et al., 2014).

14.5.5 Metabolism of Dietary Phytochemicals Many of the dietary phytochemicals, which offer biological activities beneficial to health, are in the form of glycoconjugates, polymers, or esters, which are not bioavailable in that form. Most polyphenols, a class

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of phytochemicals, are bound to highly hydrophilic polar molecules, which does not allow their absorption by passive diffusion into the small intestine enterocytes (Laparra and Sanz, 2010; Rossi et al., 2013). Many reactions that transform phytochemicals to bioactive molecules require enzymes produced by colonic microbiota. Probiotics such as lactobacilli and bifidobacteria can affect the bioavailability, biological activity, and kinetics of the phytochemicals consumed (Rossi et al., 2013). So, knowing the main ways in which the microbiota and/ or probiotics can alter the phytochemicals play an important role in the context of functional nutrition. Some bacterial strains, including bifidobacteria, synthesize a variety of glycosyl hydrolases, mainly β-glucosidase, which are necessary to process the nondigestible polysaccharides that reach the large intestine. Among the bifidobacteria that produce these enzymes Bifidobacterium adolescents, Bifidobacterium animalis, Bifidobacterium bifidum, Bifidobacterium breve, Bifidobacterium longum subsp. infantis, and Bifidobacterium pseudocatenulatum are the main ones. Thus, these enzymes are important part of the digestion of food and the processing of polyphenols that improve their bioavailability (Rossi et al., 2013). In addition, lactobacillus species that produce β-glucosidase enzymes have also been identified. Among the main species are L. acidophilus, L. casei, Lactobacillus paracasei, L. rhamnosus, and L. plantarum. However, lactobacilli have been less studied than bifidobacteria because of their ability to hydrolyze glucoconjugates from food (Rossi et al., 2013).

14.5.6 Antioxidant Properties Several studies with different probiotic bacterial strains have found that they exert some antioxidant capacity. Although little is known about the mechanism of bacterial action to modulate the formation of free radicals, systematic reviews have shown that the use of probiotics improves the oxidative status of the host (Mishra et al., 2015; Wang et al., 2017). Several mechanisms have been proposed, including the ability to chelate metal ions. Some ions (Cu+2 and Fe+2) catalyze the conversion of H2O2, a reactive oxygen species, to a more reactive and oxidizing form. The study of Streptococcus thermophilus 82 and L. casei KCTC 3260 showed that both bacterial strains have antioxidant effects on the host, by chelation of Cu+2 and Fe+2 (Wang et al., 2017). On the other hand, probiotics, like humans, have an antioxidant enzyme system. Among the main antioxidant enzymes produced by probiotics are the superoxide dismutase and catalase. Bacteria express the said enzymes to adapt to media where there is an increased amount of ROS. Studies that have evaluated the usefulness of ­probiotics that

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express these enzymes have found beneficial effects in pathological conditions where there is an increase in ROS (De LeBlanc et al., 2008; Wang et al., 2017).

14.5.7 Antimicrobial and Immunomodulatory Properties Chronic inflammation is a characteristic of MS and has a bilateral interaction with the intestinal microbiota, that is, the pro-inflammatory environment promotes a remodeling of the microorganisms, at the same time that said remodeling induces greater inflammation. Some bacterial strains have been shown to have anti-inflammatory effects, including L. reuteri. Through the production of different inhibitory factors of the immune activation mediated by LPS, the said lactobacillus reduces the secretion of TNF-α (Jones and Versalovic, 2009). On the other hand, L. reuteri is also recognized for expressing peptides with antimicrobial properties, including reuterin (Langa et al., 2013). The said peptides reduce the growth of pathogenic bacterial strains, reducing the inflammation and the condolence time of gastrointestinal diseases. The antiinflammatory activity of probiotics is specific to each strain. Among the probiotics with antiinflammatory properties are L. rhamnosus GG, Propionibacterium freudenreichii ssp. shermanii JS, and Bifidobacterium animalis ssp. lactis Bb12. A study conducted by Kekkonen et al. (2008) showed that L. rhamnosus and P. freudenreichii are able to reduce the levels of highly sensitive C-reactive protein in healthy people, while B. animalis reduced the plasma levels of IL-2. The mechanisms by which these strains reduce the markers of inflammation are not yet well understood. Although it has been recognized that a significant variety of probiotics possess anti-inflammatory activities, not much is known about their mechanisms of action. An important part has been attributed to modulate the activation of TLRs (Plantinga et  al., 2011). Also, some studies have found that the interaction of probiotic strains with dendritic cells in the intestine induces the production of IL-10, which has anti-inflammatory and immunomodulatory activities (Kang and Im, 2015). On the other hand, some probiotics induce an increase in the synthesis of immunoglobulins M, A, and G, and induce a higher production of IL-12, favoring a Th1-type response (mediated by cells) and reducing a Th2 response (Ng et al., 2009).

14.6  Probiotic Beverage as a Therapeutic Option in MS Probiotics can be consumed through a food or in nutraceuticals, in a balanced and adequate way. There is a wide variety of probiotic

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dairy products (Kanmani et al., 2013). In the present review, probiotic beverages and their benefits in the MS have been pointed out, specifically in the reduction or improvement of some biochemical markers. Owing to their nutritional contribution, and sensory and functional benefits in food, during the last decades, the use of probiotic microorganisms, such as L. acidophilus, L. paracasei among others, has increased in several types of food, especially in fermented milk drinks (Lee et al., 2015). Due to the above, clinical research has been expanded by evaluating the effectiveness of probiotic beverages on MS markers (Table 14.4). In people with moderate hypercholesterolemia [total cholesterol (TC) 5.17–7.76 mmol/L], a decrease in blood TC levels was obtained after consuming 300 g of yogurt enriched with 106 CFU of L. acidophilus and B. lactis, for 6 weeks (Asal, 2009). In turn, a double-blind placebo-controlled study conducted in Portugal on healthy women with BMI < 30, 18–65 years of age, who had consumed 125 mL of milk fermented with L. acidophilus 145 and B. longum BB536, 3 times a day for 4 weeks showed a significant reduction in LDL in those individuals who had cholesterol levels above 190 mg/dL. Also, there was reduction in HDL in the placebo group, while in the controlled there was a significant increase; as for triglycerides, only minor nonsignificant changes were observed (Andrade and Borges, 2009). In people with type 2 diabetes mellitus (DM2) between 30 and 60 years of age, a reduction in LDL levels and an increase in HDL was observed after consuming 300 g of yogurt with 3.7 × 106 CFU of L. acidophilus LA. 5 and B. lactis Bb-12 for 8 weeks (Mohamadshahi et al., 2014). Barreto et  al. (2014) conducted a double-blind case–control study in 27 women with postmenopausal MS divided into two groups, who were given 80 mL for 90 days of fermented milk with 1.25 × 107 CFU of L. plantarum, and in which there is a significant reduction of cholesterol, glucose and homocysteine, as well as a decrease in IL-6, the latter being an important cytokine in pro-inflammatory processes and characteristic in MS. This study showed that milk fermented with L. plantarum provides favorable results in relation to the risk factors for CVDs in women with postmenopausal MS. A protective effect has also been demonstrated in patients with DM2 who consumed special strains of lactic acid bacteria, attributed to their antioxidant properties, which is beneficial, due to the chronic oxidative state present in this disease. A study conducted on 64 patients with DM2 between 30 and 65 years of age, who consumed 300 g/ day of probiotic yogurt with L. acidophilus La5 and B. lactis Bb12 (106 CFU/g, ~108 CFU/day) for 6 weeks, compared to conventional yogurt demonstrated a significant decrease in basal glucose in the fasting state, as well as a decrease in HbA1c; on the other hand, an i­ncrease

Table 14.4  Effect of probiotic beverage consumption on markers of metabolic syndrome Beverage Fermented milk Probiotic yogurt Fermented milk

Probiotic Lactobacillus fermentum ME-3 Lactobacillus acidophilus y Bifidobacterium lactis Lactobacillus acidophilus, Bifidobacterium longum BB536

Study Design Health people Patients with hypercholesterolemia Women with hypercholesterolemia

Probiotic yogurt Fermented milk

B. lactis Bb12 L. acidophilus Lactobacillus gasseri SBT2055 (LG2055)

Patients with DM2

Fermented milk

L. plantarum

Postmenopausal women with MS

Probiotic yogurt

Lactobacillus acidophilus La-5, Bifidobacterium lactis Bb-12

Patients with DM 2, BMI > 25, LDL-c > 100 mg/dL

Group of Japanese with visceral adiposity

Dose

Results

Reference

150 mL (10  cfu/ mL) for 3 weeks 300 g yogurt daily for 6 weeks

Improvement of the total concentration of antioxidants in the blood Cholesterol-lowering effect in patients with hypercholesterolemia

Songisepp et al. (2005) Asal (2009)

125 mL of milk fermented 3 times a day for 4 weeks 106 to 108 CFU/ day for 6 weeks 200 g of milk for 12 weeks with a content of 107 CFU 1.25 × 107 CFU/g, 80 mL for 90 days. 3.7 × 106 CFU/mg 300 g for 8 weeks

LDL and HDL cholesterol levels were reduced significantly in those individuals who had cholesterol levels above 190 mg/dL Reduction of basal glucose (fasting) and glycosylated hemoglobin. Reduction of visceral adiposity.

Andrade and Borges (2009)

9

Significant reduction of cholesterol, glucose, homocysteine and IL-6. Decreased LDL levels and a significant increase in HDL levels

Ejtahed et al. (2012) Yukio et al. (2013)

Barreto et al. (2014) Mohamadshahi et al. (2014)

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in the superoxide dismutase (SOD) (antioxidant) was observed, without significant changes in the concentration of insulin (Ejtahed et al., 2012). Concluding that probiotic yogurt is a promising agent for the treatment of DM. Previously, the antioxidant power of probiotic beverages had already been demonstrated in the study conducted by Songisepp et al. (2005), which consisted of the administration of milk fermented with L. fermentum ME-3 to a group of healthy volunteers with an age range of 35–60 years, giving them the 150 mL portion daily for 3 weeks. At the end of the study, the total number of antioxidants in the blood has improved. In people with obesity, the consumption of 200 g of fermented milk with a probiotic content of 107 CFU of Lactobacillus gasseri SBT2055 (LG2055) for 12 weeks showed a reduction in visceral adiposity, with significant decreases in the abdominal perimeter (Yukio et al., 2013). Likewise, Bordalo et  al. (2015) reported a decrease in glycemic levels, TC, and triglycerides in people with MS who consumed milk fermented with L. bulgaricus and S. thermophilus. Jones et al. (2017) conducted a study to evaluate the effectiveness of microencapsulated L. reuteri NCIMB 30242 (bile salt hydrolase-active probiotic) to reduce the blood cholesterol in a formulation with yogurt, in 114 hypercholesterolemic subjects. The results were positive, after a period of 6 weeks of treatment, a significant reduction in LDL cholesterol (8.92%), TC (4.81%), and non-HDL cholesterol (6.01%) was found, compared to placebo (regular yogurt). There were no changes in serum concentrations of triglycerides or HDL cholesterol. Although clinical studies show the potential use of probiotic beverages as an adjuvant to the treatment of MS, more clinical information is still needed on the role of the microbiota and probiotics in this inflammatory disease. The beneficial effects of specific bacteria on the characteristics of MS have been described. However, given that the intestinal microbiota represents a modifiable characteristic in the intervention for the improvement of the metabolic profiles of the MS, the study of probiotics is an important tool that should be implemented in the dietotherapeutic intervention (Martínez et al., 2017).

14.7 Conclusion The microbiota plays an important role in the development and chronicity of inflammation in people with MS, which represents a modifiable feature in the intervention for the improvement of the metabolic profile in MS. Although more information is still needed to elucidate the role of probiotics as part of the treatment of MS, the findings with which they are counted, highlighted the clinical usefulness of probiotics as a strategy of nutritional intervention in the inflammatory and metabolic alterations of MS.

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Further Reading Gibson, G.R., Nicholson, J.K., 2009. Top-down systems biology modeling of host metabotype microbiome associations in obese rodents. J. Proteome Res. 8 (5), 2361– 2375. https://doi.org/10.1021/pr8009885.