Impact of the Gut Microbiome on Behavior and Emotions

Chapter 40

Impact of the Gut Microbiome on Behavior and Emotions Ingrid Rivera-In˜iguez1, 2, Sonia Roman1, 2, Claudia Ojeda-Granados1, 2 and Panduro Arturo1, 2 1

Department of Molecular Biology in Medicine, Civil Hospital of Guadalajara, Guadalajara, Jalisco, Mexico; 2Health Sciences Center,

University of Guadalajara, Guadalajara, Jalisco, Mexico

INTRODUCTION Behavior and emotions have allowed humans to adapt to the environment, by detecting or reacting toward harmful or dangerous situations. However, chronic incidences of negative emotions or behavioral disorders may interact with genetic and environmental factors to detonate serious diseases. Patients with gastrointestinal disorders are a good example of recurrence of feelings of depression, anxiety, and stressful personalities. Therefore, it has been suspected that behavior and emotions could have a more gastrointestinal origin. The gastrointestinal tract contains a wide variety of microorganisms that sustain essential and beneficial interactions with the host [1]. Interestingly, gut microbiota communicates with the central nervous system, synthesizes neurotransmitters, and influences neurogenesis. As a result, microbiota modulates human behavior and emotion [2]. Understanding the communication pathways between the gut microbiota and central nervous system via distinct mediators, and the mechanisms of such pathways, could be a promising strategy in the treatment of behavioral and gastrointestinal disorders.

BRAIN STRUCTURES INVOLVED IN BEHAVIOR AND EMOTIONS Behavior and emotions are regulated in the brain reward circuit, localized in the mesolimbic region [3]. In this region, different brain structures are interconnected by neurons and neurotransmitters to regulate memory, learning, emotions, cognition, and behavior. The amygdala serves as a warning system that detects stimuli inputs related to emotions and sends this information to the reticular activating system [4]. Furthermore, the amygdala regulates the endocrine response to stress, by interacting with the hypothalamicepituitaryeadrenal (HPA) axis [5]. Physiological alterations of the amygdala have been associated with behavioral disturbances in germ-free mice [6]. In humans, an impaired function of the amygdala may interfere with social behavior, as observed in patients with schizophrenia and autism spectrum disorders (ASD) [7]. Furthermore, the amygdala and the prefrontal cortex (PFC) evaluates the stimuli and establishes a memory. This region also controls motor functions that give feedback information to the hippocampal septum. This information is known as working memory [8,9]. The PFC can also suppress negative responses, such as anxiety and fear [9,10]. The orbital frontal cortex (OFC) connects to the nucleus accumbens (NAC), hypothalamus, insula, dorsal striatum area, and medial frontal cortex, and regulates the emotional value to the memorized information [11].

GUTeBRAIN AXIS The brain maintains a bidirectional communication with the gastrointestinal system by neural, immune, and endocrine pathways that ensure a healthy behavior, as seen in Fig. 40.1. The brain interacts with the gut via sympathetic and parasympathetic fibers, vagus nerve, adrenergic nerve, and portal vein [12]. In fact, the vagus nerve is considered as the principal route of communication because it connects close to 100 million of enteric neurons to the brain.

Microbiome and Metabolome in Diagnosis, Therapy, and other Strategic Applications. https://doi.org/10.1016/B978-0-12-815249-2.00040-3 Copyright © 2019 Elsevier Inc. All rights reserved.

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CC

PFC

PUT

OFC

Nac VTA SN AMY

Normal signals

Immune

Neural Vagus nerve

Adrenergic nerve

Endocrine

Neuro-hormones

Neurotransmitters

HYP

Cortisol Dendritic cell

5-HT

SCFA

FIGURE 40.1 Healthy behavior and emotions. A healthy gut microbiota is characterized by being diverse and rich in beneficial bacteria that contributes to a normal communication with the brain. This includes a normal neurotransmitter signaling, cytokine profile, and endocrine signals. 5-HT, Serotonin; AMY, Amygdala; CC, cingulate cortex; HYP, Hypothalamus; Nac, Nucleus accumbens; OFC, Orbitofrontal cortex; PFC, prefrontal cortex; PUT, Putamen; SCFA, Short-chain fatty acids; SN, Substantia nigra; VTA, Ventral tegmental área.

Efferent signals from the brain (sympathetic and parasympathetic) control different gastrointestinal functions, like motility and the secretion of hormones and enzymes [13]. Bacteria in the gut produce neurotransmitters, like dopamine and serotonin, from the metabolism of tryptophan and neuropeptides, including P substance, calcitonin, neuropeptide Y (NPY), peptide YY, corticotrophin-releasing factor, pancreatic polypeptide, vasoactive intestinal polypeptide, glucagon-like peptide 1 (GLP-1), and somatostatin, among others [14,15](Fig. 40.1). Fig. 40.2 highlights how neuroendocrine signals affect mood and behavior. Hormones mediate the secretion of neurotransmitters by gut microbiota [16]. In the presence of physiological or psychological stress, the HPA axis activates the release of corticosterone by the hypothalamus, adrenocorticotropic hormone by the pituitary gland, and cortisol by the adrenal gland [13]. The release of systemic cortisol induces a proinflammatory response, which is capable of modifying gut microbiota composition [17,18]. Also, stress hormones such as adrenaline and noradrenaline promote overgrowth of pathogenic bacteria such as Escherichia coli (E. coli O157), Yersinia enterocolitica, and Pseudomonas aeruginosa [16]. Beneficial and pathogenic bacteria interact with the immune system, by secreting antimicrobial peptides (defensins, mucin, and angiogenin 4), mucus secretion, and releasing immunoglobulin A [19]. Bacteria associated with antigen

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PFC

CC PUT Nac

SN AMY

Neural

Immune Inflammatory signaling

Adrenergic nerve

Neuro-hormones

Neurotransmitters

HYP

VTA

Vagus nerve

OFC

Endocrine

381

ROS

Cortisol LPS 5-HT

TNF-α, IL-6, IL-1β, CRP

Dendritic cell

SCFA

FIGURE 40.2 Behavioral and emotional disorders. Gut microbiota dysbiosis is characterized by low diversity and overgrowth of pathogenic bacteria that contributes to an abnormal communication with the brain. This conditions includes impaired neurotransmitter signaling, a proinflammatory profile (TNFa, INFg, IL-6, IL-1), and altered endocrine signals. 5-HT, Serotonin; CC, cingulate cortex; HYP, Hypothalamus; LPS, Lipopolysaccharides; MY, Amygdala; Nac, Nucleus accumbens; OFC, Orbitofrontal cortex; PFC, prefrontal cortex; PUT, Putamen; SCFA, Short-chain fatty acids; SN, Substantia nigra; VTA, Ventral tegmental area.

recognition of Pathogen-Associated Molecular Patterns (PAMPS), by toll-like receptors (TLRs), lead to the subsequent activation of the immune response against pathogenic bacteria [20]. Environmental factors such as stress and diet can jeopardize the integrity of the intestinal mucosa [21]. This scenario facilitates that lipopolysaccharides and pathogenic bacteria translocate into the circulation resulting in metabolic endotoxemia, which is associated with chronic disease progression [22,23]. At the same time, the fermentation of nondigestible carbohydrates by gut bacteria generates short-chain fatty acids (SCFA), such as butyrate, acetate, and propionate that modulate the immune response and can also interact with the brain [24] (Fig. 40.2).

THE LINK BETWEEN MICROBIOTA, BEHAVIOR, AND EMOTIONS Initially, the hypothesis that the brain could communicate with the gut was formulated by observing patients with hepatic encephalopathy, who experienced mood changes and cognitive impairments. Later on, the gut microbiota-brain

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communication was confirmed in animal models. Studies in germ-free mice have revealed that neurogenesis depends mostly on gut microbiota composition [25]. NIH Swiss mice exhibit a normal behavior, whereas germ-free mice have an anxiety-like behavior [26]. Interestingly, when feces from NIH Swiss mice were transferred to germ-free BALB/c mice, this anxiety-like behavior was reduced, and levels of brain-derived neurotrophic factor (BDNF) increased [27]. Furthermore, the interactions between gut microbiota and brain activity vary according to sex, as shown by male/female differences in BDNF expression in germfree mice [28]. Also, gut bacteria produce neurotransmitters such as serotonin from tryptophan metabolism. This finding was verified by Liu and colleagues, who administered Lactobacillus plantarum PS128 and found increased levels of neurotransmitters dopamine and serotonin in the brain, which were associated with behavior [29].

Gastrointestinal Disorders and Emotions The relevance of the gutebrain axis is generally accepted in irritable bowel syndrome (IBS), colitis, and other experimental mood disorders [30]. Intrauterine stress in animal models causes gut microbial dysbiosis and this, in turn, affects both gastrointestinal and central nervous system development [27]. Furthermore, IBS patients tend to have more anxiety, depression, and neurotic type personality [31]. In fact, neuroticism is a personality trait that is related to IBS, colitis, Crohn’s disease, and dyspepsia [32]. Negative emotions exacerbate symptoms like altered motility, abdominal pain, and hyperreactivity among IBS patients [33]. It is proposed that these negative feelings influence the gastrointestinal system, through signals that arise from the central nervous, endocrine, and immune systems. In fact, stress alters cortisol levels via HPA axis dysregulation, and this is associated with IBS reactivity episodes, especially in women [34]. Cortisol also causes gut dysbiosis and exacerbates the inflammation profiles related to different gastrointestinal diseases, including Crohn’s disease and colitis [35]. Moreover, high levels of anxiety and depression induce the overexpression of the heat shock protein 70 (HSP70) in polymorphonuclear cells of patients with severe ulcerative colitis, destroying the intestinal mucosa [36]. In addition, patients with colitis have a poor microbiota diversity, including reductions in Akkermansia, which promotes protection against toxins [37]. Patients with inflammatory bowel disease also present reduced abundance of Firmicutes and a higher presence of Proteobacteria, Tenericutes, and Escherichia coli [38]. Patients with Crohn’s disease have a decreased number of Firmicutes and increased number of Bacteroidetes, when compared with healthy controls [39]. Patients with depression or anxiety are at higher risk of chronic diseases such as cardiovascular disease, diabetes, cerebral vascular disease, and obesity [40e43].

Psychiatric and Social Behavior Disorders The etiology of mental disorders such as schizophrenia, attention deficit hyperactivity disorder (ADHD), and autism spectrum disorders (ASD) is complex. However, autoimmunity is highlighted as a common key player [44]. In this sense, the gut immune system could detect beneficial bacteria as pathogenic and trigger an autoimmune environment by facilitating the activity of Th17 cells and suppressing the role of the regulatory T cells (Tregs) [45]. In Table 40.1, the gut microbiota composition in different behavioral and emotional disorders is depicted. As noted before, early exposure to adverse events triggers changes in the gut microbiota. Patients with schizophrenia present immunity activation for food protein antigens and pathogens and have a detrimental bacteria profile when compared to healthy control [46].

Gut Microbiota and Emotional Disorders Neurodevelopmental programming in the offspring depends largely on gut microbiota composition, which could be affected by stressful events [47]. Intrauterine stress in animal models causes a gut dysbiosis and this, in turn, affects central nervous system development [25]. The HPA axis is affected by microbiota alterations and early exposure to stress. Changes occurring in the microbiota composition influence anxiety-type behavior in stress-induced animal models [48]. Gram negative-derived lipopolysaccharides generate a systemic low-grade inflammatory profile, during stress and depression [49]. Also, neuroinflammation provoked by an imbalance in gut microbiota seems to affect the host’s behavior [50]. Oxidative stress can also be facilitated and plausibly promote neurodegeneration. Therefore, the impact of gut microbiota dysbiosis on cognition and learning can contribute to Alzheimer’s and Parkinson’s disease [51].

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TABLE 40.1 Gut Microbiota Composition in Behavioral and Emotional Disorders Disease

Experimental Model (Reference)

Measurements

Bacteria Composition

Irritable bowel syndrome (IBS) with anxiety or depression or low quality of life

37 patients with IBS [80]

Fecal microbiota by pyrosequencing

High Firmicutes/Bacteroidetes ration in IBS patients

Major depressive disorder (MDD)

46 MDD patients and 30 healthy controls [81]

Hamilton’s depression scale (HAMDS) Montgomery-Asberg Depression Rating Scale (MADRS), fecal gut microbiota by pyrosequencing, cytokine, and BDNF levels

Increments in fecal bacteria a-diversity in MDD patients related to high levels of Bacteroidetes, Proteobacteria, and Actinobacteria and reductions in Firmicutes Reductions in Faecalibacterium were negatively correlated with symptom severity

Depression

34 depressive patients and 33 healthy controls [82] Fecal microbiota transplanted (FMT) adult male SpragueeDawley rats from depressed patients [82]

Fecal microbiota by next generation sequencing, SCFA concentration, salivary cortisol, kynurenine/ tryptophan determination, cytokine levels, lipopolysaccharidebinding protein Rats: Behavioral test, corticosterone, CRP, cytokine, LPS, SCFA levels

Reductions in phylogenetic diversity in depressed group from phylum Prevotellaceae and increases in Thermoanaerobacteriaceae FMT rats: presented anhedonia-like behaviors, anxiety-like behaviors, increased plasma kynurenine and kynurenine/tryptophan ratio, reductions in microbiota diversity and increments in acetate levels

In toddlers, a higher phylogenetic diversity was observed among subjects with more social active temperaments, than those with fear temperaments [52]. Patients with anorexia nervosa had lower bacteria diversity when compared to healthy controls, in the inpatient environment, and these results were related to high levels of depression and anxiety [53].

Eating Behavior It has been proposed that the gutebrain axis interacts with the hunger-reward system, which is modulated by both genes and environmental factors that influence emotionally driven food decisions [54]. Several human genes that encode brain and gut receptors of the hunger-satiety circuit, and also in the brain reward system, express polymorphic alleles. Some of these alleles increase the risk for altered eating behaviors and excess weight, thus indirectly altering the gut microbiota [54e56]. Metabolic syndrome is related to impaired synthesis of neurotransmitters and deficiency in melatonin and tryptophan [57], which contribute to damage in the hippocampus [58]. The hypothesis that microbiota dysbiosis may affect eating behavior was proposed by Dr. Joe Alcok in 2014. He proposed that cravings and eating without control be elicited by microbes through the neuroendocrine system, to optimize their functioning [59]. Later on, Perry and colleagues documented that gut microbiota dysbiosis generates an increased production of acetate, which in turn could elicit overeating behaviors, by affecting the secretion of ghrelin, insulin, and glucose [60]. Postabsorptive signals seem to influence dopamine levels, which is a major neurotransmitter that is implicated in rewarding addictive behaviors [61]. An important single nucleotide polymorphism is the DRD2/ANKK1 A1 polymorphism, caused by an amino acid substitution (Glu713Lys), within the 11th ankyrin repeat of the ANKK1 gene. Carriers of the DRD2/ANKK1A1 allele are at risk of alcoholism and other addictive behaviors. Recently in a Mexican-Mestizo population, the highest prevalence of the A1 allele known to date worldwide was reported that coincides with the cultural history of alcohol consumption [62].

PSYCHOBIOTICS: FROM PREBIOTICS AND PROBIOTICS TO DIETARY INTERVENTIONS Table 40.2 summarizes the different strategies aimed to modify the gut microbiota, for the treatment of behavioral and emotional disorders. Animal and clinical studies have demonstrated that probiotic supplementation in autism, personality

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TABLE 40.2 Modulation of Gut Microbiota in the Treatment of Behavioral and Emotional Disorders Component

Experimental Model (Reference)

Measurements

Key Outcomes

Probiotics L. Rhamnosus JB-1

Corticosterone-induced stress and anxiety [64]

Anxiety, depression

Reductions in anxiety and stress increases in hippocampal GABAb1b receptor expression and cortical GABAAa2 receptor expression

Fermented milk product (Bifidobacterium animalis, Streptococcus thermophiles, Lactobacillus bulgaricus, Lactococcus lactis)

Healthy women [65] Twice/day for 4 weeks

MRI: Brain activity and response to face emotions

Reductions in task response in affective viscerosensory and somatosensory networks. Improvements in brain connectivity

Lactobacillus helveticus R0052

IL-10
/
mice and wildtype 129/SvEv mice [83] 21 days of Western diet

Barnes maze: Memory and exploratory and anxiety-like behavior IFNY, IL-1b, IL-2, Il-4, IL-5, keratinocyte-derived chemokine, IL-10, IL-12, TNFa and corticosterone levels Fecal microbiota composition

Reductions in weight increases, inflammatory markers and corticosterone. Increased microbiota diversity associated with improvements in memory and reductions in anxietylike behavior

L. helveticusNS8

21 days of stress [84]

Cognition and behavior tests

Reductions in corticosterone levels and anxiety and increases in 5-HT, IL-10, and cognition

Bifidobacterium bifidum W23, Bifidobacterium lactis W52, Lactobacillus acidophilus W37, Lactobacillus brevis W63, Lactobacillus casei W56, Lactobacillus salivarius W24, Lactococcus lactis

Triple-blind randomized control study [85] Healthy volunteers Four weeks

Dysphoria assessed with Leiden index of depression sensitivity scale (LEIDS-r)

Reductions in cognitive reaction to sadness

VSL3 Streptococcus salivarius subsp., thermophilis, Bifidobacterium (B. breve, B. infanti, B. longum), Lactobacillus acidophilus, L. planarum, L. casei, and L. delbrueekisubsp. Bulgaricus

Inflammatory murine model of liver inflammation [86] C57BL/6 mice

Body weight, sickness social behavior, gut permeability, fecal microbiota, intravital microscopy cerebral vasculature, cerebral monocyte infiltration

Reductions in TNF-a, intestinal permeability, monocyte recruitment and improvements in social behavior

Probiotic yogurt (Lactobacillus acidophilus LA5 and Bifidobacterium lactisBB12) þ placebo capsule or Probiotic capsule (Actobacilluscasei, L. Acidophilus, L. Rhamnosus, L. Bulgaricus, Bifidobacterium breve, B. Longum, S. thermophilus) þ conventional yogurt (Streptococcus thermophilus and Lactobacillus bulgaricus starters) or conventional yogurt þ placebo capsule

Double-blind randomized study [87] 75 healthy petrochemical workers (male and female)

Health questionnaire (GHQ-28) Depression anxiety and stress scale (DASS), in kynurenine, tryptophan, neuropeptide Y, cortisol and ACTH levels

Improvements in health, depression, and anxiety with probiotic yogurt and probiotic capsule

Lactobacillus acidophilus, Lactobacillus casei, and Bifidobacterium bifidum

Double-blind randomized study [88] 40 patients with major depressive disorder (MDD) 8-week intervention

Depression with Beck depression inventory (BDI), fasting plasma glucose, insulin metabolism markers, lipids, c-reactive protein, oxidative stress markers, antioxidant capacity, and glutathione GSH levels

Reductions in depression scores and serum metabolic, inflammatory and oxidative stress improvements

Continued

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TABLE 40.2 Modulation of Gut Microbiota in the Treatment of Behavioral and Emotional Disordersdcont’d Component

Experimental Model (Reference)

Measurements

Key Outcomes

Randomized, doubleblind, placebocontrolled, pilot study [89] 44 patients with Inflammatory bowel syndrome with anxiety and depression

HAD scale: Anxiety and/or Depression, State-Trait Anxiety Inventory, (STAI), IBS global adequate relief, IBS symptoms, somatization, quality of life, changes in brain activation patterns (functional Magnetic Resonance Imaging, fMRI), serum inflammatory markers, neurotransmitters and BDNF, and fecal microbiota

Reduction in depression scores, in responses to negative emotional stimuli in amygdala and frontolimbic regions. Improvements in quality of life scores

Fructooligosaccharides or Oligosaccharides

Adult male Sprague eDawley Rats [90] Five weeks

Plasma glucose, PPY, GLP-1 levels, cortex and hippocampus BDNF and NMDARs protein levels and expression, Fecal microbiota

Increments in BDNF hippocampal regions, NR1 expression in hippocampal regions and frontal cortex, and NR2 in hippocampal regions, increments in PYY levels Growth of Lactobacilli and Bifidobacteria

Fructooligosaccharides (FOS) or Bimuno-galactooligosaccharides (B-GOS)

Double-blind randomized study [91] Healthy volunteers (22 males, 23 females) Three-week supplementation

Levels of salivary cortisol Computer-based Emotional Test Battery IQ test Personality, stress response, mood questionnaires, Beck depression inventory, and state-trait anxiety inventory

B-GOS reduced salivary cortisol levels and attentional vigilance to negative versus positive words

Resistant dextrin (Nutriose06) or maltodextrin

Females with type 2 Diabetes Mellitus [92]

General health questionnaire (GHQ) Depression, anxiety, and stress scale (DASS) White blood cell count, CD4, CD8, IFNg, IL12, IL4, IL10, cortisol, tryptophan, Adrenocorticotropic hormone, kynurenine, and plasma lipopolysaccharide (LPS)

Reductions in cortisol, kynurenine, IFNg, IL-12, IL-10, IL-4, LPS, CD8, GHQ, DASS

Randomized, doubleblind, placebocontrolled trial [93] Overweight and obese

Visual analogue scale for appetite Satiety quotient Three-factor eating questionnaire State-trait food cravings questionnaire trait Beck depression inventory Body esteem scale Binge eating scale Perceived stress scale State-trait anxiety inventory Energy intake, physical activity

Reductions in weight associated with improvements in food behavior and sad feelings in women. Improvements in food behavior and cognition in males.

B. longum NCC3001 subspecies longum strain (BL)

Prebiotics

Synbiotics Lactobacillus rhamnosus CGMCC1.3724 (LPR) þ oligofructose and inulin þ magnesium or Placebo

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disorders, depression, and cognitive impairment are a promising treatment strategy [15,63]. Bravo and colleagues achieved to reduce anxiety and stress, by giving L. rhamnosus JB-1 to mice, showing improvements in gamma-aminobutyric acid (GABA) receptor activity in brain structures related to emotion and behaviors [64]. In fact, the use of probiotics ameliorates brain connectivity, as shown in the supplementation of a fermented product containing Bifidobacterium animalis, Streptococcus thermophilus, Lactobacillus bulgaricus, and Lactococcus lactis to healthy women, finding signs of healthy behavior and emotions [64]. Prebiotics are another alternative, potentially enhancing SCFA such as butyrate, which activates gluconeogenesis, improves insulin sensitivity and energy efficiency and therefore is implicated in appetite and satiety. However, one of the most used prebiotics is resistant starch, with controversial changes in gut microbiota and behavior [66,67].

Healthy Diets and Supplements A westernized diet is deleterious for gut microbiota and behaviors [50]. In contrast, good sources of fats such as u-3-rich oils can modify gut microbiota and improve behavior [69]. Other dietary strategies include phytochemicals, which are rich in crucial nutrients for mental health such as magnesium, potassium, zinc, vitamin c, folic acid, and vitamin B12. By adding more fiber through the consumption of fruits and vegetables, depressive symptoms could be reduced [70].

Ethnic and Geographical Considerations Gut bacteria in the Japanese population, specifically Bacteroides plebeius, have a unique gene signature that codifies carbohydrate-active enzymes (CAZymes) porphyranases and agarases. These genes were acquired from the marine Bacteroidetes, Zobellia galactanivorans, which naturally degrade seaweeds [71]. The Hazda hunter-gatherers of Tanzania have a distinctive gut microbiota composition, enriched in Prevotella, Treponema, and unclassified Bacteroidetes that gives them the ability to digest fibrous vegetable foods and benefit from their nutrients [72]. Another example is the gut microbiome of the Inuit in the Canadian Arctic, with significantly reduced genetic diversity within the Prevotella, a genus related to their traditional diet, low in fiber and rich in animal fats and protein [73]. Furthermore, it has been documented that population groups living in communal lifestyle and consuming their seasonally traditional diets have a healthier microbiome and less microbiome-associated diseases [74]. In agreement with the genetic adaptations to traditional diets, and bacteria coevolving with humans, recommendations of the dietary pattern should include regionally available prebiotic foods, to promote a beneficial gut bacteria [75]. For example, dietary strategies based on the food components of the Mediterranean diet have proven beneficial for mental health [76]. Genetic adaptations to traditional and prehispanic foods of the Mexican populations seem to have influenced a healthier and fitter status [77,78]. Mexican prehispanic foods that have shown significant prebiotic and probiotic activities, include a healthy combination of maize-derived products and legumes, prickly pear, amaranth, chia seeds, fiber, and low-degree alcohol fermented beverages [77e79]. In other cultures, traditional foods such as soy, fermented products, turmeric, cocoa, and green tea that are rich in polyphenols, phytochemicals, and nondigestible fibers that could improve altered gut microbiota and general health.

CONCLUSION Personalized-medicine and genome-based nutrition strategies are necessary to balance the host’s genes, emotions, and diet, to prevent and alleviate gut microbiota-related diseases.

LIST OF ACRONYMS AND ABBREVIATIONS ADHD Attention deficit hyperactivity disorder ASD Autism spectrum disorders BDNF Brain-derived neurotrophic factor CNS Central nervous system GABA Gamma-aminobutyric acid GLP-1 Glucagon-like peptide 1 HPA Hypothalamic pituitary adrenal HSP70 Heat shock protein IBS Irritable bowel syndrome

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NAC Nucleus accumbens NCCDs Noncommunicable chronic diseases NPY Neuropeptide Y OFC Orbital frontal cortex PAMPS Pathogen-associated molecular patterns PFC Prefrontal cortex PYY Peptide YY SCFA Short-chain fatty acids TLRs Toll-like receptors Tregs Regulatory T cells

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FURTHER READING [1] Roman S, Panduro A. Genomic medicine in gastroenterology: a new approach or a new specialty? World J Gastroenterol 2015;21(27):8227e37.