It is well known that there exists a bi-directional communication system between the enteric nervous system and central nervous system. Recent research has attempted to understand the influence of intestinal bacteria on the brain and behavior. In this manner, it has been observed that pathogenic bacterial products such as lipopolysaccharides (LPSs) can induce behavioral changes such as acute anxiety, depressive symptoms, cognitive deficits, and increased sensitivity to visceral pain. The modulation of LPS production through probiotics, prebiotics, and symbiotics can prevent these changes. In addition to the neuronal, endocrine, and metabolic pathways, it has been observed that the immune mechanism also exerts an influence on the gut-brain axis. The cells of the immune system can undergo phenotypic changes by the induction of certain bacterial species, which can have an important participation in the development of brain disorders. Although the main effect of prebiotics is through the stimulation of probiotic bacteria, in this chapter, we review the indirect therapeutic potential of prebiotics on the brain through the intestinal microbiota, the gut-associated lymphoid tissue (GALT), and other components of the intestinal lumen. Thus, the objective is to elucidate the mechanisms underlying its effects on the gut-brain axis. Here, we will summarize the possible therapeutic effect of prebiotics on intestinal microbiota, the gut-associated lymphoid tissue (GALT), and brain.
- gut microbiota
- central nervous system
- enteric nervous system
The intestinal microbiota contributes significantly to metabolic, trophic, and protective functions. In this regard, intestinal bacteria are responsible for metabolism of many complex substances into simple components; thus, intestinal microbiota contributes to the digestion of nutrients and has a key role in the nutrition of the host, to the control of certain pathogens and to the improvement of the functions of the local immune system, preventing or participating in some pathologies such as colon cancer . In addition, intestinal bacteria are involved in vitamin synthesis and also in ion absorption [2, 3]. Through their trophic effect, the intestinal bacteria stimulate the proliferation and differentiation of cells on intestinal epithelium ; also, these bacteria may contribute to the maturation of immune cells, regulating the proliferation of pathogenic microorganisms and their toxins . In addition to the functions above described, it has been proposed that intestinal microbiota exerts indirect functions in other organs such as the liver and brain. Studies performed in humans and in animal models suggest that intestinal dysbiosis has an important role in the development of mood disorders such as depression, anxiety, and Parkinson’s disease [5, 6, 7]. For these reasons, the interest in exploring the interactions between immune system, intestinal microbiota, and central nervous system (CNS) has increased (Figure 1).
On the other hand, when bacterial probiotics are administered in adequate amounts, they confer benefits on host health. The main functions of probiotics are to prevent and ameliorate several digestive and allergic disorders. Also, the microbiota modulates ontogeny and immune system functions, as well as the interactions of the intestine-brain axis to regulate some neurological functions. However, the microbiota effects are not only in intestine but also in peripheral tissues, such as in immune system modulation and interacting with the gut-brain axis to regulate some neurologic functions.
2. The gut-associated lymphoid tissue (GALT)
2.1 Anatomy and physiology
The gut-associated lymphoid tissue (GALT) is a specialized component of mucosal-associated lymphoid tissue (MALT) or mucosal immune system that protects the individual’s intestine from invading pathogens. The intestine-associated tissue extends throughout the small and large intestine, covering an area of 260–300 m2 approximately. An important function of intestine is nutrient absorption, where an epithelial cells monolayer (also called enterocytes) separates the GALT from lumen and its content. The enterocytes monolayer on luminal surface is coated by a glucocalix layer, which protects them from acidic pH. The intestinal mucosal surface can function as a permeable barrier to the inside of the body. This permeability increases the vulnerability to infections by a variety of infectious agents that invade the human body orally. Therefore, the largest populations of plasma cells that produce antibodies are enriched on GALT, generating a local and systemic humoral immune response with high production of immunoglobulin A (IgA), promoting a robust cellular immunity with cytotoxic, regulatory, and memory functions . GALT can be divided into: (a) inductive sites, composed by lymphoid aggregates or follicles, and (b) effectors sites formed by the lamina propria and the lumen.
In Figure 2 there is a complete description of GALT, thus GALT forms nodules disseminated into the submucosa and the lamina propria. The largest aggregates form “Peyer’s patches,” which in the small intestine are located in front of the mesenteric tissue. Locally, new epithelial cells derived from stem cells are constantly produced to regenerate the epithelium. In addition to conventional enterocytes, there are also Paneth cells at the bottom of the epithelial crypts. These cells secrete lysozyme and other antibacterial substances to control the growth of pathogens. These cells are found in the small intestine, especially in the jejunum, and their granules become visible after several hours of fasting. Also, the mucus goblet cells are scattered between other cell types. On the other hand, enteroendocrine cells produce polypeptides and are distributed diffusely throughout the gastrointestinal tract. On the surface of Peyer’s patches, “M cells” also called “caveolate cells” are located, which capture antigens and function as intestinal chemoreceptors.
Beneath the epithelial lining is an underlying layer of connective tissue called lamina propria, which is connected to the lymphatic circulation and mesenteric lymph nodes. The intestine is constantly exposed to several antigens derived from the diet, microbiota, and a wide variety of bacterial, viral, fungal, and other pathogens. The immunity of this compartment is highly specialized because it is capable of both functions: (a) triggering an immune response and (b) inducing tolerance by suppressing immune response through the interaction of epithelial cells and microbiota [9, 10].
The induction of intestinal mucosa tolerance depends on several factors, such as: (a) nature of antigen (mainly protein antigens) ; (b) dose and frequency of antigen exposition [12, 13, 14]; (c) kinetics of antigen uptake, because antigenic exposition time with the immune system is key to induce tolerance ; and (d) genetic background and age of the host, because there is different susceptibility to infection, depending on age and genetic inheritance. The main antigens reaching GALT are a mixture of free amino acids and short oligopeptides, generated by gastric, pancreatic, or protease action on large proteins, which are absorbed by intestinal epithelial cells . However, some intact proteins or incomplete proteolysis products can reach inductive sites through the following three non-exclusive pathways:
The epithelium responds to stimuli from different antigens expressing chemokine and cytokine genes . Consequently, different subsets of cells carrying antigens are recruited to inductive sites .
M cells, specialized cells in both internalizing and transportation of intestinal antigens . The antigens are endocytosed or phagocytosed, transported in vesicles through the M cells cytoplasm, and released on the basal surface where they are captured by antigen-presenting cells and transported to inductive sites, which will be presented to T and B cells.
Lamina propria (LP) dendritic cells (CDs) can go through the epithelial cells to capture antigens directly from the intestinal lumen, preserving the epithelial barrier integrity .
It is well known that the intestinal epithelium provides a physical barrier that separates the trillions of commensal bacteria present into intestinal lumen from both underlying lamina propria and deeper intestinal layers. The intestinal epithelium is composed of four cellular subsets derived from a common pluripotent stem cell progenitor: (1) enterocytes which constitute the majority of intestinal epithelial cells (IECs), (2) goblet cells producing mucus, (3) enteroendocrine cells producing hormones, and (4) Paneth cells that produce antimicrobial peptides and lectins. In addition, below the intestinal epithelium, stromal cells, B cells (especially plasma IgA producing cells), T cells, macrophages, and dendritic cells are found in lamina propria. In addition, strategically positioned are intraepithelial lymphocytes or iIELs (specialized T cells) and some dendritic cells, which are located between the IECs to sample the luminal content [20, 21, 22]. Thus, intraepithelial lymphocytes are considered the first line of cellular defense against any antigen that enters orally. The iIELs belong to the lymphoid tissue associated to intestine and they are found in a ratio of 1:10 with respect to the epithelial cells along 300 m2 of intestinal surface . Most iIELs contain abundant cytoplasmic granules for cytotoxic activity; also, effector cytokines such as interferon gamma (IFN-γ), interleukin-2 (IL-2), IL-4, and IL-17 can be secreted [24, 25]. The iIELs are cells that provide an immediate and efficient immune protection to prevent the spread of pathogens. However, to avoid excessive or unnecessary inflammatory responses on intestinal barrier, the iIELs also have regulatory functions .
3. Microbial ecosystem of the gastrointestinal tract
The human intestine contains a wide variety of microorganisms, approximately 500–1000 different species, of which the Bacteria, Archaea and Eukarya are the principal ones [1, 27]. The predominant bacteria populations in the intestine are the Bacteroidetes and Firmicutes, constituting about 90% . This diverse ecosystem is called “gut microbiota,” which has a symbiotic and mutualism relationship with the host [29, 30]. The intestinal microbiota exerts its own functions and has both direct and indirect influence on host’s physiology and health, especially on metabolism. However, several pathologies, including neurological disorders such as irritable bowel syndrome, depression, anxiety, and Parkinson’s disease have been associated with alteration of the intestinal microbiota known as “dysbiosis” [5, 6, 7].
With respect to dysbiosis, the wide diversity and abundance of gut microbiota population can be modified importantly by host’s diet and age, as well as by other factors. The newborn is colonized by bacteria from birth and initially, there are no differences between bacteria population localized on different parts of body. Infants who are born via vaginal delivery are mainly colonized by Lactobacillus and Prevotella, microbial populations closely related to maternal vaginal bacteria populations . In contrast, infants born by cesarean-section (C-section) are exposed to
The high-carbohydrate and high-fat diet composition may produce dysbiosis. It was described that in mice, a Western diet (WD: high-carbohydrate and high-fat diet) intake caused dysbiosis and dysregulated bile acids (BA) synthesis with reduced endogenous ligands for BA receptors, that is, farnesoid X receptor and G-protein-coupled bile acid receptor in the liver and brain . More relevantly, a ketogenic low-carbohydrate high-fat diet induced changes in the oral microbiome of elite endurance athletes; the relative abundances of
3.1 Functions of the gut microbiota in the host
The main biological functions regulated by the gut microbiota are related to the efficiency to metabolize food and obtain energy. Polysaccharides are the main source of energy in bacterial metabolism, which are transformed into short-chain fatty acids (SCFAs). Bacterial metabolism is not limited only to SCFAs production and obtaining energy. The intestinal microbiota can synthesize several vitamins, aryl hydrocarbon receptor (AHR) ligands on host cells, polyamines , folate , indole , serotonin , and other compounds. In addition, intestinal microbiota also produces bacterial toxins called bacteriocins. To date, 13 species of bacteriocins have been found in human feces .
The major SCFAs produced by the gut microbiota are acetate, propionate, and butyrate, which are found at 80–130 mM [46, 47]. In this way, the SCFAs represent approximately 70% of the total energy captured by the intestinal epithelial cells. Interestingly, butyrate produced by
It is well known that microbiota strongly impacts on the expression of genes and proteins on host intestinal epithelial cells. In axenic mice, it has been found that in intestinal colonization by
Additionally, several studies have shown that microbiota has an important role in peripheral and intestinal immune system ontogeny, as well as intestinal epithelium renewal [52, 53]. Also, microbiota-epithelial cell interaction indirectly controls the expenditure and storage of energy in the host . Dysbiosis has been associated with a several pathologies affecting directly the digestive tract, including chronic inflammatory bowel diseases, colorectal cancer, constipation, and diarrhea; but in peripheral organs, it can also induce allergies, arthritis, or neurological disorders . In this way, correcting the dysbiosis could improve the symptoms of diseases like irritable bowel syndrome (IBS) and functional diarrhea .
Intestinal bacteria are importantly involved in development and regulation of the immune system [57, 58, 59]. On this regard, mice grown under germ-free conditions exhibited several abnormalities, including hypoplastic Peyer’s patches, IgA-producing cells reduction, relatively poorly structured spleen and lymph nodes, and decrease in proportion of Treg cells in colon . Interestingly, when mice were exposed to intestinal bacteria for several weeks, the structure and function of immune system cells were restored . Moreover, it has been shown that lipopolysaccharides from gram negative bacteria, as well as peptidoglycans from gram positive bacteria, activate Toll-like receptors (TLRs), inducing different immune responses . Also, the expression of angiogenin 4 by
3.2 Host’s immunomodulatory activity on the gut microbiota
The interactions between environmental signals and intestinal immune system are necessary to maintain a stable equilibrium and regulate the protective function of the intestinal barrier. Thus, in order to prevent microbial colonization and transepithelial migration, several chemical substances are produced by the intestinal epithelial cells, such as gastric acid, enzymes (lactoferrin, lysozyme), antimicrobial peptides (defensins), mucins, and nitric oxide . On the other hand, signaling through Toll-like receptors (TLRs) is very important for the activation of innate immune system. TLRs recognize a wide range of common antigens present in pathogens, activating the adaptive immune system for the generation of multiple highly specific and immunocompetent clones .
4. Connection between enteric nervous system (ENS) and central nervous system (CNS)
The enteric nervous system (ENS) extends from the esophagus to the anal region. The main functions are: (1) stimulation of glandular secretions, (2) motor functions such as peristalsis, and (3) ions and water exchange. The neurons found in CNS are subdivided into two main plexuses: the myenteric plexus and the submucosal plexus . The former is responsible for peristalsis and second regulates the glandular secretions and control of blood flow. There are extrinsic fibers connecting these two plexuses, which are stimulated by both sympathetic and parasympathetic nervous system, communicating directly to spinal cord, part of the vagus nerve, and pre-vertebral ganglia of the sympathetic nervous system, although the ENS is able to function independently .
Generally, there are different types and subtypes of neurons throughout the ENS: excitatory neurons of the intestine, secretomotor, vasodilator, and non-vasodilator; some of them innervate whole endocrine cells and others intrinsic visceral afferent neurons. Most of the different types of neurons participate in reflexes corresponding to each plexus (myenteric and submucosal) (Figure 3).
The neurotransmitters secreted by enteric neurons are varied, the acetylcholine (excitatory effect) and noradrenaline (inhibitory effect) being the most studied . In addition, the communication of the ENS with the CNS is not only through the secretion of these neurotransmitters. Several studies have shown that bacterial metabolites generated in the intestinal ecosystem have a direct impact on the brain. Thus, it is well known that the intestinal microbiota has an important effect on CNS, because the homeostasis and intestinal functions can be regulated by the CNS . The CNS and intestine connection may occur through several pathways, including: neuronal, hormonal, immune system, and intestinal bacterial metabolites . Regarding the neuronal connection, the intestine is directly connected to the brain through the vagus nerve; thus, intestinal microbiota may stimulate the enteric nervous system . In addition, several reports have shown that a defective communication between the brain and intestine microbiota is associated to anxiety, depression, inflammatory bowel disease, and other diseases [76, 77, 78]. Interestingly, behavior changes in elderly have been associated with decreased immune function, resulting in alteration of intestinal microbiota-brain connection .
4.1 Dysbiosis and its effect on the neuroplasticity and behavior
In the first weeks of life, microbiota diversifies into a microbial community in which anaerobic microorganisms predominate . This early colonization coincides with hypothalamic-pituitary-adrenal (HPA) axis activation, which has an important role in the innervation of the gastrointestinal (GI) tract and enteric nervous system (ENS) function. Likewise, the production of 5HT by enterochromaffin cells is regulated by the intestinal microbiota, inducing de
Several reports have shown the relation between intestine and the CNS through metabolic, neuroendocrine, and immunological pathways, impacting neuronal plasticity and cognition. Production of proinflammatory cytokines (IL-1) in intestinal lumen may affect the brain through vagus nerve . Also, bacterial products like lipopolysaccharide (LPS) can increase cytokines production, as well as induce both neuroinflammation and neurodegeneration . In addition, it was shown that WD-fed mice had intestinal dysbiosis, which was accompanied by inflammatory signaling in the brain, microglial activation, and reduced neuroplasticity . Therefore, dysbiosis of gut microbiota may increase the cytokines production and neuroinflammation, affecting mood, or it could induce psychiatric disorders such as depression and anxiety as was described in animal models  as well as in comparative studies performed in humans [5, 84]. Moreover, in maternal immune activation (MIA) mouse model, intestinal dysbiosis induced both higher production of both 4-ethylphenylsulfate (4EPS) and indolepyruvate, leading to autism spectrum disorder (ASD). Interestingly, with
A mechanism by producing substrates from bacterial metabolism such as SCFAs from the fermentation of dietary fiber has been described. The SCFAs regulate the metabolism of glucose and cholesterol . Most importantly, the SCFAs (acetate, propionate, and butyrate) treatment alleviated the psychosocial stress-induced alterations in mice; the effect observed was selective, because the stress-induced body weight gain, fecal SCFAs, and the colonic gene expression of the SCFAs receptors free fatty acid receptors 2 and 3 remained unaffected by SCFAs supplementation .
Other studies also have shown that dysbiosis may induce mood alterations. For example, dysbiosis induced by antibiotics treatment in mice leads to cognitive and behavioral alterations as well as to neurological changes [88, 89]. In addition, in juvenile mice with dysbiosis, after a 2-week antibiotic treatment, the levels of mRNA and protein of brain-derived neurotrophic factor (BDNF) and tropomyosin-related receptor kinase B (TrKB) in hippocampus CA3 and dentate gyrus subregions, respectively, significantly increased . Most importantly, patients with disorders like depression, anxiety, and eating disorder psychopathology have a significantly lower microbial alpha diversity as compared with healthy subjects . Interestingly, depression and anxiety symptoms may be improved by fecal microbiota transplantation in patients with irritable bowel syndrome (IBS), functional diarrhea (FDR), or functional constipation (FC). Thus, the increase of microbiota diversity may improve the patient’s mood .
Since its initial description in 1995, the concept of prebiotic has been in constant evolution. Currently, according to Gibson and Roberfroid, a probiotic has been defined as “any substance present in diet, which specifically stimulates the growth and/or the fermentative activity of one or a limited number of bacteria species of intestinal microbiota, generating beneficial effects on health of host as a consequence of changes on either bacterial composition or metabolic activity” .
Generally, a food ingredient is considered as a prebiotic when it has the following characteristics: (a) it must be kept in good condition until reaching the distal portions of the intestine; that is, it is not absorbed in the anterior part of the gastrointestinal tract and resists the hydrolysis of digestive enzymes  such as α-glucosidase, maltase, isomaltase, and sucrase ; (b) it must act as a selective substrate in the growth and/or metabolism of one or a limited number of beneficial bacterial species, such as Lactobacillus spp. and Bifidobacterium spp.; and finally (c) it must positively stimulate the microbiota, by increasing beneficial microorganisms and reducing pathogenic bacteria .
It is well known that proliferation of bifidobacteria and lactobacilli is favored by prebiotics; moreover, the proliferation of bacterial pathogenic strains such as
5.1 Types and sources
As already mentioned, prebiotics are normally ingested in the diet; however, only some carbohydrates (poly and oligosaccharides), whose chemical structure has β-type bonds, some peptides, some proteins, and certain lipids such as esters and ethers are food ingredients qualified as prebiotics .
Different types of oligosaccharides considered as prebiotics have been reported, among them are: fructooligosaccharides (FOS), oligofructose (OF), the inulin type fructans (ITFs), galactooligosaccharides (GOS), transgalactooligosaccharides (TOS), and lactulose. However, there are others less known such as isomaltooligosaccharides (IMOS). Xylooligosaccharides (XOS) and mananooligosaccharides (MOS) also have a probiotic potential [90, 95]. It is well known that sucrose and starch are the main carbohydrates found in higher plants, followed by glucomannans and fructans are the main reserve sources in the vegetable kingdom [96, 97].
5.2 Interaction of prebiotics in gut microbiota
The non-digestible carbohydrates or prebiotics are selectively fermented by the microbiota that produces important metabolites for the health of the host, the SCFAs acetate, propionate, and butyrate mainly. Likewise, prebiotics have a direct impact on the gut-associated lymphoid tissue (GALT) with immunomodulatory functions . The symbiotic association between the host and the microbiota is fundamental in its physiology. The increase of the beneficial populations in the intestinal lumen affects the establishment of opportunistic pathogens, contributing to the strengthening of the GALT.
5.3 Potential effects on microbiota-GALT-brain axis
The stimulation of probiotic bacteria by prebiotics contributes to the increase of the production of beneficial metabolites for the host, such as the SCFAs. However, prebiotics not only have an impact on the intestinal microbiota. Oligofructose, an inulin type fructan, can bind to cellular receptors of pathogenic bacteria and block adhesion to the surface of enterocytes, helping to prevent colonization. In the same way, β (2→1)-fructans are ligands of TLR2, TLR4, TLR5, TLR7, TLR8, and NOD2. Moreover, levan (2→6)-fructans appears to be a recognized of TLR4 to reduce IgE serum levels and Th2 responses . Bacterial metabolites travel through the vagus nerve to reach specific brain regions such as cerebellum and hippocampus and modify gene expression . It has been described that alterations in intestinal microbiota due to exposure to chronic stress are reversed with the administration of prebiotics and/or probiotics .
According to the classification of microbiota obtained by statistical analysis of sequence data, an alpha diversity has been identified, which describes the diversity of bacteria within a single individual; while beta diversity describes the diversity of specimens between different individuals. It has been shown that different types of prebiotics have an effect on the microbiota-GALT-brain axis in mice and human models. Prebiotics treatments (isolated from acorn and sago) induced increased β-diversity in heart failure patient’s fecal microbiome, while no significant change in β-diversity was seen in healthy fecal microbiome. Alpha diversity was significantly higher in both healthy and diseased fecal microbiome, which was accompanied with an increase of the beneficial bacteria and SCFAs. Moreover, prebiotics treatment ameliorated HFD-induced glucose intolerance and insulin resistance in diabetic mice. Feeding both prebiotics treatments and inulin increased SCFAs levels in the mouse gut, and decreased the gut hyperpermeability and mucosal inflammatory markers in HFD-fed mice. The expression of pro-opiomelanocortin was also modulated by prebiotics administration, suggesting an important role in the hypothalamic energy signaling in the mice . In diabetic db/db mice, the administration of oligofructose increases the expression of tight junction proteins occludin and ZO-1, which improves the integrity of the BBB in the hypothalamus and normalizes the expression of mRNA of IL-6 in the hippocampus; however, it does not improve alterations in behavior or in neurogenesis .
Moreover, the administration of prebiotic chitosan oligosaccharides (COSs) in Male Sprague-Dawley rats increases cognitive function and reduces levels of TNF-α and IL-1β, both pro-inflammatory cytokines . In a mouse model of amyotrophic lateral sclerosis, the oral administration of GOS reduced the motor neuron death and muscular atrophy and increased the levels of serum folate, vitamin B12, and homocysteine . In the same way, in a mouse model with lipopolysaccharide-induced anxiety, the administration of bimuno-galacto-oligosaccharides (B-GOSs) reduced the pro-inflammatory cytokine IL-1β and expression of cortical 5-HT2A receptors . In a mouse model of vascular dementia, the β-glucan from barley and arabinoxylan from the yeast
Interestingly, our research group previously demonstrated that the administration of oligofructose and
On the other hand, the administration of synbiotics (probiotics and prebiotics in combination) shows interesting effects. In infants with cow’s milk allergy, the treatment with based formula of amino-acid and symbiotics (a combination of fructo-oligosaccharides and
In patients with major depressive disorder (MDD), probiotics treatment (≥10 × 109 CFU of freeze-dried
The effect of the probiotics on the intestinal microbiota is quite important not only for the functions on intestine, but also for the development and function of immune system, metabolism, and central nervous system. Moreover, these systems are closely related, so that any alteration will impact their functionality. Therefore, the balance on microbiota-gut-central nervous system axis is very important to maintain the adequate functions of these systems.
Intestinal dysbiosis leads to alterations in development and function of central nervous system, which is significantly improved upon intestinal colonization with normal microbiota and probiotics treatment. To date, the interaction of microbiota-intestine-brain axis is not completely clear. For this reason, it is interesting to redirect the investigation of CNS diseases whose pathological mechanism is unknown.
We are thankful to the University of Guanajuato for their financial support (220/2019) to J R-E and 191/2019 to SLB. Cristina D. Balcón thanks CONACYT for the scholarship with support number 712500.
Conflict of interest
The authors declare no conflict of interest.
Shreiner AB, Kao JY, Young VB. The gut microbiome in health and in disease. Current Opinion in Gastroenterology. 2015; 31(1):69-75. DOI: 10.1097/MOG.0000000000000139
Guarner F, Malagelada JR. Gut flora in health and disease. The Lancet. 2003; 361(9356):512-519. DOI: 10.1016/S0140-6736(03)12489-0
Bik EM. Composition and function of the human-associated microbiota. Nutrition Reviews. 2009; 67(1):S164-S171. DOI: 10.1111/j.1753-4887.2009.00237.x
Gordon JI, Hooper LV, McNevin MS, Wong M, Bry L. Epithelial cell growth and differentiation. III. Promoting diversity in the intestine: Conversations between the microflora, epithelium, and diffuse GALT. The American Journal of Physiology. 1997; 273(3):G565-G570. DOI: 10.1152/ajpgi.1997.273.3.G565
Kleiman SC, Watson HJ, Bulik-Sullivan EC, Huh EY, Tarantino LM, Bulik CM, et al. The intestinal microbiota in acute anorexia nervosa and during Renourishment: Relationship to depression, anxiety, and eating disorder psychopathology. Psychosomatic Medicine. 2015; 77(9):969-981. DOI: 10.1097/PSY.0000000000000247
Sampson TR, Debelius JW, Thron T, Janssen S, Shastri GG, Ilhan ZE, et al. Gut microbiota regulate motor deficits and Neuroinflammation in a model of Parkinson’s disease. Cell. 2016; 167:1469-1480
Zhou ZL, Jia XB, Sun MF, Zhu YL, Qiao CM, Zhang BP, et al. Neuroprotection of fasting mimicking diet on MPTP-induced Parkinson’s disease mice via gut microbiota and metabolites. Neurotherapeutics. 2019; 16(3):741-760. DOI: 10.1007/s13311-019-00719-2
Mowat A. Anatomical basis of tolerance and immunity to intestinal antigens. Nature Reviews. Immunology. 2003; 3(4):331-341
Mayer L. Mucosal immunity. Pediatrics. 2003; 111(Supplement_3):1595-1600
MacDonald TT, Monteleone G. Immunity, inflammation, and allergy in the gut. Science. 2005; 307(5717):1920-1925
Peng H, Chang Z, Han S, Won M, Huang B. Chemical denaturation of ovalbumin abrogates the induction of oral tolerance of specific IgG antibody and DTH responses in mice. Scandinavian Journal of Immunology. 1995; 42(3):297-304
Mowat A, Strobel S, Drummond H, Ferguson A. Immunological responses to fed protein antigens in mice. I. Reversal of oral tolerance to ovalbumin by cyclophosphamide. Immunology. 1982; 45(1):105-113
Friedman A, Weiner HL. Induction of anergy or active suppression following oral tolerance is determined by antigen dosage. PNAS. 1994; 91(14):6688-6692
Meyer A, Benson J, Gienapp I, Cox K, Whitacre C. Suppression of murine chronic relapsing experimental autoimmune encephalomyelitis by the oral administration of myelin basic protein. Journal of Immunology. 1996; 157(9):4230-4238
Garside P, Mowat AM, Khoruts A. Oral tolerance in disease. Gut. 1999; 44(1):137-142
Erickson R, Kim Y. Digestion and absorption of dietary protein. Annual Review of Medicine. 1990; 41:133-139
Nagler-Anderson C. Man the barrier! Strategic defences in the intestinal mucosa. Nature Reviews. Immunology. 2001; 1(1):59-67
Clayburgh D, Shen L, Turner J. A porous defense: The leaky epithelial barrier in intestinal disease. Laboratory Investigation. 2004; 84(3):282-291
Neutra M, Mantis N, Kraehenbuhl J. Collaboration of epithelial cells with organized mucosal lymphoid tissues. Nature Immunology. 2001; 2(11):1004-1009
Rescigno M, Urbano M, Valzasina B, Francolini M, Rotta G, Bonasio R, et al. Ricciardi-Castagn… P: Dendritic cells express tight junction proteins and penetrate gut epithelial monolayers to sample bacteria. Nature Immunology. 2001; 2(4):361-367
Jabri B, Ebert E. Human CD8+ intraepithelial lymphocytes: A unique model to study the regulation of effector cytotoxic T lymphocytes in tissue. Immunological Reviews. 2007; 215:202-214
Niess JH, Brand S, Gu X, Landsman L, Jung S, McCormick BA, et al. CX3CR1-mediated dendritic cell access to the intestinal lumen and bacterial clearance. Science. 2005; 307(5707):254-258
Petit A, Ernst P, Befus A, Clark D, Rosenthal K, Ishizaka T, et al. Murine intestinal intraepithelial lymphocytes I. relationship of a novel Thy-1-,Lyt-1-,Lyt-2+, granulated subpopulation to natural killer cells and mast cells. European Journal of Immunology. 1985; 15(3):211-215
Shires J, Theodoridis E, Hayday A. Biological insights into TCRgammadelta+ and TCRalphabeta+ intraepithelial lymphocytes provided by serial analysis of gene expression (SAGE). Immunity. 2001; 15(3):419-434
Guy-Grand D, Malassis-Seris M, Briottet C, Vassalli P. Cytotoxic differentiation of mouse gut thymodependent and independent intraepithelial T lymphocytes is induced locally. Correlation between functional assays, presence of perforin and granzyme transcripts, and cytoplasmic granules. The Journal of Experimental Medicine. 1991; 173(6):1549-1552
Cheroutre H, Lambolez F, Mucida D. The light and dark sides of intestinal intraepithelial lymphocytes. Nature Reviews. Immunology. 2011; 11(7):445-456
Farooqi I, O’Rahilly S. Monogenic obesity in humans. Annual Review of Medicine. 2005; 56:443-458
Hugenholtz P, Goebel BM, Pace NR. Impact of culture-independent studies on the emerging phylogenetic view of bacterial diversity. Journal of Bacteriology. 1998; 180(18):4765-4774
Xu J, Gordon JI. Inaugural article: Honor thy symbionts. PNAS. 2003; 100(18):10452-10459
Xu J, Mahowald M, Ley R, Lozupone C, Hamady M, Martens E, et al. Evolution of symbiotic bacteria in the distal human intestine. PLoS Biology. 2007; 5(7):e156
Dominguez-Bello MG, Costello EK, Contreras M, Magris M, Hidalgo G, Fierer N, et al. Delivery mode shapes the acquisition and structure of the initial microbiota across multiple body habitats in newborns. PNAS. 2010; 107(26):11971-11975. DOI: 10.1073/pnas.1002601107
Bäckhed F, Roswall J, Peng Y, Feng Q , Jia H, Kovatcheva-Datchary P, et al. Dynamics and stabilization of the human gut microbiome during the first year of life. Cell Host & Microbe. 2015; 17(5):690-703. DOI: 10.1016/j.chom.2015.04.004
Lynch SV, Pedersen O. The human intestinal microbiome in health and disease. The New England Journal of Medicine. 2016; 375:2369-2379. DOI: 10.1056/NEJMra1600266
Eckburg PB, Bik EM, Bernstein CN, Purdom E, Dethlefsen L, Sargent M, et al. Diversity of the human intestinal microbial Flora. Science. 2005; 308(5728):1635-1638. DOI: 10.1126/science.1110591
Reyes A, Haynes M, Hanson N, et al. Viruses in the faecal microbiota of monozygotic twins and their mothers. Nature. 2010; 466:334-338
Agans R, Rigsbee L, Kenche H, Michail S, Khamis H, Paliy O. Distal gut microbiota of adolescent children is different from that of adults. FEMS Microbiology Ecology. 2011; 77(2):404-412
Mariat D, Firmesse O, Levenez F, Guimaraes V, Sokol H, Dore J, et al. The Firmicutes/Bacteroidetes ratio of the human microbiota changes with age. BMC Microbiology. 2009; 9:123
Sovran B, Hugenholtz F, Elderman M, Van Beek A, Graversen K, Huijskes M, et al. Age-associated impairment of the mucus barrier function is associated with profound changes in microbiota and immunity. Scientific Reports. 2019; 9:1437
Jena PK, Sheng L, Di Lucente J, Jin LW, Maezawa I, Wan YY. Dysregulated bile acid synthesis and dysbiosis are implicated in Western diet-induced systemic inflammation, microglial activation, and reduced neuroplasticity. The FASEB Journal. 2018; 32(5):2866-2877. DOI: 10.1096/fj.201700984RR
Murtaza N, Burke LM, Vlahovich N, Charlesson B, O’Neill HM, Ross ML, et al. Analysis of the effects of dietary pattern on the Oral microbiome of elite endurance athletes. Nutrients. 2019; 11(3):E614. DOI: 10.3390/nu11030614
Rooks MG, Garrett WS. Gut microbiota, metabolites and host immunity. Nature Reviews. Immunology. 2016; 16(6):341-352. DOI: 10.1038/nri.2016.42
Rossi M, Amaretti A, Raimondi S. Folate production by probiotic bacteria. Nutrients. 2011; 3:118-134
Shimada Y et al. Commensal bacteria-dependent indole production enhances epithelial barrier function in the colon. PLoS One. 2013; 8:e80604
Yano JM, Yu K, Donaldson GP, et al. Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis. Cell. 2015; 161:264-276
Lakshminarayanan B, Guinane CM, O’Connor PM, et al. Isolation and characterization of bacteriocin-producing bacteria from the intestinal microbiota of elderly Irish subjects. Journal of Applied Microbiology. 2013; 114:886-898
Cummings JH. Fermentation in the human large intestine: Evidence and implications for health. Lancet. 1983; 1:1206-1209
Cummings JH, Pomare EW, Branch WJ, Naylor CP, Macfarlane GT. Short chain fatty acids in human large intestine, portal, hepatic and venous blood. Gut. 1987; 28:1221-1227
Donohoe DR et al. The microbiome and butyrate regulate energy metabolism and autophagy in the mammalian colon. Cell Metabolism. 2011; 13:517-526
Asanuma N, Kawato M, Ohkawara S, Hino T. Characterization and transcription of the genes encoding enzymes involved in butyrate production in Butyrivibrio fibrisolvens. Current Microbiology. 2003; 47:203-207
Lee WJ, Hase K. Gut microbiota–generated metabolites in animal health and disease. Nature Chemical Biology. 2014; 10:416-424
Hooper LV, Wong MH, Thelin A, Hansson L, Falk PG, Gordon JI. Molecular analysis of commensal host-microbial relationships in the intestine. Science. 2001; 291(5505):881-884
Slack E, Hapfelmeier S, Stecher B, Velykoredko Y, Stoel M, Lawson MAE, et al. Innate and adaptive immunity cooperate flexibly to maintain host-microbiota mutualism. Science. 2009; 325(5940):617-620
Lee YK, Mazmanian SK. Has the microbiota played a critical role in the evolution of the adaptive immune system? Science. 2010; 330(6012):1768-1773
Backhed F, Ding H, Wang T, Hooper LV, Koh GY, Nagy A, et al. The gut microbiota as an environmental factor that regulates fat storage. PNAS. 2004; 101(44):15718-15723
Neish A. Microbes in gastrointestinal health and disease. Gastroenterology. 2009; 136(1):65-80
Kurokawa S. The effect of fecal microbiota transplantation on psychiatric symptoms T among patients with irritable bowel syndrome, functional diarrhea and functional constipation: An open-label observational study. Journal of Affective Disorders. 2018; 235:506-512
Round J, Mazmanian S. The gut microbiota shapes intestinal immune responses during health and disease. Nature Reviews. Immunology. 2009; 9(5):313-323
Brestoff JR, Artis D. Commensal bacteria at the interface of host metabolism and the immune system. Nature Immunology. 2013; 14:676-684
Fulde M, Hornef MW. Maturation of the enteric mucosal innate immune system during the postnatal period. Immunological Reviews. 2014; 260:21-34
Macpherson A, Harris N. Interactions between commensal intestinal bacteria and the immune system. Nature Reviews. Immunology. 2004; 4(6):478-485
Kamada N, Chen GY, Inohara N, Nuñez G. Control of pathogens and pathobionts by the gut microbiota. Nature Immunology. 2013; 14:685-690
Hooper L, Stappenbeck T, Hong C, Gordon J. Angiogenins: A new class of microbicidal proteins involved in innate immunity. Nature Immunology. 2003; 4(3):269-273
Mazmanian S, Liu C, Tzianabos A, Kasper D. An immunomodulatory molecule of symbiotic bacteria directs maturation of the host immune system. Cell. 2005; 122(1):107-118
Mazmanian S, Round J, Kasper D. A microbial symbiosis factor prevents intestinal inflammatory disease. Nature. 2008; 453(7195):620-625
Fukuda S et al. Bifidobacteria can protect from enteropathogenic infection through production of acetate. Nature. 2011; 469:543-547
Presley LL, Wei B, Braun J, Borneman J. Bacteria associated with Immunoregulatory cells in mice. Applied and Environmental Microbiology. 2010; 76(3):936-941
Garrett W, Lord G, Punit S, Lugo-Villarino G, Mazmanian S, Ito S, et al. Communicable ulcerative colitis induced by T-bet deficiency in the innate immune system. Cell. 2007; 131(1):33-45
Otte JM, Kiehne K, Herzig KH. Antimicrobial peptides in innate immunity of the human intestine. Journal of Gastroenterology. 2003; 38(8):717-726. DOI: 10.1007/s00535-003-1136-5
Sanz Y, Nadal I, Sanchez E. Probiotics as drugs against human gastrointestinal infections. Recent Patents on Anti-Infective Drug Discovery. 2007; 2(2):148-156
Carabotti M, Scirocco A, Maselli MA, Severi C. The gut-brain axis: Interactions between enteric microbiota, central and enteric nervous systems. Annals of Gastroenterology. 2015; 28(2):203-209
Hall JE. Guyton and Hall Textbook of Medical Physiology: Enhanced E-Book. Philadelphia, PA: Saunders Elsevier; 2010
Furness JB. Types of neurons in the enteric nervous system. Journal of the Autonomic Nervous System. 2000; 81(1-3):87-96. DOI: 10.1016/S0165-1838(00)00127-2
Moloney RD, Dinan TG, Cryan JF. P.2.031 the CBA/J mouse as a genetic model of visceral hypersensitivity with co-morbid anxiety and depression: Role of glutamate transport. European Neuropsychopharmacology. 2013; 23:S51-S52
Ochoa-Repáraz J, Kasper LH. Current Obesity Reports. 2016; 5:51. DOI: 10.1007/s13679-016-0191-1
Forsythe P, Bienenstock J, Kunze WA. Vagal pathways for microbiome-brain-gut Axis communication. In: Lyte M, Cryan J, editors. Microbial Endocrinology: The Microbiota-Gut-Brain Axis in Health and Disease. Advances in Experimental Medicine and Biology. Vol. 817. New York, NY: Springer; 2014
Collins SM, Surette M, Bercik P. The interplay between the intestinal microbiota and the brain. Nature Reviews Microbiology. 2012; 10:735-742
Cryan JF, Dinan TG. Mind-altering microorganisms: The impact of the gut microbiota on brain and behavior. Nature Reviews Neuroscience. 2012; 13:701-712
Savignac HM. Prebiotic administration normalizes lipopolysaccharide (LPS)-induced anxiety and cortical 5-HT2A receptor and IL1-β levels in male mice. Brain, Behavior, and Immunity. 2016; 52:120-131
Erny D. Host microbiota constantly control maturation and function of microglia in the CNS. Nature Neuroscience. 2015; 18:965-977
Mitsou E, Kirtzalidou E, Oikonomou I, Liosis G, Kyriacou A. Fecal microflora of Greek healthy neonates. Anaerobe. 2008; 14(2):94-101
Hickman RA et al. Consequences of gut Dysbiosis on the human brain. INTECH. 2016; 3:41-64
Mohammadi G et al. The effects of probiotic formulation pretreatment (lactobacillus helveticus R0052 and Bifidobacterium longum R0175) on a lipopolysaccharide rat model. Journal of the American College of Nutrition. 2019; 2019, 38(3):209-217
Jena PK et al. Dysregulated bile acid synthesis and dysbiosis areimplicated in Western diet–induced systemicinflammation, microglial activation, andreduced neuroplasticity. The FASEB Journal. 2018, 2018; 32:2866-2877
Heym N, Heasman BC, Hunter K, et al. The role of microbiota and inflammation in self-judgement and empathy: Implications for understanding the brain-gut-microbiome axis in depression. Psychopharmacology. 2019; 236(5):1459-1470
Hsiao EY, McBride SW, Hsien S, et al. Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders. Cell. 2013; 155:1451-1463
Leung K, Thuret S. Gut microbiota: A modulator of brain plasticity and cognitive function in ageing. Healthcare. 2015; 3:898-916
van de Wouw M. 2018 short-chain fatty acids: Microbial metabolites that alleviate stress-induced brain-gut axis alterations. The Journal of Physiology. 2018; 596(20):4923-4944
Bercik P, Denou E, Collins J, Jackson W, Lu J, Jury J, et al. The intestinal microbiota affect central levels of brain-derived neurotropic factor and behavior in mice. Gastroenterology. 2011; 141(2):599-609.e3. DOI: 10.1053/j.gastro.2011.04.052
Bistoletti M et al. Antibiotic treatment-induced dysbiosis differently affects BDNF and TrkB expression in the brain and in the gut of juvenile mice. PLoS One. 2019; 14(2):e0212856
Hernández HA, Coronel RC, Monge ZM, Quintana HC. Microbiota, Probióticos, Prebióticos y Simbióticos. Pediatría Integral. 2015; 9(5):337-354
Walton GE, Swann JR, y Gibson GR. Chapter 2: Prebiotics. Rosenberg E, Delong EF, Lory S, Stackebrandt E. y Thompson F. (Eds). The Prokaryotes: New York: Springer Science Business Media; 25-43
Huazano-García A, López MG. Applied Biochemistry and Biotechnology. 2018; 184:25. DOI: 10.1007/s12010-017-2526-0
García Y, López MG, Bocourt R, Rodríguez Z, Urías SJ. Herrera M. Fermentación in vitro del extracto de Agave fourcroydes (henequén) por bacterias ácido lácticas. Revista Cubana de Ciencia Agrícola. 2012a; 2(46):203-209
Morales KD. y Vélez RJF. Prebióticos: Su importancia en la salud humana y propiedades funcionales en tecnología de alimentos. Temas Selectos de Ingeniería de Alimentos. 2013; 1(7):12-24
Pérez C. D., López G. y Ros G. 2004. Principales prebióticos y sus efectos en la alimentación humana. Anales de Veterinaria de Murcia. 20:5-20
Mancilla-Margalli NA, López MG. Water-soluble carbohydrates and fructan structure patterns from agave and Dasylirion species. Journal of Agricultural and Food Chemistry. 2006; 54(20):7832-7839. DOI: 10.1021/jf060354v
Urías-Silvas J, Cani P, Delmée E, Neyrinck A, López M, Delzenne N. Physiological effects of dietary fructans extracted from Agave tequilana Gto. And Dasylirion spp. British Journal of Nutrition. 2008; 99(2):254-261. DOI: 10.1017/S0007114507795338
Franco-Robles E, López MG. Implication of Fructans in health: Immunomodulatory and antioxidant mechanisms. The Scientific World Journal. 2015; 2015:289267. DOI: 10.1155/2015/289267
Mayer EA, Knight R, Mazmanian SK, Cryan JF, Tillisch K. Gut microbes and the brain: Paradigm shift in neuroscience. Journal of Neuroscience. 2014; 34(46):15490-15496. DOI: 10.1523/JNEUROSCI.3299-14.2014
Sarkar A, Lehto SM, Harty S, Dinan TG, Cryan JF, Burnet P. Psychobiotics and the manipulation of bacteria-gut-brain signals. Trends in Neurosciences. 2016; 39(11):763-781. DOI: 10.1016/j.tins.2016.09.002
Ahmadi S, Nagpal R, Wang S, et. al. Prebiotics from acorn and sago prevent high-fat-diet-induced insulin resistance via microbiome–gut–brain axis modulation. 2019; 67:1-13. DOI: 10.1016/j.jnutbio.2019.01.011
Fernández de Cossío L, Fourrier C, Sauvant J, Everard A, Capuron L, Cani PD, et al. Impact of prebiotics on metabolic and behavioral alterations in a mouse model of metabolic syndrome. Brain, Behavior, and Immunity. 2017; 64:33-49. DOI: 10.1016/j.bbi.2016.12.022
Jia S, Lu Z, Gao Z, An J, Wu X, Li X, et al. Chitosan oligosaccharides alleviate cognitive deficits in an amyloid-β1-42-induced rat model of Alzheimer’s disease. International Journal of Biological Macromolecules. 2016; 83:416-425. DOI: 10.1016/j.ijbiomac.2015.11.011
Song L. Galactooligosaccharide improves the animal survival and alleviates motor neuron death in SOD1 G93A mouse model of amyotrophic lateral sclerosis. Neuroscience. 2013; 246:281-290
Han HS, Jang JH, Jang JH, Choi JS, Kim YJ, Lee C, et al. Water extract of Triticum aestivum L. and its components demonstrate protective effect in a model of vascular dementia. Journal of Medicinal Food. 2010; 13(3):572-578
Franco-Robles E, Ramírez-Emiliano J, López MG. Agave fructans and oligofructose decrease oxidative stress in brain regions involved in learning and memory of overweight mice. Natural Product Research. 2018; 33(10):1527-1530. DOI: 10.1080/14786419.2017.1423297
Franco-Robles E, López MG. Agavins increase Neurotrophic factors and decrease oxidative stress in the brains of high-fat diet-induced obese mice. Molecules. 2016; 21:998
Wopereis H, van Ampting MTJ, Cetinyurek-Yavuz A, Slump R, Candy DCA, Butt AM, et al. A specific synbiotic-containing amino acid-based formula restores gut microbiota in non-IgE mediated cow’s milk allergic infants: A randomized controlled trial. Clinical and Translational Allergy. 2019; 9:27. DOI: 10.1186/s13601-019-0267-6
Warda AK et al. Heat-killed lactobacilli alter both microbiota composition and behaviour. Behavioural Brain Research. 2019; 362:213-223
Kazemi A et al. Effect of prebiotic and probiotic supplementation on circulating pro-inflammatory cytokines and urinary cortisol levels in patients with major depressive disorder: A double-blind, placebo-controlled randomized clinical trial. Journal of Functional Foods. 2019; 52:596-602
Schmidt K, Cowen PJ, Harmer CJ, Tzortzis G, Errington S, Burnet PW. Prebiotic intake reduces the waking cortisol response and alters emotional bias in healthy volunteers. Psychopharmacology. 2015; 232(10):1793-1801