Candidate genes and sensory functions in health and irritable bowel syndrome

Adrenergic and serotonergic (ADR-SER) mechanisms alter gut (GI) function; these effects are mediated through G protein transduction. Candidate genetic variations in ADR-SER were significantly associated with somatic scores in irritable bowel syndrome (IBS) and gastric emptying but not small bowel or colonic transit. Our aim was to assess whether candidate ADR-SER genes are associated with motor and sensory GI functions in IBS and subgroups on the basis of bowel dysfunction. In 122 patients with IBS and 39 healthy controls, we assessed gastrointestinal somatic symptoms and affect by validated questionnaires. We measured: gastric volume (GV), maximum tolerated volume, rectal compliance, sensation thresholds and ratings, and genetic variations including alpha2A (C-1291G), alpha2C (Del 332-325), GNbeta3 (C825T), and 5-HTTLPR. Demographics and genotype distributions were similar in the patients with IBS subgrouped on bowel function. There were significant associations between 5-HTTLPR SS genotype and absence of IBS symptoms and between 5-HTTLPR LS/SS genotype and increased rectal compliance and increased pain ratings, particularly at 12 and 24 mmHg distensions. GNbeta3 was associated only with fasting GV; we did not detect associations between alpha2A genotype and the gastrointestinal sensory or motor functions tested. We concluded that 5-HTTLPR LS/SS genotype is associated with both increased pain sensation and increased rectal compliance though the latter effect is unlikely to contribute to increased pain sensation ratings with LS/SS genotype. The data suggest the hypotheses that the endophenotype of visceral hypersensitivity in IBS may be partly related to genetic factors, and the association of GNbeta3 with fasting GV may explain, in part, the reported association of GNbeta3 with dyspepsia.     

The blood-brain barrier: connecting the gut and the brain

The BBB prevents the unrestricted exchange of substances between the central nervous system (CNS) and the blood. The blood-brain barrier (BBB) also conveys information between the CNS and the gastrointestinal (GI) tract through several mechanisms. Here, we review three of those mechanisms. First, the BBB selectively transports some peptides and regulatory proteins in the blood-to-brain or the brain-to-blood direction. The ability of GI hormones to affect functions of the BBB, as illustrated by the ability of insulin to alter the BBB transport of amino acids and drugs, represents a second mechanism. A third mechanism is the ability of GI hormones to affect the secretion by the BBB of substances that themselves affect feeding and appetite, such as nitric oxide and cytokines. By these and other mechanisms, the BBB regulates communications between the CNS and GI tract.     

Histochemistry and function of bombesin-like peptides

Bombesin-like peptides are a group of brain-gut peptides found in several neuronal groups in the central nervous system and in peripheral intrinsic gut neurons and sensory neurons. The SIF cells (small intensely fluorescent cells) of the sympathetic ganglia also contain immunoreactivity for these peptides. These peptides are present in some pulmonary endocrine cells and tumors originating from these cells. Chromatographic studies suggest that several different peptides, possibly originating from at least two different precursors, are present in mammalian tissues. Authentic amphibian peptide bombesin does not appear to be found in mammalian tissues. Functional studies indicate that these peptides may be involved in many important functions, including sensory transmission, regulation of central autonomic pathways, thermoregulation, secretion of pituitary hormones, gastric and pancreatic secretion, food intake and satiety.     

Immunolocalisation of vasoactive intestinal peptide and substance P in the developing gut of Dicentrarchus labrax (L.)

This study was carried out on the sea bass (Dicentrarchus labrax) to follow, during development, the appearance and distribution of substance P (SP) and vasoactive intestinal peptide (VIP), which act on gut motility. The results suggest that SP and VIP play an important role as neuromodulators, influencing the motility of the digestive tract starting from the early stages of gut development, even prior to exotrophic feeding. In the peptidergic nervous system, the appearance of immunoreactivity to SP began at the rectum and followed a distal to proximal gradient, whereas for VIP, it began proximally and progressed along a proximal to distal gradient. The two peptides also appeared in gut epithelial cells. In some regions, all the cells were positive. From this distribution of positive cells, we conclude that these peptides may also have other roles, besides being neurotransmitters in the enteric nervous system and hormones of the gastro-entero-pancreatic system. VIP and SP might have paracrine and/or autocrine activity in the physiological maturation of the gut epithelium, as it has already been hypothesised for other peptides.     

Oral inoculation with herpes simplex virus type 1 infects enteric neuron and mucosal nerve fibers within the gastrointestinal tract in mice.

Herpes simplex virus type 1 (HSV-1) is commonly encountered first during childhood as an oral infection. After this initial infection resolves, the virus remains in a latent form within innervating sensory ganglia for the life of the host. We have previously shown, using a murine model, that HSV-1 placed within the lumen of the esophagus gains access to nerves within the gut wall and establishes a latent infection in sensory ganglia (nodose ganglia) of the tenth cranial nerve (R. M. Gesser, T. Valyi-Nagy, S. M. Altschuler, and N. W. Fraser, J. Gen. Virol. 75:2379-2386, 1994). Peripheral processes of neurons in these ganglia travel through the vagus nerve and function as primary sensory receptors in most of the gastrointestinal tract, relaying information from the gut wall and mucosal surface to secondary neurons within the brain stem. In the work described here, we further examined the spread of HSV-1 through the enteric nervous system after oral inoculation. By immunohistochemistry, HSV-1 was found to infect myenteric ganglia in Auerbach's plexus between the inner and outer muscle layers of the gut wall, submucosal ganglia (Meisner's plexus), and periglandular ganglion plexuses surrounding submucosal glands. Virus-infected nerve fibers were also seen projecting through the mucosal layer to interact directly with surface epithelial cells. These intramucosal nerve fibers may be a conduit by which intraluminal virus is able to gain access to the enteric nervous system from the gastrointestinal lumen.     

Integrative neuroimmunomodulation of gastrointestinal function during enteric parasitism.

Enteric helminths have a significant impact on the structure, function, and neural control of the gastrointestinal (GI) tract of the host. Interactions between the host's nervous and immune systems redirect activity in neuronal circuits intrinsic to the gut into an alternative repertoire of defensive and adaptive motor programs. Gut inflammation and activation of the enteric neuroimmune axis play integral roles in the dynamic interaction between host and parasite that occurs at the mucosal surface. Three inter-related themes are stressed in this review to underscore the pivotal role that neural control mechanisms play in the host's GI tract functional responses to enteric parasitism. First, we address the discovery that signaling molecules of both parasite and host origin can reorient the dynamic ecology of enteric host-parasite interactions. Second, we explore what has been learned from investigations of altered gut propulsive and secretomotor reflex activities that occur during enteric parasitic infections and the emerging picture derived from these studies that elucidates how nerves help facilitate and orchestrate functional reorganization of the parasitized gut. Third, we provide an overview of the direct impact that enteric parasitism has on nerve cell function and neurotransmission pathways in both the enteric and central nervous systems of the host. In summary, this review highlights and clarifies the complex mechanisms underlying integrative neuroimmunophysiological responses to the presence of both invasive and noninvasive enteric helminths and identifies directions for future research investigations in this highly important but understudied area.     

An aberrant retinal pathway and visual centers in Xenopus tadpoles share a common cell surface molecule, A5 antigen

A monoclonal antibody A5 (MAb-A5), which was raised against Xenopus tadpole tectal cells, recognizes a cell surface-related protein molecule (A5 antigen) expressed on the visual centers of Xenopus tadpoles (S. Takagi, T. Tsuji, T. Amagai, T. Takamatsu, and H. Fujisawa, 1987, Dev. Biol. 122, 90-100). The present immunohistochemistry using MAb-A5 indicated that, in addition to the visual centers, A5 antigen was expressed on the general somatic sensory tract in the medulla and spinal cord of Xenopus tadpoles. As the general somatic sensory tract has been shown to be a pathway for ectopically transplanted retinal axons (M. Constantine-Paton and R. R. Capranica, 1976, J. Comp. Neurol. 170, 17-32; M. J. Katz and R. J. Lasek, 1979, J. Comp. Neurol. 183, 817-832), we examined whether retinal axons transplanted close to the spinal cord or medulla preferentially grow into the A5 antigen-positive general somatic sensory tract. We performed eye transplantation at embryonic stages and detected precise locations and trajectories of transplanted retinal axons within the medulla and spinal cord in tadpoles after filling retinal axons with horseradish peroxidase (HRP). HRP histochemistry in combination with MAb-A5 immunohistochemistry indicated that almost all HRP-filled transplanted retinal axons joined the A5 antigen-positive general somatic sensory tract. These findings suggest the involvement of A5 antigen in specific cell-cell recognition between retinal axons and their targets.     

Boring's formulation: a scheme for identifying functional neuron groups in a sensory system

In 1935 Edwin Boring proposed that each attribute of sensation reflects the activity of a different neural circuit. If this idea is valid, it could facilitate both psychophysical and neurophysiological research on sensory systems. We think it likely that Boring's formulation is correct for three reasons: 1) Different sensory attributes reflect conscious information about different parameters of a stimulus. To be measured by any device, each of these parameters must be individually computed. Different neural circuits would appear to be necessary for the nervous system to carry out these different computations. 2) Perceived information about different sensory attributes can be made to diverge by appropriate manipulations of the stimuli. If there is a rigorous relationship between conscious sensory experience and neural activity, such a divergence implies that different sensory attributes are served by different neural circuits. 3) Accurate information about a sensory attribute requires that a human observer's attention be focused on that attribute. Changes in direction of attention are thought to involve a process of switching from one neural circuit to another, and provide another way to cause perceived information about different sensory attributes to diverge.     

Gastrointestinal hormones regulating appetite

The role of gastrointestinal hormones in the regulation of appetite is reviewed. The gastrointestinal tract is the largest endocrine organ in the body. Gut hormones function to optimize the process of digestion and absorption of nutrients by the gut. In this capacity, their local effects on gastrointestinal motility and secretion have been well characterized. By altering the rate at which nutrients are delivered to compartments of the alimentary canal, the control of food intake arguably constitutes another point at which intervention may promote efficient digestion and nutrient uptake. In recent decades, gut hormones have come to occupy a central place in the complex neuroendocrine interactions that underlie the regulation of energy balance. Many gut peptides have been shown to influence energy intake. The most well studied in this regard are cholecystokinin (CCK), pancreatic polypeptide, peptide YY, glucagon-like peptide-1 (GLP-1), oxyntomodulin and ghrelin. With the exception of ghrelin, these hormones act to increase satiety and decrease food intake. The mechanisms by which gut hormones modify feeding are the subject of ongoing investigation. Local effects such as the inhibition of gastric emptying might contribute to the decrease in energy intake. Activation of mechanoreceptors as a result of gastric distension may inhibit further food intake via neural reflex arcs. Circulating gut hormones have also been shown to act directly on neurons in hypothalamic and brainstem centres of appetite control. The median eminence and area postrema are characterized by a deficiency of the blood-brain barrier. Some investigators argue that this renders neighbouring structures, such as the arcuate nucleus of the hypothalamus and the nucleus of the tractus solitarius in the brainstem, susceptible to influence by circulating factors. Extensive reciprocal connections exist between these areas and the hypothalamic paraventricular nucleus and other energy-regulating centres of the central nervous system. In this way, hormonal signals from the gut may be translated into the subjective sensation of satiety. Moreover, the importance of the brain-gut axis in the control of food intake is reflected in the dual role exhibited by many gut peptides as both hormones and neurotransmitters. Peptides such as CCK and GLP-1 are expressed in neurons projecting both into and out of areas of the central nervous system critical to energy balance. The global increase in the incidence of obesity and the associated burden of morbidity has imparted greater urgency to understanding the processes of appetite control. Appetite regulation offers an integrated model of a brain-gut axis comprising both endocrine and neurological systems. As physiological mediators of satiety, gut hormones offer an attractive therapeutic target in the treatment of obesity.     

Gastrointestinal satiety signals I. An overview of gastrointestinal signals that influence food intake

An overview is presented of those signals generated by the gastrointestinal (GI) tract during meals that interact with the central nervous system to create a sensation of fullness and satiety. Although dozens of enzymes, hormones, and other factors are secreted by the GI tract in response to food in the lumen, only a handful are able to influence food intake directly. Most of these cause meals to terminate and hence are called satiety signals, with CCK being the most investigated. Only one GI signal, ghrelin, that increases meal size has been identified. The administration of exogenous CCK or other satiety signals causes smaller meals to be consumed, whereas blocking the action of endogenous CCK or other satiety signals causes larger meals to be consumed. Satiety signals are relayed to the hindbrain, either indirectly via nerves such as the vagus from the GI tract or else directly via the blood. Most factors that influence how much food is eaten during individual meals act by changing the sensitivity to satiety signals. This includes adiposity signals as well as habits and learning, the social situation, and stressors.     

Distribution of bombesin- and cholecystokinin-like immunoreactivity in rat and dog brain and gastrointestinal tract

Using a specific bombesin radioimmunoassay and an immunoassay for cholecystokinin which sees all C-terminal fractions, the distribution of bombesin-like (BLI) and cholecystokinin-like (CCK-LI) immunoreactivity in the brain and gastrointestinal tract of the rat and dog has been studied. Both peptides are found in the brain and gut but the rat contains more CCK and BLI than the dog; this is particularly noted in the stomach, colon and cerebral cortex whereas the small intestine of both species contains equivalent amounts of peptides. This contrasts with other comparative studies, mainly on nervous system CCK, which find no major distribution differences in man, monkey, pig and rat. This finding suggests that CCK-LI and BLI peptides may have a more predominant role in the rat than in the dog.     

Histochemical localization of galactose-containing glycoconjugates in sensory neurons and their processes in the central and peripheral nervous system of the rat

We studied the distribution of sugar residues in the oligosaccharide chains of complex carbohydrates in tissue sections of rat spinal cord, brainstem, and sensory ganglia using twelve lectin-horseradish peroxidase conjugates. Glycoconjugates containing terminal galactose residues were localized apparently in the Golgi apparatus in a population of predominantly small B-type neurons in spinal and trigeminal ganglia. Large A-type neurons rarely showed reactivity with galactose-binding lectins. A cells stained for glycoconjugates with N-glycosidically linked oligosaccharides and glycogen. The central and peripheral processes of the small neurons, mostly unmyelinated C fibers in sensory roots and spinal nerves, contained an abundance of glycoconjugates with terminal alpha-galactose residues. The central projections and terminals of small to medium-sized primary sensory neurons in the spinal and trigeminal ganglia were visualized in Lissauer's tract and the substantia gelatinosa in the spinal cord, and in the spinal trigeminal tract and the nucleus trigeminus in the lower medulla with lectins specific for terminal alpha-galactose residues. In addition, fibers of the solitary system and the area postrema were reactive with these lectins. The peripheral and central nervous system elements with affinity for galactopyranosyl-specific lectins correspond in distribution with neuroanatomical regions thought to be involved in the transmission and relay of somatic and visceral afferent inputs such as pain and temperature. Such specific localization of a glycosubstance to a distinct subpopulation of neurons and their peripheral and central processes suggests that the particular glycoconjugate may be of physiological significance.     

Interactive relationship between Trp metabolites and gut microbiota: The impact on human pathology of disease

Tryptophan (Trp), an α-amino acid, is the precursor of serotonin (5-hydroxytryptamine, 5-HT), which is involved in a variety of features of metabolic function and human nutrition. Evidence highlights the role of Trp metabolites (exclusively 5-HT) in the gastrointestinal (GI) tract; however, the mechanisms of action involved in the release of 5-HT in the GI tract are still unknown. Considering the fact that variations of 5-HT may facilitate the growth of certain GI disorders, gaining a better understanding of the function and release of 5-HT in the GI tract would be beneficial. Additionally, investigating Trp metabolism may clarify the relationship between Trp and gut microbiota. It is believed that other metabolites of Trp (mostly that of the kynurenine pathway) may play a significant role in controlling gut microbiota function. In this review, we have attempted to summarize the current research investigating the relationship of gut microbiota, Trp and 5-HT metabolism (with particular attention paid to their metabolite type, as well as a discussion of the research methods used in each study). Taking together, regarding the role that Trp/5-HT plays in a range of physical and mental diseases, the gut bacterial types, as well as the related disorders, have been exclusively considered.     

The role of gut hormones in controlling the food intake. What is their role in emerging diseases?

Central nervous system (CNS) receives peripheral relevant information that are able to regulate individual's energy balance through metabolic, neural, and endocrine signals. Ingested nutrients come into contact with multiple sites in the gastrointestinal tract that have the potential to alter peptide and neural signaling. There is a strong relationship between CNS and those peripheral signals (as gastrointestinal hormones) in the control of food intake. The purpose of this review is to give updated information about the role of gut hormones as mediators of feeding behavior and of different nutrients in modulating gut hormones production. The role of gut hormones in the pathogenesis of emerging diseases as obesity and non-alcoholic fatty liver disease (NAFLD) is also discussed together with the possible role of these peripheral signals as targets of future therapeutic options.     

Presence of endothelin-1 and endothelin-3 in peripheral tissues and central nervous system of the pig.

The distribution of endothelin (ET) peptides in the pig was studied in a variety of tissues using selective radioimmunoassays combined with reverse-phase high performance liquid chromatography (HPLC). The levels of ET-like immunoreactivity (LI) were overall relatively low. The highest levels of ET-LI were found in blood vessels, cerebral and coronary arteries containing 3190 +/- 910 and 1330 +/- 450 fmol/g, respectively. Veins generally contained higher levels of ET-LI per tissue weight than corresponding arteries. Peripheral sympathetic and sensory ganglia contained a higher concentration of ET-LI than the studied central nervous system (CNS) areas. In the CNS the highest concentration of ET-LI was found in a non-neuronal structure, the choroid plexus. The levels of ET-LI were also relatively high in the respiratory tract (100-400 fmol/g). In the heart, the endocardium contained the highest levels (190 +/- 44 fmol/g). In the kidney, the concentration of ET-LI was 3-fold higher in the medulla than in the cortex. In the gastrointestinal tract all levels were below 100 fmol/g, except for the colon which contained 120 +/- 50 fmol/g. The characterization of ET-LI in extracts of some of these tissues revealed that ET-1 dominated in the lung, spleen and hypothalamus while ET-3 and ET-1 were present in approximately equal amounts in renal medulla and thoracic spinal cord. The HPLC analysis provided no clear-cut evidence for significant presence of vasoactive intestinal contractor, ET-2 or big ET-1(1-39) in the lung, spleen, kidney, spinal cord or hypothalamus. It is concluded that mature ET-1 and ET-3 are the predominant ET peptides in peripheral tissues and CNS.     

Peptidomics and peptide hormone processing in the Drosophila midgut

Peptide hormones are key messengers in the signaling network between the nervous system, endocrine glands, energy stores and the gastrointestinal tract that regulates feeding and metabolism. Studies on the Drosophila nervous system have uncovered parallels and homologies in homeostatic peptidergic signaling between fruit flies and vertebrates. Yet, the role of enteroendocrine peptides in the regulation of feeding and metabolism has not been explored, with research hampered by the unknown identity of peptides produced by the fly's intestinal tract. We performed a peptidomic LC/MS analysis of the fruit fly midgut containing the enteroendocrine cells. By MS/MS fragmentation, we found 24 peptides from 9 different preprohormones in midgut extracts, including MIP-4 and 2 forms of AST-C. DH(31), CCHamide1 and CCHamide2 are biochemically characterized for the first time. All enteroendocrine peptides represent brain-gut peptides, and apparently are processed by Drosophila prohormone convertase 2 (AMON) as suggested by impaired peptide detectability in amon mutants and localization of amon-driven GFP to enteroendocrine cells. Because of its genetic amenability and peptide diversity, Drosophila provides a good model system to study peptide signaling. The identification of enteroendocrine peptides in the fruit fly provides a platform to address functions of gut peptide hormones in the regulation of feeding and metabolism.     

Migration of neural crest-derived enteric nervous system precursor cells to and within the gastrointestinal tract

The enteric nervous system, the intrinsic innervation of the gastrointestinal tract, consists of large numbers of phenotypically diverse neurons and glial cells, arranged in complex interconnecting plexuses situated between the smooth muscle layers of the gut wall. Recently, the enteric nervous system has attracted much attention from developmental biologists whose efforts have focused on analysing the cellular origins of enteric nervous system precursor cells, how these cells migrate to and within the gut and the identification of signalling mechanisms which cause migrating cells to differentiate into the appropriate phenotypes in the appropriate locations. This review summarises the state of knowledge concerning the early stages of enteric nervous system development and concentrates on: (i) the embryological origins of the neural crest cells which colonise the gastrointestinal tract, (ii) their spatiotemporal migration within the gut, (iii) the possible pre-specification of neural crest cells as enteric nervous system precursors and (iv) factors influencing their directional migration within the gut.     

Diversity of probiotic adhesion genes in the gastrointestinal tract of goats

Gastrointestinal (GI) microflora is an important system in the host, as it has both pathogenic and probiotic bacteria. Most of the studies were focused on the human gut microflora and the available information on the intestinal microflora of goats was limited. This urged the need to inspect the impacts of the goat's gut microflora. Metagenomic investigation of probiotic bacteria in the GI tract of goat is one of the challenging streams because of the less available data of the uncultivable bacteria. In our report, comparative analysis of metagenomic and enrichment samples of goat intestinal content was done and this approach will be helpful in analyzing the identification of uncultivable and cultivable probiotic bacteria. This study mainly focused on three key probiotic adhesion genes, such as EF-Tu, mapA, and mub. The GI of four different goats were investigated for these genes. The data from this study showed that there is a wide diversity of these genes among goat intestinal samples.     

Physiological changes in the gastrointestinal tract and host protective immunity: learning from the mouse-Trichinella spiralis model

Infection and inflammation in the gastrointestinal (GI) tract induces a number of changes in the GI physiology of the host. Experimental infections with parasites represent valuable models to study the structural and physiological changes in the GI tract. This review addresses research on the interface between the immune system and GI physiology, dealing specifically with 2 major components of intestinal physiology, namely mucin production and muscle function in relation to host defence, primarily based on studies using the mouse-Trichinella spiralis system. These studies demonstrate that the infection-induced T helper 2 type immune response is critical in generating the alterations of infection-induced mucin production and muscle function, and that this immune-mediated alteration in gut physiology is associated with host defence mechanisms. In addition, by manipulating the host immune response, it is possible to modulate the accompanying physiological changes, which may have clinical relevance. In addition to enhancing our understanding of immunological control of GI physiological changes in the context of host defence against enteric infections, the data acquired using the mouse-T. spiralis model provide a basis for understanding the pathophysiology of a wide range of GI disorders associated with altered gut physiology.     

A microbial world within us

The microbial world within us includes a vast array of gastrointestinal (GI) tract communities that play an important role in health and disease. Significant progress has been made in recent years in describing the intestinal microbial composition based on the application of 16S ribosomal RNA (rRNA)-based approaches. These were not only instrumental in providing a phylogenetic framework of the more than 1000 different intestinal species but also illustrated the temporal and spatial diversity of the microbial GI tract composition that is host-specific and affected by the genotype. However, our knowledge of the molecular and cellular bases of host-microbe interactions in the GI tract is still very limited. Here an overview is presented of the most recent developments and applications of novel culture-independent approaches that promise to unravel the mechanisms of GI tract functionality and subsequent possibilities to exploit specifically these mechanisms in order to improve gut health.