Gut Axis Research Articles

Mucosal mast cells are pivotal elements in inflammatory bowel disease that connect the dots: Stress, intestinal hyperpermeability and inflammation

Mast cells (MC) are pivotal elements in several physiological and immunological functions of the gastro-intestinal (GI) tract. MC translate the stress signals that has been transmitted through brain gut axis into release of proinflammatory mediators that can cause stimulation of nerve endings that could affect afferent nerve terminals and change their perception, affect intestinal motility, increase intestinal hyperpermeability and, in susceptible individuals, modulate the inflammation. Thus, it is not surprising that MC are an important element in the pathogenesis of inflammatory bowel disease and non inflammatory GI disorders such as IBS and mast cell enterocolitis.

Total ghrelin plasma level in patients with the restrictive type of anorexia nervosa

Ghrelin is produced mainly in the stomach and is an essential link of the brain–gut axis. Ghrelin stimulates hunger centers in hypothalamus controlling food intake and body mass gain. The aim of the study is to analyze the total ghrelin plasma level in patients suffering from restrictive type of anorexia nervosa (AN-R). According to DSM-IV classification a group of 30 AN-R patients was investigated before and after 3 and 6 months of therapy. Therapy included normocaloric diet and cognitive–behavioral psychotherapy (CBT). The control group consisted of 20 girls without any eating disorders. Before the therapy the total ghrelin plasma level in AN-R patients was significantly higher than in the control group. After 3 and 6 months of treatment the total ghrelin plasma level in AN-R patients was significantly lower than in the control group. In AN-R patients, the total ghrelin plasma level is connected with the pathological feeding behavior.

Serotonin transporter gene polymorphisms in irritable bowel syndrome

Irritable bowel syndrome (IBS) is a symptomatic motility and sensory disorder of the lower gastrointestinal (GI) tract and is characterized by abdominal pain/ discomfort, bloating and altered bowel activity. It is usually classified according to the predominant bowel habit – IBS with constipation (C-IBS), IBS with diarrhoea (D-IBS) or IBS with alternating symptoms of both constipation and diarrhoea. Despite intensive research, the complicated and multifactorial pathophysiology underlying IBS is not completely understood. Recently, there is growing emphasis on identifying specific biological pathways that contribute to the complex pathophysiology of this disease.

Review article: modulation of the brain–gut axis as a therapeutic approach in gastrointestinal disease

The importance of bi-directional brain-gut interactions in gastrointestinal illness is increasingly being recognized, most prominently in the area of functional gastrointestinal disorders. Numerous current and emerging therapies aimed at normalizing brain-gut interactions are a focus of interest, particularly for irritable bowel syndrome and functional dyspepsia. A literature search was completed for preclinical and clinical studies related to central modulation of gastrointestinal functions and published in English between 1980 and 2006. Existing data, while sparse, support the use of different classes of antidepressant drugs, including tricyclics, and selective and non-selective serotonin reuptake inhibitors in irritable bowel syndrome. Serotonin receptor agonists and antagonists with peripheral and possibly central effects are effective in treating specific subtypes of irritable bowel syndrome. Based largely on theoretical and preclinical evidence, several novel compounds that selectively target receptors at multiple levels within the brain-gut axis such as neurokinin, somatostatin and corticotropin-releasing factor receptor antagonists are promising. This review discusses the rationale for modulation of the brain-gut axis in the treatment of functional gastrointestinal disorders and highlights the most promising current and future therapeutic strategies.

Emerging drugs for irritable bowel syndrome

Irritable bowel syndrome (IBS) is one of the most common chronic gastrointestinal disorders, yet its pathophysiology is incompletely understood and pharmacological treatments remain unsatisfactory. Current therapeutic choices include a range of drugs aimed at normalising bowel habits, reducing pain or treating comorbid psychological symptoms. However, this individual symptom-targeted approach remains unsatisfactory in terms of global symptom relief and patient satisfaction. In the last decade, further characterisation of IBS pathophysiology has provided new and exciting targets at different levels of the brain–gut axis for the development of several candidate drugs. Advances in clinical trial design will help to evaluate these compounds in different IBS patient populations.

Spatio-temporal patterns of intestine-specific transcription factor expression during postnatal mouse gut development

The small intestine matures from a primitive tube into morphologically and functionally distinct regions during gut development. Maximal expression of the genes encoding the digestive enzymes lactase–phlorizin hydrolase and sucrase–isomaltase is spatially restricted to distinct segments along the anterior–posterior axis of the small intestine and is temporally regulated during postnatal maturation. Transcription factors capable of interacting with the intestinal lactase and sucrase gene promoters are candidate regulators of spatio-temporal patterning during gut development and maturation. We aimed to quantitatively examine and compare the relative expression levels of a set of intestine-specific transcription factors along the anterior–posterior gut axis during postnatal maturation. Our analysis was focused on the transcription factors capable of regulating the intestinal lactase and sucrase–isomaltase genes. A real-time PCR protocol was used to quantitatively examine and compare spatially and temporally the relative transcript abundance levels for intestine-specific factors during postnatal intestinal maturation. Distinct spatial expressions patterns were detected along the length of the small intestine for PDX-1, Cdx-2, GATA-4, GATA-5, GATA-6, HNF-1α, HNF-1β and CDP transcription factor genes. There is a general decline in transcript abundance for the factor genes during postnatal maturation. Defining the spatio-temporal expression patterns for intestine-specific transcription factor genes contributes to investigation of the roles that factor gradients play in mediating gut development and differentiation.

Nutritional modulation of the “brain–;gut axis”

The "brain-gut axis" is a multicomponent conceptual model describing the bidirectional communication pathways connecting cognitive and emotional centres in the brain with neuroendocrine centres, the enteric nervous system and the immune system. This model enables novel explanations for the comorbidity of affective disorders, especially concerning mood and anxiety, in functional gastrointestinal disorders, the visceral hypersensitivity, as well as the effect of various acute and chronic stressors on gastrointestinal function. Furthermore, it offers the possibility to develop new biomarkers of integrated brain-gut function. This review discusses the possibilities to modify brain-gut interaction by nutritional means, offered by the brain-gut axis concept. Dietary interventions directed at serotonergic metabolism and its action in the brain, the hypothalamic-pituitary-adrenal axis, the metabolism of long-chain polyunsaturated fatty acids affecting both brain function and inflammatory cytokine profiles, and gut hormones are elaborated. The central role of the autonomic nervous system is also discussed. It is concluded that the concept of the brain-gut axis indeed enables the development of novel dietary intervention strategies in functional gastrointestinal disorders, but results directly transferable to daily practice are not immediately anticipated.

Circulating Ghrelin in Patients Undergoing Elective Cholecystectomy

Secreted predominantly from the stomach (1), ghrelin is a peptide identified in 1999 as an endogenous ligand of the growth hormone (GH) secretagogue receptor located on the pituitary gland, thus fulfilling the criteria of a brain–gut peptide (2)(3). The brain–gut axis serves as an effector of anabolism by regulating growth, feeding, and metabolism via vagal afferent-mediating ghrelin signaling (2)(4). The role of ghrelin as a brain–gut peptide emphasizes the significance of afferent vagal fibers as a major pathway to the brain, serving the purpose of maintaining physiologic homeostasis (2)(4). The importance of ghrelin as a “hunger hormone” with orexigenic effects mediated by the hypothalamic peptides, agouti-related peptide, and neuropeptide Y, and the fact that it is the most potent peripheral signal of diminishing energy stores, implies that ghrelin release might be the most important of the many redundant mechanisms ensuring human survival in times of famine (4). However, the wide tissue distribution of ghrelin suggests that it may have other functions as well (5). Further characterization of the functions of ghrelin is fundamental to discovering new approaches to the diagnosis and treatment of different disease entities, including those related to the catabolic response to surgical trauma (2). In this preliminary study, we report the pattern of ghrelin secretion in different perioperative periods in patients undergoing elective cholecystectomy. Thirty patients [17 females; age range, 20–45 years; body mass index (BMI), 18–25 kg/m2] with ultrasound-confirmed cholecystolithiasis undergoing elective cholecystectomy via laparoscopy or laparotomy at the Surgical Department at the Hospital Umberto I° of Rome were recruited to the study. All patients presented a low surgical risk (American Society of Anesthetists’ score 1 or 2). Patients with a diagnosis of choledocholitiasis, jaundice, acute cholecystitis, and pancreatitis; those with a history of metabolic, endocrine, hepatic, cardiac, …

Functional dyspepsia pathogenesis and therapeutic options—Implications for management

Functional dyspepsia is far more common than dyspepsia due to organic disease, both in the community and general practice. Proposed aetiopathogenic factors include gastric acid, Helicobacter pylori infection, delayed emptying, hypersensitivity or impaired accommodation of the stomach, dysfunction of the duodenum or brain–gut axis, psychosocial morbidity and post-infective mucosal damage. More effective therapy will depend on the development of drugs targeted at these putative pathophysiological mechanisms. On current evidence tricyclic antidepressants appear to be more effective than either acid suppressants or H. pylori eradication.

Intestinal perception: mechanisms and assessment

Physiological stimuli in the gut induce regulatory reflexes to accomplish the digestive process, but are normally not perceived. However, under some circumstances, gut stimuli may activate perception pathways and induce conscious sensations. Experimental evidence gathered during the past decade suggests that patients with functional gut disorders and unexplained abdominal symptoms may have a sensory dysfunction of the gut, so that physiological stimuli would induce symptoms. Assessment of visceral sensitivity is still poorly developed, but in analogy to somatosensory testing, differential stimulation of visceral afferents may be achieved by a combination of stimulation techniques, which may help to characterize sensory dysfunctions. Visceral afferent input is modulated by a series of mechanisms at different levels of the brain-gut axis, and conceivably, a dysfunction of these regulatory mechanisms could cause hyperalgesia. The sensory dysfunction in functional patients seems to be associated with altered reflex activity, and both mechanisms may interact to produce the symptoms. Evidence of a gut sensory-reflex dysfunction as a common pathophysiological mechanism in different functional gastrointestinal disorders would suggest that they are different forms of the same process, and that the clinical manifestations depend on the specific pathways affected.

S.02.02 Cognitive impairment and functional outcome in bipolar disorder

Brain–gut interactions affect psychological wellbeing and symptom reporting in functional gastrointestinal disorders; the presence of anxiety or depression is associated with the development of new-onset gastrointestinal symptoms, and the presence of gastrointestinal symptoms is associated with the development of psychological disorders de novo. In inflammatory bowel diseases (IBD), the reporting of irritable bowel syndrome (IBS)-type symptoms by patients with quiescent disease is common, and is associated with psychological disorders, impaired quality of life, and increased health-care use. In IBD, data from observational studies suggest that psychological disorders might be associated with relapse of disease activity, and that inflammatory activity is associated with the development of new psychological disorders, as has been described for functional gastrointestinal disorders such as IBS and functional dyspepsia. The brain–gut axis provides the physiological link between the CNS and gastrointestinal tract that might facilitate these relationships. In IBS, treatments targeting disordered brain–gut axis activity, including psychological therapies and antidepressants, might lead to improved symptoms and quality of life. However, in IBD, the benefit of these treatments is less certain because of a scarcity of interventional studies. Despite the scarcity of trials, observational data suggest that the effect of disordered brain–gut axis activity in IBD is substantial, and scope remains for further well designed trials of psychological therapies and antidepressants, particularly in the subset of patients who have coexistent psychological disorders, or in those who report IBS-type symptoms. Integrating these treatments into a biopsychosocial model of care has the potential to improve both psychological wellbeing and quality of life in some patients with IBD, reducing health-care use and altering the natural history of disease.

Central nervous system involvement in functional gastrointestinal disorders

Although functional gastrointestinal disorders (FGID) are common, their pathophysiology remains incompletely understood. It is generally accepted that dysfunction of the bidirectional pathways between the gastrointestinal tract and the central nervous system (the ‘brain–gut axis’) at any level can cause FGID symptoms. In this review article, we focus on the role of the central nervous system in the brain–gut axis. First, we describe the functional anatomy of the brain–gut axis. Second, we focus on the results from brain-imaging studies both in healthy volunteers and in FGID patients. These new investigational techniques made identification of brain regions critically involved in processing of visceral afferent information possible. Differences in central nervous system response to visceral stimuli between controls and FGID patients will be highlighted. Third, we will address the issue of high comorbidity with psychiatric disorders. Some hypotheses about common pathophysiological substrates will be discussed.

Visceral hypersensitivity in functional disorders of the upper gastrointestinal tract

Visceral hypersensitivity is now recognised as a major pathophysiological mechanism in functional gastrointestinal disorders of the upper gastrointestinal tract. In patients with non-cardiac chest pain and functional dyspepsia, a high prevalence of visceral hypersensitivity has been indeed observed. In these patients, luminal physiological stimuli can be perceived as unpleasant or even painful. Although the fine mechanisms underlying such “aberrant perceptions” are yet not fully clarified, it is thought that an altered activation of the gut-wall receptors, an altered conduction of sensory inputs at the level of neural pathways, or an impaired processing of the sensations at the level of brain, may occur along the brain–gut axis. So far, drugs able to reduce hypersensitivity, that target each of the constituents of the stimuli–perception chain, have the therapeutic potential to reduce visceral hypersensitivity and, thus, to improve the symptoms. In this context, the availability of new agonists/antagonists to neurotransmitters offers a new exciting tool for the treatment of functional disorders of the upper gastrointestinal tract.

Transcriptional regulation of the lactase-phlorizin hydrolase promoter by PDX-1.

Lactase-phlorizin hydrolase gene expression is spatially restricted along the anterior-posterior gut axis. Lactase gene transcription is maximal in the distal duodenum and jejunum in adult mammals and is barely detectable in the proximal duodenum. By contrast, pancreatic duodenal homeobox-1 (PDX-1) protein is expressed maximally in the proximal duodenum. This study aimed to determine the role of PDX-1 in regulating lactase gene promoter activity in intestinal epithelial cells. Caco-2 cells were cotransfected with lactase promoter-reporter constructs in the presence of a PDX-1 expression vector and assayed for luciferase activity. PDX-1 cotransfection results in repression of lactase promoter activity. Sequence analysis of the lactase promoter revealed a putative PDX-1 DNA binding site in the proximal 100-bp lactase gene promoter. EMSAs demonstrated that PDX-1 can interact with the lactase promoter binding site but not with a site in which the core PDX-1 binding sequence TAAT is mutated. Site-directed mutagenesis of the PDX-1 core binding site in the lactase promoter-reporter construct suggests that PDX-1 can function independently of DNA binding to its consensus binding site. Stable overexpression of PDX-1 results in repression of the endogenous human lactase gene in differentiated Caco-2 cells. Given the contrasting spatial expression pattern, PDX-1 may function to specify the anterior boundary of lactase expression in the small intestine and is thus a candidate regulator of anterior spatial restriction in the gut.

The gut microenvironment of helicid snails (Gastropoda: Pulmonata): in-situ profiles of pH, oxygen, and hydrogen determined by microsensors

In-situ profiles of pH, oxygen, and hydrogen were measured in isolated guts of starved terrestrial gastropods belonging to four species, Cornu aspersum (syn. Helix aspersa), Elona quimperiana, Helix pomatia, and Helix lucorum (excepted pH), using Clark-type oxygen and hydrogen microsensors and liquid-ion-exchanger pH microelectrodes. The pH profiles in the two phyllophagous species, H. pomatia and C. aspersum, increased by 0.9 and 1.4 from the crop to the distal intestine (pH 6.4 and 7.4, respectively). In the saprophagous E. quimperiana, as in H. pomatia, the pH along the gut axis remained acidic (5.1–6.6), suggesting saprophagous habits in the latter. In all four species, no oxygen was detected in the gut lumen. Nevertheless, steep oxygen gradients around the gut epithelium indicated high oxygen-uptake rates. The estimated respiratory activity of the intestine ranged between 6.5 (E. quimperiana) and 13.1 (H. lucorum) μmol O2·g fresh mass–1·h–1. Hydrogen accumulated in the intestine and digestive gland of all snails tested, with the highest values in E. quimperiana and H. pomatia (58 and 78 μM, respectively). These results provide the basis for a better understanding of the microbial and biochemical processes involved in digestion.

Effect of ileocolonic transposition on gut morphology, gene expression, and function

Intestinal morphology and expression of brush border enzymes can be dramatically altered by nutrient composition and position along the longitudinal gut axis. In contrast, endocrine gene expression appears to be relatively “imprinted” and is not significantly altered by positional changes. The purpose of our study was to assess the effects of transposing the ileum into the colonic position on intestinal morphology, gene expression, and enzyme activity. For this study, male Sprague-Dawley rats underwent either transposition of an approximately 8-cm segment of distal ileum into the colonic position or sham operation. Rats were sacrificed 2 months after operation and transposed or sham ileum was assessed. We found that transposition of the ileum to the colonic position resulted in no change in the ileal mucosal architecture. Furthermore, no change in the expression of the endocrine genes neurotensin and PYY or the apoptotic genes was detected. Although sucrase-isomaltase activity was decreased in the transposed ileum, this decrease did not achieve statistical significance. These results demonstrate that the ileum can be successfully interposed into the colonic position. In this location, the ileum functions normally without changes in the villus morphology or gene expression pattern despite the change in position and composition of the luminal content.

Regulation of TRAIL Expression by the Phosphatidylinositol 3-Kinase/Akt/GSK-3 Pathway in Human Colon Cancer Cells

The intestinal mucosa is a rapidly-renewing tissue characterized by cell proliferation, differentiation, and eventual apoptosis with progression up the vertical gut axis. The inhibition of phosphatidylinositol (PI) 3-kinase by specific chemical inhibitors or overexpression of the lipid phosphatase PTEN enhances enterocyte-like differentiation in human colon cancer cell models of intestinal differentiation. In this report, we examined the role of PI 3-kinase inhibition in the regulation of apoptotic gene expression in human colon cancer cell lines HT29, HCT-116, and Caco-2. Inhibition of PI 3-kinase with the chemical inhibitor wortmannin increased TNF-related apoptosis-inducing ligand (TRAIL; Apo2) mRNA and protein expression. Similarly, overexpression of the tumor suppressor protein PTEN, an antagonist of PI 3-kinase signaling, resulted in the increased expression of TRAIL. Activation of PI 3-kinase by pretreatment with IGF-1, a gut trophic factor, markedly attenuated the induction of TRAIL by wortmannin. Moreover, overexpression of active Akt, a downstream target of PI 3-kinase, or inhibition of GSK-3, a downstream target of active Akt, completely blocked the induction of TRAIL by wortmannin. Consistent with findings that TRAIL is induced by agents that enhance intestinal cell differentiation, TRAIL expression was specifically localized to the differentiated cells of the colon and small bowel. Adenovirus-mediated overexpression of TRAIL increased DNA fragmentation of HCT-116 cells, demonstrating the functional activity of TRAIL induction. Taken together, our findings demonstrate induction of the TRAIL by inhibition of PI 3-kinase in colon cancer cell lines. These results identify TRAIL, a novel TNF family member, as a downstream target of the PI 3-kinase/Akt/GSK-3 pathway and may have important implications for better understanding the role of the PI 3-kinase pathway in intestinal cell homeostasis.

Irritable bowel syndrome: newer pharmacological agents acting on the gut

The objectives of this brief review are to provide an update on the clinical pharmacology and clinical trials of new potential therapies for irritable bowel syndrome (IBS). These medications include: 5-HT 3 antagonists, 5-HT 4 agonists, α 2-adrenergic agonists, κ opioid agonists, neurokinin antagonists, neostigmine, probiotics and antibiotics. While these approaches offer promise and a substantial rationale based on modulating the brain gut axis, the potential for central effects and the clinical efficacy of some of these agents are still being explored, and proof of concept studies needs to be supported by robust evidence of positive risk–benefit.

Gastrointestinal perception: pathophysiological implications.

Physiological gut stimuli during the digestive process are not normally perceived. However, gut stimuli activate a variety of afferent pathways and in some circumstances may induce conscious sensations. Experimental evidence gathered during the past decade suggests that patients with functional gut disorders and unexplained abdominal symptoms may have a sensory dysfunction of the gut, so that physiological stimuli would induce symptoms. Assessment of visceral sensitivity is still poorly developed, but in analogy to somatosensory testing, differential stimulation of visceral afferents may be achieved by a combination of stimulation techniques, which may help to characterize sensory dysfunctions. Visceral afferent input is modulated by a series of mechanisms at different levels of the brain gut axis, and conceivably, a dysfunction of these regulatory mechanisms could cause hyperalgesia. The sensory dysfunction in functional patients seems associated to altered reflex activity, and both mechanisms may interact to produce the symptoms. Evidence of a gut sensory-reflex dysfunction as a common pathophysiological mechanism in different functional gastrointestinal disorders, would suggest that they are different forms of the same process, and that the clinical manifestations depend on the specific pathways affected.

Vesicular glutamate transporter 2 in the brain-gut axis.

Previous reports have indicated that vesicular glutamate transporters (VGLUTs) are found only in central neurons. We show that neurons in the gut, which also contain glutamate and markers of intrinsic primary afferent neurons, display VGLUT2 immunoreactivity in several species, including humans. Glutamatergic (VGLUT2-immunoreactive) varicosities, which often co-stored choline acetyltransferase and the vesicular acetylcholine transporter, were apposed to a subset of nerve cell bodies in the submucosal and myenteric plexus. Retrograde tracing with FluoroGold demonstrated that VGLUT2 is found in nodose and dorsal root ganglia neurons innervating the stomach. Thus, VGLUT2 is found in intrinsic and extrinsic primary afferent neurons, which suggests that glutamate is as primary afferent neurotransmitter that transfers information from the mucosa to the enteric plexuses and brain.