[show abstract][hide abstract] ABSTRACT: Gas-related symptoms represent very common complaints in children. The reduction of gas production can be considered as a valuable target in controlling symptoms. alpha-galactosidase has been shown to reduce gas production and related symptoms in adults.Aim: To evaluate the efficacy and tolerability of alpha-galactosidase in the treatment of gas-related symptoms in pediatric patients.
Single center, randomized, double-blind, placebo-controlled, parallel group study performed in tertiary care setting. Fifty-two pediatric patients (32 female, age range 4--17) with chronic or recurrent gas-related symptoms were randomized to receive placebo (n = 25) or alpha-galactosidase (n = 27). Both treatments were given as drops or tablets, according to body weight for 2 weeks. The primary endpoint was the reduction in global distress measured by the Faces Pain Scale-Revised (FPS-R) at the end of treatment compared to baseline. Secondary endpoints were the reduction in severity and frequency of gas-related symptoms as recorded by parents and/or children.
alpha-galactosidase significantly reduced global distress (p = 0.02) compared to placebo. The digestive enzyme decreased the number of days with moderate to severe bloating (p = 0.03) and the proportion of patients with flatulence (p = 0.02). No significant differences were found for abdominal spasms and abdominal distension. No adverse events were reported during treatment.
Although larger and longer trials are needed to confirm this result, alpha-galactosidase seems to be a safe, well tolerated and effective treatment for gas-related symptoms in the pediatric population.Trial registration: ClinicalTrials.gov - NCT01595932.
[show abstract][hide abstract] ABSTRACT: The debate about the ethical and scientific issues regarding the use of animals in research is mainly focused on these questions: a) whether preclinical studies in animals are still ethically acceptable; b) whether it is possible to establish more soundly their predictivity; c) what measures should be taken to reduce the clinical attrition often due to biased preclinical assessment of potential efficacy of new drugs. This review aims at a critical revision of animal models of chemically induced intestinal inflammation in drug development. These models, notwithstanding differences among species, still represent a major source of information about biological systems and can have undisputable translational value, provided that appropriate measures are taken to ensure that experiments are both scientifically and ethically justified. These measures include: a) more stringent application to preclinical experiments of standards used in clinical studies (such as sample size, randomization, inclusion/exclusion criteria, blinding); b) selection of the animal model after careful pathophysiological scrutiny bearing in mind inherent limitations of each model (e.g. acute self-limiting vs chronic disease, animal species, role of the intestinal immune system and microbiome); and c) experimental design duly considering the specific pharmacological profile of each agent to be screened (such as bioavailability, route of administration, full consideration of the pharmacological spectrum). In this perspective, the new European legislation is an opportunity to fully apply these standards so that in vivo animal models can provide an invaluable mean to study complex physiological and biochemical interactions, which cannot be completely simulated in silico and/or in vitro.
[show abstract][hide abstract] ABSTRACT: Taste signalling molecules are found in the gastrointestinal (GI) tract suggesting that they participate to chemosensing. We tested whether fasting and refeeding affect the expression of the taste signalling molecule, α-transducin (G(αtran) ), throughout the pig GI tract and the peptide content of G(αtran) cells. The highest density of G(αtran) -immunoreactive (IR) cells was in the pylorus, followed by the cardiac mucosa, duodenum, rectum, descending colon, jejunum, caecum, ascending colon and ileum. Most G(αtran) -IR cells contained chromogranin A. In the stomach, many G(αtran) -IR cells contained ghrelin, whereas in the upper small intestine many were gastrin/cholecystokinin-IR and a few somatostatin-IR. G(αtran) -IR and G(αgust) -IR colocalized in some cells. Fasting (24 h) resulted in a significant decrease in G(αtran) -IR cells in the cardiac mucosa (29.3 ± 0.8 versus 64.8 ± 1.3, P < 0.05), pylorus (98.8 ± 1.7 versus 190.8 ± 1.9, P < 0.0 l), caecum (8 ± 0.01 versus 15.5 ± 0.5, P < 0.01), descending colon (17.8 ± 0.3 versus 23 ± 0.6, P < 0.05) and rectum (15.3 ± 0.3 versus 27.5 ± 0.7, P < 0.05). Refeeding restored the control level of G(αtran) -IR cells in the cardiac mucosa. In contrast, in the duodenum and jejunum, G(αtran) -IR cells were significantly reduced after refeeding, whereas G(αtran) -IR cells density in the ileum was not changed by fasting/refeeding. These findings provide further support to the concept that taste receptors contribute to luminal chemosensing in the GI tract and suggest they are involved in modulation of food intake and GI function induced by feeding and fasting.
Journal of Cellular and Molecular Medicine 02/2013; · 4.75 Impact Factor
[show abstract][hide abstract] ABSTRACT: There is increasingly convincing evidence supporting the participation of the gut microenvironment in the pathophysiology of irritable bowel syndrome (IBS). Studies particularly suggest an interplay between luminal factors (eg, foods and bacteria residing in the intestine), the epithelial barrier, and the mucosal immune system. Decreased expression and structural rearrangement of tight junction proteins in the small bowel and colon leading to increased intestinal permeability have been observed, particularly in postinfectious IBS and in IBS with diarrhea. These abnormalities are thought to contribute to the outflow of antigens through the leaky epithelium, causing overstimulation of the mucosal immune system. Accordingly, subsets of patients with IBS show higher numbers and an increased activation of mucosal immunocytes, particularly mast cells. Immune factors, released by these cells, including proteases, histamine, and prostanoids, participate in the perpetuation of the permeability dysfunction and contribute to the activation of abnormal neural responses involved in abdominal pain perception and changes in bowel habits. All these mechanisms represent new targets for therapeutic approaches in IBS. Probiotics are an attractive therapeutic option in IBS given their recognized safety and by virtue of positive biological effects they can exert on the host. Of importance for the IBS pathophysiology is that preclinical studies have shown that selective probiotic strains exhibit potentially useful properties including anti-inflammatory effects, improvement of mucosal barrier homeostasis, beneficial effects on intestinal microbiota, and a reduction of visceral hypersensitivity. The effect of probiotics on IBS is positive in most randomized, controlled studies, although the gain over the placebo is small. Identifying tailored probiotic approaches for subgroups of IBS patients represents a challenge for the future.
[show abstract][hide abstract] ABSTRACT: Diarrhea is defined as reduced stool consistency, increased water content and number of evacuations per day. A wide array of causes and pathophysiological mechanisms underlie acute and chronic forms of diarrhea. This review focuses on the major clinical aspects which should aid clinicians to diagnose chronic diarrhea. Clinical history, physical examination and stool evaluation and the predominant stool characteristic, i.e., bloody, watery, and fatty diarrhea, may narrow the differential diagnosis. Although mainly involved in acute diarrhea, many different infectious agents, including bacteria, viruses and protozoa, can be identified in chronic bloody/inflammatory diarrhea by appropriate microbiological tests and colonoscopic biopsy analysis. Osmotic diarrhea can be the result of malabsorption or maldigestion, with a subsequent passage of fat in the stool leading to steatorrhea. Secretory diarrhea is due to an increase of fluid secretion in the small bowel lumen, a mechanism often identified in gastroenteropancreatic neuroendocrine tumors. The evaluation of the fecal osmotic gap may help to characterize whether a chronic diarrhea is osmotic or secretory. Fatty diarrhea (steatorrhea) occurs if fecal fat output exceeds the absorptive/digestive capacity of the intestine. Steatorrhea results from malabsorption or maldigestion states and tests should differentiate between these two conditions. Individualized diagnostic work ups tailored on pathophysiological and clinical features are expected to reduce costs for patients with chronic diarrhea.
Internal and Emergency Medicine 10/2012; 7 Suppl 3:255-62. · 2.35 Impact Factor
[show abstract][hide abstract] ABSTRACT: Intestinal motor and sensory dysfunctions in traumatic complete or incomplete spinal cord injury (SCI) are frequent and result in altered mechanisms of defecation. The aim of this study is to investigate sigmoid compliance and perception in chronic SCI patients. Sigmoid responses to fixed-tension distentions were assessed using a tensostat in six patients (six men, 42 ± 4 years) with chronic complete transection of the spinal cord (high-SCI; five tetraplegic C5-C7 and one paraplegic T4-T6) and impaired evacuation (i.e. constipation). A group of 10 healthy individuals (six men, 25 ± 1 years) served as controls. SCI patients had higher sigmoid compliance at the highest distention level than the controls (10.3 ± 2.4 vs. 5.1 ± 0.8 ml/mmHg; P<0.05). Perception scores at first sensation were higher in SCI patients (2.3 ± 0.7 vs. 1.1 ± 0.1; P<0.05), but were not different at the highest distention levels (3.7 ± 0.8 vs. 3 ± 1; NS). The most commonly reported sensation by patients was distention/bloating and was referred less commonly to the hypogastrium compared with distention/bloating in controls. An increased sigmoid compliance can be detected in constipated SCI patients. The preservation of some degree of visceral sensations, although abnormally referred, could imply the occurrence of sensory input remodeling at the spinal level.
European journal of gastroenterology & hepatology 03/2012; 24(3):340-5. · 1.66 Impact Factor
[show abstract][hide abstract] ABSTRACT: CIPO is the very “tip of the iceberg” of functional gastrointestinal disorders, being a rare and frequently misdiagnosed condition characterized by an overall poor outcome. Diagnosis should be based on clinical features, natural history and radiologic findings. There is no cure for CIPO and management strategies include a wide array of nutritional, pharmacologic, and surgical options which are directed to minimize malnutrition, promote gut motility and reduce complications of stasis (ie, bacterial overgrowth). Pain may become so severe to necessitate major analgesic drugs. Underlying causes of secondary CIPO should be thoroughly investigated and, if detected, treated accordingly. Surgery should be indicated only in a highly selected, well characterized subset of patients, while isolated intestinal or multivisceral transplantation is a rescue therapy only in those patients with intestinal failure unsuitable for or unable to continue with TPN/HPN. Future perspectives in CIPO will be directed toward an accurate genomic/proteomic phenotying of these rare, challenging patients. Unveiling causative mechanisms of neuro-ICC-muscular abnormalities will pave the way for targeted therapeutic options for patients with CIPO.
Gastroenterology clinics of North America 12/2011; 40(4):787-807. · 2.56 Impact Factor
[show abstract][hide abstract] ABSTRACT: The potential relevance of systemic and gastrointestinal immune activation in the pathophysiology and symptom generation in the irritable bowel syndrome (IBS) is supported by a number of observations. Infectious gastroenteritis is the strongest risk factor for the development of IBS and increased rates of IBS-like symptoms have been detected in patients with inflammatory bowel disease in remission or in celiac disease patients on a gluten free diet. The number of T cells and mast cells in the small and large intestine of patients with IBS is increased in a large proportion of patients with IBS over healthy controls. Mediators released by immune cells and likely from other non-immune competent cells impact on the function of enteric and sensory afferent nerves as well as on epithelial tight junctions controlling mucosal barrier of recipient animals, isolated human gut tissues or cell culture systems. Antibodies against microbiota antigens (bacterial flagellin), and increased levels of cytokines have been detected systemically in the peripheral blood advocating the existence of abnormal host-microbial interactions and systemic immune responses. Nonetheless, there is wide overlap of data obtained in healthy controls; in addition, the subsets of patients showing immune activation have yet to be clearly identified. Gender, age, geographic differences, genetic predisposition, diet and differences in the intestinal microbiota likely play a role and further research has to be done to clarify their relevance as potential mechanisms in the described immune system dysregulation. Immune activation has stimulated interest for the potential identification of biomarkers useful for clinical and research purposes and the development of novel therapeutic approaches.
Journal of neurogastroenterology and motility 10/2011; 17(4):349-59.
[show abstract][hide abstract] ABSTRACT: Visceral hypersensitivity is currently considered a key pathophysiological mechanism involved in pain perception in large subgroups of patients with functional gastrointestinal disorders, including irritable bowel syndrome (IBS). In IBS, visceral hypersensitivity has been described in 20%-90% of patients. The contribution of the central nervous system and psychological factors to visceral hypersensitivity in patients with IBS may be significant, although still debated. Peripheral factors have gained increasing attention following the recognition that infectious enteritis may trigger the development of persistent IBS symptoms, and the identification of mucosal immune, neural, endocrine, microbiological, and intestinal permeability abnormalities. Growing evidence suggests that these factors play an important role in pain transmission from the periphery to the brain via sensory nerve pathways in large subsets of patients with IBS. In this review, we will report on recent data on mechanisms involved in visceral hypersensitivity in IBS, with particular attention paid to peripheral mechanisms.
Current Gastroenterology Reports 05/2011; 13(4):308-15.
[show abstract][hide abstract] ABSTRACT: OBJECTIVES: Serotonin (5-hydroxytryptamine, 5-HT) metabolism may be altered in gut disorders, including in the irritable bowel syndrome (IBS). We assessed in patients with IBS vs. healthy controls (HCs) the number of colonic 5-HT-positive cells; the amount of mucosal 5-HT release; their correlation with mast cell counts and mediator release, as well as IBS symptoms; and the effects of mucosal 5-HT on electrophysiological responses in vitro.
The American Journal of Gastroenterology 03/2011; 106(7):1290-1298. · 7.55 Impact Factor
[show abstract][hide abstract] ABSTRACT: Serotonin (5-hydroxytryptamine, 5-HT) metabolism may be altered in gut disorders, including in the irritable bowel syndrome (IBS). We assessed in patients with IBS vs. healthy controls (HCs) the number of colonic 5-HT-positive cells; the amount of mucosal 5-HT release; their correlation with mast cell counts and mediator release, as well as IBS symptoms; and the effects of mucosal 5-HT on electrophysiological responses in vitro.
We enrolled 25 Rome II IBS patients and 12 HCs. IBS symptom severity and frequency were graded 0-4. 5-HT-positive enterochromaffin cells and tryptase-positive mast cells were assessed with quantitative immunohistochemistry on colonic biopsies. Mucosal 5-HT and mast cell mediators were assessed by high-performance liquid chromatography or immunoenzymatic assay, respectively. The impact of mucosal 5-HT on electrophysiological activity of rat mesenteric afferent nerves was evaluated in vitro.
Compared with HCs, patients with IBS showed a significant increase in 5-HT-positive cell counts (0.37 ± 0.16% vs. 0.56 ± 0.26%; P=0.039), which was significantly greater in patients with diarrhea-predominant IBS vs. constipation-predominant IBS (P=0.035). Compared with HCs, 5-HT release in patients with IBS was 10-fold significantly increased (P < 0.001), irrespective of bowel habit, and was correlated with mast cell counts. A significant correlation was found between the mucosal 5-HT release and the severity of abdominal pain (r(s)=0.582, P=0.047). The area under the curve, but not peak sensory afferent discharge evoked by IBS samples in rat jejunum, was significantly inhibited by the 5-HT₃ receptor antagonist granisetron (P<0.005).
In patients with IBS, 5-HT spontaneous release was significantly increased irrespective of bowel habit and correlated with mast cell counts and the severity of abdominal pain. Our results suggest that increased 5-HT release contributes to development of abdominal pain in IBS, probably through mucosal immune activation.
The American Journal of Gastroenterology 03/2011; 106(7):1290-8. · 7.55 Impact Factor
[show abstract][hide abstract] ABSTRACT: Evidence suggests that mucosal and luminal factors, including low-grade immune activation, increased mucosal permeability and altered host-microbiota interactions, contribute to IBS pathophysiology. In this issue of the American Journal of Gastroenterology, Brint and colleagues provide the first evidence of increased expression of toll-like receptors (TLRs) in patients with IBS. TLRs are known to be involved in the translation of bacterial signals into anti-bacterial innate immune responses. These results hold promise for a better understanding of the role of microbiota and immune activation in the pathophysiology of IBS and also provide novel pharmacological targets for this common troublesome disorder.
The American Journal of Gastroenterology 02/2011; 106(2):337-9. · 7.55 Impact Factor
[show abstract][hide abstract] ABSTRACT: Intestinal microbiota is essential for gut homeostasis. Specifically, the microorganisms inhabiting the gut lumen interact with the intestinal immune system, supply key nutrients for the major components of the gut wall, and modulate energy metabolism. Host-microbiome interactions can be either beneficial or deleterious, driving gastrointestinal lymphoid tissue activities and shaping gut wall structures. This overview briefly focuses on the potential role played by abnormalities in gut microbiota and relative responses of the gastrointestinal tract in the determination of important pathological conditions such as the irritable bowel syndrome, inflammatory bowel diseases and colorectal cancer.
Internal and Emergency Medicine 10/2010; 5 Suppl 1:S57-63. · 2.35 Impact Factor
[show abstract][hide abstract] ABSTRACT: Infectious agents, such as neurotropic viruses, are proposed to disrupt the enteric neuromuscular system, leading to dysmotility, although the mechanisms are unknown. Our purpose was to assess whether herpes simplex virus type-1 (HSV-1) establishes an enteric-neuronal infection and induces gut dysmotility.
Rats were inoculated with HSV-1 intranasally and after 4 weeks intragastrically. After 1-10 weeks, infection was determined by molecular analysis whereas neuromuscular function was evaluated by pharmacologic/electrical stimulation of longitudinal ileal segments and by gastrointestinal transit and by [(3)H]acetylcholine release measurements. Inflammation in the neuromuscular layer was assessed by myeloperoxidase and cytokine levels and by anti-CD3(+) immunohistochemistry.
After 1-10 weeks of intragastric inoculation, HSV-1 latency-associated messenger RNA transcripts were detected in the brain and in ileal neurons with no signs of illness or histologic gut abnormalities. By using a recombinant HSV-1 carrying the lacZ gene, HSV-1 virions were localized in myenteric ganglia by in situ X-gal staining. Interleukin-2 and IFN-gamma levels were increased significantly 1 and 6 weeks after inoculation. CD3(+) cells were found around the myenteric ganglia 6 weeks after inoculation. Smooth muscle responses to carbachol, CaCl(2), and gut transit were increased significantly after 1 and 6 weeks, whereas KCl- and electrical field stimulation-mediated contractions were modified significantly only 1-2 weeks after HSV-1 administration. The release of [(3)H]acetylcholine was reduced significantly in ileum segments after 1 and 6 weeks.
After intragastric inoculation, HSV-1 establishes a latent infection in the rat myenteric ganglia, which leads to gut dysmotility.
[show abstract][hide abstract] ABSTRACT: Irritable bowel syndrome (IBS) is a functional disorder of multifactorial origin. Recent interest has been directed to the potential role of intestinal microbiota in the pathophysiology and symptom generation of this syndrome. This hypothesis is supported by the evidence of an infectious trigger in a proportion of patients, the identification of changes in bacterial composition and the detection of antibodies against flagellin, a component of indigenous flora, and by the potential therapeutic modulation of intestinal microbiota with probiotics and nonabsorbable antibiotics in IBS. The study by Lyra et al. assessed fecal microbiota in IBS patients and controls by applying a set of 14 quantitative real-time PCR assays targeting 16S ribosomal RNA gene phylotypes putatively associated with IBS, based on 16S ribosomal RNA gene library sequence analysis. In addition, microbiota composition was investigated over time by applying statistically advanced analyses at three timepoints during 6 months of follow-up. The authors showed that the intestinal flora of patients with diarrhea-predominant IBS diverged significantly not only from controls but also from the other IBS subgroups. The results by Lyra et al. further support the hypothesis that intestinal microbial flora has a role in IBS pathophysiology, and foster the idea that abnormal microbiota may act by triggering local and systemic immune responses linked to symptom generation. Further studies are now needed to clarify the key role of intestinal microbiota (as opposed to a secondary effect) in this common human disease.