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Cremon C.,University of Bologna | Cremon C.,S. Orsola Malpighi University Hospital | Carini G.,University of Bologna | Wang B.,McMaster Brain Body Institute | And 9 more authors.
American Journal of Gastroenterology | Year: 2011

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. Methods: 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. Results: Compared with HCs, patients with IBS showed a significant increase in 5-HT-positive cell counts (0.370.16% vs. 0.560.26%; 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-HT 3 receptor antagonist granisetron (P<0.005). Conclusions: 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. © 2011 by the American College of Gastroenterology.

Alamilla J.,National Autonomous University of Mexico | Alamilla J.,McMaster University | Perez-Burgos A.,National Autonomous University of Mexico | Perez-Burgos A.,McMaster Brain Body Institute | And 2 more authors.
BioMed Research International | Year: 2014

The suprachiasmatic nuclei (SCN) constitute a circadian clock in mammals, where γ-amino-butyric acid (GABA) neurotransmission prevails and participates in different aspects of circadian regulation. Evidence suggests that GABA has an excitatory function in the SCN in addition to its typical inhibitory role. To examine this possibility further, we determined the equilibrium potential of GABAergic postsynaptic currents (EGABA) at different times of the day and in different regions of the SCN, using either perforated or whole cell patch clamp. Our results indicate that during the day most neurons in the dorsal SCN have an EGABA close to -30 mV while in the ventral SCN they have an EGABA close to -60 mV; this difference reverses during the night, in the dorsal SCN neurons have an EGABA of -60 mV and in the ventral SCN they have an EGABA of -30 mV. The depolarized equilibrium potential can be attributed to the activity of the Na(+)-K(+)-2Cl(-) (NKCC) cotransporter since the equilibrium potential becomes more negative following addition of the NKCC blocker bumetanide. Our results suggest an excitatory role for GABA in the SCN and further indicate both time (day versus night) and regional (dorsal versus ventral) modulation of E GABA in the SCN. © 2014 Javier Alamilla et al.

Mao Y.-K.,McMaster Brain Body Institute | Kasper D.L.,Harvard University | Wang B.,McMaster University | Forsythe P.,McMaster Brain Body Institute | And 5 more authors.
Nature Communications | Year: 2013

Symbionts or probiotics are known to affect the nervous system. To understand the mechanisms involved, it is important to measure sensory neuron responses and identify molecules responsible for this interaction. Here we test the effects of adding Lactobacillus rhamnosus (JB-1) and Bacteroides fragilis to the epithelium while making voltage recordings from intestinal primary afferent neurons. Sensory responses are recorded within 8 s of applying JB-1 and excitability facilitated within 15 min. Bacteroides fragilis produces similar results, as does its isolated, capsular exopolysaccharide, polysaccharide A. Lipopolysaccharide-free polysaccharide A completely mimics the neuronal effects of the parent organism. Experiments with a mutant Bacteroides fragilis devoid of polysaccharide A shows that polysaccharide A is necessary and sufficient for the neuronal effects. Complex carbohydrates have not been reported before as candidates for such signalling between symbionts and the host. These observations indicate new neuronal targets and invite further study of bacterial carbohydrates as inter-kingdom signalling molecules between beneficial bacteria and sensory neurons. © 2013 Macmillan Publishers Limited.

Wu R.Y.,McMaster Brain Body Institute | Pasyk M.,McMaster Brain Body Institute | Wang B.,McMaster University | Forsythe P.,McMaster Brain Body Institute | And 9 more authors.
Neurogastroenterology and Motility | Year: 2013

Background Commensal bacteria such as probiotics that are neuroactive acutely affect the amplitudes of intestinal migrating motor complexes (MMCs). What is lacking for an improved understanding of these motility effects are region specific measurements of velocity and frequency. We have combined intraluminal pressure recordings with spatiotemporal diameter maps to analyze more completely effects of different strains of beneficial bacteria on motility. Methods Intraluminal peak pressure (PPr) was measured and video recordings made of mouse ex vivo jejunum and colon segments before and after intraluminal applications of Lactobacillus rhamnosus (JB-1) or Lactobacillus reuteri (DSM 17938). Migrating motor complex frequency and velocity were calculated. Key Results JB-1 decreased jejunal frequencies by 56% and 34% in colon. Jejunal velocities increased 171%, but decreased 31% in colon. Jejunal PPr decreased by 55% and in colon by 21%. DSM 17938 increased jejunal frequencies 63% and in colon 75%; jejunal velocity decreased 57%, but increased in colon 146%; jejunal PPr was reduced 26% and 12% in colon. TRAM-34 decreased frequency by 71% and increased velocity 200% for jejunum, but increased frequency 46% and velocity 50% for colon; PPr was decreased 59% for jejunum and 39% for colon. Conclusions & Inferences The results show that probiotics and other beneficial bacteria have strain and region-specific actions on gut motility that can be successfully discriminated using spatiotemporal mapping of diameter changes. Effects are not necessarily the same in colon and jejunum. Further research is needed on the detailed effects of the strains on enteric neuron currents for each gut region. © 2013 Blackwell Publishing Ltd.

Forsythe P.,McMaster University | Forsythe P.,McMaster Brain Body Institute | Forsythe P.,Firestone Institute for Respiratory Health | Kunze W.,McMaster University | And 3 more authors.
BMC Medicine | Year: 2016

Introduction: The microbiota-gut-brain axis is a term that is commonly used and covers a broad set of functions and interactions between the gut microbiome, endocrine, immune and nervous systems and the brain. The field is not much more than a decade old and so large holes exist in our knowledge. Discussion: At first sight it appears gut microbes are largely responsible for the development, maturation and adult function of the enteric nervous system as well as the blood brain barrier, microglia and many aspects of the central nervous system structure and function. Given the state of the art in this exploding field and the hopes, as well as the skepticism, which have been engendered by its popular appeal, we explore recent examples of evidence in rodents and data derived from studies in humans, which offer insights as to pathways involved. Communication between gut and brain depends on both humoral and nervous connections. Since these are bi-directional and occur through complex communication pathways, it is perhaps not surprising that while striking observations have been reported, they have often either not yet been reproduced or their replication by others has not been successful. Conclusions: We offer critical and cautionary commentary on the available evidence, and identify gaps in our knowledge that need to be filled so as to achieve translation, where possible, into beneficial application in the clinical setting. © 2016 Forsythe et al.

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