Gastroesophageal reflux disease (GERD) is characterized by regurgitation of gastric juices into the esophagus. This has an erosive effect on the mucosa with accompanying symptoms, such as heartburn, acid regurgitation and positional-/exertion–induced chest pain. The associated inflammation in the multi-layered squamous epithelium of the esophagus (esophagitis) can usually be seen macroscopically at gastroscopy and is always possible to demonstrate microscopically as well-characterized changes. GERD is abundant in the adult population in the Western world, and the incidence appears to be increasing. Serious manifestations of GERD include the appearance of esophageal injury (esophagitis) and columnar lined esophagus (Barrett’s esophagus) and, in rare cases, peptic stricture. The glandular-transformed (metaplastic) mucosa carries its clinical significance by constituting the basis for continued cell transformation (development of dysplasia), which eventually might lead to esophageal adenocarcinoma (EAC). EAC is an aggressive form of cancer whose incidence continues to increase in particular in the Western part of the world. In this article the potential mechanisms for the development of the metaplastic glandular epithelium and its progression to dysplasia and cancer is reviewed. In addition, recommendations are given on how important signals about future risks can be captured and managed and how these risks can be minimized and preferably prevented.

Gastroesofageal refluxsjukdom (GERD) karakteriseras av en ökad mängd magsaft som regurgiterar till esofagus och har en frätande effekt på slemhinnan med symtom som halsbränna, sura uppstötningar och lägesberoende/ansträngningsutlöst bröstsmärta. Den tillhörande inflammationen i matstrupens flerskiktade skiv epitel (esofagit) kan oftast, men inte alltid, ses makroskopiskt vid gastroskopi, men påvisas mikro skopiskt i form av karakteristiska förändringar [1]. GERD är vanlig hos den vuxna befolkningen i västvärlden, och incidensen tycks öka. Detta innebär att många individer lider av hög symtombörda och nedsatt livskvalitet, vilket kan kopplas till betydande kostnader och socio ekonomiska konsekvenser [2-6]. En tydlig och allvarlig manifestation av GERD är uppkomsten av esofageal skada i form av esofagit och körtelomvandlad slemhinna (metaplasi) och/eller peptisk striktur (i dag mycket ovanligt). Den körtelomvandlade slemhinnan, som ursprungligen alltid kallades Barretts esofagus, får stor klinisk betydelse när intestinal metaplasi uppstår. Detta ger förutsättningar för fortsatt cellomvandling (dysplasiutveckling), som i förlängningen kan leda till körtelcancer (adenokarcinom) i esofagus (EAC). EAC är en aggressiv form av cancer vars incidens ökar i vår del av världen [2, 7-9]. Denna artikel beskriver uppkomsten av det metaplastiska körtelepitelet och dess progress till dysplasi och cancer samt ger rekommendationer om hur viktiga signaler om framtida risker kan fångas upp, hanteras och förebyggas.

Irritable bowel syndrome (IBS) is a chronic pain disorder characterized by disturbed interactions between the gut and the brain with depression as a common comorbidity. In both IBS and depression, structural brain alterations of the insular cortices, key structures for pain processing and interoception, have been demonstrated but the specificity of these findings remains unclear. We compared the gray matter volume (GMV) of insular cortex (IC) subregions in IBS women and healthy controls (HC) and examined relations to gastrointestinal (GI) symptoms and glutamate + glutamine (Glx) concentrations. We further analyzed GMV of IC subregions in women with major depression (MDD) compared to HC and addressed possible differences between depression, IBS, IBS with depression and HC.

Irritable bowel syndrome (IBS) is a symptom-based disorder of gut-brain interactions generating abdominal pain. It is also associated with a vulnerability to develop extraintestinal symptoms, with fatigue often reported as one of the most disturbing. Fatigue is related to brain function and inflammation in several disorders, however, the mechanisms of such relations in IBS remain elusive. This study aimed to elucidate fatigue and its association with a resting state network of mesocorticolimbic regions of known importance in fatigue, and to explore the possible role of circulating TNF-α levels in IBS and healthy controls (HC). Resting state functional magnetic resonance imaging (fMRI) was conducted in 88 IBS patients and 47 HC of similar age and gender to investigate functional connectivity between mesocorticolimbic regions. Further, fatigue impact on daily life and plasma levels of the proinflammatory cytokine tumor necrosis factor-α (TNF-α), of known relevance to immune activation in IBS, were also measured. The selected mesocorticolimbic regions indeed formed a functionally connected network in all participants. The nucleus accumbens (NAc), in particular, exhibited functional connectivity to all other regions of interest. In IBS, fatigue impact on daily life was negatively correlated with the connectivity between NAc and dorsolateral prefrontal cortex bilaterally (left p = 0.019; right p = 0.038, corrected for multiple comparisons), while in HC, fatigue impact on daily life was positively correlated to the connectivity between the right NAc and anterior middle insula in both hemispheres (left p = 0.009; right p = 0.011). We found significantly higher levels of TNF-α in IBS patients compared to HC (p = 0.001) as well as a positive correlation between TNF-α and fatigue impact on daily life in IBS patients (rho = 0.25, p = 0.02) but not in HC (rho = −0.13, p = 0.37). There was no association between functional connectivity in the mesocorticolimbic network and plasma levels of TNF-α in either group In summary, this novel multimodal study provides the first evidence that the vulnerability to fatigue in IBS is associated with connectivity within a mesocorticolimbic network as well as immune activation. These findings warrant further investigation, both peripherally and potentially with measurements of central immune activation as well.

Background

Barrier dysfunction is recognized as a pathogenic factor in ulcerative colitis (UC) and irritable bowel syndrome (IBS), but it is unclear to what extent the factors related to barrier dysfunction are disease-specific. The aim of this study was to compare these aspects in UC patients in remission, IBS patients, and healthy controls (HCs).

Methods

Colonic biopsies were collected from 13 patients with UC in remission, 15 patients with IBS-mixed, and 15 HCs. Ulcerative colitis patients had recently been treated for relapse, and biopsies were taken from earlier inflamed areas. Biopsies were mounted in Ussing chambers for measurements of intestinal paracellular permeability to 51chromium (Cr)-ethylenediaminetetraacetic acid (EDTA). In addition, biopsies were analyzed for mast cells and eosinophils by histological procedures, and plasma tumor necrosis factor (TNF)-α was assessed by ELISA.

Results

Ussing chamber experiments revealed an increased 51Cr-EDTA permeability in UC and IBS (P < 0.05). The 51Cr-EDTA permeability was higher in UC compared with IBS (P < 0.005). There were increased numbers of mucosal mast cells and eosinophils in UC and IBS and more eosinophils in UC compared with IBS (P < 0.05). Also, increased extracellular granule content was found in UC compared with HCs (P < 0.05). The 51Cr-EDTA permeability correlated significantly with eosinophils in all groups. Plasma TNF-α concentration was higher in UC compared with IBS and HCs (P < 0.0005).

Conclusions

Results indicate a more permeable intestinal epithelium in inactive UC and IBS compared with HCs. Ulcerative colitis patients, even during remission, demonstrate a leakier barrier compared with IBS. Both eosinophil numbers and activation state might be involved in the increased barrier function seen in UC patients in remission.

Irritable bowel syndrome (IBS) is a chronic visceral pain disorder with female predominance, characterized by recurrent abdominal pain and disturbed bowel habits in the absence of an identifiable organic cause. This prevalent and debilitating disease, which accounts for a substantial economic and individual burden, lacks exact diagnostic tools and effective treatment, since its pathophysiology remains uncertain. The bidirectional and multilayered brain-gut axis is a well-established disease model, however, the interactions between central and peripheral mechanisms along the brain-gut axis remain incompletely understood. One of the welldescribed triggering factors, yet accounting for only a fraction of IBS prevalence, is bacterial gastroenteritis that affects mucosal barrier function. Altered gut microbiota composition as well as disturbed intestinal mucosal barrier function and its neuroimmune regulation have been reported in IBS, however, the impact of live bacteria, neither commensal nor pathogenic, on intestinal barrier has not been studied yet. Furthermore, abnormal central processing of visceral sensations and psychological factors such as maladaptive coping have previously been suggested as centrally-mediated pathophysiological mechanisms of importance in IBS. Brain imaging studies have demonstrated an imbalance in descending pain modulatory networks and alterations in brain regions associated with interoceptive awareness and pain processing and modulation, particularly in anterior insula (aINS), although biochemical changes putatively underlying these central alterations remain poorly understood. Most importantly, however, possible associations between these documented changes on central and peripheral levels, which may as complex interactions contribute to disease onset and chronification of symptoms, are widely unknown.

This thesis aimed to investigate the peripheral and central mechanisms in women with IBS compared to female healthy controls (HC) and to explore possible mutual associations between these mechanisms.

In Paper I, we studied paracellular permeability and passage of live bacteria, both commensal and pathogenic through colonic biopsies mounted in Ussing chambers. We explored the regulation of the mucosal barrier function by mast cells and the neuropeptide vasoactive intestinal polypeptide (VIP) as well as a correlation between mucosal permeability and gastrointestinal and psychological symptoms. We observed increased paracellular permeability and the passage of commensal and pathogenic live bacteria in patients with IBS compared with HC, which was diminished by blocking the VIP receptors as well as after stabilizing mast cells in both groups. Moreover, higher paracellular permeability was associated with less somatic and psychological symptoms in patients.

In Paper II, we aimed to determine the association between colonic mucosa paracellular permeability and structural and resting state functional brain connectivity. We demonstrated different patterns of associations between mucosa permeability and functional and structural brain connectivity in IBS patients compared to HC. Specifically, lower paracellular permeability in IBS, similar to the levels detected in HC, was associated with more severe IBS symptoms and increased functional and structural connectivity between intrinsic brain resting state network and descending pain modulation brain regions. Our findings further suggested that this association between mucosa permeability and functional brain connectivity was mainly mediated by coping strategies.

In Paper III, we investigated putative alterations in excitatory and inhibitory neurotransmission of aINS, as the brain’s key node of the salience network crucially involved in cognitive control, in IBS patients relative to HC and addressed possible connections with both symptoms and psychological factors. We found decreased concentrations of the excitatory neurotransmitter Glx in bilateral aINS in IBS patients compared to HC, while inhibitory neurotransmitter GABA+ levels were comparable. Further, we demonstrated hemisphere-specific associations between abdominal pain, coping and aINS excitatory neurotransmitter concentration.

In conclusion, this thesis broadens the knowledge on peripheral and central mechanisms in IBS and presents novel findings that bring together the ends of brain-gut axis. Our results depict association between mucosal permeability, IBS symptoms and functional and structural connectivity engaging brain regions involved in emotion and pain modulation as well as underlying neurotransmitter alterations.

Irritable bowel syndrome (IBS) is a visceral pain condition with psychological comorbidity. Brain imaging studies in IBS demonstratealtered function in anterior insula (aINS), a key hub for integration of interoceptive, affective, and cognitive processes. However,alterations in aINS excitatory and inhibitory neurotransmission as putative biochemical underpinnings of these functional changesremain elusive. Using quantitative magnetic resonance spectroscopy, we compared women with IBS and healthy women (healthycontrols [HC]) with respect to aINS glutamate 1 glutamine (Glx) and g-aminobutyric acid (GABA1) concentrations and addressedpossible associations with symptoms. Thirty-nine women with IBS and 21 HC underwent quantitative magnetic resonancespectroscopy of bilateral aINS to assess Glx and GABA1 concentrations. Questionnaire data from all participants and prospectivesymptom-diary data from patients were obtained for regression analyses of neurotransmitter concentrations with IBS-related andpsychological parameters. Concentrations of Glx were lower in IBS compared with HC (left aINS P , 0.05, right aINS P , 0.001),whereas no group differences were detected for GABA1concentrations. Lower right-lateralized Glx concentrations in patients weresubstantially predicted by longer pain duration, while less frequent use of adaptive pain‐coping predicted lower Glx in left aINS. Ourfindings provide first evidence for reduced excitatory but unaltered inhibitory neurotransmitter levels in aINS in IBS. The results alsoindicate a functional lateralization of aINS with a stronger involvement of the right hemisphere in perception of abdominal pain and ofthe left aINS in cognitive pain regulation. Our findings suggest that glutaminergic deficiency may play a role in pain processing in IBS.

Introduction

The Anterior Cingulate Cortex (ACC) is a key region of the central autonomic brain network. Irritable Bowel Syndrome (IBS) is characterized abdominal pain and bowel habit disturbances. Autonomic dysregulation has been reported in IBS as well as altered ACC activation in pregenual ACC during visceral stimulation 1 2. Glutamate is the major excitatory and Gamma-aminobutyric acid (GABA) the major inhibitory neurotransmitter in the brain.

Aim & Methods

We aimed to measure neurotransmitter concentration in the pregenual ACC, in stool consistency subgroups with IBS by using quantitative neurotransmitter Magnetic Resonance Spectroscopy (qMRS)Seven patients with IBS-mixed (6 women) and five patients with IBS -diarrhea (4 women) according to Rome 3 were included. Mean age was 34.2 years (SD 5.3) with no significant difference between subgroups.  Patients completed symptom severity score (IBS-SSS). Quantitative MRS was measured in a 3T MRI scanner. A water-suppressed MEGA-PRESS sequence (TR 2.0 s, TE 68 ms) was used with the editing pulses placed at 1.90 ppm (‘ON-dynamics’) and at 7.46 ppm (‘OFF-dynamics’) with a voxel (3x3x3 cm3) placed in the pACC. Each MEGA-PRESS measurement resulted in a sequence of 40 OFF- and ON-dynamics, where each was computed by 8 phase cycles. Directly after each water-suppressed MEGA-PRESS measurement, a shorter 2-dynamic unsuppressed water MEGA-PRESS measurement was performed within the same voxel, which was used to obtain the concentrations in physically well-defined units of [mM]. The GABA concentrations were computed by averaging the difference spectra obtained by subtracting each OFF-dynamic from subsequent ON-dynamic and using LCModel (Version 6.3) for the final quantification. The Glutamate concentrations were obtained by only averaging the OFF-dynamics, which were not affected by the editing pulses. Additionally, all dynamics were phase and frequency corrected prior to the averaging. For group comparison unpaired T-tests were used.

Results

Patients had moderate to severe symptoms with IBS-SSS of 367 (SD 79.7). There was no significant difference between IBS subgroups in terms of IBS-SSS. Mean pACC GABA concentration was 1.66 (SD 0.17) mM in IBS-M and 1.65 (SD 0.27) mM in IBS-D. There was no significant difference between groups (p=0.9). Mean pACC Glutamate concentration was 4.54 (0.35) mM in IBS-M and 5.13 (SD 0.64) mM in IBS-D. There was no significant difference between groups, although a trend with p=0.06 was observed.

Conclusion

Further qMRS data have to be collected in IBS patients as well as healthy controls to evaluate if IBS subgroups demonstrate alterations in pACC glutamate and GABA concentrations