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Reduced excitatory neurotransmitter levels in anterior insulae are associated with abdominal pain in irritable bowel syndrome
Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Magtarmmedicinska kliniken.
Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV. Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Medicinska fakulteten. Institute of Medical Psychology and Behavioral Immunobiology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för radiologiska vetenskaper. Linköpings universitet, Medicinska fakulteten. Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV.ORCID-id: 0000-0002-7809-2481
Linköpings universitet, Medicinska fakulteten. Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV.
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2019 (Engelska)Ingår i: Pain, ISSN 0304-3959, E-ISSN 1872-6623, Vol. 160, nr 9, s. 2004-2012Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

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.

Ort, förlag, år, upplaga, sidor
Lippincott Williams & Wilkins, 2019. Vol. 160, nr 9, s. 2004-2012
Nyckelord [en]
Irritable bowel syndrome, Functional magnetic resonance imaging, Quantitative magnetic resonance spectroscopy, Insula, Visceral pain, Coping
Nationell ämneskategori
Radiologi och bildbehandling
Identifikatorer
URN: urn:nbn:se:liu:diva-160012DOI: 10.1097/j.pain.0000000000001589PubMedID: 31045748OAI: oai:DiVA.org:liu-160012DiVA, id: diva2:1347873
Tillgänglig från: 2019-09-02 Skapad: 2019-09-02 Senast uppdaterad: 2019-09-09Bibliografiskt granskad
Ingår i avhandling
1. Peripheral and Central Mechanisms in Irritable Bowel Syndrome: in search of links
Öppna denna publikation i ny flik eller fönster >>Peripheral and Central Mechanisms in Irritable Bowel Syndrome: in search of links
2019 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

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.

Ort, förlag, år, upplaga, sidor
Linköping: Linköping University Electronic Press, 2019. s. 95
Serie
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1678
Nationell ämneskategori
Neurovetenskaper Neurologi Gastroenterologi Kirurgi Klinisk vetenskap
Identifikatorer
urn:nbn:se:liu:diva-156669 (URN)10.3384/diss.diva-156669 (DOI)9789176850930 (ISBN)
Disputation
2019-06-05, Berzeliussalen, Campus US, Linköping, 09:00 (Engelska)
Opponent
Handledare
Tillgänglig från: 2019-05-07 Skapad: 2019-05-07 Senast uppdaterad: 2019-09-02Bibliografiskt granskad

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Avdelningen för Kirurgi, Ortopedi och OnkologiMedicinska fakultetenMagtarmmedicinska klinikenCentrum för medicinsk bildvetenskap och visualisering, CMIVInstitutionen för klinisk och experimentell medicinAvdelningen för radiologiska vetenskaperMedicinsk strålningsfysikAvdelningen för neuro- och inflammationsvetenskap
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