A multi-modal approach addressing brain-gut-interaction in Irritable Bowel Syndrome
General, Cognitive and Mathematical Psychology
Human Cognitive and Systems Neuroscience
Final Report Abstract
Irritable Bowel Syndrome is a chronic and often debilitating disease, characterized by recurrent abdominal pain and disturbed bowel habits. Both, changes affecting the gastrointestinal (GI) tract as well as altered brain structure and function are commonly reported and the role of psychological factors is increasingly acknowledged in IBS. Inspired by the concept of IBS as a disorder of a bidirectional brain-gut communication, this research fellowship applied a multi-modal approach to elucidate central, psychological and peripheral changes and their interactions in the pathophysiology of IBS. Using magnetic resonance imaging, brain functional and structural connectivity were assessed in a large sample of patients with IBS (N=90) and matched healthy controls (HC; N=46), well-characterized based on physical examination, diagnostic criteria, symptom diaries and questionnaire data of disease-related and psychological dimensions. To address the first aim of the research fellowship, a subsample of patients and HC additionally underwent colonic biopsies in order to test whether increased epithelial permeability (EP) as a measure of intestinal barrier function was associated with higher symptom severity and alterations in functional and structural brain connectivity. Multi-modal results revealed patients exhibiting EP within a normal range to have higher severity of IBS, anxiety and depression symptoms and to more frequent use maladaptive pain coping strategies compared to patients with abnormally high EP, suggesting a differential involvement of modulatory mechanisms, likely on a central level. Within the brain, functional as well as structural connectivity involving regions of emotional processing and endogenous pain modulation, particularly amygdala and rostral ventromedial medulla (RVM), showed a positive correlation with EP in HC but were negatively associated with EP in IBS. Most pronounced alterations in structural and functional connectivity were observed in patients with no evidence of peripheral changes, suggesting this subgroup to have a compromised endogenous pain modulation system, which patients exhibiting intestinal barrier dysfunction appeared to more effectively engage. Our data are in support of both, top-down as well as bottom-up mechanisms to underlie GI symptoms and their regulation in IBS. The second aim was to elucidate a putative dysbalance of excitatory and inhibitory neurotransmission in key regions of emotional processing and modulation in IBS, which may underlie functional brain changes as well as emotional disturbances, both consistently observed in patients. Using quantitative magnetic resonance spectroscopy (qMRS) in two independent subsamples, concentrations of Glutamate+glutamine (Glx) and γ-Aminobutyric acid (GABA+) were assessed within rostral anterior cingulate cortex (rACC) and anterior insula (AI). Within rACC, GABA+ concentrations were significantly increased in IBS relative to controls, whereas Glx levels appeared unaltered. Changes in GABA+ were tightly and distinctly linked to anxiety symptoms in patients. Interestingly, most pronounced increases in rACC GABAergic neurotransmitter concentrations in IBS patients with high severity of anxiety were accompanied by decreased functional connectivity of this key hub of emotion regulation and pain modulation. These findings suggest dysregulated rACC inhibitory neurotransmission in IBS, which may be linked to frequently comorbid anxiety in patients with IBS. Analyses of AI neurotransmitter concentrations revealed reduced Glx, yet unaltered GABA+ concentrations in patients. Reductions in excitatory neurotransmitter levels in the right hemisphere were associated with higher IBS pain severity and somatization in patients, whereas left AI Glx concentrations were positively related to more frequent use of adaptive pain coping strategies. Our findings provide first evidence of disturbed AI excitatory neurotransmission in IBS and support a functional lateralization of AI on a biochemical level. Disturbed AI excitatory neurotransmission may play a key role in pain processing and its cognitive regulation in IBS. Ultimately, these findings provide substantial new insights in central alterations on a biochemical level and in disturbed brain-gut communication contributing to the complex pathophysiology of IBS.
Publications
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(2017). Brain functional connectivity is associated with visceral sensitivity in women with Irritable Bowel Syndrome. Neuroimage Clin.
Icenhour A, Witt, ST, Elsenbruch S, Lowén M, Engström M, Tillisch K, Myer EA, Walter S
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(2017). Vasoactive Intestinal Polypeptide and Mast Cells Regulate Increased Passage of Colonic Bacteria in Patients With Irritable Bowel Syndrome. Gastroenterology
Bednarska O, Walter SA, Casado-Bedmar M, Ström M, Salvo-Romero E, Vicario M, Mayer EA, Keita AV
