Towards a systems view of IBS

Abstract

Despite an extensive body of reported information about peripheral and central mechanisms involved in the pathophysiology of IBS symptoms, no comprehensive disease model has emerged that would guide the development of novel, effective therapies. In this Review, we will first describe novel insights into some key components of brain-gut interactions, starting with the emerging findings of distinct functional and structural brain signatures of IBS. We will then point out emerging correlations between these brain networks and genomic, gastrointestinal, immune and gut-microbiome-related parameters. We will incorporate this new information, as well as the reported extensive literature on various peripheral mechanisms, into a systems-based disease model of IBS, and discuss the implications of such a model for improved understanding of the disorder, and for the development of more-effective treatment approaches in the future.

Figure 1

Brain–gut axis. Schematic of the brain–gut axis, including inputs from the gut microbiota, the ENS, the immune system and the external environment. The model includes both peripheral and central components, which are in bidirectional interactions. Bottom-up influences are shown on the right side, top-down influences on the left side of the graph. Abbreviations: ENS, enteric nervous system; HPA, hypothalamic–pituitary–adrenal; PBMC, peripheral blood mononuclear cell; SNS, sympathetic nervous system. Modified with permission from Nature Publishing Group © Irwin, M.R. & Cole, S.W. Nat. Rev. Immunol. 11, 625–632 (2011).

Figure 2

Brain networks contributing to IBS symptoms. Depicted are task-related brain networks that have been described in the literature and for which structural and functional alterations have been reported in patients wiht IBS. The box in the centre describes the clinical symptoms related to the network inputs. Outputs most relevant for IBS pathophysiology occur in the form of descending pain modulation and autonomic nervous system activity. Abbreviations: Amyg, amygdala; aINS, anterior insula; aMCC, anterior midcingulate cortex; BG, basal ganglia; dlPFC, dorsolateral prefrontal cortex; Hipp, hippocampus; Hypo, hypothalamus; LCC, locus coeruleus complex; M1, primary motor cortex; M2, supplementary motor cortex; mPFC, medial prefrontal cortex; NTS, solitary nucleus; OFC, orbitofrontal cortex; PAG, periaqueductal grey; pgACC, pregenual anterior cingulate cortex; pINS, posteria insula; PPC, posterior parietal cortex; sgACC, subgenual anterior cingulate cortex; Thal, thalamus; vlPFC, ventrolateral prefrontal cortex.

Figure 3

Cross-sectional integrated brain–gut model of IBS pathophysiology. Proposed model for involvement of brain–gut axis in the generation of cardinal IBS symptoms (chronic abdominal pain associated with altered bowel habits). Under normal circumstances, visceral and external signals are evaluated by the salience network, which generates brain outputs in terms of targeted ANS responses (regulating gastrointestinal and immune function) and descending pain modulatory activity (regulating pain sensitivity at the dorsal horn level). Target organ alterations (either peripherally or ANS stimulated) are signalled back to the brain via neural, endocrine or immune-related channels. These signals are processed within subregions of the INS, and depending on their subjective salience, are consciously perceived (associated with activation of anterior INS) as normal gut sensations, discomfort or pain. IBS symptoms can arise from several primary peripheral or central mechanisms, but once brain–gut interactions are altered, causality is difficult to determine. Abbreviations: Amyg, amygdala; ANS, autonomic nervous system; dACC, dorsal anterior cingulate cortex; dlPFC, dorsolateral prefrontal cortex; Hypo, hypothalamus; INS, insula; orbFC, orbitofrontal cortex; PAG, periaqueductal grey; rACC, rostral anterior cingulate cortex; RVM, rostral ventromedial medulla.

Figure 4

Longitudinal brain–gut model of IBS pathophysiology. The interaction between genetic and epigenetic influences result in central and peripheral gene expression profiles that underlie the shaping of brain-based and gut-based intermediate phenotypes. Epigenetic factors provide the input from environmental influences on the development of intermediate phenotypes. Brain and gut intermediate phenotypes interact bidirectionally to shape the clinical phenotype of IBS. Abbreviations: AM, amygdala; HF, hippocampal formation; OFC, orbitofrontal cortex; PFC, prefrontal cortex; sACC, subgenual anterior cingulate cortex.

Figure 5

Systems biological model of IBS. Schematic illustrating a systems biological view of components involved in the development of IBS at the cellular and molecular level. Systems-based interactions between central and peripheral components of the brain–gut axis can be studied at the level of the genome, epigenome, transcriptome, proteome, metabolome and brain connectome.