The neurobiology of irritable bowel syndrome

Abstract

Irritable bowel syndrome (IBS) is the most prevalent disorder of brain-gut interactions that affects between 5 and 10% of the general population worldwide. The current symptom criteria restrict the diagnosis to recurrent abdominal pain associated with altered bowel habits, but the majority of patients also report non-painful abdominal discomfort, associated psychiatric conditions (anxiety and depression), as well as other visceral and somatic pain-related symptoms. For decades, IBS was considered an intestinal motility disorder, and more recently a gut disorder. However, based on an extensive body of reported information about central, peripheral mechanisms and genetic factors involved in the pathophysiology of IBS symptoms, a comprehensive disease model of brain-gut-microbiome interactions has emerged, which can explain altered bowel habits, chronic abdominal pain, and psychiatric comorbidities. In this review, we will first describe novel insights into several key components of brain-gut microbiome interactions, starting with reported alterations in the gut connectome and enteric nervous system, and a list of distinct functional and structural brain signatures, and comparing them to the proposed brain alterations in anxiety disorders. We will then point out the emerging correlations between the brain networks with the genomic, gastrointestinal, immune, and gut microbiome-related parameters. We will incorporate this new information into a systems-based disease model of IBS. Finally, we will discuss the implications of such a model for the improved understanding of the disorder and the development of more effective treatment approaches in the future.

Fig. 1. The brain-gut-microbiome system.

The brain connectome, gut connectome and gut microbiome communicate in a bidirectional way. The response characteristics of the system are determined by vulnerability genes interacting with different influences from the exposome. The different loops use neural, endocrine, paracrine and immune signaling mechanisms. Perturbations (stressors) of the different nodes of the system (brain, gut, immune, microbiota) result in non-linear effects and alterations in response characteristics manifesting as psychiatric and/or gut symptoms. ANS autonomic nervous system, SNS sympathetic nervous system, PBMCs peripheral blood mononuclear cells, SCFAs short chain fatty acids, AhR aryl hydrocarbon receptor.

Fig. 2. Bidirectional interactions of the gut microbiome with the Enteric Nervous System, the enteroendocrine system, the gut-associated immune system, and the brain.

Alterations in these interactions can present as psychiatric and/or IBS symptoms. Modified with permission from [79].

Fig. 3. Programming of the brain and gut connectome based on shared vulnerability genes and environmental influences.

a Vulnerability genes and prenatal influences (including maternal health, nutrition, and stress level) on BGM system development. b the brain and gut transcriptome is influenced by mode of delivery, early adversity, and early nutrition, leading to the development of distinct intermediate brain gut phenotypes c which shape the adult response to influences from the exposome (diet, psychosocial stress).