The Gut-Brain Axis in Inflammatory Bowel Disease-Current and Future Perspectives

Abstract

The gut-brain axis is a bidirectional communication system driven by neural, hormonal, metabolic, immunological, and microbial signals. Signaling events from the gut can modulate brain function and recent evidence suggests that the gut-brain axis may play a pivotal role in linking gastrointestinal and neurological diseases. Accordingly, accumulating evidence has suggested a link between inflammatory bowel diseases (IBDs) and neurodegenerative, as well as neuroinflammatory diseases. In this context, clinical, epidemiological and experimental data have demonstrated that IBD predisposes a person to pathologies of the central nervous system (CNS). Likewise, a number of neurological disorders are associated with changes in the intestinal environment, which are indicative for disease-mediated gut-brain inter-organ communication. Although this axis was identified more than 20 years ago, the sequence of events and underlying molecular mechanisms are poorly defined. The emergence of precision medicine has uncovered the need to take into account non-intestinal symptoms in the context of IBD that could offer the opportunity to tailor therapies to individual patients. The aim of this review is to highlight recent findings supporting the clinical and biological link between the gut and brain, as well as its clinical significance for IBD as well as neurodegeneration and neuroinflammation. Finally, we focus on novel human-specific preclinical models that will help uncover disease mechanisms to better understand and modulate the function of this complex system.

Keywords: IBD; MS; PD; ex vivo organ models; gut-brain axis.

Figure 1

Impact of intestinal inflammation on gut–brain communication. The figure was generated with biorender.com (8 July 2021). Multiple pathways exist through which gut–brain communication can be modulated including neural, hormonal, metabolic, immunological, and microbial signals. Signaling events from the gut can modulate brain function, and recent evidence suggests that a dysregulated gut–brain axis plays a pivotal role in linking gastrointestinal and neurological diseases involving neuroinflammation as well as neurodegeneration. Cytokines released by the mucosal immune system in response to local inflammation or infection can be released in the periphery reaching the CNS via the bloodstream. Similarly, circulating gut-primed immune cells can cross the blood–brain barrier (BBB) and modulate immune responses in the CNS. In addition, bacterial metabolites, such as short-chain fatty acids (SCFAs) are neuroactive metabolites of dietary fibers that can further influence gut–brain communication and neuroinflammation. In addition to immune signals and microbial metabolites, signaling from the vagus and enteric nervous system affect gut mucosal and anatomically distant tissues such as the CNS. These peripheral signals promote neuroinflammation and neurodegeneration.