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.
Highlights
Inflammatory Bowel Diseases (IBDs) are prototypic immune-mediated inflammatory diseases (IMIDs) that affect the gastrointestinal (GI) tract and have a globally increasing prevalence and multifactorial etiology
It is currently believed that pain, including neuro-immune interactions in the inflamed gut, mediate an increase in intestinal permeability that leads to an aggravation of disease activity and that resolution of inflammation is associated with reduced abdominal pain [15,17]
The interaction of alterations in leucine-rich repeat kinase 2 (LRRK2) function and Crohn’s Disease (CD) mechanisms is still unknown, increasing evidence supports the fact that LRRK2 plays a role in mediating autophagy in Paneth cells, which would explain its strong association with CD because defects in Paneth cell autophagy have been described as hallmarks of this IBD prototype [52]
Summary
Inflammatory Bowel Diseases (IBDs) are prototypic immune-mediated inflammatory diseases (IMIDs) that affect the gastrointestinal (GI) tract and have a globally increasing prevalence and multifactorial etiology. The interaction of alterations in LRRK2 function and CD mechanisms is still unknown, increasing evidence supports the fact that LRRK2 plays a role in mediating autophagy in Paneth cells, which would explain its strong association with CD because defects in Paneth cell autophagy have been described as hallmarks of this IBD prototype [52] In line with this notion, preclinical studies using mice with a LRRK2 deficiency showed a specific impairment in the expression of antimicrobial peptides by Paneth cells [53]. Further systematic studies are needed to better delineate the genetics between IBD and MS
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