Nutritional therapies targeting the neuronal AhR for functional bowel disorders and IBS in children


Irritable bowel syndrome (IBS) is the most common disorder of the gut-brain interactions diagnosed in gastroenterology in children and adults. In addition to the increased bowel reactions such as cramps and diarrhea, pain receptors seem to be more sensitive. IBS etiology is multifactorial and its physiopathology is complex, involving colonic hypersensitivity, epithelial dysfunction, low-grade mucosal inflammation, and changes in gut microbiota composition.

Gut microbiota alterations are considered a vital factor in IBS pathophysiology. Most research has focused primarily on bacterial intestinal communities. Recent study’s point towards sympathetic neurons in the supra-mesenteric ganglion are being modulated by the gut microbiota. Our results identify a gut-brain-gut circuit whereby distinct microbes and microbial metabolites modulate activation of gut sympathetic neurons and brainstem sensory nuclei capable of integrating gut-specific stimuli. Recently, influence of tryptophan metabolism, particularly kynurenine pathway metabolites on brain function and behavior impairments, including anxiety, depression as well as cognitive performance and visceral pain perception has been the focus of increasing investigations.

Gut microbiota plays an essential role in the catabolism of dietary tryptophan (Trp) into several metabolites, which modulate mucosal immunity and homeostasis, intestinal motility and neurobiological functions. Trp metabolism follows three pathways: the serotonin pathway in enterochromaffin cells, the kynurenine pathway in epithelial and immune cells, and the indole pathway in the gut microbiota. A wide range of bacterial species are able to produce indole including Lactobacillus, Clostridium, and Bacteroides spp. Indole derivatives are enabled to bind and activate aryl hydrocarbon receptor (AhR), inducing expression of downstream cytokines as interleukin-22 and thereby regulating the epithelial integrity and immunity. Recently, microbiota-induced expression of AhR in colonic neurons has been shown to be important in neuronal programming by microbiota to maintain gut motility and thus to regulate intestinal physiology. Earlier data is clearly indicative of an evident dysregulation in multiple pathways of Trp metabolism may be involved in IBS. Recent exciting data has arisen demonstrating a critical role for AhR activation in mediating enteric neuronal function in the gut wall.

Here, we aim to identify AhR-dependent signaling in intestinal neurons that drive IBS symptoms. With this grant, we aim to establish the role of nutrition in intestinal hypersensitivity and motility disturbances in pediatric IBS, leading to a better understanding of adult IBS as well. In particular, we are interested in 1) mapping Trp-metabolites that act as agonists for the nuclear receptor AhR and its downstream signaling pathway genes such as IL22 in pediatric IBS patients versus those that do not show IBS complaints, 2) identifying unique AhR-dependant signatures in intestinal neurons in relation to visceral pain and identify the neuronal subtype in the gut tissue, 3) establishing in neuronal cells AhR downstream genes through the use of ChIP seq profiling.

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