Gut dysbiosis disrupts stem cell functions via NGF/TrkA signaling pathway in diarrhea-predominant irritable bowel syndrome

Project: Research project

Project Details

Description

Irritable Bowel Syndrome (IBS) is one of the most prevalent functional bowel disorders characterized by symptoms including abdominal pain, bloating, abdominal distention and bowel habit abnormalities. Altered gut microbiota, also known as gut dysbiosis, is associated with the pathogenesis of IBS. We previously reported that neonatal maternal separation (NMS) in rodents, a widely accepted experimental model of diarrhea- predominant IBS (IBS-D), induces gut dysbiosis characterized by the enrichment of bacteria producing saturated long-chain fatty acids. Modulation of gut dysbiosis by antibiotics effectively ameliorates bowel dysfunctions of NMS rats (Microbiome 2018). In our preliminary study, similar changes in dysbiotic pattern were observed in the fecal samples from IBS-D patients, suggesting that our observations on gut dysbiosis made in IBS-like animal model are clinically relevant. Despite the significant association between gut dysbiosis and functional gastrointestinal disorders, the mechanism by which gut dysbiosis leads to bowel dysfunctions remains unclear.

Recently, we reported increased expression of Nerve Growth Factor (NGF) and its specific receptor, tropomyosin kinase receptor A (TrkA), within intestinal mucosa of NMS mice. The aberrant activation of NGF/TrkA signaling in turn promotes the self- renewal of intestine stem cells and directs their differentiation into serotonin-producing enterochromaffin (EC) cells. The increased production of serotonin resulted from EC cell hyperplasia eventually triggers visceral hyperalgesia in NMS mice. More importantly, our study showed the significant upregulation of NGF in the sera from IBS-D patients and a positive correlation between NGF and serotonin. (Nature Communications, 2019). In the follow-up study, we found that pseudo germ-free rats colonized with fecal microbiota from IBS-like donors exhibit increased transcriptional expression of NGF and TrkA in colon tissues. These findings reveal the causal relationship between dysbiosis and aberrant activation of NGF/TrkA signaling in the pathogenesis of functional bowel disorders. Based on these findings, we hypothesize that gut dysbiosis resulted from NMS may induce the upregulation of NGF and trigger the colonic activation of NGF/TrkA signaling, thereby contributing to disrupted intestinal homeostasis by altering the self-renewal and differentiation of stem cells.

To address this hypothesis, we will investigate (1) whether dysbiosis triggers the aberrant activation of NGF/TrkA signaling in NMS mice; (2) whether gut dysbiosis contributes to altered stem cell functions of NMS mice and (3) whether dysbiosis- induced bowel dysfunctions in NMS mice is NGF/TrkA signaling-dependent. The information derived from this proposal will uncover the complete chain of events that link dysbiosis with the pathogenesis of functional bowel disorders, contributing to the development of new therapeutic strategies for the management of IBS.

StatusFinished
Effective start/end date1/01/2131/12/23

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