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A Breakthrough Research Regarding The Role Of Intestinal Serotonin Transporter (SERT) In Diarrheal Diseases Associated With Infections or Inflammation by Ravinder Gill

Caused by infectious agents, Diarrheal disease is amongst the leading cause of death in children under 5 years old, and continues to pose a serious health peril in infants. It accounts for killing 1.5 million infants every year. An effort made by Ravinder K. Gill*, in partnership with corresponding researchers to bring together the best discoveries and create novel efficacious drugs to treat diarrhea. The author with the perspective to prevent the deadly diarrheal disease and prolong life presided over a series of clinical research to discover new mechanisms underlying diarrhea. One of her breakthrough studies aimed at investigation on how a food-fetch bacterium, EPEC (enteropathogenic E. coli) modulates the intestinal serotonin transporter (SERT) to stimulate diarrhea. Intestinal serotonin transporter (SERT), implicated in modulation of luminal 5-HT (5-hydroxytryptamine, serotonin) presence, is a crucial component to target because of its involvement in various diarrheal disorders. Because of the involvement of SERT in the pathophysiology of gut disorders, the author asserts the consequences of these researches may assign a new and better insight into curative modalities for intestinal infections or diarrheal disorders.

Due to the lack of a known toxin, pathophysiology of EPEC-incited early diarrhea remained elusive for many years. In order to directly examine the direct effect EPEC infection inhibition on SERT activity, the author conducted fully distinguishing Caco-2 monolayers that were infected with kind of wild EPEC strain E2348/69. EPEC infection showed to decrease apical 5-HT uptake as early as 15 min, touching maximal inhibition at 30-60 min.

Realizing the actuality of the prevailing treatments of Diarrheal and other complex inflammatory bowel diseases that are restricted in results thus warranting improved aimed curative, author Ali Esmaili, Saad F Nazir and Megha Singhal brought to public notice about the mechanism(s) underlying EPEC linked diarrheal are multi-factorial and the potential of EPEC to block SERT in the intestinal epithelial cells through prompting of protein tyrosine phosphatases such as SHP2.

The evidence-based findings of the researcher implicate a significant decline in intestinal 5-HT transporter (SERT) and the subsequent high 5-HT levels in the pathophysiology of intestinal dysfunction. Thus, SERT stumbled upon as a hopeful appropriate for the treatment of gut disorders. Therefore, revealing the importance of regulation of SERT for long-term maintenance of normal 5-HT homeostasis in health and disease. Still so, Ravinder K. Gill* cautions the detailed characterization of SERT recycling and signaling pathways in Intestinal epithelial cells to be inadequate. Dr. Gill initiated novel subsequent studies to examine the roles of growth factors such as TGF-β1 in the regulation of SERT. Whether TGF-β1 affects SERT was unknown and thus warranted all-encompassing inspection. Still growth factors have lately materialized as prospective arbitration for treatment of intestinal inflammation and reconstruction in animal models and human subjects. For example, under physiological conditions, TGF-β1, specifically, effective in amending inflammatory responses aids in epithelial defense process, regulates extracellular matrix turnover, differentiation and function of immune and non-immune cells. In her seminal works, Dr. Gill and colleagues showed that TGF-β1 stimulates SERT function and demonstrated a crucial role of PI3K in TGF-β1 mediated acceleration of SERT activity, utilizing the doctrinal in vitro model epithelium, Caco-2 monolayers grown as monolayers and as spheres in 3 dimensions to mimic the native intestine.  PI3-kinases is known to regulates various signal transduction pathways including the protein PDK1, serine/threonine kinases Akt, adaptor proteins (GAB-1), protein tyrosine kinase exchange factors for GTP-binding proteins. 

Moreover, several studies rendered in-depth understanding into the roles of PI3-K, their catalytic products and their succeeding effectors in membrane trafficking. PI3-Kinases pathway can persuade cellular functions via AKT-dependent or AKT self-reliant mechanisms as no phosphorylation of AKT was realized in response to TGF-β1. The data collected further indicated that TGF-β1 raise the recruitment of SERT on the apical plasma membrane and given mechanistic connection that PI3K is fundamental for this apical recruitment. The rise in surface expression of SERT taking place because of elevated exocytic retrieval of SERT by TGF-β1 confirms the role of PI3K in regulated exocytosis.

Another striking recent finding from Ravinder Gill’s laboratory provides a novel mechanism by which serotonin can activate a nuclear receptor, Aryl hydrocarbon receptor (AhR). This study led by a graduate student, Christopher Manzella utilizing transgenic mouse models and in vitro cells showed that serotonin via SERT leads to activation of AhR, subsequently causing induction of the cytochrome P450, family 1 enzymes CYP1A1, which are involved in the metabolism of polycyclic aromatic hydrocarbons and other xenobiotics in the intestine.  AhR is a receptor for environmental components such as combustion products in cigarette smoke and bacterial products. AhR has gained recent attention as an attractive target for the treatment of intestinal disorders such as inflammatory bowel disease (IBD). Interestingly, microarray analysis of intestines of mice lacking the transporter, (SERT KO mice) revealed that multiple AhR responsive genes in addition to Cyp1a1 were downregulated, including anti-microbial chemokine Ccl20 and the growth factor Areg. In addition, genes associated with Crohn’s disease susceptibility such as TNFSF15 and CLDN8 (claudin) were altered in SERT KO mice. This analysis directly links SERT deficiency to the pathophysiology of intestinal inflammatory disorders. These studies hold the potential of unfolding a novel link by which serotonergic signaling can influence the contribution of the environmental agents to pathogenesis of various gut disorders including IBD.

Accumulating the outcomes derived out of the research indicates modulation of SERT/AhR axis may aid in the development of an original new pharmacotherapy to modulate the serotonergic mechanism in treatment of gut disorders such as infectious diarrheal diseases and inflammatory bowel diseases.

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