Potentiation of serotonin signaling leads to increased carbohydrate and lipid absorption in the murine small intestine

Park, Christine J.; Armenia, Sarah J.; Shaughnessy, Matthew P.; Greig, Chasen J.; Cowles, Robert A.

doi:10.1016/j.jpedsurg.2019.02.027

Cited by 11 publications

(13 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…When we compared morphometric and proliferative parameters of SERTKO animals to WT, we found significant increases in all measured parameters throughout all areas of the bowel. This is in agreement with previous findings from our laboratory, although our previous work did not find a difference in the proximal small bowel (Park et al ). While there are several potential explanations for this discrepancy between those findings and the current results, it is likely related to differences between study designs including the use of a larger age range, both sexes, and harvesting only 3 regions of bowel in the Park, et al study.…”

Section: Discussionsupporting

confidence: 94%

“…We chose D‐Ala‐Lys‐AMCA as a surrogate for peptide absorption as it is a dipeptide which has been shown to be a specific substrate of the PEPT1 transporter in the small intestine (Groneberg et al ). We now know from other experiments in our laboratory that, in the intact mouse, carbohydrate, and fat absorption are increased in the setting of enhanced serotonin signaling (Park et al ), and since we have shown differences in how the proximal and distal small intestine respond to serotonin, here we sought to evaluate glucose and protein absorption in isolated segments rather than the whole mouse. We analyzed absorption in the proximal, middle and distal small bowel, and while not all increases observed in the proximal regions met statistical significance, both substrates had significantly increased absorption in the distal small bowel.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Potentiated serotonin signaling in serotonin re‐uptake transporter knockout mice increases enterocyte mass and small intestinal absorptive function

2019

Self Cite

View full text Add to dashboard Cite

Genetic knockout of the serotonin reuptake transporter (SERT) potentiates serotonin signaling and increases crypt-cell proliferation, neuroplasticity, and mucosal surface area. However, it remains unknown whether these changes occur throughout the small intestine and whether they increase nutrient absorption. We hypothesized that serotonin-mediated mucosal growth would occur throughout the intestine and would increase enterocyte mass and absorptive function. Following institutional approval, intestinal segments spanning the bowel were harvested from 10 to 12 week-old SERT knockout (SERTKO) and wild-type (WT) C57Bl/6 mice. Histologic sections were used to measure villus height (VH), crypt depth (CD), and crypt proliferation index (CPI). Plasma citrulline was measured colorimetrically. Glucose and peptide absorption in isolated segments of small bowel were calculated using a previously described method for quantification after luminal instillation of substrate. At baseline, morphometric (VH/CD) and proliferative (CPI) parameters varied from jejunum to ileum. Enhanced 5-HT signaling significantly increased plasma citrulline levels and morphometric/proliferative parameters in all regions analyzed. Glucose absorption in WT mice varied throughout the small intestine, and SERTKO mice demonstrated significant increases in the middle and distal bowel. WT peptide absorption was similar throughout the small bowel, and SERTKO mice had significant increases in the proximal and distal bowel. Enhanced serotonin signaling results in increased morphometric and proliferative parameters throughout the small intestine, and results in increased enterocyte mass and intestinal absorptive function. These data further advance the concept that the serotonin system is an attractive therapeutic target for increasing functional intestinal mucosa.

show abstract

Section: Discussionsupporting

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Potentiated serotonin signaling in serotonin re‐uptake transporter knockout mice increases enterocyte mass and small intestinal absorptive function

2019

Self Cite

View full text Add to dashboard Cite

show abstract

“…When SERT is deleted, cells have to increase endogenous serotonin biosynthesis. It was shown that TPH expression is upregulated in the gut of SERTKO mice, while the absorption of carbohydrates, fats and peptides were also elevated [ 24 , 25 ], suggesting that SERT-KO mice have metabolic disorders that may promote tumorigenesis under the induction of carcinogenic factors.…”

Section: Discussionmentioning

confidence: 99%

Targeting SERT promotes tryptophan metabolism: mechanisms and implications in colon cancer treatment

Xiao

et al. 2021

J Exp Clin Cancer Res

View full text Add to dashboard Cite

Background Serotonin signaling has been associated with tumorigenesis and tumor progression. Targeting the serotonin transporter to block serotonin cellular uptake confers antineoplastic effects in various tumors, including colon cancer. However, the antineoplastic mechanism of serotonin transporter inhibition and serotonin metabolism alterations in the absence of serotonin transporter have not been elucidated, especially in colon cancer, which might limit anti-tumor effects associating with targeting serotonin transporter. Methods The promotion in the uptake and catabolism of extracellular tryptophan and targeting serotonin transporter was detected by using quantitative reverse-transcription polymerase chain reaction, western blotting and liquid chromatography tandem mass spectrometry. Western blotting Immunoprecipitation and immunofluorescence was utilized to research the serotonylation of mTOR by serotonin and serotonin transporter inhibition. The primary mouse model, homograft model and tissue microarry was used to explore the tryptophan pathway in colon cancer. The cell viability assay, western blotting, xenograft and primary colon cancer mouse model were used to identify whether the combination of sertraline and tryptophan restriction had a synergistic effect. Results Targeting serotonin transporter through genetic ablation or pharmacological inhibition in vitro and in vivo induced a compensatory effect by promoting the uptake and catabolism of extracellular tryptophan in colon cancer. Mechanistically, targeting serotonin transporter suppressed mTOR serotonylation, leading to mTOR inactivation and increased tryptophan uptake. In turn, this process promoted serotonin biosynthesis and oncogenic metabolite kynurenine production through enhanced tryptophan catabolism. Tryptophan deprivation, or blocking its uptake by using trametinib, a MEK inhibitor, can sensitize colon cancer to selective serotonin reuptake inhibitors. Conclusions The present study elucidated a novel feedback mechanism involved in the regulation of serotonin homeostasis and suggested innovative strategies for selective serotonin reuptake inhibitors-based treatment of colon cancer.

show abstract

“…5 Furthermore, the absorptive function of the intestine is enhanced in animals with potentiated serotonin signaling, correlating with the observed increase in mucosal surface area. [62][63][64] This change in absorptive capacity does not reflect an increased proportion of absorptive enterocytes in villi. The fact that the cellular composition of the epithelium is not altered in these animals suggests that cellular division is induced in stem cells at the base of the intestinal crypt, or in the adjacent undifferentiated transit-amplifying cells.…”

Section: Q17mentioning

confidence: 92%

Serotonin as a Mitogen in the Gastrointestinal Tract: Revisiting a Familiar Molecule in a New Role

Shah

Park

Shaughnessy

et al. 2021

Cellular and Molecular Gastroenterology and Hepatology

Self Cite

View full text Add to dashboard Cite

show abstract

Potentiation of serotonin signaling leads to increased carbohydrate and lipid absorption in the murine small intestine

Cited by 11 publications

References 35 publications

Potentiated serotonin signaling in serotonin re‐uptake transporter knockout mice increases enterocyte mass and small intestinal absorptive function

Potentiated serotonin signaling in serotonin re‐uptake transporter knockout mice increases enterocyte mass and small intestinal absorptive function

Targeting SERT promotes tryptophan metabolism: mechanisms and implications in colon cancer treatment

Serotonin as a Mitogen in the Gastrointestinal Tract: Revisiting a Familiar Molecule in a New Role

Contact Info

Product

Resources

About