Category Archives: Basic Science

Targeting Intestinal Epithelial Serotonin for Treating Disorders of Gut-Brain Interaction and Mood

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Briefly noted: LY Hung et al. Gastroenterol 2025; 168: 754-768. Open Access! Intestinal Epithelial Serotonin as a Novel Target for Treating Disorders of Gut-Brain Interaction and Mood

This study used transgenic, surgical, and pharmacological approaches to study the effects of intestinal epithelial serotonin reuptake transporter or serotonin on mood and gastrointestinal function, as well as relevant communication pathways.

Key findings:

  • Serotonin reuptake transporter ablation targeted to the intestinal epithelium promoted anxiolytic and antidepressive-like effects without causing adverse effects on the gastrointestinal tract or brain; conversely, epithelial serotonin synthesis inhibition increased anxiety and depression-like behaviors. 
  • In utero SSRI exposure is a significant and specific risk factor for development of the DGBI, functional constipation, in the first year of life.

My take: While this lengthy article presents data mainly from mice studies, it further supports the likelihood that SSRI selective targeting of the gut epithelium may improve anxiety, depression and comorbid DGBI. Selective targeting of the GI tract would reduce adverse effects of these medications.

Related blog posts:

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A Path Forward for Microvillous Inclusion Disease?

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I Kaji et al. Gastroenterol 2020; 159: 1390-1405. Full free text: Lysophosphatidic Acid Increases Maturation of Brush Borders and SGLT1 Activity in MYO5B-deficient Mice, a Model of Microvillus Inclusion Disease

Key finding: Lysophosphatidic acid (LPA)partially restored the brush border height and the localization of SGLT1 and NHE3 in small intestine of MYO5B-knockout mice and enteroids. There are a number of high quality figures that illustrate these effects:

From Figure 1. Changes in  jejunal morphologies by MYO5B deletion and administration of LPA

Editorial, S Abtahi, JR Turner. Gastroenterol 2020; 159:1233-1235: Full free text: Exploiting Alternative Brush Border Trafficking Routes to Treat Microvillous Inclusion Disease

Background (from editorial):

  • Small bowel biopsies in MVID include enterocytes that have either sparse, blunted microvilli or lack microvilli completely. Large cytoplasmic inclusions with prominent luminal microvilli are, however, present along with increased numbers of subapical lysosomes and other small vesicles
  • Biochemically, brush border expression of the Na+-glucose cotransporter SGLT1 (Slc5a1), the N+-H+ exchanger NHE3 (Slc9a3), and aquaporin 7 are markedly decreased in patients with MVID
  • Myo5b knockout in mice induces histopathologic and clinical features of MVID, including villous blunting, growth failure, and increased stool water, that is, diarrhea
  • Previous studies have shown that NHE3 trafficking from the apical storage pool to the brush border could be triggered by lysophosphatidic acid (LPA)

Key points from editorial

  • Kaji et al treated adult Myo5bf/f x vil-CreERT2 mice with …oral or systemic LPA administration. Villous blunting, microvillous loss, and apical lysosomal expansion were substantially reversed after 4 days of systemic LPA treatment
  • Although the morphologic and physiologic responses induced by LPA are striking, the weight loss that began within 2 days of Myo5b knockout was not attenuated. Thus, despite being remarkably beneficial when assessed using laboratory assays, LPA has not yet been shown to be an effective therapeutic agent.

My take (borrowed from editorial): This study shows “there are multiple trafficking pathways to the brush border and that one of these can be exploited to overcome defects in another.”

More “Survivin” in Crohn’s disease

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Survivin is a member of the inhibitors of apoptosis family.  It helps regulate cell division and prevents cell death.  (Gastroenterology 2012; 143: 1017-26).  While survivin has been shown to be important in cancer, it appears to be important in inflammatory and autoimmune disorders.

In the referenced study, lamina propria T cells (LPT) were isolated from mucosal samples of patients with Crohn’s disease (CD), ulcerative colitis (UC), and controls.  Expression of survivin was assessed by immunohistochemistry, confocal microscopy, and immunoblotting.

LPTs from patients with Crohn’s disease had increased survivin levels; this was not seen in control patients or UC patients.  Furthermore, the investigators showed that the survivin (bound to heat shock protein) was resistant to proteasome degradation.

Implications of this study: 

Survivin may have crucial consequences for CD and other inflammatory/autoimmune diseases; cell proliferation and apoptosis alteration may be important in the pathogenesis of  in these disorders.