Biology subjects

Barrett, K. E.

Publications and source records attributed to Barrett, K. E..

3 recordsLinked to original sources

bioRxiv2021

The Effect of a Fennel Extract on the STAT Signaling and Intestinal Barrier Function

BackgroundFoeniculum vulgare, F. vulgare, commonly known as fennel, is believed to be one of the worlds oldest medicinal herbs and has been exploited by people for centuries as a nutritional aid for digestive disorders. In many southeast Asian countries it is ingested as an after-meal snack, mukhvas, due to its breath-freshening and digestive aid properties. F. vulgare is used in some countries, such as Iran, as a complementary and alternative treatment for inflammatory bowel disease (IBD). MethodsThis study investigated the effects of F. vulgare on the barrier function of the intestinal epithelium Signal Transducer and Activator of Transcription (STAT) pathway, which is active in inflammatory bowel disease. To study the protective effects of F. vulgare extract in vitro, monolayers derived from the T84 colonic cell line were challenged with interferon-gamma (IFN-{gamma}) and monitored with and without F. vulgare extract. To complement our in vitro studies, the dextran sodium sulfate induced murine colitis model was employed to ascertain whether the protective effect of F. vulgare extract can be recapitulated in vivo. ResultsF. vulgare extract was shown to exert a protective effect on TEER in both T84 and murine models and showed increases in tight junction-associated mRNA in T84 cell monolayers. Both models demonstrated significant decreases in phosphorylated STAT1 (pSTAT1), indicating reduced activation of the STAT pathway. Additionally, mice treated with F. vulgare showed significantly lower ulcer indices than control mice. ConclusionsWe conclude barrier function of the gastrointestinal tract is improved by F. vulgare, suggesting the potential utility of this agent as an alternative or adjunctive therapy in IBD.

pharmacology and toxicology↗

bioRxiv2020

Aberrant Epithelial Differentiation Contributes to Pathogenesis in a Murine Model of Congenital Tufting Enteropathy

Background & AimsCongenital Tufting Enteropathy (CTE) is an intractable diarrheal disease of infancy caused by mutation of Epithelial Cell Adhesion Molecule (EpCAM). The cellular and molecular basis of CTE pathology has been elusive. We hypothesized that the loss of EpCAM in CTE results in altered lineage differentiation and defects in absorptive enterocytes thereby contributing to CTE pathogenesis. MethodsIntestine from CTE mice was evaluated for specific markers by RT-qPCR, western blotting and immunostaining. Body weight, blood glucose and intestinal enzyme activity were also investigated. A CTE enteroid model was used to assess whether the decreased census of secretory cells could be rescued. ResultsCTE mice exhibited alterations in brush-border function, disaccharidase activity and glucose absorption, potentially contributing to nutrient malabsorption and impaired weight gain. Altered cell differentiation in CTE mice led to decreased secretory cells and increased numbers of absorptive cells, though the absorptive enterocytes lacked key features, causing brush border malfunction. Further, treatment with Notch signaling inhibitor, DAPT, increased the numbers of major secretory cell types in CTE enteroids (Graphical abstract 1). ConclusionsAlterations in intestinal epithelial cell differentiation in CTE mice favor an increase in absorptive cells at the expense of secretory cells. Although the proportion of absorptive enterocytes is increased, they lack key functional properties. We conclude that these effects underlie pathogenic features of CTE such as malabsorption and diarrhea, and ultimately the failure to thrive seen in patients. The ability of DAPT to reverse aberrant differentiation suggests a possible therapeutic strategy. SynopsisA murine model of Congenital Tufting Enteropathy exhibits altered intestinal cell differentiation, leading to increased absorptive and decreased secretory cells, which can be reversed with DAPT. Absorptive enterocytes in these mice are also dysfunctional, contributing to disease pathogenesis. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=196 SRC="FIGDIR/small/330522v2_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@6700d7org.highwire.dtl.DTLVardef@6855b9org.highwire.dtl.DTLVardef@1d41207org.highwire.dtl.DTLVardef@1eb9f05_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2019

Nod-like receptors are critical for gut-brain axis signaling

Gut-brain axis signaling is critical for maintaining health and homeostasis. Stressful life events can impact gut-brain signaling, leading to altered mood, cognition and intestinal dysfunction. Here we identify nucleotide binding oligomerization domain (Nod)-like receptors (NLR), Nod1 and Nod2, as novel regulators for gut-brain signaling. NLR are innate immune pattern recognition receptors expressed in the gut and brain, important in the regulation of gastrointestinal (GI) physiology. We found that mice deficient in both Nod1 and Nod2 (NodDKO) demonstrate signs of stress-induced anxiety, cognitive impairment and depression in the context of a hyperactive hypothalamic-pituitary-adrenal axis. These deficits were coupled with impairments in the serotonergic pathway in the brain, decreased hippocampal neurogenesis, and reduced neural activation. In addition, NodDKO mice had increased GI permeability and altered serotonin signaling in the gut following exposure to acute stress. Administration of the selective serotonin reuptake inhibitor, fluoxetine, abrogated behavioral impairments and restored serotonin signaling. We also identified that intestinal epithelial cell-specific deletion of Nod1 (VilCre+Nod1f/f), but not Nod2, increased susceptibility to stress-induced anxiety-like behavior and cognitive impairment following exposure to stress. Together these data suggest that intestinal epithelial NLR are novel modulators of gut-brain communication and may serve as potential novel therapeutic targets for the treatment of gut-brain disorders.

physiology↗