PGE2 is a direct and robust mediator of anion/fluid secretion by human intestinal epithelial cells

Fujii, Satoru; Suzuki, Kohei; Kawamoto, Ami; Ishibashi, Fumiaki; Nakata, Toru; Murano, Tatsuro; Ito, Go; Shimizu, Hiromichi; Mizutani, Tomohiro; Tsuchiya, Kiichiro; Nakamura, Toshio; Araki, Akihiro; Ohtsuka, Kazuo; Okamoto, Ryuichi; Watanabe, Mamoru

doi:10.1038/srep36795

Cited by 37 publications

(37 citation statements)

References 57 publications

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“…Because mucus production has been shown to depend on fluid secretion in mouse small intestine 33,34 , we tested if this property of PGE2 was responsible for its ability to rapidly increase mucus height. PGE2-induced fluid secretion can be blocked by inhibiting ion channels 12 , and so we pretreated the human Colon Chip with a combination of 3 different ion channel inhibitors, CFTRinh-172, XE-991, and bumetanide, which are chemical inhibitors of the cystic fibrosis transmembrane conductance regulator (CFTR), KV7 (KCNQ) voltage-gated potassium channel, and NKCC1 Na-K-Cl cotransporter, respectively, before infusing PGE2. The combination of the 3 different ion channel inhibitors led to a significant reduction in the PGE2-induced increase in mucus height confirming the importance of ion transport in this hydration response (Figure 4E, Supplementary Figure 7).…”

Section: Modeling the Response Of Colonic Epithelium To Pge2 On-chipmentioning

confidence: 99%

Human colon-on-a-chip enables continuous in vitro analysis of colon mucus layer accumulation and physiology

Sontheimer-Phelps

Chou

Tovaglieri

et al. 2019

Preprint

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Background & AimsThe mucus layer in the human colon protects against commensal bacteria and pathogens, and defects in its unique bilayered structure contribute to intestinal disorders, such as ulcerative colitis. However, our understanding of colon physiology is limited by the lack of in vitro models that replicate human colonic mucus layer structure and function. Here, we investigated if combining organ-on-a-chip and organoid technologies can be leveraged to develop a human-relevant in vitro model of colon mucus physiology.MethodsA human colon-on-a-chip (Colon Chip) microfluidic device lined by primary patient-derived colonic epithelial cells was used to recapitulate mucus bilayer formation, and to visualize mucus accumulation in living cultures non-invasively.ResultsThe Colon Chip supports spontaneous goblet cell differentiation and accumulation of a mucus bilayer with impenetrable and penetrable layers, and a thickness similar to that observed in human colon, while maintaining a subpopulation of proliferative epithelial cells. Live imaging of the mucus layer formation on-chip revealed that stimulation of the colonic epithelium with prostaglandin E2, which is elevated during inflammation, causes rapid mucus volume expansion via an NKCC1 ion channel-dependent increase in its hydration state, but no increase in de novo mucus secretion.ConclusionThis study is the first to demonstrate production of colonic mucus with a physiologically relevant bilayer structure in vitro, which can be analyzed in real-time non-invasively. The Colon Chip may offer a new preclinical tool to analyze the role of mucus in human intestinal homeostasis as well as diseases, such as ulcerative colitis and cancer.

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Section: Modeling the Response Of Colonic Epithelium To Pge2 On-chipmentioning

confidence: 99%

Human colon-on-a-chip enables continuous in vitro analysis of colon mucus layer accumulation and physiology

Sontheimer-Phelps

Chou

Tovaglieri

et al. 2019

Preprint

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“…Prostaglandins (PGs) are important lipid mediators that regulate numerous physiological and pathophysiological processes in the gut (Fujii et al, ). During homeostasis, PGs have a protective role in the gastrointestinal (GI) mucosa and are critical to the maintenance of mucosal epithelial barrier integrity (Morteau, ).…”

Section: Introductionmentioning

confidence: 99%

“…Taken together, our data suggest that LbGG increases release of COX-2-mediated PGE 2 , contributing to the maintenance of mucosal homeostasis in the colon and CMFs are among the major contributors to this process. KEYWORDS lactic acid bacteria, mechanism of action, metabolic processes, microbial cell interaction, COX-2 1 | INTRODUCTION Prostaglandins (PGs) are important lipid mediators that regulate numerous physiological and pathophysiological processes in the gut (Fujii et al, 2016). During homeostasis, PGs have a protective role in the gastrointestinal (GI) mucosa and are critical to the maintenance of mucosal epithelial barrier integrity (Morteau, 2000).…”

mentioning

confidence: 99%

Lactobacillus rhamnosusGG increases cyclooxygenase-2 expression and prostaglandin E2 secretion in colonic myofibroblasts via a MyD88-dependent mechanism during homeostasis

Uribe

Villéger

Bressollier

et al. 2018

Cellular Microbiology

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Prostaglandin E2 (PGE ) plays a critical role in intestinal mucosal tolerance and barrier integrity. Cyclooxygenase-2 (COX-2)-dependent PGE production involves mobilisation of arachidonic acid. Lactobacillus rhamnosus GG (LbGG) is one of the most widely used probiotics reported to colonise the colonic mucosa. LbGG contributes to the protection of the small intestine against radiation injury through the repositioning of mucosal COX-2 expressing cells. However, it is unknown if LbGG modulates PGE production in the colonic mucosa under homeostasis and the major cellular elements involved in these processes. Colonic epithelial and CD90 mesenchymal stromal cells, also known as (myo) fibroblasts (CMFs), are abundant innate immune cells in normal colonic mucosa able to produce PGE . Herein, we tested the hypothesis that under colonic mucosal homeostasis, LbGG modulates the eicosanoid pathway resulting in increased PGE production in both epithelial and stromal cells. Among the five tested human colonic epithelial cell lines, only exposure of Caco-2 to LbGG for 24 hr led to the mobilisation of arachidonic acid with concomitant increase in the components within the leukotriene and COX-2-dependent PGE pathways. By contrast, CMFs isolated from the normal human colonic mucosa responded to LbGG with increased expression of COX-2 and PGE in the prostaglandin pathway, but not 5-LO in the leukotriene pathway. Oral gavage of C57BL/6 mice for 5 days with LbGG (5 × 10 Colony-Forming Unit (CFU)/dose) increased COX-2 expression in the colonic mucosa. The majority of cells upregulating COX-2 protein expression were located in the colonic lamina propria and colocalised with α-SMA cells corresponding to the CMF phenotype. This process was myeloid differentiation factor-88-dependent, because silencing of myeloid differentiation factor-88 expression in CMFs abrogated LbGG-induced upregulation of COX-2 in culture and in vivo. Taken together, our data suggest that LbGG increases release of COX-2-mediated PGE , contributing to the maintenance of mucosal homeostasis in the colon and CMFs are among the major contributors to this process.

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“…The electrolyte disturbances can be explained on a cellular and molecular level. Cl -secretion through the Cl -channel at the apical membrane of the colonic epithelium can be stimulated by elevated levels of cAMP [14][15][16][17]. Elevated Cl -secretion will in turn stimulate intraluminal loss of sodium (Na + ) since the increased Cl -efflux creates a more lumen negative transepithelial voltage, which promotes paracellular secretion of Na + and water [14,15].…”

Section: Pathophysiologymentioning

confidence: 99%

Chronic Diarrhea with Renal Insufficiency and Electrolyte Disturbances due to a Large Rectal Polyp

Bulcke¹

2017

GHOA

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Large villous adenomas in the distal colon can cause chronic secretory diarrhea evolving to severe electrolyte depletion, hypovolemia and renal insufficiency. This rare clinical presentation is known as the McKittrick-Wheelock syndrome (MWS) and can lead to death if not treated adequately. The main pathophysiological mechanisms in the development of MWS are the increased mucus production by the polyp, cyclic adenosine monophosphate (cAMP) mediated potassium (K+), chloride (Cl-) and sodium (Na+) loss and the insufficient colon reabsorption capacity as a result of the distal location of the polyp in the colon. We report a 74 year old woman with the McKittrick-Wheelock syndrome and review previously published reports to get a deeper insight into the pathophysiological mechanisms.

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PGE2 is a direct and robust mediator of anion/fluid secretion by human intestinal epithelial cells

Cited by 37 publications

References 57 publications

Human colon-on-a-chip enables continuous in vitro analysis of colon mucus layer accumulation and physiology

Human colon-on-a-chip enables continuous in vitro analysis of colon mucus layer accumulation and physiology

Lactobacillus rhamnosusGG increases cyclooxygenase-2 expression and prostaglandin E2 secretion in colonic myofibroblasts via a MyD88-dependent mechanism during homeostasis

Chronic Diarrhea with Renal Insufficiency and Electrolyte Disturbances due to a Large Rectal Polyp

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