Farnesoid X receptor enhances epithelial ACE2 expression and inhibits virally induced IL-6 secretion: implications for intestinal symptoms of SARS-CoV-2.

Intestinal inflammation and diarrhea are often associated with SARS-CoV-2 infection. The angiotensin converting enzyme 2 (ACE2) receptor plays a key role in SARS-CoV-2 pathogenesis, facilitating entry of the virus into epithelial cells, while also regulating mucosal inflammatory responses. Here, we investigated roles for the nuclear bile acid receptor farnesoid X receptor (FXR) in regulating ACE2 expression and virally mediated inflammatory responses in intestinal epithelia.

Pentacyclic triterpenes modulate farnesoid X receptor expression in colonic epithelial cells: Implications for colonic secretory function.

The nuclear bile acid receptor, farnesoid X receptor (FXR), is an important regulator of intestinal and metabolic function. Previous studies suggest that pentacyclic triterpenes (PCTs), a class of plant-derived bioactive phytochemical, can modulate FXR activity and may therefore offer therapeutic benefits. Here, we investigated the effects of a prototypical PCT, hederagenin (HG), on FXR expression, activity, and antisecretory actions in colonic epithelial cells.

Intestinal secretory mechanisms and diarrhea.

One of the primary functions of the intestinal epithelium is to transport fluid and electrolytes to and from the luminal contents. Under normal circumstances, absorptive and secretory processes are tightly regulated such that absorption predominates, thereby enabling conservation of the large volumes of water that pass through the intestine each day. However, in conditions of secretory diarrhea, this balance becomes dysregulated, so that fluid secretion, driven primarily by Cl secretion, overwhelms absorptive capacity, leading to increased loss of water in the stool.

Contributions of bile acids to gastrointestinal physiology as receptor agonists and modifiers of ion channels.

Bile acids (BAs) are known to be important regulators of intestinal motility and epithelial fluid and electrolyte transport. Over the past two decades, significant advances in identifying and characterizing the receptors, transporters, and ion channels targeted by BAs have led to exciting new insights into the molecular mechanisms involved in these processes. Our appreciation of BAs, their receptors, and BA-modulated ion channels as potential targets for the development of new approaches to treat intestinal motility and transport disorders is increasing.

Novel polyurethane based particulate formulations of infliximab reduce inflammation in DSS induced murine model of colitis - A preliminary study.

Our recent study showed that novel infliximab (INF) loaded polyesterurethane (INF-PU) and INF-PU-PEG particulate formulations reduced inflammation in an in-vitro epithelial inflammation model. In this study we investigated therapeutic potential of novel INF-PU and INF-PU-PEG particulate formulations to reduce inflammation in a dextran sodium sulfate (DSS) induced murine model of colitis. Severity of colitis was assessed by measurement of disease activity index (DAI) score, inflammatory markers (neutrophil infiltration, TNFα) and histological score.

Expression, regulation and function of Aquaporin-3 in colonic epithelial cells.

The human colon balances water and electrolyte absorption and secretion while also forming a barrier protecting the body from the entry of harmful components. Aquaporin-3 (AQP3) is a water, glycerol and HO transporting channel expressed in colonic epithelia. Although expression of colonic epithelial AQP3 is altered in several intestinal disorders, such as inflammatory bowel disease and irritable bowel syndrome, the regulation and specific roles of AQP3 remain to be fully defined.

Functional and Phylogenetic Diversity of BSH and PVA Enzymes.

Bile salt hydrolase (BSH) and penicillin V acylase (PVA) are related enzymes that are classified as choloylglycine hydrolases (CGH). BSH enzymes have attracted significant interest for their ability to modulate the composition of the bile acid pool, alter bile acid signaling events mediated by the host bile acid receptors FXR and TGR5 and influence cholesterol homeostasis in the host, while PVA enzymes have been widely utilised in an industrial capacity in the production of semi-synthetic antibiotics. The similarities between BSH and PVA enzymes suggest common evolution of these enzymes and shared mechanisms for substrate binding and catalysis.

The secondary bile acids, ursodeoxycholic acid and lithocholic acid, protect against intestinal inflammation by inhibition of epithelial apoptosis.

Increased epithelial permeability is a key feature of IBD pathogenesis and it has been proposed that agents which promote barrier function may be of therapeutic benefit. We have previously reported the secondary bile acid, ursodeoxycholic acid (UDCA), to be protective in a mouse model of colonic inflammation and that its bacterial metabolism is required for its beneficial effects. The current study aimed to compare the effects of UDCA, LCA, and a non-metabolizable analog of UDCA, 6-methyl-UDCA (6-MUDCA), on colonic barrier function and mucosal inflammation in a mouse model of colonic inflammation.

Ursodeoxycholic acid: a promising therapeutic target for inflammatory bowel diseases?

The secondary bile acid ursodeoxycholic acid (UDCA) has long been known to have medicinal properties. As the therapeutically active component of bear bile, it has been used for centuries in traditional Chinese medicine to treat a range of conditions, while manufactured UDCA has been used for decades in Western medicine to treat cholestatic liver diseases. The beneficial qualities of UDCA are thought to be due to its well-established cytoprotective and anti-inflammatory actions.

Guts and Gall: Bile Acids in Regulation of Intestinal Epithelial Function in Health and Disease.

Epithelial cells line the entire surface of the gastrointestinal tract and its accessory organs where they primarily function in transporting digestive enzymes, nutrients, electrolytes, and fluid to and from the luminal contents. At the same time, epithelial cells are responsible for forming a physical and biochemical barrier that prevents the entry into the body of harmful agents, such as bacteria and their toxins. Dysregulation of epithelial transport and barrier function is associated with the pathogenesis of a number of conditions throughout the intestine, such as inflammatory bowel disease, chronic diarrhea, pancreatitis, reflux esophagitis, and cancer.

The bile acids, deoxycholic acid and ursodeoxycholic acid, regulate colonic epithelial wound healing.

The intestinal epithelium constitutes an innate barrier which, upon injury, undergoes self-repair processes known as restitution. Although bile acids are known as important regulators of epithelial function in health and disease, their effects on wound healing processes are not yet clear. Here we set out to investigate the effects of the colonic bile acids, deoxycholic acid (DCA) and ursodeoxycholic acid (UDCA), on epithelial restitution.

Bile acids deoxycholic acid and ursodeoxycholic acid differentially regulate human β-defensin-1 and -2 secretion by colonic epithelial cells.

Bile acids and epithelial-derived human β-defensins (HβDs) are known to be important factors in the regulation of colonic mucosal barrier function and inflammation. We hypothesized that bile acids regulate colonic HβD expression and aimed to test this by investigating the effects of deoxycholic acid (DCA) and ursodeoxycholic acid on the expression and release of HβD1 and HβD2 from colonic epithelial cells and mucosal tissues. DCA (10-150 µM) stimulated the release of both HβD1 and HβD2 from epithelial cell monolayers and human colonic mucosal tissue In contrast, ursodeoxycholic acid (50-200 µM) inhibited both basal and DCA-induced defensin release.

Ursodeoxycholic acid and lithocholic acid exert anti-inflammatory actions in the colon.

Ursodeoxycholic acid and lithocholic acid exert anti-inflammatory actions in the colon. 312: G550-G558, 2017. First published March 30, 2017; doi:10.

The Farnesoid X Receptor: Good for BAD.

Diarrhea is a feature of several chronic intestinal disorders that are associated with increased delivery of bile acids into the colon. Although the prevalence of bile acid diarrhea is high, affecting approximately 1% of the adult population, current therapies often are unsatisfactory. By virtue of its capacity to inhibit colonic epithelial fluid secretion and to down-regulate hepatic bile acid synthesis through induction of the ileal fibroblast growth factor 19 release, the nuclear bile acid receptor, farnesoid X receptor, represents a promising target for the development of new therapeutic approaches.

Characterization of AQPs in Mouse, Rat, and Human Colon and Their Selective Regulation by Bile Acids.

In normal individuals, the epithelium of the colon absorbs 1.5-2 l of water a day to generate dehydrated feces. However, in the condition of bile acid malabsorption (BAM), an excess of bile acids in the colon results in diarrhea.

Ursodeoxycholic acid inhibits TNFα-induced IL-8 release from monocytes.

Monocytes are critical to the pathogenesis of inflammatory bowel disease (IBD) as they infiltrate the mucosa and release cytokines that drive the inflammatory response. Ursodeoxycholic acid (UDCA), a naturally occurring bile acid with anti-inflammatory actions, has been proposed as a potential new therapy for IBD. However, its effects on monocyte function are not yet known.

Bile acids stimulate chloride secretion through CFTR and calcium-activated Cl- channels in Calu-3 airway epithelial cells.

Bile acids resulting from the aspiration of gastroesophageal refluxate are often present in the lower airways of people with cystic fibrosis and other respiratory distress diseases. Surprisingly, there is little or no information on the modulation of airway epithelial ion transport by bile acids. The secretory effect of a variety of conjugated and unconjugated secondary bile acids was investigated in Calu-3 airway epithelial cells grown under an air-liquid interface and mounted in Ussing chambers.

Oxygen in the regulation of intestinal epithelial transport.

The transport of fluid, nutrients and electrolytes to and from the intestinal lumen is a primary function of epithelial cells. Normally, the intestine absorbs approximately 9 l of fluid and 1 kg of nutrients daily, driven by epithelial transport processes that consume large amounts of cellular energy and O2. The epithelium exists at the interface of the richly vascularised mucosa, and the anoxic luminal environment and this steep O2 gradient play a key role in determining the expression pattern of proteins involved in fluid, nutrient and electrolyte transport.

New highly toxic bile acids derived from deoxycholic acid, chenodeoxycholic acid and lithocholic acid.

We have prepared a new panel of 23 BA derivatives of DCA, chenodeoxycholic acid (CDCA) and lithocholic acid (LCA) in order to study the effect of dual substitution with 3-azido and 24-amidation, features individually associated with cytotoxicity in our previous work. The effect of the compounds on cell viability of HT-1080 and Caco-2 was studied using the 3-[4,5-dimethylthizol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay. Compounds with high potency towards reduction of cell viability were further studied using flow cytometry in order to understand the mechanism of cell death.

Farnesoid X receptor agonists attenuate colonic epithelial secretory function and prevent experimental diarrhoea in vivo.

Objective: Bile acids are important regulators of intestinal physiology, and the nuclear bile acid receptor, farnesoid X receptor (FXR), is emerging as a promising therapeutic target for several intestinal disorders. Here, we investigated a role for FXR in regulating intestinal fluid and electrolyte transport and the potential for FXR agonists in treating diarrhoeal diseases.

Design: Electrogenic ion transport was measured as changes in short-circuit current across voltage-clamped T84 cell monolayers or mouse tissues in Ussing chambers.

Ursodeoxycholic acid attenuates colonic epithelial secretory function.

Dihydroxy bile acids, such as chenodeoxycholic acid (CDCA), are well known to promote colonic fluid and electrolyte secretion, thereby causing diarrhoea associated with bile acid malabsorption. However, CDCA is rapidly metabolised by colonic bacteria to ursodeoxycholic acid (UDCA), the effects of which on epithelial transport are poorly characterised. Here, we investigated the role of UDCA in the regulation of colonic epithelial secretion.

Epidermal growth factor chronically upregulates Ca(2+)-dependent Cl(-) conductance and TMEM16A expression in intestinal epithelial cells.

Dysregulated epithelial fluid and electrolyte transport is a common feature of many intestinal disorders. However, molecular mechanisms that regulate epithelial transport processes are still poorly understood, thereby limiting development of new therapeutics. Previously, we showed that epidermal growth factor (EGF) chronically enhances intestinal epithelial secretory function.