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

Mroz, Magdalena S.; Keating, Niamh; Ward, JB; Sarker, Rafiquel; Amu, Sylvie; Aviello, Gabriella; Donowitz, Mark; Fallon, Padraic G.; Keely, Stephen J.

doi:10.1136/gutjnl-2013-305088

Cited by 69 publications

(73 citation statements)

References 43 publications

(44 reference statements)

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“…Depending on their concentrations within the colonic lumen, BA can have, via FXR signaling, not only a prosecretory but also an anitsecretory effect (Keating et al, 2009). Intraluminal BA in moderate quantities can prevent fluid accumulation in the intestine by inhibition of the Na + channel and K + -ATPase expression (Mroz et al, 2013); expression of both transporters was described as decreased in UC colitis (Greig et al, 2004;Sullivan et al, 2009). Our studies in adolescent IBD reveal low ileal FGF-19 levels in CD and UC.…”

Section: Discussionmentioning

confidence: 94%

Inflammatory Bowel Disease Alters Intestinal Bile Acid Transporter Expression

et al. 2014

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The enterohepatic circulation of bile acids (BAs) critically depends on absorption of BA in the terminal ileum and colon, which can be affected by inflammatory bowel disease (IBD). Diarrhea in IBD is believed to result in part from BA malabsorption (BAM). We explored whether IBD alters mRNA expression of key intestinal BA transporters, BA detoxifying systems, and nuclear receptors that regulate BA transport and detoxification. Using real-time polymerase chain reaction, mucosal biopsy specimens from the terminal ileum in Crohn's disease (CD) patients and from the descending colon in ulcerative colitis (UC) patients were assessed for mRNA expression. Levels were compared with healthy controls. The main ileal BA uptake transporter, the apical sodium dependent bile acid transporter, was downregulated in active CD and UC and in CD in remission. Other significant changes such as repression of breast cancer-related protein and sulphotransferase 2A1 were seen only during active disease. In UC, pancolitis (but not exclusively left-sided colitis) was associated with altered expression of major BA transporters [multidrug resistance-associated protein 3 (MRP3), MRP4, multidrug resistance gene 1, organic solute transporter a/b] and nuclear receptors (pregnane X receptor, vitamin D receptor) in the descending colon. UC pancolitis leads to broad changes and CD ileitis to selective changes in intestinal BA transporter expression. Early medical manipulation of intestinal BA transporters may help prevent BAM.

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Section: Discussionmentioning

confidence: 94%

Inflammatory Bowel Disease Alters Intestinal Bile Acid Transporter Expression

et al. 2014

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“…Subsequent studies have shown that the antisecretory actions of DCA and CDCA are mimicked by the FXR agonists GW4064 and OCA 54 . Thus, activation of the FXR with either of these agonists led to a dose-dependent inhibition of subsequent Ca 2+ and adenosine 3′,5′-cyclic monophosphate–dependent Cl - secretory responses, both in cell culture and in ex vivo colonic tissues from mice.…”

Section: Bile Acids and Colonic Fluid And Electrolyte Transportmentioning

confidence: 99%

The Farnesoid X Receptor: Good for BAD

Keely

Walters

2016

Cellular and Molecular Gastroenterology and Hepatology

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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. Here, we review our current understanding of the pathophysiology of bile acid diarrhea and the current evidence supporting a role for farnesoid X receptor agonists in treatment of the disease.

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“…Bile acid diarrhea results from excessive bile acid synthesis in the liver, bile acid malabsorption and a reduction in engagement of the FGF-19-mediated feedback loop that normally controls bile acid synthesis [18] . In contrast, in healthy subjects, bile acids engage the FXR and TGR5 receptors to control electrolyte homeostasis and prevent excessive water loss through diarrhea [18,47] .…”

Section: Irritable Bowel Syndrome and Diarrheamentioning

confidence: 99%

Disease-Associated Changes in Bile Acid Profiles and Links to Altered Gut Microbiota

Joyce

Gahan²

2017

Dig Dis

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The gastrointestinal microbiota plays a central role in the host metabolism of bile acids through deconjugation and dehydroxylation reactions, which generate unconjugated free bile acids and secondary bile acids respectively. These microbially generated bile acids are particularly potent signalling molecules that interact with host bile acid receptors (including the farnesoid X receptor, vitamin D receptor and TGR5 receptor) to trigger cellular responses that play essential roles in host lipid metabolism, electrolyte transport and immune regulation. Perturbations of microbial populations in the gut can therefore profoundly alter bile acid profiles in the host to impact upon the digestive and signalling properties of bile acids in the human superorganism. A number of recent studies have clearly demonstrated the occurrence of microbial disturbances allied to alterations in host bile acid profiles that occur across a range of disease states. Intestinal diseases including irritable bowel syndrome, inflammatory bowel disease (IBD), short bowel syndrome and Clostridium difficile infection all exhibit concurrent alterations in the composition of the gut microbiota and changes to host bile acid profiles. Similarly, extraintestinal diseases and syndromes such as asthma and obesity may be linked to aberrant bile acid profiles in the host. Here, we focus upon recent studies that highlight the links between alterations to gut microbial communities and altered bile acid profiles across a range of diseases from asthma to IBD.

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

Abstract: These data reveal a novel antisecretory role for the FXR in colonic epithelial cells and suggest that FXR agonists have excellent potential for development as a new class of antidiarrheal drugs.

Cited by 69 publications

References 43 publications

Inflammatory Bowel Disease Alters Intestinal Bile Acid Transporter Expression

Inflammatory Bowel Disease Alters Intestinal Bile Acid Transporter Expression

The Farnesoid X Receptor: Good for BAD

Disease-Associated Changes in Bile Acid Profiles and Links to Altered Gut Microbiota

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