Altered FXR signalling is associated with bile acid dysmetabolism in short bowel syndrome-associated liver disease

Pereira‐Fantini, Prue M.; Lapthorne, Susan; Joyce, Susan A.; Dellios, Nicole L.; Wilson, Guineva; Fouhy, Fiona; Thomas, Sarah; Scurr, Michelle; Hill, Colin; Gahan, Cormac G. M.; Cotter, Paul D.; Fuller, Peter J.; Hardikar, Winita; Bines, Julie E

doi:10.1016/j.jhep.2014.06.025

Cited by 75 publications

(88 citation statements)

References 55 publications

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“…In a piglet model of SBS, altered gut microbial composition was correlated with intestinal and circulating bile acid signatures [12,13] . SBS resulted in reproducible and long-term alterations to the microbiota that included a relative reduction in the phylum Firmicutes, including 7α-dehydroxylating Clostridium species and Ruminococcus species with a known role in bile acid metabolism [12,13] .…”

Section: Short Bowel Syndromementioning

confidence: 99%

“…SBS resulted in reproducible and long-term alterations to the microbiota that included a relative reduction in the phylum Firmicutes, including 7α-dehydroxylating Clostridium species and Ruminococcus species with a known role in bile acid metabolism [12,13] . This correlates with reductions in secondary and tertiary bile acid profiles in animals with SBS.…”

Section: Short Bowel Syndromementioning

confidence: 99%

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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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Section: Short Bowel Syndromementioning

confidence: 99%

Section: Short Bowel Syndromementioning

confidence: 99%

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

Joyce

Gahan²

2017

Dig Dis

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“…From a more general point of view, it is also tempting to speculate that alterations of the enterohepatic FGF19 signaling axis could contribute to the pathophysiology of some other liverspecific complications (e.g., gallstone formation, primary sclerosing cholangitis or NAFLD) that are frequently associated with IBD [90][91][92]. Recent studies also started to elucidate the potential role of the BA-FXR-FGF19 axis for other enterohepatic co-morbidities (i.e., short bowel syndrome/intestinal-failure associated liver disease), suggesting that the impact of FGF19 on liver health might be very broad even beyond IBD [93,94].…”

Section: Inflammatory Bowel Diseasementioning

confidence: 99%

Mechanisms of enterohepatic fibroblast growth factor 15/19 signaling in health and disease

Jahn

Rau

Hermanns

et al. 2015

Cytokine & Growth Factor Reviews

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“…Extensive small intestinal resection alone in pigs without simultaneous PN causes histologic liver fibrosis and steatosis together with increased hepatic expression of proinflammatory cytokines in association with an altered intestinal microbiota, bile acid metabolism, and farnesoid receptor X (FRX) signaling. 12 In children with IF, loss of the distal small intestine (ileum) irrespective of PN delivery correlates closely with histologic liver fibrosis and decreased levels of circulating fibroblast growth factor (FGF) 19. 6 An impaired FXR-FGF 19 axis has the potential to promote liver injury via a multitude of mechanisms by interfering with the control of bile acid homeostasis, biliary secretion, lipid metabolism, and inflammation in the liver and by failing to prevent bacterial overgrowth and intestinal barrier dysfunction in the gut.…”

Section: Discussionmentioning

confidence: 99%

“…4,5 In accordance with experimental studies, PN-dependent children with IF display an overabundance of lipopolysaccharideproducing Proteobacteria in their intestinal microbiota in association with histologic liver injury, intestinal inflammation, and increased levels of serum proinflammatory cytokines. 11 Liver fibrosis is observed with increasing frequency after extensive distal small intestinal resection in children 6,8 and even without a history of PN administration in pigs, 12 supporting an essential role of disturbed intestinal homeostasis in the pathogenesis of IFALD.…”

mentioning

confidence: 97%

Features of liver tissue remodeling in intestinal failure during and after weaning off parenteral nutrition

Mutanen

Sorsa

Jalanko

et al. 2016

Surgery

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Background. Intestinal failure is associated frequently with liver injury, which persists after weaning off parenteral nutrition. We compared features of liver remodeling in intestinal failure during and after weaning off parenteral nutrition. Methods. Liver biopsies and serum samples were obtained from 25 intestinal failure patients at a median age of 9.7 years (interquartile range: 4.6-18) and from age-matched control patients. Seven patients had been receiving parenteral nutrition for 53 months (22-160), and 18 patients had been weaned off parenteral nutrition 6.3 years (2.4-17) earlier, after having received parenteral nutrition for 10 months (3.3-34). Expression of alpha-smooth muscle actin, collagen 1, proinflammatory cytokines, growth factors, and matrix metalloproteinases (MMPs) was measured.Results. Significant increases in immunohistochemical expression of alpha-smooth muscle actin and collagen 1 were observed predominantly in portal areas and were similar to increases seen in patients currently receiving parenteral nutrition and in patients weaned off parenteral nutrition. Gene and protein expressions of alpha-smooth muscle actin and collagen were interrelated. Gene expression of ACTA2, encoding alpha-smooth muscle actin, was increased only in patients who were receiving parenteral nutrition currently. Comparable upregulation of interleukin-1 (a and ß), epidermal growth factor, integrin-ß6, and MMP9 gene expression was observed in both patient groups, irrespective of whether they were receiving parenteral nutrition currently. Liver expression and serum levels of TIMP1 and MMP7 were increased only in the patients on parenteral nutrition currently but were not increased after weaning off parenteral nutrition. Conclusion. Intestinal failure is characterized by abnormal activation of hepatic myofibroblast and accumulation of collagen both during and after weaning off parenteral nutrition. Persistent transcriptional upregulation of proinflammatory and fibrogenic cytokines after weaning off parenteral nutrition suggests that factors other than parenteral nutrition may contribute to intestinal failureassociated liver disease. (Surgery 2016;160:632-42.)

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Altered FXR signalling is associated with bile acid dysmetabolism in short bowel syndrome-associated liver disease

Cited by 75 publications

References 55 publications

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

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

Mechanisms of enterohepatic fibroblast growth factor 15/19 signaling in health and disease

Features of liver tissue remodeling in intestinal failure during and after weaning off parenteral nutrition

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