Crosstalk between Bile Acids and Gut Microbiota and Its Impact on Farnesoid X Receptor Signalling

2017 ◽  
Vol 35 (3) ◽  
pp. 246-250 ◽  
Author(s):  
Annika Wahlström ◽  
Petia Kovatcheva-Datchary ◽  
Marcus Ståhlman ◽  
Fredrik Bäckhed ◽  
Hanns-Ulrich Marschall
Keyword(s):  
Bile Acid ◽  
Gut Microbiota ◽  
Bile Acids ◽  
Mouse Models ◽  
Acid Composition ◽  
Farnesoid X Receptor ◽  
Special Importance ◽  
Human Gut ◽  
Substantial Impact ◽  
Human Gut Microbiota

Background: The gut microbiota has a substantial impact on health and disease. The human gut microbiota influences the development and progression of metabolic diseases; however, the underlying mechanisms are not fully understood. The nuclear farnesoid X receptor (FXR), which regulates bile acid homeostasis and glucose and lipid metabolism, is activated by primary human and murine bile acids, chenodeoxycholic acid and cholic acid, while rodent specific primary bile acids tauromuricholic acids antagonise FXR activation. The gut microbiota deconjugates and subsequently metabolises primary bile acids into secondary bile acids in the gut and thereby changes FXR activation and signalling. Key Message: Mouse models have been used to study the crosstalk between bile acids and the gut microbiota, but the substantial differences in bile acid composition between humans and mice need to be considered when interpreting data from such studies and for the development of so-called humanised mouse models. Conclusion: It is of special importance to elucidate how a human gut microbiota influences bile acid composition and FXR signalling in colonised mice.

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

2017 ◽  
Vol 35 (3) ◽  
pp. 169-177 ◽  
Author(s):  
Susan A. Joyce ◽  
Cormac G.M. Gahan
Keyword(s):  
Bile Acid ◽  
Gut Microbiota ◽  
Bile Acids ◽  
Farnesoid X Receptor ◽  
Gastrointestinal Microbiota ◽  
Signalling Molecules ◽  
Disease States ◽  
Irritable Bowel ◽  
Bile Acid Profiles ◽  
Bile Acid Receptors

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.

scholarly journals Bile Acid Administration Elicits an Intestinal Antimicrobial Program and Reduces the Bacterial Burden in Two Mouse Models of Enteric Infection

2017 ◽  
Vol 85 (6) ◽  
Author(s):  
Sarah Tremblay ◽  
Guillaume Romain ◽  
Mélisange Roux ◽  
Xi-Lin Chen ◽  
Kirsty Brown ◽  
...  
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Mouse Models ◽  
Bacterial Infections ◽  
Immune Cell ◽  
Paneth Cell ◽  
Farnesoid X Receptor ◽  
Enteric Infection ◽  
Content Type ◽  
Acid Administration

ABSTRACT In addition to their chemical antimicrobial nature, bile acids are thought to have other functions in the homeostatic control of gastrointestinal immunity. However, those functions have remained largely undefined. In this work, we used ileal explants and mouse models of bile acid administration to investigate the role of bile acids in the regulation of the intestinal antimicrobial response. Mice fed on a diet supplemented with 0.1% chenodeoxycholic acid (CDCA) showed an upregulated expression of Paneth cell α-defensins as well as an increased synthesis of the type-C lectins Reg3b and Reg3g by the ileal epithelium. CDCA acted on several epithelial cell types, by a mechanism independent from farnesoid X receptor (FXR) and not involving STAT3 or β-catenin activation. CDCA feeding did not change the relative abundance of major commensal bacterial groups of the ileum, as shown by 16S analyses. However, administration of CDCA increased the expression of ileal Muc2 and induced a change in the composition of the mucosal immune cell repertoire, decreasing the proportion of Ly6G+ and CD68+ cells, while increasing the relative amount of IgGκ+ B cells. Oral administration of CDCA to mice attenuated infections with the bile-resistant pathogens Salmonella enterica serovar Typhimurium and Citrobacter rodentium, promoting lower systemic colonization and faster bacteria clearance, respectively. Our results demonstrate that bile acid signaling in the ileum triggers an antimicrobial program that can be potentially used as a therapeutic option against intestinal bacterial infections.

scholarly journals Gut Dysbiosis and Abnormal Bile Acid Metabolism in Colitis-Associated Cancer

2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
Li Liu ◽  
Min Yang ◽  
Wenxiao Dong ◽  
Tianyu Liu ◽  
Xueli Song ◽  
...  
Keyword(s):  
Bile Acid ◽  
Gut Microbiota ◽  
Bile Acids ◽  
Acid Metabolism ◽  
Farnesoid X Receptor ◽  
Mucosal Barrier ◽  
Bile Acid Metabolism ◽  
Preventive Strategy ◽  
Gut Dysbiosis ◽  
Bile Acid Receptors

Background. Patients with prolonged inflammatory bowel disease (IBD) can develop into colorectal cancer (CRC), also called colitis-associated cancer (CAC). Studies have shown the association between gut dysbiosis, abnormal bile acid metabolism, and inflammation process. Here, we aimed to investigate these two factors in the CAC model. Methods. C57BL/6 mice were randomly allocated to two groups: azoxymethane/dextran sodium sulfate (AOM/DSS) and control. The AOM/DSS group received AOM injection followed by DSS drinking water. Intestinal inflammation, mucosal barrier, and bile acid receptors were determined by real-time PCR and immunohistochemistry. Fecal microbiome and bile acids were detected via 16S rRNA sequencing and liquid chromatography-mass spectrometry. Results. The AOM/DSS group exhibited severe mucosal barrier impairment, inflammatory response, and tumor formation. In the CAC model, the richness and biodiversity of gut microbiota were decreased, along with significant alteration of composition. The abundance of pathogens was increased, while the short-chain fatty acids producing bacteria were reduced. Interestingly, Clostridium XlV and Lactobacillus, which might be involved in the bile acid deconjugation, transformation, and desulfation, were significantly decreased. Accordingly, fecal bile acids were decreased, accompanied by reduced transformation of primary to secondary bile acids. Given bile acid receptors, the ileum farnesoid X receptor-fibroblast growth factor 15 (FXR-FGF15) axis was downregulated, while Takeda G-protein receptor 5 (TGR5) was overexpressed in colonic tumor tissues. Conclusion. Gut dysbiosis might alter the metabolism of bile acids and promote CAC, which would provide a potential preventive strategy of CAC by regulating gut microbiota and bile acid metabolism.

scholarly journals Ge-Gen-Jiao-Tai-Wan Affects Type 2 Diabetic Rats by Regulating Gut Microbiota and Primary Bile Acids

2021 ◽  
Vol 2021 ◽  
pp. 1-13
Author(s):  
Han Chen ◽  
Ye Yao ◽  
Wenbo Wang ◽  
Dongsheng Wang
Keyword(s):  
Bile Acid ◽  
Gut Microbiota ◽  
Bile Acids ◽  
Intestinal Flora ◽  
Diabetic Rats ◽  
Farnesoid X Receptor ◽  
Rrna Gene ◽  
Fecal Transplant ◽  
Type 2 Diabetic

The Ge-Gen-Jiao-Tai-Wan (GGJTW) formula has been used to treat type 2 diabetes mellitus (T2DM) in China for a long time. Our previous study has proved that GGJTW could alleviate the type 2 diabetic symptoms, but the underlying mechanisms are still unclear. This study aimed to investigate the changes in gut microbiota and primary bile acids (PBAs) to determine the potential mechanisms of GGJTW in treating T2DM.The fecal transplant method and pseudogerm-free rats were used in our study.The16S rRNA gene sequencing method was used to analyze the changes in the intestinal flora, and PBAs in the colon contents were detected. Finally, the expression of farnesoid X receptor (FXR), G protein-coupled membrane receptor 5 (TGR5), and glucagon-like peptide-1 (GLP-1) was assessed. Following GGJTW treatment, we observed a decrease in blood glucose levels and improvements in glucose tolerance and serum lipid levels. Furthermore, we found that GGJTW could regulate the composition of the gut microbiota and upregulate the diabetic beneficial phylum Firmicutes and bile-acid-related genus Lactobacillus. PBAs in the colon contents were increased in the GGJTW-treated group, accompanied by upregulated expression of the bile acid receptors FXR and TGR5 and increased concentrations of GLP-1. These results indicated that GGJTW could alleviate symptoms of type 2 diabetic rats by regulating the gut microbiota, promoting the production of PBAs, and upregulating the PBA-FXR/TGR5-GLP-1 pathway.

Phase I study of ursodeoxycholic acid in combination with 5-fluorouracil, leucovorin, oxaliplatin, and bevacizumab for metastatic colorectal cancer.

2013 ◽  
Vol 31 (4_suppl) ◽  
pp. 569-569
Author(s):  
Lily L. Lai ◽  
Ken Chiu ◽  
Dean Lim ◽  
Joseph Chao ◽  
Paul Henry Frankel
Keyword(s):  
Bile Acid ◽  
Phase I ◽  
Ursodeoxycholic Acid ◽  
Bile Acids ◽  
Mouse Models ◽  
Phase I Study ◽  
Cancer Metabolism ◽  
Farnesoid X Receptor ◽  
Oral Glucose ◽  
Acid Activation

569 Background: Emerging data links cancer growth with aberrant metabolism. These findings suggest that treatment directed against CRC metabolism may improve survival outcomes. Bile acids are involved in the metabolism of cholesterol and glucose. The bile acid, ursodeoxycholic acid (UDCA), protects against intestinal polyp development in animal and human studies. UDCA effects may be mediated through the nuclear receptor, farnesoid X receptor (FXR), since bile acids are the receptor’s endogenous ligands. FXR is a tumor suppressor in mouse models and a prognostic biomarker in patients with CRC. Bile acid activation of FXR in mouse models suppresses intestinal tumorigenesis. We sought to determine dose and safety of UDCA when added to standard therapy for mCRC. Methods: Patients with mCRC were accrued to an institutionally approved Phase I study. At the end of a 7-day run-in period of oral UDCA, standard doses of 5-fluorouracil, leucovorin, oxaliplatin, and bevacizumab were added. UDCA doses were escalated using a 3+3 design to determine MTD. The use of a run-in period allowed for correlative studies to identify serum biomarkers of FXR activation. Results: 11 patients were treated on three dose levels (250, 500, and 750 mg/day in divided doses). Patients were treated on protocol for a median time of 6 months with a median follow-up of 15 months. Patients were taken off protocol for progression of disease (n = 7); for declining performance status (n = 1); for toxicity (n=1); for patient refusal (n= 1). One patient remains on protocol at this time. No Grade 4 or higher toxicity was identified. Grade 3 toxicities were recorded in 5 patients; the majority was hematologic. Oral glucose tolerance tests, serum glucose and insulin levels, and serum FGF-19 were determined before and after UDCA treatment. Conclusions: UDCA, given with standard chemotherapy and biologic treatment, is safe and well tolerated in patients with mCRC. Further studies are needed to determine the efficacy of targeting FXR and cancer metabolism in mCRC. Supported by a grant from The Phase One Foundation. Clinical trial information: NCT00873275.

In vitro study of the interaction between human gut microbiota and herbal extracts using willow bark extract as an example

Planta Medica ◽  
2016 ◽  
Vol 81 (S 01) ◽  
pp. S1-S381
Author(s):  
EM Pferschy-Wenzig ◽  
K Koskinen ◽  
C Moissl-Eichinger ◽  
R Bauer
Keyword(s):  
Gut Microbiota ◽  
In Vitro Study ◽  
Vitro Study ◽  
Bark Extract ◽  
Herbal Extracts ◽  
Human Gut ◽  
Human Gut Microbiota ◽  
Willow Bark

Metabolization of the herbal combination STW-5 by human gut microbiota in vitro

2017 ◽  
Author(s):  
EM Pferschy-Wenzig ◽  
A Roßmann ◽  
K Koskinen ◽  
H Abdel-Aziz ◽  
C Moissl-Eichinger ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Human Gut ◽  
Human Gut Microbiota

Substrate use prioritization by a coculture of five species of gut bacteria fed mixtures of arabinoxylan, xyloglucan, β-glucan, and pectin

2020 ◽  
Author(s):  
Y Liu ◽  
AL Heath ◽  
B Galland ◽  
N Rehrer ◽  
L Drummond ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Dietary Fiber ◽  
Plant Cell Wall ◽  
Bacterial Species ◽  
Short Chain ◽  
Emergent Properties ◽  
Human Gut ◽  
Fermentation Products ◽  
Plant Polysaccharides ◽  
Human Gut Microbiota

© 2020 American Society for Microbiology. Dietary fiber provides growth substrates for bacterial species that belong to the colonic microbiota of humans. The microbiota degrades and ferments substrates, producing characteristic short-chain fatty acid profiles. Dietary fiber contains plant cell wall-associated polysaccharides (hemicelluloses and pectins) that are chemically diverse in composition and structure. Thus, depending on plant sources, dietary fiber daily presents the microbiota with mixtures of plant polysaccharides of various types and complexity. We studied the extent and preferential order in which mixtures of plant polysaccharides (arabinoxylan, xyloglucan, β-glucan, and pectin) were utilized by a coculture of five bacterial species (Bacteroides ovatus, Bifidobacterium longum subspecies longum, Megasphaera elsdenii, Ruminococcus gnavus, and Veillonella parvula). These species are members of the human gut microbiota and have the biochemical capacity, collectively, to degrade and ferment the polysaccharides and produce short-chain fatty acids (SCFAs). B. ovatus utilized glycans in the order β-glucan, pectin, xyloglucan, and arabinoxylan, whereas B. longum subsp. longum utilization was in the order arabinoxylan, arabinan, pectin, and β-glucan. Propionate, as a proportion of total SCFAs, was augmented when polysaccharide mixtures contained galactan, resulting in greater succinate production by B. ovatus and conversion of succinate to propionate by V. parvula. Overall, we derived a synthetic ecological community that carries out SCFA production by the common pathways used by bacterial species for this purpose. Systems like this might be used to predict changes to the emergent properties of the gut ecosystem when diet is altered, with the aim of beneficially affecting human physiology. This study addresses the question as to how bacterial species, characteristic of the human gut microbiota, collectively utilize mixtures of plant polysaccharides such as are found in dietary fiber. Five bacterial species with the capacity to degrade polymers and/or produce acidic fermentation products detectable in human feces were used in the experiments. The bacteria showed preferential use of certain polysaccharides over others for growth, and this influenced their fermentation output qualitatively. These kinds of studies are essential in developing concepts of how the gut microbial community shares habitat resources, directly and indirectly, when presented with mixtures of polysaccharides that are found in human diets. The concepts are required in planning dietary interventions that might correct imbalances in the functioning of the human microbiota so as to support measures to reduce metabolic conditions such as obesity.

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