Project description:Bile acids (BAs) are a fundamental class of lipid emulsifying metabolites that are synthesized by hepatocytes, important for fat-soluble vitamin absorption, and maintained in vivo through enterohepatic circulation between the liver and ileum1. However, BAs are also lipophilic detergents and can be cytotoxic in enterohepatic tissues2. Whereas several nuclear receptors are known to prevent BA-driven toxicity in hepatocytes and intestinal enterocytes3, the mechanisms by which mucosal immune cells protect themselves from BAs in the ileum remains poorly understood. We recently reported that CD4+ T effector (Teff) cells upregulate expression of the xenobiotic transporter, MDR1, in the ileum to protect against BA toxicity and suppress Crohn’s disease-like small bowel inflammation4. Here, we identify the BA- and xenobiotic-sensing nuclear receptor, constitutive androstane receptor (CAR/NR1I3), as a key regulator of MDR1 expression in mucosal Teff cells. CAR promotes large-scale transcriptional reprogramming of Teff cells in the small intestine lamina propria (siLP), which shares similarities with CAR-dependent gene expression in hepatocytes and involves the induction of both detoxifying enzymes and transporters, as well as anti-inflammatory cytokines, such as Il10. Accordingly, loss of CAR in Teff cells exacerbates, whereas pharmacologic CAR activation suppresses, BA-driven ileitis in T cell-reconstituted Rag1-/- mice. Further, CAR transcriptional activity is evident in human CD4+ T cells, but only in 4+7+CCR9+ Teff cells that are licensed for small bowel homing. In these cells, CAR activation also promotes cyto-protective and anti-inflammatory gene expression, including a core set of transcriptional targets that are similarly regulated by CAR in mouse mucosal Teff cells and hepatocytes. Together, these results suggest that mucosal T cells rely on CAR to activate a hepatocyte-like transcriptional response in the ileum that detoxifies BAs and safeguards immune homeostasis. Pharmacologic activation of this program may offer an unexpected strategy to treat small bowel Crohn’s disease.

Project description:BACKGROUND: Intestinal bacteria are known to regulate the bile acid (BA) homeostasis via intestinal biotransformation of BAs and stimulating the expression of fibroblast growth factor 19 through intestinal nuclear farnesoid X receptor (FXR). On the other hand, BAs directly regulate the gut microbiota with their strong antimicrobial activities. It remains unclear, however, how mammalian BAs cross-talk with gut microbiome and shape microbial composition in a dynamic and interactive way.RESULTS: We quantitatively profiled small molecule metabolites derived from host-microbial co-metabolism in mice, demonstrating that Bas were the most significant factor correlated with microbial alterations among all types of endogenous metabolites. HFD intervention resulted in a rapid and significant increase in intestinal BA pool within 12 hrs followed by alteration in microbial composition at 24 hrs, providing supporting evidence that BAs are major dietary factors regulating gut microbiota. Feeding mice with BAs along with normal diet induced obese phenotype and obesity-associated gut microbial composition, similar to HFD fed mice. Finally, inhibition of hepatic BA biosynthesis under HFD conditions attenuated the HFD-induced gut microbiome alterations. Inhibition of BAs and direct suppression of micriobiota improved obese phenotypes.CONCLUSIONS: Our study highlights a liver - BAs - gut microbiome metabolic axis that drives significant modifications of BA and microbiota compositions capable of triggering metabolic disorders, suggesting new therapeutic strategies targeting BA metabolism for metabolic diseases. The untargeted metabolome profile assay for this study can be found in the MetaboLights study <a href='https://www.ebi.ac.uk/metabolights/MTBLS545' rel='noopener noreferrer' target='_blank'>MTBLS545</a>.The targeted bile acid analysis assay for this study can be found in the MetaboLights study <a href='https://www.ebi.ac.uk/metabolights/MTBLS547' rel='noopener noreferrer' target='_blank'>MTBLS547</a>.The targeted fatty acid analysis assay for this study can be found in the MetaboLights study <a href='https://www.ebi.ac.uk/metabolights/MTBLS548' rel='noopener noreferrer' target='_blank'>MTBLS548</a>.

Project description:Intrahepatic cholestasis of pregnancy (ICP) is estimated to impact between 0.4% and 5% of pregnancies worldwide. This disease is associated with elevated maternal bile acids and frequently untoward neonatal outcomes such as respiratory distress and asphyxia. Multiple candidate genes have been implicated, but none have provided insight into the mechanisms of neonatal respiratory distress and death. Herein our studies demonstrate that maternal cholestasis (due to Abcb11 deficiency) produces 100% neonatal death within 24h due to atelectasis producing pulmonary hypoxia, which recapitulates the respiratory distress and asphyxia of human ICP. We show that these neonates have elevated pulmonary bile acids that are associated with disrupted structure of pulmonary surfactant. Maternal absence of Nr1i2 superimposed upon Abcb11 deficiency strongly increased neonatal survival and is directly related to reduced maternal bile acid concentrations. The mechanism accounting for reduced serum bile acids in the mothers deficient in both Nr1i2 and Abcb11 appears related to disrupted reabsorption of intestinal bile acids due to changes in transporter expression. These findings provide novel insights into pulmonary failure by revealing bile acids capability to disrupt the structure of surfactant producing collapsed alveoli, pulmonary failure and ultimately death. These findings have important implications for neonatal health especially when maternal bile acids are elevated during pregnancy and highlight a potential pathway and targets amenable to therapeutic intervention to ameliorate this condition. We used microarrays to measure changes in gene expression profiles in lung tissues from Abcb11+/- lungs after interbreeding C57BL/6 wild-type female or C57BL/6 Abcb11-/- female mice against either C57BL/6 wild-type male mice or C57BL/6 Abcb11-/- male mice to create only heterozygote offspring. We also measured profiles in liver tissues from age-matched C57BL/6 wild-type and C57BL/6 Abcb11-/- mice. Lung tissues were collected from day E17.5, E18.5 and neonatal (N0) mice. Liver tissues were collected from 1.5-month-old C57BL/6 wildtype and Abcb11-/- mice.

Project description:BACKGROUND: Intestinal bacteria are known to regulate the bile acid (BA) homeostasis via intestinal biotransformation of BAs and stimulating the expression of fibroblast growth factor 19 through intestinal nuclear farnesoid X receptor (FXR). On the other hand, BAs directly regulate the gut microbiota with their strong antimicrobial activities. It remains unclear, however, how mammalian BAs cross-talk with gut microbiome and shape microbial composition in a dynamic and interactive way.RESULTS: We quantitatively profiled small molecule metabolites derived from host-microbial co-metabolism in mice, demonstrating that Bas were the most significant factor correlated with microbial alterations among all types of endogenous metabolites. HFD intervention resulted in a rapid and significant increase in intestinal BA pool within 12 hrs followed by alteration in microbial composition at 24 hrs, providing supporting evidence that BAs are major dietary factors regulating gut microbiota. Feeding mice with BAs along with normal diet induced obese phenotype and obesity-associated gut microbial composition, similar to HFD fed mice. Finally, inhibition of hepatic BA biosynthesis under HFD conditions attenuated the HFD-induced gut microbiome alterations. Inhibition of BAs and direct suppression of micriobiota improved obese phenotypes.CONCLUSIONS: Our study highlights a liver - BAs - gut microbiome metabolic axis that drives significant modifications of BA and microbiota compositions capable of triggering metabolic disorders, suggesting new therapeutic strategies targeting BA metabolism for metabolic diseases. The untargeted metabolome profile assay for this study can be found in the MetaboLights study <a href='https://www.ebi.ac.uk/metabolights/MTBLS545' rel='noopener noreferrer' target='_blank'>MTBLS545</a>.The targeted short chain fatty acid analysis assay for this study can be found in the MetaboLights study <a href='https://www.ebi.ac.uk/metabolights/MTBLS546' rel='noopener noreferrer' target='_blank'>MTBLS546</a>.The targeted bile acid analysis assay for this study can be found in the MetaboLights study <a href='https://www.ebi.ac.uk/metabolights/MTBLS547' rel='noopener noreferrer' target='_blank'>MTBLS547</a>.

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Cholangiopathy and biliary fibrosis in Cyp2c70-deficient mice are fully reversed by ursodeoxycholic acid

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