“…Six of the acyl esters detected in public data were previously undescribed fatty acid bile acid conjugates (FABACs). Although several FABACs have been synthesized for the treatment of gallstones, to the best of our knowledge, they have not been reported in biological samples 24 , 25 . Fig.…”
Determining the structure and phenotypic context of molecules detected in untargeted metabolomics experiments remains challenging. Here we present reverse metabolomics as a discovery strategy, whereby tandem mass spectrometry spectra acquired from newly synthesized compounds are searched for in public metabolomics datasets to uncover phenotypic associations. To demonstrate the concept, we broadly synthesized and explored multiple classes of metabolites in humans, including N-acyl amides, fatty acid esters of hydroxy fatty acids, bile acid esters and conjugated bile acids. Using repository-scale analysis1,2, we discovered that some conjugated bile acids are associated with inflammatory bowel disease (IBD). Validation using four distinct human IBD cohorts showed that cholic acids conjugated to Glu, Ile/Leu, Phe, Thr, Trp or Tyr are increased in Crohn’s disease. Several of these compounds and related structures affected pathways associated with IBD, such as interferon-γ production in CD4+ T cells3 and agonism of the pregnane X receptor4. Culture of bacteria belonging to the Bifidobacterium, Clostridium and Enterococcus genera produced these bile amidates. Because searching repositories with tandem mass spectrometry spectra has only recently become possible, this reverse metabolomics approach can now be used as a general strategy to discover other molecules from human and animal ecosystems.
“…Six of the acyl esters detected in public data were previously undescribed fatty acid bile acid conjugates (FABACs). Although several FABACs have been synthesized for the treatment of gallstones, to the best of our knowledge, they have not been reported in biological samples 24 , 25 . Fig.…”
Determining the structure and phenotypic context of molecules detected in untargeted metabolomics experiments remains challenging. Here we present reverse metabolomics as a discovery strategy, whereby tandem mass spectrometry spectra acquired from newly synthesized compounds are searched for in public metabolomics datasets to uncover phenotypic associations. To demonstrate the concept, we broadly synthesized and explored multiple classes of metabolites in humans, including N-acyl amides, fatty acid esters of hydroxy fatty acids, bile acid esters and conjugated bile acids. Using repository-scale analysis1,2, we discovered that some conjugated bile acids are associated with inflammatory bowel disease (IBD). Validation using four distinct human IBD cohorts showed that cholic acids conjugated to Glu, Ile/Leu, Phe, Thr, Trp or Tyr are increased in Crohn’s disease. Several of these compounds and related structures affected pathways associated with IBD, such as interferon-γ production in CD4+ T cells3 and agonism of the pregnane X receptor4. Culture of bacteria belonging to the Bifidobacterium, Clostridium and Enterococcus genera produced these bile amidates. Because searching repositories with tandem mass spectrometry spectra has only recently become possible, this reverse metabolomics approach can now be used as a general strategy to discover other molecules from human and animal ecosystems.
“…Aramchol is an arachidic and cholic acid conjugate that was shown to inhibit stearoyl CoA desaturase in vitro and de novo lipogenesis in animal models on high fat diet . A randomised, double‐blind, placebo‐controlled trial of 60 patients with biopsy‐confirmed NAFLD evaluating 100 and 300 mg Aramchol daily for 3 months showed a 12.57%±22.14% reduction in liver fat content in the 300 mg dose group, compared with an insignificant reduction in the 100 mg group and an increase in those on placebo.…”
Section: Drugs In Phase Ii/iii Developmentmentioning
SummaryBackground: Non-alcoholic fatty liver disease is the fastest growing cause of liver disease in the Western world, yet there is no approved pharmacotherapy. While lifestyle modifications remain the mainstay of treatment, only a proportion of individuals are able to make or sustain them, and so more treatment options are required.Aim: To review the potential benefit of drugs used in clinical practice, those entering phase II trials, and compounds being investigated in pre-clinical studies.Methods: A literature search was performed using PubMed to identify relevant studies; linked references were also reviewed.
“…Moreover, feeding experiments in mice demonstrated that the addition of 0.5% ( w / w ) cholic acid (CA) to a high-fat diet (HFD) prevented weight gain and associated comorbidities [ 27 , 28 ], although underlying interactions with the gut microbiota are unclear. Other studies in rodents demonstrated positive effects of fatty and bile acid conjugates on diet-induced non-alcoholic fatty liver (NAFLD) and hypercholesterolemia [ 29 , 30 ]. In humans, oral bile acid treatment is common in patients with primary bile acid synthesis deficiency [ 31 ], but effects on the gut microbiota are unknown.…”
BackgroundAs the gut microbiota contributes to metabolic health, it is important to determine specific diet-microbiota interactions that influence host metabolism. Bile acids and dietary fat source can alter phenotypes of diet-induced obesity, but the interplay with intestinal microorganisms is unclear. Here, we investigated metabolic consequences of diets enriched in primary bile acids with or without addition of lard or palm oil, and studied gut microbiota structure and functions in mice.ResultsIn combination with bile acids, dietary lard fed to male C57BL/6N mice for a period of 8 weeks enhanced fat mass accumulation in colonized, but not in germ-free mice when compared to palm oil. This was associated with impaired glucose tolerance, lower fasting insulin levels, lower counts of enteroendocrine cells, fatty liver, and elevated amounts of hepatic triglycerides, cholesteryl esters, and monounsaturated fatty acids. Lard- and bile acid-fed mice were characterized by shifts in dominant gut bacterial communities, including decreased relative abundances of Lachnospiraceae and increased occurrence of Desulfovibrionaceae and the species Clostridium lactatifermentans and Flintibacter butyricus. Metatranscriptomic analysis revealed shifts in microbial functions, including lipid and amino acid metabolism.ConclusionsCaution is required when interpreting data from diet-induced obesity models due to varying effects of dietary fat source. Detrimental metabolic consequences of a diet enriched with lard and primary bile acids were dependent on microbial colonization of the host and were linked to hepatic lipid rearrangements and to alterations of dominant bacterial communities in the cecum.Electronic supplementary materialThe online version of this article (10.1186/s40168-018-0510-8) contains supplementary material, which is available to authorized users.
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