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Open accessJournal ArticleDOI: 10.1038/S41467-021-21744-W

Hyocholic acid species as novel biomarkers for metabolic disorders

05 Mar 2021-Nature Communications (Nature Publishing Group)-Vol. 12, Iss: 1, pp 1487-1487
Abstract: Hyocholic acid (HCA) is a major bile acid (BA) species in the BA pool of pigs, a species known for its exceptional resistance to spontaneous development of diabetic phenotypes. HCA and its derivatives are also present in human blood and urine. We investigate whether human HCA profiles can predict the development of metabolic disorders. We find in the first cohort (n = 1107) that both obesity and diabetes are associated with lower serum concentrations of HCA species. A separate cohort study (n = 91) validates this finding and further reveals that individuals with pre-diabetes are associated with lower levels of HCA species in feces. Serum HCA levels increase in the patients after gastric bypass surgery (n = 38) and can predict the remission of diabetes two years after surgery. The results are replicated in two independent, prospective cohorts (n = 132 and n = 207), where serum HCA species are found to be strong predictors for metabolic disorders in 5 and 10 years, respectively. These findings underscore the association of HCA species with diabetes, and demonstrate the feasibility of using HCA profiles to assess the future risk of developing metabolic abnormalities.

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10 results found


Open accessJournal ArticleDOI: 10.1002/ADVS.202100536
Jing Zhang1, Yueqiong Ni2, Yueqiong Ni3, Lingling Qian1  +14 moreInstitutions (4)
04 Jun 2021-Advanced Science
Abstract: Although obesity occurs in most of the patients with type 2 diabetes (T2D), a fraction of patients with T2D are underweight or have normal weight Several studies have linked the gut microbiome to obesity and T2D, but the role of gut microbiota in lean individuals with T2D having unique clinical characteristics remains unclear A metagenomic and targeted metabolomic analysis is conducted in 182 lean and abdominally obese individuals with and without newly diagnosed T2D The abundance of Akkermansia muciniphila (A muciniphila) significantly decreases in lean individuals with T2D than without T2D, but not in the comparison of obese individuals with and without T2D Its abundance correlates inversely with serum 3β-chenodeoxycholic acid (βCDCA) levels and positively with insulin secretion and fibroblast growth factor 15/19 (FGF15/19) concentrations The supplementation with A muciniphila is sufficient to protect mice against high sucrose-induced impairment of glucose intolerance by decreasing βCDCA and increasing insulin secretion and FGF15/19 Furthermore, βCDCA inhibits insulin secretion and FGF15/19 expression These findings suggest that decreased abundance of A muciniphila is linked to the impairment of insulin secretion and glucose homeostasis in lean T2D, paving the way for new therapeutic options for the prevention or treatment of diabetes

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Topics: Akkermansia muciniphila (70%), Glucose homeostasis (56.99%), Type 2 diabetes (53%) ... show more

3 Citations


Open accessJournal ArticleDOI: 10.1093/JMCB/MJAB027
Wei Jia1, Wei Jia2, Cynthia Rajani3, Xiaojiao Zheng1  +1 moreInstitutions (3)
Abstract: Hyocholic acid species (HCA, hyodeoxycholic acid, and their glycine and taurine conjugated forms) comprise 80% of the composition of pig bile (Haslewood, 1956). An interesting fact about pigs is that they do not get diabetes even though they eat almost anything and in abundant amounts, a diabetes-promoting diet. The first use of pig bile for treatment of 'xiao-ke', a condition known today as diabetes, was recorded ∼400 years ago by the Chinese medical practitioners in the Compendium of Materia Medica (Li, 1573‒1593). Recently, we found HCA species as novel biomarkers for metabolic diseases (Zheng et al., 2021b) and also identified the role of HCA species in the prevention of diabetes as well as their mechanism of action (Zheng et al., 2021a). Although bile acids (BAs) are mostly associated with their aid in food digestion, they have also been shown to act as signaling molecules by binding to two particular receptors, farnesoid X receptor (FXR) and the G-protein-coupled receptor, TGR5. Experiments were thus directed to the effect of HCA binding to these two BA receptors on glycemic regulation in both in vivo and in vitro models.

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Topics: Hyodeoxycholic acid (57.99%), G protein-coupled bile acid receptor (56.99%), Farnesoid X receptor (56%) ... show more

1 Citations


Open accessJournal ArticleDOI: 10.3389/FPHAR.2021.784231
Abstract: The prevalence of diabetes mellitus has been increasing for decades worldwide. To develop safe and potent therapeutics, animal models contribute a lot to the studies of the mechanisms underlying its pathogenesis. Dietary induction using is a well-accepted protocol in generating insulin resistance and diabetes models. In the present study, we reported the multi-omics profiling of the liver and sera from both peripheral blood and hepatic portal vein blood from Macaca fascicularis that spontaneously developed Type-2 diabetes mellitus with a chow diet (sDM). The other two groups of the monkeys fed with chow diet and high-fat high-sugar (HFHS) diet, respectively, were included for comparison. Analyses of various omics datasets revealed the alterations of high consistency. Between the sDM and HFHS monkeys, both the similar and unique alterations in the lipid metabolism have been demonstrated from metabolomic, transcriptomic, and proteomic data repeatedly. The comparison of the proteome and transcriptome confirmed the involvement of fatty acid binding protein 4 (FABP4) in the diet-induced pathogenesis of diabetes in macaques. Furthermore, the commonly changed genes between spontaneous diabetes and HFHS diet-induced prediabetes suggested that the alterations in the intra- and extracellular structural proteins and cell migration in the liver might mediate the HFHS diet induction of diabetes mellitus.

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Topics: Prediabetes (61%), Insulin resistance (55%), Diabetes mellitus (54%)

Open accessPosted ContentDOI: 10.1101/2021.10.18.464061
Marjolein Heddes1, Baraa Altaha1, Yunhui Niu1, Sandra Reitmeier1  +3 moreInstitutions (1)
18 Oct 2021-bioRxiv
Abstract: Diurnal (i.e., 24-hour) oscillations of the gut microbiome have been described in various species including mice and humans. However, the driving force behind these rhythms remains less clear. In this study, we differentiate between endogenous and exogenous time cues driving microbial rhythms. Our results demonstrate that fecal microbial oscillations are maintained in mice kept in the absence of light, supporting a role of the hosts circadian system rather than representing a diurnal response to environmental changes. Intestinal epithelial cell-specific ablation of the core clock gene Bmal1 disrupts rhythmicity of microbiota. Targeted metabolomics functionally link intestinal clock-controlled bacteria to microbial-derived products, in particular branched-chain fatty acids and secondary bile acids. Microbiota transfer from intestinal clock-deficient mice into germ-free mice altered intestinal gene expression, enhanced lymphoid organ weights and suppressed immune cell recruitment. These results highlight the importance of functional intestinal clocks for circadian microbiota composition and function, which is required to balance the hosts gastrointestinal homeostasis.

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Topics: Circadian clock (56.99%), CLOCK (56%), Circadian rhythm (51%)

Open accessJournal ArticleDOI: 10.1002/CCTC.202101307
22 Oct 2021-Chemcatchem
Abstract: The biocatalyzed conversion of hyocholic acid (3α,6α,7α‐trihydroxy‐5β‐cholan‐24‐oic acid) into ω‐muricholic acid (3α,6α,7β‐trihydroxy‐5β‐cholan‐24‐oic acid) has been obtained exploiting a small library of 7α‐ and 7β‐HSDHs (hydroxysteroid dehydrogenases). The process has been optimized and performed avoiding the isolation of the 7‐oxo intermediate using the appropriate coupled enzymes for the in situ cofactor regeneration. Moreover, the biocatalyzed reduction of 6,7‐dioxolithocholic acid (3α‐hydroxy‐6,7‐dioxo‐5β‐cholan‐24‐oic acid) was also investigated.

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37 results found


Open accessJournal ArticleDOI: 10.1126/SCIENCE.1241214
Vanessa K. Ridaura1, Jeremiah J. Faith1, Federico E. Rey1, Jiye Cheng1  +23 moreInstitutions (7)
06 Sep 2013-Science
Abstract: How much does the microbiota influence the host's phenotype? Ridaura et al. ([1241214][1] ; see the Perspective by [ Walker and Parkhill ][2]) obtained uncultured fecal microbiota from twin pairs discordant for body mass and transplanted them into adult germ-free mice. It was discovered that adiposity is transmissible from human to mouse and that it was associated with changes in serum levels of branched-chain amino acids. Moreover, obese-phenotype mice were invaded by members of the Bacteroidales from the lean mice, but, happily, the lean animals resisted invasion by the obese microbiota. [1]: http://www.sciencemag.org/content/341/6150/1241214.full [2]: /lookup/doi/10.1126/science.1243787

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2,432 Citations


Open accessJournal ArticleDOI: 10.1172/JCI57132
Carey N. Lumeng1, Alan R. SaltielInstitutions (1)
Abstract: The obesity epidemic has forced us to evaluate the role of inflammation in the health complications of obesity. This has led to a convergence of the fields of immunology and nutrient physiology and the understanding that they are inextricably linked. The reframing of obesity as an inflammatory condition has had a wide impact on our conceptualization of obesity-associated diseases. In this Review, we highlight the cellular and molecular mechanisms at play in the generation of obesity-induced inflammation. We also emphasize how defining the immune regulation in metabolic tissues has broadened the understanding of the diversity of inflammatory responses.

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1,726 Citations


Journal ArticleDOI: 10.1038/NATURE04330
26 Jan 2006-Nature
Abstract: While bile acids (BAs) have long been known to be essential in dietary lipid absorption and cholesterol catabolism, in recent years an important role for BAs as signalling molecules has emerged. BAs activate mitogen-activated protein kinase pathways, are ligands for the G-protein-coupled receptor (GPCR) TGR5 and activate nuclear hormone receptors such as farnesoid X receptor alpha (FXR-alpha; NR1H4). FXR-alpha regulates the enterohepatic recycling and biosynthesis of BAs by controlling the expression of genes such as the short heterodimer partner (SHP; NR0B2) that inhibits the activity of other nuclear receptors. The FXR-alpha-mediated SHP induction also underlies the downregulation of the hepatic fatty acid and triglyceride biosynthesis and very-low-density lipoprotein production mediated by sterol-regulatory-element-binding protein 1c. This indicates that BAs might be able to function beyond the control of BA homeostasis as general metabolic integrators. Here we show that the administration of BAs to mice increases energy expenditure in brown adipose tissue, preventing obesity and resistance to insulin. This novel metabolic effect of BAs is critically dependent on induction of the cyclic-AMP-dependent thyroid hormone activating enzyme type 2 iodothyronine deiodinase (D2) because it is lost in D2-/- mice. Treatment of brown adipocytes and human skeletal myocytes with BA increases D2 activity and oxygen consumption. These effects are independent of FXR-alpha, and instead are mediated by increased cAMP production that stems from the binding of BAs with the G-protein-coupled receptor TGR5. In both rodents and humans, the most thermogenically important tissues are specifically targeted by this mechanism because they coexpress D2 and TGR5. The BA-TGR5-cAMP-D2 signalling pathway is therefore a crucial mechanism for fine-tuning energy homeostasis that can be targeted to improve metabolic control.

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1,635 Citations


Open accessJournal ArticleDOI: 10.1016/J.CMET.2016.05.005
12 Jul 2016-Cell Metabolism
Abstract: The gut microbiota is considered a metabolic "organ" that not only facilitates harvesting of nutrients and energy from the ingested food but also produces numerous metabolites that signal through their cognate receptors to regulate host metabolism. One such class of metabolites, bile acids, is produced in the liver from cholesterol and metabolized in the intestine by the gut microbiota. These bioconversions modulate the signaling properties of bile acids via the nuclear farnesoid X receptor and the G protein-coupled membrane receptor 5, which regulate numerous metabolic pathways in the host. Conversely, bile acids can modulate gut microbial composition both directly and indirectly through activation of innate immune genes in the small intestine. Thus, host metabolism can be affected through microbial modifications of bile acids, which lead to altered signaling via bile acid receptors, but also by altered microbiota composition.

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Topics: Farnesoid X receptor (60%), Bile acid (60%), Gut flora (56.99%) ... show more

939 Citations


Journal ArticleDOI: 10.1056/NEJMRA0906948
Mark I. McCarthy1Institutions (1)
Abstract: The quickening pace of genetic discovery has resulted in the identification of more than 80 loci with proven roles in development of monogenic and multifactorial forms of nonautoimmune diabetes and obesity.

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860 Citations


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202110