Gut microbiota-associated bile acid deconjugation accelerates hepatic steatosis in ob/ob mice

Park, Mi‐Young; Kim, Su Jeong; Ko, Eun Kyeul; Ahn, Sung‐Hoon; Seo, Hyewon; Sung, Mi‐Kyung

doi:10.1111/jam.13158

Cited by 45 publications

(41 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Mice lacking expression of FXR in the intestine also have decreased insulin resistance and lower fatty livers than their wild-type counterparts 79, 82 . A recent study found that ob/ob mice had altered gut microbiota compositions, less taurine-conjugated bile acids, increased intestinal FXR expression levels, and elevated FXR signaling compared to their lean ob/+ littermates 84 , in agreement with the studies in tempol-treated and FXR intestine-deficient mice 79 .…”

Section: Fxr Mediates the Influence Of Gut Microbiota On Nafld Develosupporting

confidence: 72%

An Intestinal Microbiota–Farnesoid X Receptor Axis Modulates Metabolic Disease

2016

View full text Add to dashboard Cite

The gut microbiota is associated with metabolic diseases including obesity, insulin resistance and non-alcoholic fatty liver disease (NAFLD), as demonstrated by correlative studies and by transplant of microbiota from obese humans and mice into germ-free mice. Modification of the microbiota by treatment of high-fat diet (HFD)-fed mice with tempol or antibiotics resulted in decreased adverse metabolic phenotypes. This was due to lower levels of the genera Lactobacillus and decreased bile salt hydrolase (BSH) activity. The decreased BSH resulted in increased levels of tauro-β-muricholic acid (T-β-MCA), a substrate of BSH and a potent farnesoid X receptor (FXR) antagonist. Mice lacking expression of FXR in the intestine were resistant to HFD-induced obesity, insulin resistance and NAFLD thus confirming that intestinal FXR is involved in the potentiation of metabolic disease. A potent intestinal FXR antagonist glycine-β-muricholic acid (Gly-MCA) that is resistant to BSH, was developed that when administered to HFD-treated mice, mimics the effect of the altered microbiota on HFD-induced metabolic disease. Gly-MCA had similar effects on genetically obese leptin-deficient mice. The decreased in adverse metabolic phenotype by tempol, antibiotics and Gly-MCA was due to decreased serum ceramides. Mice lacking FXR in intestine also have lower serum ceramides, are metabolic fit and resistant to HFD-induced metabolic disease, and this is reversed by injection of C16:0 ceramide. In mouse ileum, due to the presence of endogenous FXR agonists produced in the liver, FXR target genes involved in ceramide synthesis are activated and when Gly-MCA is administered, they are repressed, which likely accounts for the decrease in serum ceramides. These studies reveal that ceramides produced in the ileum under control of FXR, influence metabolic diseases.

show abstract

Section: Fxr Mediates the Influence Of Gut Microbiota On Nafld Develosupporting

confidence: 72%

An Intestinal Microbiota–Farnesoid X Receptor Axis Modulates Metabolic Disease

2016

View full text Add to dashboard Cite

show abstract

“…During normal enterohepatic circulation, primary bile acids, synthesized by the liver, undergo deconjugation to secondary bile acids by the gut microbiota . Because the primary bile acids are preferential ligands for FXR and secondary bile acids are preferential ligands for TGR5, this provides an interesting mechanism by which gut microbes can modulate bile acid signaling properties (Figure 1E).…”

Section: Mucosal Atrophy Central Line Infection–driven Liver Injurymentioning

confidence: 99%

Mechanisms of Parenteral Nutrition–Associated Liver and Gut Injury

et al. 2019

View full text Add to dashboard Cite

Parenteral nutrition (PN) has revolutionized the care of patients with intestinal failure by providing nutrition intravenously. Worldwide, PN remains a standard tool of nutrition delivery in neonatal, pediatric, and adult patients. Though the benefits are evident, patients receiving PN can suffer serious cholestasis due to lack of enteral feeding and sometimes have fatal complications from liver injury and gut atrophy, including PN-associated liver disease or intestinal failure-associated liver disease. Recent studies into gut-systemic cross talk via the bile acid-regulated farnesoid X receptor (FXR)-fibroblast growth factor 19 (FGF19) axis, gut microbial control of the TGR5-glucagon-like peptide (GLP) axis, sepsis, and role of prematurity of hepatobiliary receptors are greatly broadening our understanding of PN-associated injury. It has also been shown that the composition of ω-6/ω-3 polyunsaturated fatty acids given parenterally as lipid emulsions can variably drive damage to hepatocytes and cell integrity. This manuscript reviews the mechanisms for the multifactorial pathogenesis of liver disease and gut injury with PN and discusses novel ameliorative strategies. (Nutr Clin Pract. 2020;35:63-71)

show abstract

“…However, differentiating between the direct effects of diet and dietary components vs. changes in host metabolic health (e.g., glucose homeostasis, insulin resistance, or overt diabetes) on microbial ecology has not been systematically investigated. Studies in rodent models of diabetes, including ob/ob mice and Zucker diabetic fatty rats, have identified differences in the gut microbiota between mutant and wild-type animals fed similar diets (24,25,50,61). Although these models control for diet type, the insulin resistance and diabetes phenotype in these animals are driven through defects in leptin production or leptin signaling, which are extremely rare in the pathogenesis of obesity and type 2 diabetes mellitus (T2DM) in humans.…”

Section: Introductionmentioning

confidence: 99%

Diabetes-associated alterations in the cecal microbiome and metabolome are independent of diet or environment in the UC Davis Type 2 Diabetes Mellitus Rat model

Piccolo

Graham

Stanhope

et al. 2018

American Journal of Physiology-Endocrinology and Metabolism

View full text Add to dashboard Cite

The composition of the gut microbiome is altered in obesity and type 2 diabetes; however, it is not known whether these alterations are mediated by dietary factors or related to declines in metabolic health. To address this, cecal contents were collected from age-matched, chow-fed male UCD-T2DM rats before the onset of diabetes (pre-diabetic PD, n=15); 2 wk recently-diabetic (RD, n=10); 3 mo (D3M, n=11); and 6 mo (D6M, n=8) post-onset of diabetes. Bacterial species and functional gene counts were assessed by shotgun metagenomic sequencing of bacterial DNA in cecal contents, while metabolites were identified by GC-QTOF-MS. Metagenomic analysis showed a shift from Firmicutes species in early stages of diabetes (PD+RD) towards an enrichment of Bacteroidetes species in later stages of diabetes (D3M+D6M). In total, 45 bacterial species discriminated early and late stages of diabetes with 25 of these belonging to either Bacteroides or Prevotella genera. Furthermore, 61 bacterial gene clusters discriminated early and later stages of diabetes with elevations of enzymes related to stress response (e.g., glutathione and glutaredoxin), and amino acid, carbohydrate, and bacterial cell wall metabolism. Twenty-five metabolites discriminated early vs late stages of diabetes, with the largest differences observed in abundances of dehydroabietic acid and phosphate. Alterations in the gut microbiota and cecal metabolome track diabetes progression in UCD-T2DM rats when controlling for diet, age, and housing environment. Results suggest that diabetes-specific host signals impact the ecology and end-product metabolites of the gut microbiome when diet is held constant.

show abstract

Gut microbiota-associated bile acid deconjugation accelerates hepatic steatosis in ob/ob mice

Abstract: We provided evidences that changes in the gut microbiota and their metabolites can alter the profile of BAs, thereby providing a mechanism by which an altered microbiota profile contributes to the development of NAFLD.

Cited by 45 publications

References 50 publications

An Intestinal Microbiota–Farnesoid X Receptor Axis Modulates Metabolic Disease

An Intestinal Microbiota–Farnesoid X Receptor Axis Modulates Metabolic Disease

Mechanisms of Parenteral Nutrition–Associated Liver and Gut Injury

Diabetes-associated alterations in the cecal microbiome and metabolome are independent of diet or environment in the UC Davis Type 2 Diabetes Mellitus Rat model

Contact Info

Product

Resources

About