scholarly journals Perinatal High-Salt Diet Induces Gut Microbiota Dysbiosis, Bile Acid Homeostasis Disbalance, and NAFLD in Weanling Mice Offspring

Nutrients ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 2135
Author(s):  
Qing Guo ◽  
Yi Tang ◽  
Ying Li ◽  
Ziyuan Xu ◽  
Di Zhang ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Bile Acid ◽  
Gut Microbiota ◽  
Lithocholic Acid ◽  
High Salt ◽  
Alcoholic Fatty Liver ◽  
Hepatic Expression ◽  
Tnf Α ◽  
Junction Protein ◽  
Gut Microbiota Dysbiosis

A perinatal high-salt (HS) diet was reported to elevate plasma triglycerides. This study aimed to investigate the hypothesis that a perinatal HS diet predisposed offspring to non-alcoholic fatty liver disease (NAFLD), the hepatic manifestation of abnormal lipid metabolism, and the possible mechanism. Female C57BL/6 mice were fed a control diet (0.5% NaCl) or HS diet (4% NaCl) during pregnancy and lactation and their offspring were sacrificed at weaning. The perinatal HS diet induced greater variation in fecal microbial beta-diversity (β-diversity) and increased bacteria abundance of Proteobacteria and Bacteroides. The gut microbiota dysbiosis promoted bile acid homeostasis disbalance, characterized by the accumulation of lithocholic acid (LCA) and deoxycholic acid (DCA) in feces. These alterations disturbed gut barrier by increasing the expression of tight junction protein (Tjp) and occludin (Ocln), and increased systemic lipopolysaccharide (LPS) levels and hepatic inflammatory cytokine secretion (TNF-α and IL-6) in the liver. The perinatal HS diet also inhibited hepatic expression of hepatic FXR signaling (CYP7A1 and FXR), thus triggering increased hepatic expression of pro-inflammatory cytokines (TNF-α and IL-6) and hepatic lipid metabolism-associated genes (SREBP-1c, FAS, ACC), leading to unique characteristics of NAFLD. In conclusion, a perinatal HS diet induced NAFLD in weanling mice offspring; the possible mechanism was related to increased bacteria abundance of Proteobacteria and Bacteroides, increased levels of LCA and DCA in feces, and increased expressions of hepatic FXR signaling.

scholarly journals Gut Microbiota Dysbiosis Is Associated with Elevated Bile Acids in Parkinson’s Disease

Metabolites ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 29
Author(s):  
Peipei Li ◽  
Bryan A. Killinger ◽  
Elizabeth Ensink ◽  
Ian Beddows ◽  
Ali Yilmaz ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Lipid Metabolism ◽  
Bile Acid ◽  
Gut Microbiota ◽  
Bile Acids ◽  
Lithocholic Acid ◽  
Acid Synthesis ◽  
Cholesterol Homeostasis ◽  
Secondary Bile Acid

The gut microbiome can impact brain health and is altered in Parkinson’s disease (PD). The vermiform appendix is a lymphoid tissue in the cecum implicated in the storage and regulation of the gut microbiota. We sought to determine whether the appendix microbiome is altered in PD and to analyze the biological consequences of the microbial alterations. We investigated the changes in the functional microbiota in the appendix of PD patients relative to controls (n = 12 PD, 16 C) by metatranscriptomic analysis. We found microbial dysbiosis affecting lipid metabolism, including an upregulation of bacteria responsible for secondary bile acid synthesis. We then quantitatively measure changes in bile acid abundance in PD relative to the controls in the appendix (n = 15 PD, 12 C) and ileum (n = 20 PD, 20 C). Bile acid analysis in the PD appendix reveals an increase in hydrophobic and secondary bile acids, deoxycholic acid (DCA) and lithocholic acid (LCA). Further proteomic and transcriptomic analysis in the appendix and ileum corroborated these findings, highlighting changes in the PD gut that are consistent with a disruption in bile acid control, including alterations in mediators of cholesterol homeostasis and lipid metabolism. Microbially derived toxic bile acids are heightened in PD, which suggests biliary abnormalities may play a role in PD pathogenesis.

scholarly journals Ileal bile acid transporter inhibitor improves hepatic steatosis by changing the gut microbiota dysbiosis in NAFLD model mice

2020 ◽  
Author(s):  
Masahiro Matsui ◽  
Shinya Fukunishi ◽  
Takashi Nakano ◽  
Takaaki Ueno ◽  
Kazuhide Higuchi ◽  
...  
Keyword(s):  
Bile Acid ◽  
Gut Microbiota ◽  
Hepatic Steatosis ◽  
Body Weight Gain ◽  
Alcoholic Fatty Liver ◽  
Fecal Microbiome ◽  
Α Diversity ◽  
Bile Acid Transporter ◽  
Acid Transporter ◽  
Gut Microbiota Dysbiosis

Abstract Background & Aim: Non-alcoholic fatty liver disease (NAFLD) which is characterized by excessive fat deposition in the liver that is not attributable to consumption of alcohol, highly prevalent in all countries. However, therapeutic agents approved for the treatment of NAFLD are lacking. An ileal bile acid transporter inhibitor (IBATi) which represents a new mode of treatment of chronic idiopathic constipation, leads to increased delivery of bile acids to the colon. We investigated the effect of IBATi for NAFLD through modification of the gut microbiota in mice. Results When HFD mice were treated with IBATi, their body weight gain and serum LDL levels were significantly suppressed and NAFLD activity score was significantly decreased. Treatment with IBATi ameliorated the increase of ileal Fgf15 mRNA and the decrease hepatic Cyp7a1 mRNA in HFD mice. The microbial compositions of the feces from these mice were analyzed using 16S rRNA sequencing. The decrease of α-diversity in gut microbiota induced by HFD was recovered by the IBATi treatment. To establish a cause-effect of the improvement efficacy of IBATi for NAFLD, we recolonized antibiotic solution-treated mice reared in SPF conditions by fecal microbiome transplantation (FMT) using stool from the HFD or HFD + IBATi mice. From FMT, the gut microbiota from HFD + IBATi mice prevented hepatic steatosis caused by HFD. Conclusions IBATi improves hepatic steatosis by changing the gut microbiota dysbiosis in NAFLD model mice.

Fecal Microbiome and Bile Acid Metabolome in Adult Short Bowel Syndrome

2021 ◽  
Author(s):  
Harold J. Boutte ◽  
Jacqueline Chen ◽  
Todd N. Wylie ◽  
Kristine M. Wylie ◽  
Yan Xie ◽  
...  
Keyword(s):  
Bile Acid ◽  
Gut Microbiota ◽  
Short Bowel Syndrome ◽  
Lithocholic Acid ◽  
Intestinal Failure ◽  
Patient Specific ◽  
Rrna Gene ◽  
Healthy Controls ◽  
Fecal Microbiome ◽  
Short Bowel

Background & Aims: Loss of functional small bowel surface area causes short bowel syndrome (SBS), intestinal failure, and parenteral nutrition (PN) dependence. The gut adaptive response following resection may be difficult to predict, and it may take up to two years to determine which patients will wean from PN. Here we examined features of gut microbiota and bile acid (BA) metabolism in determining adaptation and ability to wean from PN. Methods: Stool and sera were collected from healthy controls and from SBS patients (n=52) with ileostomy, jejunostomy, ileocolonic and jejunocolonic anastomoses fed with PN plus enteral nutrition or who were exclusively enterally fed. We undertook 16S rRNA gene sequencing, BA profiling and 7α-hydroxy-4-cholesten-3-one (C4) quantitation with LC-MS/MS, and serum amino acid analyses. Results: SBS patients exhibited altered gut microbiota with reduced gut microbial diversity compared to healthy controls. We observed differences in the microbiomes of SBS patients with ileostomy vs. jejunostomy, jejunocolonic vs. ileocolonic anastomoses, and PN-dependence compared to those who weaned from PN. Stool and serum BA composition and C4 concentrations were also altered in SBS patients, reflecting adaptive changes in enterohepatic BA cycling. Stools from patients who weaned from PN were enriched in secondary BAs including deoxycholic acid and lithocholic acid. Conclusions: Shifts in gut microbiota and BA metabolites may generate a favorable luminal environment in select SBS patients, promoting the ability to wean from PN. Pro-adaptive microbial species and select BA may provide novel targets for patient-specific therapies for SBS.

scholarly journals ChREBP-Mediated Regulation of Lipid Metabolism: Involvement of the Gut Microbiota, Liver, and Adipose Tissue

2020 ◽  
Vol 11 ◽  
Author(s):  
Katsumi Iizuka ◽  
Ken Takao ◽  
Daisuke Yabe
Keyword(s):  
Adipose Tissue ◽  
Fatty Acid ◽  
Lipid Metabolism ◽  
Gut Microbiota ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Acid Synthesis ◽  
Whole Body ◽  
Acetyl Coa ◽  
Alcoholic Fatty Liver

Carbohydrate response element-binding protein (ChREBP) plays an important role in the development of type 2 diabetes, dyslipidemia, and non-alcoholic fatty liver disease, as well as tumorigenesis. ChREBP is highly expressed in lipogenic organs, such as liver, intestine, and adipose tissue, in which it regulates the production of acetyl CoA from glucose by inducing Pklr and Acyl expression. It has recently been demonstrated that ChREBP plays a role in the conversion of gut microbiota-derived acetate to acetyl CoA by activating its target gene, Acss2, in the liver. ChREBP regulates fatty acid synthesis, elongation, and desaturation by inducing Acc1 and Fasn, elongation of long-chain fatty acids family member 6 (encoded by Elovl6), and Scd1 expression, respectively. ChREBP also regulates the formation of very low-density lipoprotein by inducing the expression of Mtp. Furthermore, it plays a crucial role in peripheral lipid metabolism by inducing Fgf21 expression, as well as that of Angptl3 and Angptl8, which are known to reduce peripheral lipoprotein lipase activity. In addition, ChREBP is involved in the production of palmitic-acid-5-hydroxystearic-acid, which increases insulin sensitivity in adipose tissue. Curiously, ChREBP is indirectly involved in fatty acid β-oxidation and subsequent ketogenesis. Thus, ChREBP regulates whole-body lipid metabolism by controlling the transcription of lipogenic enzymes and liver-derived cytokines.

scholarly journals Gut Microbiota Dysbiosis Associated with Bile Acid Metabolism in Neonatal Cholestasis Disease

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Meng Li ◽  
Sixiang Liu ◽  
Mingying Wang ◽  
Hongwei Hu ◽  
Jianwen Yin ◽  
...  
Keyword(s):  
Bile Acid ◽  
Gut Microbiota ◽  
Acid Metabolism ◽  
Bile Acid Metabolism ◽  
Neonatal Cholestasis ◽  
Gut Microbiota Dysbiosis

scholarly journals A metabolic pathway for bile acid dehydroxylation by the gut microbiome

2019 ◽  
Author(s):  
Masanori Funabashi ◽  
Tyler L. Grove ◽  
Victoria Pascal ◽  
Yug Varma ◽  
Molly E. McFadden ◽  
...  
Keyword(s):  
Bile Acid ◽  
Gut Microbiota ◽  
Lithocholic Acid ◽  
Primary Biliary Cholangitis ◽  
Bile Acid Pool ◽  
Secondary Bile Acid ◽  
Acid Pool ◽  
Road Map ◽  
Host Physiology

ABSTRACTThe gut microbiota synthesize hundreds of molecules, many of which are known to impact host physiology. Among the most abundant metabolites are the secondary bile acids deoxycholic acid (DCA) and lithocholic acid (LCA), which accumulate at ~500 μM and are known to block C. difficile growth1, promote hepatocellular carcinoma2, and modulate host metabolism via the GPCR TGR53. More broadly, DCA, LCA and their derivatives are a major component of the recirculating bile acid pool4; the size and composition of this pool are a target of therapies for primary biliary cholangitis and nonalcoholic steatohepatitis. Despite the clear impact of DCA and LCA on host physiology, incomplete knowledge of their biosynthetic genes and a lack of genetic tools in their native producer limit our ability to modulate secondary bile acid levels in the host. Here, we complete the pathway to DCA/LCA by assigning and characterizing enzymes for each of the steps in its reductive arm, revealing a strategy in which the A-B rings of the steroid core are transiently converted into an electron acceptor for two reductive steps carried out by Fe-S flavoenzymes. Using anaerobic in vitro reconstitution, we establish that a set of six enzymes is necessary and sufficient for the 8-step conversion of cholic acid to DCA. We then engineer the pathway into Clostridium sporogenes, conferring production of DCA and LCA on a non-producing commensal and demonstrating that a microbiome-derived pathway can be expressed and controlled heterologously. These data establish a complete pathway to two central components of the bile acid pool, and provide a road map for deorphaning and engineering pathways from the microbiome as a critical step toward controlling the metabolic output of the gut microbiota.

scholarly journals Mouse Model of Non-Alcoholic Fatty Liver Disease That Replicates the Human Disease

2020 ◽  
Vol 4 (Supplement_2) ◽  
pp. 700-700
Author(s):  
Kristy St.Rose ◽  
Jun Yan ◽  
Jorge Caviglia
Keyword(s):  
Gene Expression ◽  
Liver Disease ◽  
Gut Microbiota ◽  
Fatty Liver Disease ◽  
Liver Tumors ◽  
Western Diet ◽  
Alcoholic Fatty Liver ◽  
Alcoholic Fatty Liver Disease ◽  
Gut Microbiota Dysbiosis ◽  
Ay Mice

Abstract Objectives To develop a mouse model of non-alcoholic fatty liver disease (NAFLD) that replicates the characteristic of the disease in humans, including development of obesity, dysbiosis, fibrosis and liver tumors. Methods Agouti yellow (Ay) mice, which have hyperphagia, were fed a Western diet (WD) (42% kcal from fat, 341 g/Kg sucrose, and 0.2% cholesterol) and a drinking solution containing fructose and glucose equivalent to 42 g/L of high fructose corn syrup (HFCS). Wild-type mice fed a low-fat diet (LFD) (10% kcal from fat) served as lean controls. After 16 weeks of diet treatment, tissues were collected and analyzed. Obesity was evaluated via body weight and body composition. NAFLD was evaluated by histology and confirmed by liver lipid quantification, plasma ALT and AST levels, expression of inflammation-related genes, and fibrosis-specific staining. Gene expression profile was evaluated by RNAseq. Gut microbiota dysbiosis was evaluated by 16S rRNA metagenomics. Results Ay mice fed the Western diet and HFCS for 16 weeks developed obesity and NAFLD. Histological evaluation determined that the mice developed non-alcoholic steatohepatitis (NASH) with steatosis, liver injury, inflammation, and fibrosis. This was confirmed by the following analyses: In these mice, steatosis, quantified by liver TAG content, increased 4X when compared to lean controls. Liver injury, assessed by measuring plasma ALT and AST, increased 11X and 4X, respectively. Inflammation, evaluated by liver mRNA expression of Tnf and CCl2, increased 6X and 12X, respectively. Fibrosis, quantified morphometrically, increased 2.5X. Gene expression profiling showed increases in inflammation- and fibrosis-related pathways, similar to NASH in humans. In addition, these mice developed gut microbiota dysbiosis, with increased Bacteroidetes and Proteobacteria and decreased Firmicutes, as reported in NASH in humans. Finally, 60% of the Ay mice developed liver tumors when fed the WD + HFCS diet for one year. Conclusions Ay mice fed a Western diet and HFCS developed obesity, gut microbiota dysbiosis, and NASH, including fibrosis and tumors, replicating the characteristics of NASH in humans. We present this as a new model for studying NASH physiopathology and testing new therapies. Funding Sources NIH CUNY.

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