bims-liverm 2023-03-26 papers

Issue of 2023–03–26
seven papers selected by

Microbiol Spectr. 2023 Mar 21. e0333022

Amelioration of Colitis by a Gut Bacterial Consortium Producing Anti-Inflammatory Secondary Bile Acids.

Chunhua Zhou, Ying Wang, Cun Li, Zhiyong Xie, Lei Dai.

The Integrative Human Microbiome Project and other cohort studies have indicated that inflammatory bowel disease is accompanied by dysbiosis of gut microbiota, decreased production of secondary bile acids, and increased levels of primary bile acids. Secondary bile acids, such as ursodeoxycholic acid (UDCA) and lithocholic acid (LCA), have been reported to be anti-inflammatory, yet it remains to be studied whether introducing selected bacteria strains to restore bile acid metabolism of the gut microbiome can alleviate intestinal inflammation. In this study, we screened human gut bacterial strains for bile acid metabolism and designed a consortium of three species, including Clostridium AP sp000509125, Bacteroides ovatus, and Eubacterium limosum, and named it BAC (bile acid consortium). We showed that the three-strain gut bacterial consortium BAC is capable of converting conjugated primary bile acids taurochenodeoxycholic acid and glycochenodeoxycholic acid to secondary bile acids UDCA and LCA in vitro. Oral gavage treatment with BAC in mice resulted in protective effects against dextran sulfate sodium (DSS)-induced colitis, including reduced weight loss and increased colon length. Furthermore, BAC treatment increased the fecal level of bile acids, including UDCA and LCA. BAC treatment enhanced intestinal barrier function, which may be attributed to the increased activation of the bile acid receptor TGR5 by secondary bile acids. Finally, we examined the remodeling of gut microbiota by BAC treatment. Taken together, the three-strain gut bacterial consortium BAC restored the dysregulated bile acid metabolism and alleviated DSS-induced colitis. Our study provides a proof-of-concept demonstration that a rationally designed bacterial consortium can reshape the metabolism of the gut microbiome to treat diseases. IMPORTANCE Secondary bile acids have been reported to be anti-inflammatory, yet it remains to be studied whether introducing selected bacteria strains to restore bile acid metabolism of the gut microbiome can alleviate intestinal inflammation. To address this gap, we designed a consortium of human gut bacterial strains based on their metabolic capacity to produce secondary bile acids UDCA and LCA, and we evaluated the efficacy of single bacterial strains and the bacterial consortium in treating the murine colitis model. We found that oral gavage of the bacterial consortium to mice restored secondary bile acid metabolism to increase levels of UDCA and LCA, which induced the activation of TGR5 to improve gut-barrier integrity and reduced the inflammation in murine colitis. Overall, our study demonstrates that rationally designed bacterial consortia can reshape the metabolism of the gut microbiome and provides novel insights into the application of live biotherapeutics for treating IBD.

Keywords: bacterial consortium; colitis; gut microbiome; metabolomics; secondary bile acids; targeted metabolomics

DOI: https://doi.org/10.1128/spectrum.03330-22

bioRxiv. 2023 Mar 08. pii: 2023.03.06.531297. [Epub ahead of print]

Pioneer factor Foxa2 mediates chromatin conformation changes in ligand-dependent activation of nuclear receptor FXR.

Yi Hao, Lu Han, Anqi Wu, Irina M Bochkis.

Activation of nuclear receptors, a family of ligand-dependent transcription factors, is used extensively in development of drug targets. We have previously shown that pioneer factor Foxa2 opens chromatin for binding of nuclear receptors FXR and LXRα during acute ligand activation. FXR is activated by bile acids and deletion of Foxa2 in the liver results in intrahepatic cholestasis. We hypothesized that Foxa2 also enables chromatin conformational changes during ligand activation. We performed Foxa2 HiChIP to assess Foxa2-dependent long-range interactions in mouse livers treated with either vehicle control or FXR agonist GW4064. HiChIP contact analysis shows that global chromatin interactions are dramatically increased during FXR activation. Ligand-treated livers exhibit extensive redistribution of topological associated domains (TAD and substantial increase in Foxa2-anchored loops, suggesting Foxa2 is involved in dynamic chromatin conformational changes. We demonstrate that chromatin conformation, including genome-wide interactions, TADs, intra-chromosomal and inter-chromosomal Foxa2-anchored loops, drastically changes upon addition of FXR agonist. Hence, we determine a novel role for Foxa2 in enabling these conformational changes, extending its function in bile acid metabolism.

DOI: https://doi.org/10.1101/2023.03.06.531297

J Lipid Res. 2023 Mar 21. pii: S0022-2275(23)00034-2. [Epub ahead of print] 100361

Identification of bile acid-CoA:amino acid N-acyltransferase as the hepatic N-acyl taurine synthase for polyunsaturated fatty acids.

Samuel A J Trammell, Luke F Gamon, Kamil Gotfryd, Katja Thorøe Michler, Bandar D Alrehaili, Iben Rix, Filip K Knop, Pontus Gourdon, Yoon-Kwang Lee, Michael J Davies, Matthew P Gillum, Trisha J Grevengoed.

N-acyl taurines (NATs) are bioactive lipids with emerging roles in glucose homeostasis and lipid metabolism. The acyl-chains of hepatic and biliary NATs are enriched in poly-unsaturated fatty acids (PUFAs). Dietary supplementation with a class of PUFAs, the omega-3 fatty acids, increases their cognate NATs in mice and humans. However, the synthesis pathway of the PUFA-containing NATs remains undiscovered. Here, we report that human livers synthesize NATs and that the acyl-chain preference is similar in murine liver homogenates. In the mouse, we found that hepatic NAT synthase activity localizes to the peroxisome and depends upon an active-site cysteine. Using unbiased metabolomics and proteomics, we identified bile acid-CoA:amino acid N-acyltransferase (BAAT) as the likely hepatic NAT synthase in vitro. Subsequently, we confirmed that BAAT knockout livers lack up to 90% of NAT synthase activity and that biliary PUFA-containing NATs are significantly reduced compared to wildtype. In conclusion, we identified the in vivo PUFA-NAT synthase in the murine liver and expanded the known substrates of the bile acid-conjugating enzyme, BAAT, beyond classic bile acids to the synthesis of a novel class of bioactive lipids.

Keywords: Bile acids and salts/biosynthesis; Bile acids and salts/metabolism, Liver; N-acyl amino acid; N-acyl taurine; Omega-3 fatty acids; fatty acid amide hydrolase; metabolomics; peroxisomes; proteomics

DOI: https://doi.org/10.1016/j.jlr.2023.100361

Mol Nutr Food Res. 2023 Mar 20. e2200636

Bile acid alterations characterize the early onset and progression of nonalcoholic fatty liver disease in young mice fed with high fat and fructose diet.

Wenqing Xiang, Ana Liu, Cuifang Xu, Danni Zhang, Wei Li, Yan Ni.

SCOPE: Bile acid (BA) dysregulations are closely associated with non-alcoholic fatty liver disease (NAFLD) in both children and adults. Most of the previous clinical and animal studies investigated BA disturbances in the blood or feces samples. How BAs change within the enterohepatic circulation during the onset and progression of NAFLD as biomarkers deserves to be explored.
METHODS AND RESULTS: Four-week-old male mice were fed with a high-fat diet plus 4% w/v fructose drinking water (HFF) or chow diet with tap water (ND) for 4 and 12 weeks, correspondingly. In comparison, eight-week-old mice were fed with HFF or ND for 12 weeks. Targeted identification and quantification of BAs were performed to evaluate the systematic changes of BA profiles in six different anatomical sites of enterohepatic circulation, including liver, portal serum, ileum contents, cecum contents, feces, and urine. Compared to the ND group, the dysregulated BA metabolism had occurred in the HFF group after the 4-week intervention, represented by increased primary BAs and decreased hyocholic acid (HCA) species. After 12 weeks, the impact was more significant with increased secondary BA synthesis and excretion, particularly for lithocholic acid (LCA) species. More interestingly, the BA changes were more significant in younger mice in response to the same period of 12-week diet intervention.
CONCLUSIONS: We found the enterohepatic circulation of BAs changed and progressed along with the development of NAFLD, and the younger mice might be more susceptible to an unhealthy diet. HCA and LCA species are potential biomarkers for predicting and evaluating the development of NAFLD. This article is protected by copyright. All rights reserved.

Keywords: NAFLD; bile acids; early and advanced stage; enterohepatic circulation; young and adult comparison

DOI: https://doi.org/10.1002/mnfr.202200636

Zhonghua Gan Zang Bing Za Zhi. 2023 Jan 20. 31(1): 105-108

[Research progress of the regulatory role of autophagy in metabolic liver diseases].

Y X Li, F Ren, Y Chen.

Autophagy is one of several hepatic metabolic processes in which starved cells are supplied with glucose, free fatty acids, and amino acids to produce energy and synthesize new macromolecules. Moreover, it regulates the quantity and quality of mitochondria and other organelles. As the liver is a vital metabolic organ, specific forms of autophagy are necessary for maintaining liver homeostasis. Protein, fat, and sugar are the three primary nutrients that can be altered by different metabolic liver diseases. Drugs that have an effect on autophagy can either promote or inhibit autophagy, and as a result, it can either increase or inhibit the three major nutritional metabolisms that are affected by liver disease. Thus, this opens up a novel therapeutic option for liver disease.

Keywords: Cell autophagy; Liver disease; Metabolic regulation

DOI: https://doi.org/10.3760/cma.j.cn501113-20201106-00601

Front Pharmacol. 2023 ;14 1099935

Polygoni Multiflori Radix interferes with bile acid metabolism homeostasis by inhibiting Fxr transcription, leading to cholestasis.

Yihang Dai, Zhixin Jia, Cong Fang, Meixia Zhu, Xiaoning Yan, Yinhuan Zhang, Hao Wu, Menghan Feng, Lirong Liu, Beibei Huang, Yueting Li, Jie Liu, Hongbin Xiao.

Objective: To explore the possible mechanisms of cholestasis induced by Polygoni Multiflori Radix (PM). Methods: Low and high doses of water extract of PM were given to mice by gavage for 8 weeks. The serum biochemical indexes of aspartate aminotransferase (AST), alanine aminotransferase (ALT), glutamyltransferase (GGT) alkaline phosphatase (ALP) and so on were detected in the second, fourth, sixth, and eighth weeks after administration. At the end of the eighth week of administration, the bile acid metabolic profiles of liver and bile were screened by high-performance liquid chromatography tandem triple quadrupole mass spectrometry (HPLC-QQQ-MS/MS). Liver pathological changes were observed by hematoxylin and eosin staining. Real-time quantitative polymerase chain reaction (RT-qPCR) was used to detect the mRNA transcription of the target genes and Western blotting (WB) was used to the detect target protein expression. Results: Biochemical tests results showed the values of ALP and GGT were two and three times greater than the normal values respectively, and the value of R was less than 2. Histopathology also showed that PM caused lymphocyte infiltration, a small amount of hepatocyte necrosis and nuclear fragmentation in mouse liver. The proliferation of bile duct epithelial cells was observed in the high group. These results indicated that PM may lead to cholestatic liver injury. HPLC-QQQ-MS/MS analysis with the multivariate statistical analysis revealed significant alterations of individual bile acids in liver and gallbladder as compared to those of the control group. RT-qPCR showed that the transcription of Fxr, Shp, Bsep, Bacs, Mdr2, and Ugt1a1 were downregulated and that of Cyp7a1, Mrp3, and Cyp3a11 was significantly upregulated in the treatment group. WB demonstrated that PM also markedly downregulated the protein expression of FXR, BSEP, and MDR2, and upregulated CYP7A1. Conclusion: PM inhibited the expression of FXR, which reduced the expression of MDR2 and BSEP, leading to the obstruction of bile acids outflow, and increased the expression of CYP7A1, resulting in an increase of intrahepatic bile acid synthesis, which can lead to cholestasis.

Keywords: Radix Polygoni Multiflori; bile acid metabolism; bile salt output pump; cholestasis; cholesterol-7α-hydroxylase; farnesoid X receptor

DOI: https://doi.org/10.3389/fphar.2023.1099935

FASEB J. 2023 Apr;37(4): e22881

FGF1 ameliorates obesity-associated hepatic steatosis by reversing IGFBP2 hypermethylation.

Jie Wang, Feng Zhang, Weiwei Yang, Dandan Gao, Linglong Yang, Chenhua Yu, Chengshui Chen, Xiaokun Li, Jin-San Zhang.

Obesity is a major contributing factor for metabolic-associated fatty liver disease (MAFLD). Fibroblast growth factor (FGF) 1 is the first paracrine FGF family member identified to exhibit promising metabolic regulatory properties capable of conferring glucose-lowering and insulin-sensitizing effect. This study explores the role and molecular underpinnings of FGF1 in obesity-associated hepatic steatosis. In a mouse high-fat diet (HFD)-induced MAFLD model, chronic treatment with recombinant FGF1(rFGF1) was found to effectively reduce the severity of insulin resistance, hyperlipidemia, and inflammation. FGF1 treatment decreased lipid accumulation in the mouse liver and palmitic acid-treated AML12 cells. These effects were associated with decreased mature form SREBF1 expression and its target genes FASN and SCD1. Interestingly, we uncovered that rFGF1 significantly induced IGFBP2 expression at both mRNA and protein levels in HFD-fed mouse livers and cultured hepatocytes treated with palmitic acid. Adeno-associated virus-mediated IGFBP2 suppression significantly diminished the therapeutic benefit of rFGF1 on MAFLD-associated phenotypes, indicating that IGFBP2 plays a crucial role in the FGF1-mediated reduction of hepatic steatosis. Further analysis revealed that rFGF1 treatment reduces the recruitment of DNA methyltransferase 3 alpha to the IGFBP2 genomic locus, leading to decreased IGFBP2 gene methylation and increased mRNA and protein expression. Collectively, our findings reveal FGF1 modulation of lipid metabolism via epigenetic regulation of IGFBP2 expression, and unravel the therapeutic potential of the FGF1-IGFBP2 axis in metabolic diseases associated with obesity.

Keywords: DNMT3A; FGF1; IGFBP2; metabolic-associated fatty liver disease; methylation; obesity

DOI: https://doi.org/10.1096/fj.202201950R