|
1
|
Chen W, Qiu C, Hao J, Liao J, Lurmann F, Pavlovic N, Habre R, Jones DP, Bastain TM, Breton CV, Chen Z. Maternal metabolomics linking prenatal exposure to fine particulate matter and birth weight: a cross-sectional analysis of the MADRES cohort. Environ Health 2025; 24:14. [PMID: 40158186 PMCID: PMC11954335 DOI: 10.1186/s12940-025-01162-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2024] [Accepted: 02/19/2025] [Indexed: 04/01/2025]
Abstract
BACKGROUND Prenatal exposure to air pollution has been associated with an increased risk of low birth weight. Disrupted metabolism may serve as an underlying mechanism, but the specific metabolic pathways involved remain unclear. METHODS In the Maternal and Developmental Risks from Environmental and Social Stressors (MADRES) study, 382 third-trimester maternal serum samples were analyzed for untargeted metabolomics using liquid chromatography with Fourier transform high-resolution mass spectrometry. Ambient concentrations of fine particulate matter (PM2.5), particulate matter ≤ 10 μm in diameter (PM10), nitrogen dioxide (NO2), and ozone (O3) were estimated using inverse-distance-squared weighted spatial interpolation based on daily residential histories. Birth weight was retrieved from medical records. Linear regression identified metabolomic features associated with air pollution exposure or birth weight, followed by Mummichog pathway enrichment and mediation analyses for the selected features. RESULTS Second-trimester PM2.5 exposure was associated with lower birth weight. Fourteen metabolic pathways were significantly associated with second-trimester PM2.5 exposure, with C21-steroid hormone biosynthesis and metabolism showing the most significant association. Sixteen metabolic pathways were significantly associated with birth weight, with vitamin A (retinol) metabolism being the most significantly enriched pathway. Seven pathways were associated with both PM2.5 exposure and birth weight, including C21-steroid hormone biosynthesis and metabolism, bile acid biosynthesis, tyrosine metabolism, ascorbate (vitamin C) and aldarate metabolism, vitamin D3 (cholecalciferol) metabolism, vitamin A (retinol) metabolism, and pyrimidine metabolism. Overweight or obese women exhibited more metabolomic features and metabolic pathways associated with PM2.5 exposure compared to underweight or normal-weight women. No associations were observed between PM10, NO2, or O3 and birth weight. CONCLUSIONS Maternal metabolic pathways involving steroid metabolism, oxidative stress and inflammation, vitamin metabolism, and DNA damage may link prenatal PM2.5 exposure to lower birth weight, with overweight or obese women potentially more susceptible to these metabolic disruptions.
Collapse
Affiliation(s)
- Wu Chen
- Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Chenyu Qiu
- Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Jiayuan Hao
- Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Jiawen Liao
- Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | | | | | - Rima Habre
- Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Dean P Jones
- Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Department of Medicine, School of Medicine, Emory University, Atlanta, GA, USA
| | - Theresa M Bastain
- Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Carrie V Breton
- Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Zhanghua Chen
- Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
| |
Collapse
|
|
2
|
Wei Y, Mao H, Liu Q, Fang W, Zhang T, Xu Y, Zhang W, Chen B, Zheng Y, Hu X. Lipid metabolism and microbial regulation analyses provide insights into the energy-saving strategies of hibernating snakes. Commun Biol 2025; 8:45. [PMID: 39800781 PMCID: PMC11725596 DOI: 10.1038/s42003-025-07493-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Accepted: 01/08/2025] [Indexed: 01/16/2025] Open
Abstract
Hibernation is a necessary means for animals to maintain survival while coping with low temperatures and food shortages. While most studies have largely focused on mammalian hibernation, its reptilian equivalent has been less studied. In order to provide insights into the energy metabolism and potential microbial regulatory mechanisms in hibernating snakes, the serum, liver, gut content samples were measured by multi-omic methods. Here we show the active snakes have more vigorous lipid metabolism, whereas snakes in hibernation groups have higher sphingolipid metabolism. Furthermore, the results indicate that the potential energy supply pathway was gluconeogenesis. Microbial analysis reveals that Proteobacteria and Firmicutes showed dynamic changes with the transformation among active, pre-hibernation and hibernation periods. The correlation analysis reveals the potential role of Romboutsia, Providencia and Vagococcus in regulating above metabolism by producing certain metabolites. The results advance the understanding of the complex energy-saving strategy in hibernating poikilotherms.
Collapse
Affiliation(s)
- Yuting Wei
- College of Animal Science and Technology, Jiangxi Agricultural University, Nanchang, China
| | - Huirong Mao
- College of Animal Science and Technology, Jiangxi Agricultural University, Nanchang, China
| | - Qiuhong Liu
- College of Animal Science and Technology, Jiangxi Agricultural University, Nanchang, China
| | - Wenjie Fang
- College of Animal Science and Technology, Jiangxi Agricultural University, Nanchang, China
| | - Tianxiang Zhang
- Institute of Wildlife Conservation, Jiangxi Academy of Forestry, Nanchang, China
| | - Yongtao Xu
- Jiangxi Provincial Key Laboratory of Conservation Biology, Jiangxi Agricultural University, Nanchang, China
- College of Forestry, Jiangxi Agricultural University, Nanchang, China
| | - Weiwei Zhang
- Jiangxi Provincial Key Laboratory of Conservation Biology, Jiangxi Agricultural University, Nanchang, China
- College of Forestry, Jiangxi Agricultural University, Nanchang, China
| | - Biao Chen
- College of Animal Science and Technology, Jiangxi Agricultural University, Nanchang, China
| | - Yunlin Zheng
- College of Animal Science and Technology, Jiangxi Agricultural University, Nanchang, China
| | - Xiaolong Hu
- College of Animal Science and Technology, Jiangxi Agricultural University, Nanchang, China.
- Jiangxi Provincial Key Laboratory of Conservation Biology, Jiangxi Agricultural University, Nanchang, China.
| |
Collapse
|
|
3
|
Zhang Y, Chen Z, Xiao Y, Wu T, Yang H, Liu Y, Zhou R, Xiong Y, Xiong Y, Yang X, Zhou J, Zhou H, Zhang W, Shu Y, Li X, Guo F, Yin J, Liao S, Li Q, Zhu P. Effects of Compound Probiotics on Pharmacokinetics of Cytochrome 450 Probe Drugs in Rats. Drug Metab Dispos 2024; 52:1297-1312. [PMID: 39214665 DOI: 10.1124/dmd.124.001837] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2024] [Revised: 08/26/2024] [Accepted: 08/28/2024] [Indexed: 09/04/2024] Open
Abstract
Compound probiotics have been widely used and commonly coadministered with other drugs for treating various chronic illnesses, yet their effects on drug pharmacokinetics remain underexplored. This study elucidated the impact of VSL#3 on the metabolism of probe drugs for cytochrome P450 enzymes (P450s), specifically omeprazole, tolbutamide, midazolam, metoprolol, phenacetin, and chlorzoxazone. Male Wistar rats were administered drinking water containing VSL#3 or not for 14 days and then intragastrically administered a P450 probe cocktail; this was done to investigate the host P450's metabolic phenotype. Stool, liver/jejunum, and serum samples were collected for 16S ribosomal RNA sequencing, RNA sequencing, and bile acid profiling. The results indicated significant differences in both α and β diversity of intestinal microbial composition between the probiotic and vehicle groups in rats. In the probiotic group, the bioavailability of omeprazole increased by 269.9%, whereas those of tolbutamide and chlorpropamide decreased by 28.1% and 27.4%, respectively. The liver and jejunum exhibited 1417 and 4004 differentially expressed genes, respectively, between the two groups. In the probiotic group, most of P450 genes were upregulated in the liver but downregulated in the jejunum. The expression of genes encoding metabolic enzymes and drug transporters also changed. The serum-conjugated bile acids in the probiotic group were significantly reduced. Shorter duodenal villi and longer ileal villi were found in the probiotic group. In summary, VSL#3 administration altered the gut microbiota, host drug-processing gene expression, and intestinal structure in rats, which could be reasons for pharmacokinetic changes. SIGNIFICANCE STATEMENT: This study focused on the effects of the probiotic VSL#3 on the pharmacokinetic profile of cytochrome P450 probe drugs and the expression of host drug metabolism genes. Compared with previous studies, the present study provides a comprehensive explanation for the host drug metabolism profile modified by probiotics, combined here with the bile acid profile and histopathological analysis.
Collapse
Affiliation(s)
- Yanjuan Zhang
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China (Y.Z., Y.X., T.W., H.Y., Y.L., R.Z., Yal.X., Yan.X., X.Y., J.Z., H.Z., W.Z., Q.L., P.Z.); Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha, China (Y.Z., Y.X., T.W., H.Y., Y.L., R.Z., Yal.X., Yan.X., X.Y., J.Z., H.Z., W.Z., Q.L., P.Z.); Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha, China (Y.Z., Y.X., T.W., H.Y., Y.L., R.Z., Yal.X., Yan.X., X.Y., J.Z., H.Z., W.Z., Q.L., P.Z.); National Clinical Research Center for Geriatric Disorders, Changsha, China (Y.Z., Y.X., T.W., H.Y., Y.L., R.Z., Yal.X., Yan.X., X.Y., J.Z., H.Z., W.Z., Q.L., P.Z.); Department of Hypertension, Xingsha Hospital, Changsha, China (Z.C., F.G., J.Y., S.L.); Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland at Baltimore, Maryland (Y.S.); and Key Specialty of Clinical Pharmacy, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China (X.L.)
| | - Zhi Chen
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China (Y.Z., Y.X., T.W., H.Y., Y.L., R.Z., Yal.X., Yan.X., X.Y., J.Z., H.Z., W.Z., Q.L., P.Z.); Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha, China (Y.Z., Y.X., T.W., H.Y., Y.L., R.Z., Yal.X., Yan.X., X.Y., J.Z., H.Z., W.Z., Q.L., P.Z.); Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha, China (Y.Z., Y.X., T.W., H.Y., Y.L., R.Z., Yal.X., Yan.X., X.Y., J.Z., H.Z., W.Z., Q.L., P.Z.); National Clinical Research Center for Geriatric Disorders, Changsha, China (Y.Z., Y.X., T.W., H.Y., Y.L., R.Z., Yal.X., Yan.X., X.Y., J.Z., H.Z., W.Z., Q.L., P.Z.); Department of Hypertension, Xingsha Hospital, Changsha, China (Z.C., F.G., J.Y., S.L.); Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland at Baltimore, Maryland (Y.S.); and Key Specialty of Clinical Pharmacy, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China (X.L.)
| | - Yayi Xiao
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China (Y.Z., Y.X., T.W., H.Y., Y.L., R.Z., Yal.X., Yan.X., X.Y., J.Z., H.Z., W.Z., Q.L., P.Z.); Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha, China (Y.Z., Y.X., T.W., H.Y., Y.L., R.Z., Yal.X., Yan.X., X.Y., J.Z., H.Z., W.Z., Q.L., P.Z.); Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha, China (Y.Z., Y.X., T.W., H.Y., Y.L., R.Z., Yal.X., Yan.X., X.Y., J.Z., H.Z., W.Z., Q.L., P.Z.); National Clinical Research Center for Geriatric Disorders, Changsha, China (Y.Z., Y.X., T.W., H.Y., Y.L., R.Z., Yal.X., Yan.X., X.Y., J.Z., H.Z., W.Z., Q.L., P.Z.); Department of Hypertension, Xingsha Hospital, Changsha, China (Z.C., F.G., J.Y., S.L.); Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland at Baltimore, Maryland (Y.S.); and Key Specialty of Clinical Pharmacy, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China (X.L.)
| | - Tianyuan Wu
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China (Y.Z., Y.X., T.W., H.Y., Y.L., R.Z., Yal.X., Yan.X., X.Y., J.Z., H.Z., W.Z., Q.L., P.Z.); Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha, China (Y.Z., Y.X., T.W., H.Y., Y.L., R.Z., Yal.X., Yan.X., X.Y., J.Z., H.Z., W.Z., Q.L., P.Z.); Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha, China (Y.Z., Y.X., T.W., H.Y., Y.L., R.Z., Yal.X., Yan.X., X.Y., J.Z., H.Z., W.Z., Q.L., P.Z.); National Clinical Research Center for Geriatric Disorders, Changsha, China (Y.Z., Y.X., T.W., H.Y., Y.L., R.Z., Yal.X., Yan.X., X.Y., J.Z., H.Z., W.Z., Q.L., P.Z.); Department of Hypertension, Xingsha Hospital, Changsha, China (Z.C., F.G., J.Y., S.L.); Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland at Baltimore, Maryland (Y.S.); and Key Specialty of Clinical Pharmacy, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China (X.L.)
| | - Haijun Yang
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China (Y.Z., Y.X., T.W., H.Y., Y.L., R.Z., Yal.X., Yan.X., X.Y., J.Z., H.Z., W.Z., Q.L., P.Z.); Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha, China (Y.Z., Y.X., T.W., H.Y., Y.L., R.Z., Yal.X., Yan.X., X.Y., J.Z., H.Z., W.Z., Q.L., P.Z.); Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha, China (Y.Z., Y.X., T.W., H.Y., Y.L., R.Z., Yal.X., Yan.X., X.Y., J.Z., H.Z., W.Z., Q.L., P.Z.); National Clinical Research Center for Geriatric Disorders, Changsha, China (Y.Z., Y.X., T.W., H.Y., Y.L., R.Z., Yal.X., Yan.X., X.Y., J.Z., H.Z., W.Z., Q.L., P.Z.); Department of Hypertension, Xingsha Hospital, Changsha, China (Z.C., F.G., J.Y., S.L.); Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland at Baltimore, Maryland (Y.S.); and Key Specialty of Clinical Pharmacy, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China (X.L.)
| | - Yujie Liu
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China (Y.Z., Y.X., T.W., H.Y., Y.L., R.Z., Yal.X., Yan.X., X.Y., J.Z., H.Z., W.Z., Q.L., P.Z.); Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha, China (Y.Z., Y.X., T.W., H.Y., Y.L., R.Z., Yal.X., Yan.X., X.Y., J.Z., H.Z., W.Z., Q.L., P.Z.); Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha, China (Y.Z., Y.X., T.W., H.Y., Y.L., R.Z., Yal.X., Yan.X., X.Y., J.Z., H.Z., W.Z., Q.L., P.Z.); National Clinical Research Center for Geriatric Disorders, Changsha, China (Y.Z., Y.X., T.W., H.Y., Y.L., R.Z., Yal.X., Yan.X., X.Y., J.Z., H.Z., W.Z., Q.L., P.Z.); Department of Hypertension, Xingsha Hospital, Changsha, China (Z.C., F.G., J.Y., S.L.); Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland at Baltimore, Maryland (Y.S.); and Key Specialty of Clinical Pharmacy, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China (X.L.)
| | - Rong Zhou
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China (Y.Z., Y.X., T.W., H.Y., Y.L., R.Z., Yal.X., Yan.X., X.Y., J.Z., H.Z., W.Z., Q.L., P.Z.); Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha, China (Y.Z., Y.X., T.W., H.Y., Y.L., R.Z., Yal.X., Yan.X., X.Y., J.Z., H.Z., W.Z., Q.L., P.Z.); Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha, China (Y.Z., Y.X., T.W., H.Y., Y.L., R.Z., Yal.X., Yan.X., X.Y., J.Z., H.Z., W.Z., Q.L., P.Z.); National Clinical Research Center for Geriatric Disorders, Changsha, China (Y.Z., Y.X., T.W., H.Y., Y.L., R.Z., Yal.X., Yan.X., X.Y., J.Z., H.Z., W.Z., Q.L., P.Z.); Department of Hypertension, Xingsha Hospital, Changsha, China (Z.C., F.G., J.Y., S.L.); Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland at Baltimore, Maryland (Y.S.); and Key Specialty of Clinical Pharmacy, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China (X.L.)
| | - Yalan Xiong
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China (Y.Z., Y.X., T.W., H.Y., Y.L., R.Z., Yal.X., Yan.X., X.Y., J.Z., H.Z., W.Z., Q.L., P.Z.); Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha, China (Y.Z., Y.X., T.W., H.Y., Y.L., R.Z., Yal.X., Yan.X., X.Y., J.Z., H.Z., W.Z., Q.L., P.Z.); Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha, China (Y.Z., Y.X., T.W., H.Y., Y.L., R.Z., Yal.X., Yan.X., X.Y., J.Z., H.Z., W.Z., Q.L., P.Z.); National Clinical Research Center for Geriatric Disorders, Changsha, China (Y.Z., Y.X., T.W., H.Y., Y.L., R.Z., Yal.X., Yan.X., X.Y., J.Z., H.Z., W.Z., Q.L., P.Z.); Department of Hypertension, Xingsha Hospital, Changsha, China (Z.C., F.G., J.Y., S.L.); Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland at Baltimore, Maryland (Y.S.); and Key Specialty of Clinical Pharmacy, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China (X.L.)
| | - Yanling Xiong
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China (Y.Z., Y.X., T.W., H.Y., Y.L., R.Z., Yal.X., Yan.X., X.Y., J.Z., H.Z., W.Z., Q.L., P.Z.); Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha, China (Y.Z., Y.X., T.W., H.Y., Y.L., R.Z., Yal.X., Yan.X., X.Y., J.Z., H.Z., W.Z., Q.L., P.Z.); Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha, China (Y.Z., Y.X., T.W., H.Y., Y.L., R.Z., Yal.X., Yan.X., X.Y., J.Z., H.Z., W.Z., Q.L., P.Z.); National Clinical Research Center for Geriatric Disorders, Changsha, China (Y.Z., Y.X., T.W., H.Y., Y.L., R.Z., Yal.X., Yan.X., X.Y., J.Z., H.Z., W.Z., Q.L., P.Z.); Department of Hypertension, Xingsha Hospital, Changsha, China (Z.C., F.G., J.Y., S.L.); Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland at Baltimore, Maryland (Y.S.); and Key Specialty of Clinical Pharmacy, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China (X.L.)
| | - Xuechun Yang
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China (Y.Z., Y.X., T.W., H.Y., Y.L., R.Z., Yal.X., Yan.X., X.Y., J.Z., H.Z., W.Z., Q.L., P.Z.); Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha, China (Y.Z., Y.X., T.W., H.Y., Y.L., R.Z., Yal.X., Yan.X., X.Y., J.Z., H.Z., W.Z., Q.L., P.Z.); Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha, China (Y.Z., Y.X., T.W., H.Y., Y.L., R.Z., Yal.X., Yan.X., X.Y., J.Z., H.Z., W.Z., Q.L., P.Z.); National Clinical Research Center for Geriatric Disorders, Changsha, China (Y.Z., Y.X., T.W., H.Y., Y.L., R.Z., Yal.X., Yan.X., X.Y., J.Z., H.Z., W.Z., Q.L., P.Z.); Department of Hypertension, Xingsha Hospital, Changsha, China (Z.C., F.G., J.Y., S.L.); Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland at Baltimore, Maryland (Y.S.); and Key Specialty of Clinical Pharmacy, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China (X.L.)
| | - Jian Zhou
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China (Y.Z., Y.X., T.W., H.Y., Y.L., R.Z., Yal.X., Yan.X., X.Y., J.Z., H.Z., W.Z., Q.L., P.Z.); Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha, China (Y.Z., Y.X., T.W., H.Y., Y.L., R.Z., Yal.X., Yan.X., X.Y., J.Z., H.Z., W.Z., Q.L., P.Z.); Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha, China (Y.Z., Y.X., T.W., H.Y., Y.L., R.Z., Yal.X., Yan.X., X.Y., J.Z., H.Z., W.Z., Q.L., P.Z.); National Clinical Research Center for Geriatric Disorders, Changsha, China (Y.Z., Y.X., T.W., H.Y., Y.L., R.Z., Yal.X., Yan.X., X.Y., J.Z., H.Z., W.Z., Q.L., P.Z.); Department of Hypertension, Xingsha Hospital, Changsha, China (Z.C., F.G., J.Y., S.L.); Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland at Baltimore, Maryland (Y.S.); and Key Specialty of Clinical Pharmacy, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China (X.L.)
| | - Honghao Zhou
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China (Y.Z., Y.X., T.W., H.Y., Y.L., R.Z., Yal.X., Yan.X., X.Y., J.Z., H.Z., W.Z., Q.L., P.Z.); Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha, China (Y.Z., Y.X., T.W., H.Y., Y.L., R.Z., Yal.X., Yan.X., X.Y., J.Z., H.Z., W.Z., Q.L., P.Z.); Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha, China (Y.Z., Y.X., T.W., H.Y., Y.L., R.Z., Yal.X., Yan.X., X.Y., J.Z., H.Z., W.Z., Q.L., P.Z.); National Clinical Research Center for Geriatric Disorders, Changsha, China (Y.Z., Y.X., T.W., H.Y., Y.L., R.Z., Yal.X., Yan.X., X.Y., J.Z., H.Z., W.Z., Q.L., P.Z.); Department of Hypertension, Xingsha Hospital, Changsha, China (Z.C., F.G., J.Y., S.L.); Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland at Baltimore, Maryland (Y.S.); and Key Specialty of Clinical Pharmacy, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China (X.L.)
| | - Wei Zhang
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China (Y.Z., Y.X., T.W., H.Y., Y.L., R.Z., Yal.X., Yan.X., X.Y., J.Z., H.Z., W.Z., Q.L., P.Z.); Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha, China (Y.Z., Y.X., T.W., H.Y., Y.L., R.Z., Yal.X., Yan.X., X.Y., J.Z., H.Z., W.Z., Q.L., P.Z.); Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha, China (Y.Z., Y.X., T.W., H.Y., Y.L., R.Z., Yal.X., Yan.X., X.Y., J.Z., H.Z., W.Z., Q.L., P.Z.); National Clinical Research Center for Geriatric Disorders, Changsha, China (Y.Z., Y.X., T.W., H.Y., Y.L., R.Z., Yal.X., Yan.X., X.Y., J.Z., H.Z., W.Z., Q.L., P.Z.); Department of Hypertension, Xingsha Hospital, Changsha, China (Z.C., F.G., J.Y., S.L.); Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland at Baltimore, Maryland (Y.S.); and Key Specialty of Clinical Pharmacy, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China (X.L.)
| | - Yan Shu
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China (Y.Z., Y.X., T.W., H.Y., Y.L., R.Z., Yal.X., Yan.X., X.Y., J.Z., H.Z., W.Z., Q.L., P.Z.); Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha, China (Y.Z., Y.X., T.W., H.Y., Y.L., R.Z., Yal.X., Yan.X., X.Y., J.Z., H.Z., W.Z., Q.L., P.Z.); Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha, China (Y.Z., Y.X., T.W., H.Y., Y.L., R.Z., Yal.X., Yan.X., X.Y., J.Z., H.Z., W.Z., Q.L., P.Z.); National Clinical Research Center for Geriatric Disorders, Changsha, China (Y.Z., Y.X., T.W., H.Y., Y.L., R.Z., Yal.X., Yan.X., X.Y., J.Z., H.Z., W.Z., Q.L., P.Z.); Department of Hypertension, Xingsha Hospital, Changsha, China (Z.C., F.G., J.Y., S.L.); Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland at Baltimore, Maryland (Y.S.); and Key Specialty of Clinical Pharmacy, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China (X.L.)
| | - Xiong Li
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China (Y.Z., Y.X., T.W., H.Y., Y.L., R.Z., Yal.X., Yan.X., X.Y., J.Z., H.Z., W.Z., Q.L., P.Z.); Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha, China (Y.Z., Y.X., T.W., H.Y., Y.L., R.Z., Yal.X., Yan.X., X.Y., J.Z., H.Z., W.Z., Q.L., P.Z.); Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha, China (Y.Z., Y.X., T.W., H.Y., Y.L., R.Z., Yal.X., Yan.X., X.Y., J.Z., H.Z., W.Z., Q.L., P.Z.); National Clinical Research Center for Geriatric Disorders, Changsha, China (Y.Z., Y.X., T.W., H.Y., Y.L., R.Z., Yal.X., Yan.X., X.Y., J.Z., H.Z., W.Z., Q.L., P.Z.); Department of Hypertension, Xingsha Hospital, Changsha, China (Z.C., F.G., J.Y., S.L.); Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland at Baltimore, Maryland (Y.S.); and Key Specialty of Clinical Pharmacy, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China (X.L.)
| | - Fugang Guo
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China (Y.Z., Y.X., T.W., H.Y., Y.L., R.Z., Yal.X., Yan.X., X.Y., J.Z., H.Z., W.Z., Q.L., P.Z.); Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha, China (Y.Z., Y.X., T.W., H.Y., Y.L., R.Z., Yal.X., Yan.X., X.Y., J.Z., H.Z., W.Z., Q.L., P.Z.); Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha, China (Y.Z., Y.X., T.W., H.Y., Y.L., R.Z., Yal.X., Yan.X., X.Y., J.Z., H.Z., W.Z., Q.L., P.Z.); National Clinical Research Center for Geriatric Disorders, Changsha, China (Y.Z., Y.X., T.W., H.Y., Y.L., R.Z., Yal.X., Yan.X., X.Y., J.Z., H.Z., W.Z., Q.L., P.Z.); Department of Hypertension, Xingsha Hospital, Changsha, China (Z.C., F.G., J.Y., S.L.); Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland at Baltimore, Maryland (Y.S.); and Key Specialty of Clinical Pharmacy, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China (X.L.)
| | - Jianhui Yin
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China (Y.Z., Y.X., T.W., H.Y., Y.L., R.Z., Yal.X., Yan.X., X.Y., J.Z., H.Z., W.Z., Q.L., P.Z.); Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha, China (Y.Z., Y.X., T.W., H.Y., Y.L., R.Z., Yal.X., Yan.X., X.Y., J.Z., H.Z., W.Z., Q.L., P.Z.); Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha, China (Y.Z., Y.X., T.W., H.Y., Y.L., R.Z., Yal.X., Yan.X., X.Y., J.Z., H.Z., W.Z., Q.L., P.Z.); National Clinical Research Center for Geriatric Disorders, Changsha, China (Y.Z., Y.X., T.W., H.Y., Y.L., R.Z., Yal.X., Yan.X., X.Y., J.Z., H.Z., W.Z., Q.L., P.Z.); Department of Hypertension, Xingsha Hospital, Changsha, China (Z.C., F.G., J.Y., S.L.); Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland at Baltimore, Maryland (Y.S.); and Key Specialty of Clinical Pharmacy, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China (X.L.)
| | - Shang Liao
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China (Y.Z., Y.X., T.W., H.Y., Y.L., R.Z., Yal.X., Yan.X., X.Y., J.Z., H.Z., W.Z., Q.L., P.Z.); Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha, China (Y.Z., Y.X., T.W., H.Y., Y.L., R.Z., Yal.X., Yan.X., X.Y., J.Z., H.Z., W.Z., Q.L., P.Z.); Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha, China (Y.Z., Y.X., T.W., H.Y., Y.L., R.Z., Yal.X., Yan.X., X.Y., J.Z., H.Z., W.Z., Q.L., P.Z.); National Clinical Research Center for Geriatric Disorders, Changsha, China (Y.Z., Y.X., T.W., H.Y., Y.L., R.Z., Yal.X., Yan.X., X.Y., J.Z., H.Z., W.Z., Q.L., P.Z.); Department of Hypertension, Xingsha Hospital, Changsha, China (Z.C., F.G., J.Y., S.L.); Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland at Baltimore, Maryland (Y.S.); and Key Specialty of Clinical Pharmacy, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China (X.L.)
| | - Qing Li
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China (Y.Z., Y.X., T.W., H.Y., Y.L., R.Z., Yal.X., Yan.X., X.Y., J.Z., H.Z., W.Z., Q.L., P.Z.); Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha, China (Y.Z., Y.X., T.W., H.Y., Y.L., R.Z., Yal.X., Yan.X., X.Y., J.Z., H.Z., W.Z., Q.L., P.Z.); Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha, China (Y.Z., Y.X., T.W., H.Y., Y.L., R.Z., Yal.X., Yan.X., X.Y., J.Z., H.Z., W.Z., Q.L., P.Z.); National Clinical Research Center for Geriatric Disorders, Changsha, China (Y.Z., Y.X., T.W., H.Y., Y.L., R.Z., Yal.X., Yan.X., X.Y., J.Z., H.Z., W.Z., Q.L., P.Z.); Department of Hypertension, Xingsha Hospital, Changsha, China (Z.C., F.G., J.Y., S.L.); Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland at Baltimore, Maryland (Y.S.); and Key Specialty of Clinical Pharmacy, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China (X.L.)
| | - Peng Zhu
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China (Y.Z., Y.X., T.W., H.Y., Y.L., R.Z., Yal.X., Yan.X., X.Y., J.Z., H.Z., W.Z., Q.L., P.Z.); Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha, China (Y.Z., Y.X., T.W., H.Y., Y.L., R.Z., Yal.X., Yan.X., X.Y., J.Z., H.Z., W.Z., Q.L., P.Z.); Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha, China (Y.Z., Y.X., T.W., H.Y., Y.L., R.Z., Yal.X., Yan.X., X.Y., J.Z., H.Z., W.Z., Q.L., P.Z.); National Clinical Research Center for Geriatric Disorders, Changsha, China (Y.Z., Y.X., T.W., H.Y., Y.L., R.Z., Yal.X., Yan.X., X.Y., J.Z., H.Z., W.Z., Q.L., P.Z.); Department of Hypertension, Xingsha Hospital, Changsha, China (Z.C., F.G., J.Y., S.L.); Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland at Baltimore, Maryland (Y.S.); and Key Specialty of Clinical Pharmacy, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China (X.L.)
| |
Collapse
|
|
4
|
Zhang W, Yao W, Meng Y, Luo F, Han M, Mu Q, Jiang L, He W, Fan X, Wang W, Wang B. Effect of Moniezia Benedeni infection on ileal transcriptome profile characteristics of sheep. BMC Genomics 2024; 25:933. [PMID: 39370521 PMCID: PMC11457389 DOI: 10.1186/s12864-024-10853-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Accepted: 09/30/2024] [Indexed: 10/08/2024] Open
Abstract
BACKGROUND The intestinal mucosal immune system, renowned for its precise and sensitive regulation, can provide comprehensive and effective protection for the body, among which the ileum is a critical induction site for regulating mucosal immune homeostasis. Moniezia benedeni parasitizes the small intestine of sheep and can cause serious pathological damage or even death to the host when the infection is severe. In this study, 5 sheep infected with Moniezia benedeni were selected as the infected group, and 5 uninfected sheep were selected as the control group. The ileal transcriptome profile characteristics of Moniezia benedeni infection were analyzed based on RNA-seq sequencing technology, aiming to lay a foundation for further exploring the perception mechanism of sheep intestines to Moniezia benedeni infection and formulating effective prevention and control strategies. RESULTS The results showed that a total of 3,891 differentially expressed genes (DEGs) were detected in the ileum tissues of sheep between the infected and control groups with 2,429 up-regulated genes and 1,462 down-regulated genes. GO and KEGG pathway enrichment analysis of differential genes, as well as Clue GO analysis showed that differential genes were significantly enriched in immune and metabolic-related biological processes and signaling pathways. Particularly, in immune-related signaling pathways, the B cell receptor signaling pathway was significantly down-regulated, while in metabolic regulation related signaling pathways, Bile secretion, Fat digestion and absorption and Vitamin digestion and absorption were notably up-regulated. On this basis, the differential core genes related to immune metabolism were verified by qRT-PCR method. The results showed that OVAR, CD3E, CD8A, CD4 and CD28 were significantly up-regulated (P < 0.05), while CIITA, BLNK, BCL6 and CD79A were significantly down-regulated (P < 0.05), which were consistent with transcriptome sequencing data. CONCLUSIONS The results demonstrated that Moniezia benedeni infection significantly affected the immune and metabolic processes in sheep ileum, particularly, it significantly inhibited the activation process of host B cells, and also led to an overactive function of bile acid metabolism. This finding provides a solid foundation for further elucidating the response mechanism of Peyer's patches in sheep ileum to Moniezia tapeworm infection.
Collapse
Affiliation(s)
- Wangdong Zhang
- College of Veterinary Medicine, Gansu Agricultural University, Lanzhou, 730070, China
| | - Wanling Yao
- College of Veterinary Medicine, Gansu Agricultural University, Lanzhou, 730070, China
| | - Yongcheng Meng
- College of Veterinary Medicine, Gansu Agricultural University, Lanzhou, 730070, China
| | - Fuzhen Luo
- College of Veterinary Medicine, Gansu Agricultural University, Lanzhou, 730070, China
| | - Mengling Han
- College of Veterinary Medicine, Gansu Agricultural University, Lanzhou, 730070, China
| | - Qian Mu
- College of Veterinary Medicine, Gansu Agricultural University, Lanzhou, 730070, China
| | - Lidong Jiang
- College of Veterinary Medicine, Gansu Agricultural University, Lanzhou, 730070, China
| | - Wanhong He
- College of Veterinary Medicine, Gansu Agricultural University, Lanzhou, 730070, China
| | - Xiping Fan
- College of Veterinary Medicine, Gansu Agricultural University, Lanzhou, 730070, China
| | - Wenhui Wang
- College of Veterinary Medicine, Gansu Agricultural University, Lanzhou, 730070, China
| | - Baoshan Wang
- College of Veterinary Medicine, Gansu Agricultural University, Lanzhou, 730070, China.
| |
Collapse
|
|
5
|
Hebiguchi T, Morii M, Watanabe R, Yoshino H, Mezaki Y. Massive bowel resection modulates the expression of genes involved in lipid and cholesterol metabolism in rats. MICROPUBLICATION BIOLOGY 2024; 2024. [PMID: 39381641 PMCID: PMC11461028 DOI: 10.17912/micropub.biology.001253] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Figures] [Subscribe] [Scholar Register] [Received: 06/07/2024] [Revised: 07/29/2024] [Accepted: 09/05/2024] [Indexed: 10/10/2024]
Abstract
We have previously shown that vitamin A-absorptive function was enhanced in bowel-resected rats via increased expression of cellular retinol-binding protein II (CRBP II). Recently, CRBP II was shown to bind not only to retinol but also to monoacylglycerols to modulate gut endocrine signaling. We hypothesized that the increased CRBP II in bowel-resected rats had broader effects than vitamin A metabolism. Acetyl-CoA carboxylase 1 (fatty-acid biosynthesis) and sterol O-acyltransferase 1 (cholesterol esterification) expressions were down-regulated in the bowel-resected rats. Adjustment of nutritional absorption may take place in a limited area of the small intestine by the modulation of gene expression.
Collapse
Affiliation(s)
- Taku Hebiguchi
- Department of Pediatric Surgery, Akita University Graduate School of Medicine, Akita-city, Akita, Japan
- Department of Pediatric Surgery, Akita Kousei Medical Center, Akita-city, Akita, Japan
| | - Mayako Morii
- Department of Pediatric Surgery, Akita University Graduate School of Medicine, Akita-city, Akita, Japan
| | - Ryo Watanabe
- Department of Pediatric Surgery, Akita University Graduate School of Medicine, Akita-city, Akita, Japan
| | - Hiroaki Yoshino
- Department of Pediatric Surgery, Akita University Graduate School of Medicine, Akita-city, Akita, Japan
- Department of Pediatric Surgery, Akita Red Cross Hospital, Akita-city, Akita, Japan
| | - Yoshihiro Mezaki
- Department of Laboratory Medicine, Jikei University Graduate School of Medicine, Minato-ku, Tokyo, Japan
| |
Collapse
|
|
6
|
Li Z, Zheng D, Zhang T, Ruan S, Li N, Yu Y, Peng Y, Wang D. The roles of nuclear receptors in cholesterol metabolism and reverse cholesterol transport in nonalcoholic fatty liver disease. Hepatol Commun 2024; 8:e0343. [PMID: 38099854 PMCID: PMC10727660 DOI: 10.1097/hc9.0000000000000343] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2023] [Accepted: 10/28/2023] [Indexed: 12/18/2023] Open
Abstract
As the most prevalent chronic liver disease globally, NAFLD encompasses a pathological process that ranges from simple steatosis to NASH, fibrosis, cirrhosis, and HCC, closely associated with numerous extrahepatic diseases. While the initial etiology was believed to be hepatocyte injury caused by lipid toxicity from accumulated triglycerides, recent studies suggest that an imbalance of cholesterol homeostasis is of greater significance. The role of nuclear receptors in regulating liver cholesterol homeostasis has been demonstrated to be crucial. This review summarizes the roles and regulatory mechanisms of nuclear receptors in the 3 main aspects of cholesterol production, excretion, and storage in the liver, as well as their cross talk in reverse cholesterol transport. It is hoped that this review will offer new insights and theoretical foundations for the study of the pathogenesis and progression of NAFLD and provide new research directions for extrahepatic diseases associated with NAFLD.
Collapse
|
|
7
|
Loman BR, Alzoubi Z, Lynch AJ, Jaggers RM, Jordan K, Grant CV, Rogers LK, Pyter LM, Bailey MT. Paclitaxel chemotherapy disrupts microbiota-enterohepatic bile acid metabolism in mice. Gut Microbes 2024; 16:2410475. [PMID: 39353099 PMCID: PMC11445932 DOI: 10.1080/19490976.2024.2410475] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2024] [Revised: 07/23/2024] [Accepted: 09/24/2024] [Indexed: 10/04/2024] Open
Abstract
Balanced interactions between the enteric microbiota and enterohepatic organs are essential to bile acid homeostasis, and thus normal gastrointestinal function. Disruption of these interactions by cancer treatment instigates bile acid malabsorption, leading to treatment delays, malnutrition, and decreased quality of life. However, the nature of chemotherapy-induced bile acid malabsorption remains poorly characterized with limited treatment options. Therefore, this study sought to characterize changes in hepatic, enteric, and microbial bile acid metabolism in a mouse model of chemotherapy-induced toxicity. Consistent with clinical bile acid malabsorption, chemotherapy increased fecal excretion of primary bile acids and water, while diminishing microbiome diversity, secondary bile acid formation, and small intestinal bile acid signaling. We identified new contributors to pathology of bile acid malabsorption in the forms of lipopolysaccharide-induced cholestasis and colonic crypt hyperplasia from reduced secondary bile acid signaling. Chemotherapy reduced markers of hepatic bile flow and bile acid synthesis, elevated markers of fibrosis and endotoxemia, and altered transcription of genes at all stages of bile acid metabolism. Primary hepatocytes exposed to lipopolysaccharide (but not chemotherapy) replicated chemotherapy-induced transcriptional differences, while gut microbial transplant into germ-free mice replicated very few differences. In the colon, chemotherapy-altered bile acid profiles (particularly higher tauromuricholic acid and lower hyodeoxycholic acid) coincided with crypt hyperplasia. Exposing primary colonoids to hyodeoxycholic acid reduced proliferation, while gut microbiota transplant enhanced proliferation. Together, these investigations reveal complex involvement of the entire microbiota-enterohepatic axis in chemotherapy-induced bile acid malabsorption. Interventions to reduce hepatic lipopolysaccharide exposure and enhance microbial bile acid metabolism represent promising co-therapies to cancer treatment.
Collapse
Affiliation(s)
- Brett R Loman
- Center for Microbial Pathogenesis, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH, USA
- Division of Nutritional Sciences, University of Illinois at Urbana-Champaign, Urbana, IL, USA
- Department of Animal Sciences, University of Illinois at Urbana-Champaign, Urbana, IL, USA
| | - Zainab Alzoubi
- Division of Nutritional Sciences, University of Illinois at Urbana-Champaign, Urbana, IL, USA
| | - Alexis J Lynch
- Center for Microbial Pathogenesis, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH, USA
| | - Robert M Jaggers
- Center for Microbial Pathogenesis, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH, USA
| | - Kelley Jordan
- Institute for Behavioral Medicine Research, The Ohio State University, Columbus, OH, USA
| | - Corena V Grant
- Institute for Behavioral Medicine Research, The Ohio State University, Columbus, OH, USA
| | - Lynette K Rogers
- Center for Perinatal Research, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH, USA
- Department of Pediatrics, The Ohio State University, Columbus, OH, USA
| | - Leah M Pyter
- Institute for Behavioral Medicine Research, The Ohio State University, Columbus, OH, USA
- Department of Psychiatry and Behavioral Health, The Ohio State University, Columbus, OH, USA
- Department of Neuroscience, The Ohio State University, Columbus, OH, USA
| | - Michael T Bailey
- Center for Microbial Pathogenesis, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH, USA
- Institute for Behavioral Medicine Research, The Ohio State University, Columbus, OH, USA
- Department of Pediatrics, The Ohio State University, Columbus, OH, USA
| |
Collapse
|
|
8
|
Sadowska A, Poniedziałek-Czajkowska E, Mierzyński R. The Role of the FGF19 Family in the Pathogenesis of Gestational Diabetes: A Narrative Review. Int J Mol Sci 2023; 24:17298. [PMID: 38139126 PMCID: PMC10743406 DOI: 10.3390/ijms242417298] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2023] [Revised: 12/02/2023] [Accepted: 12/07/2023] [Indexed: 12/24/2023] Open
Abstract
Gestational diabetes mellitus (GDM) is one of the most common pregnancy complications. Understanding the pathogenesis and appropriate diagnosis of GDM enables the implementation of early interventions during pregnancy that reduce the risk of maternal and fetal complications. At the same time, it provides opportunities to prevent diabetes, metabolic syndrome, and cardiovascular diseases in women with GDM and their offspring in the future. Fibroblast growth factors (FGFs) represent a heterogeneous family of signaling proteins which play a vital role in cell proliferation and differentiation, repair of damaged tissues, wound healing, angiogenesis, and mitogenesis and also affect the regulation of carbohydrate, lipid, and hormone metabolism. Abnormalities in the signaling function of FGFs may lead to numerous pathological conditions, including metabolic diseases. The FGF19 subfamily, also known as atypical FGFs, which includes FGF19, FGF21, and FGF23, is essential in regulating metabolic homeostasis and acts as a hormone while entering the systemic circulation. Many studies have pointed to the involvement of the FGF19 subfamily in the pathogenesis of metabolic diseases, including GDM, although the results are inconclusive. FGF19 and FGF21 are thought to be associated with insulin resistance, an essential element in the pathogenesis of GDM. FGF21 may influence placental metabolism and thus contribute to fetal growth and metabolism regulation. The observed relationship between FGF21 and increased birth weight could suggest a potential role for FGF21 in predicting future metabolic abnormalities in children born to women with GDM. In this group of patients, different mechanisms may contribute to an increased risk of cardiovascular diseases in women in later life, and FGF23 appears to be their promising early predictor. This study aims to present a comprehensive review of the FGF19 subfamily, emphasizing its role in GDM and predicting its long-term metabolic consequences for mothers and their offspring.
Collapse
Affiliation(s)
| | - Elżbieta Poniedziałek-Czajkowska
- Chair and Department of Obstetrics and Perinatology, Medical University of Lublin, Jaczewskiego 8, 20-090 Lublin, Poland; (A.S.); (R.M.)
| | | |
Collapse
|
|
9
|
Anand A, Aoyagi H. Understudied Hyperphosphatemia (Chronic Kidney Disease) Treatment Targets and New Biological Approaches. MEDICINA (KAUNAS, LITHUANIA) 2023; 59:959. [PMID: 37241191 PMCID: PMC10221414 DOI: 10.3390/medicina59050959] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Revised: 04/19/2023] [Accepted: 04/28/2023] [Indexed: 05/28/2023]
Abstract
Hyperphosphatemia is a secondary disorder of chronic kidney disease that causes vascular calcifications and bone-mineral disorders. As per the US Centers for Disease Control and Prevention, renal damage requires first-priority medical attention for patients with COVID-19; according to a Johns Hopkins Medicine report, SARS-CoV-2 can cause renal damage. Therefore, addressing the research inputs required to manage hyperphosphatemia is currently in great demand. This review highlights research inputs, such as defects in the diagnosis of hyperphosphatemia, flaws in understanding the mechanisms associated with understudied tertiary toxicities, less cited adverse effects of phosphate binders that question their use in the market, socioeconomic challenges of renal treatment and public awareness regarding the management of a phosphate-controlled diet, novel biological approaches (synbiotics) to prevent hyperphosphatemia as safer strategies with potential additional health benefits, and future functional food formulations to enhance the quality of life. We have not only introduced our contributions to emphasise the hidden aspects and research gaps in comprehending hyperphosphatemia but also suggested new research areas to strengthen approaches to prevent hyperphosphatemia in the near future.
Collapse
Affiliation(s)
- Ajeeta Anand
- Institute of Life Sciences and Bioengineering, Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba 305-8572, Japan
| | - Hideki Aoyagi
- Institute of Life Sciences and Bioengineering, Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba 305-8572, Japan
- Institute of Life and Environmental Sciences, University of Tsukuba, Tsukuba 305-8572, Japan
| |
Collapse
|
|
10
|
Zeng J, Fan J, Zhou H. Bile acid-mediated signaling in cholestatic liver diseases. Cell Biosci 2023; 13:77. [PMID: 37120573 PMCID: PMC10149012 DOI: 10.1186/s13578-023-01035-1] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Accepted: 04/18/2023] [Indexed: 05/01/2023] Open
Abstract
Chronic cholestatic liver diseases, such as primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), are associated with bile stasis and gradually progress to fibrosis, cirrhosis, and liver failure, which requires liver transplantation. Although ursodeoxycholic acid is effective in slowing the disease progression of PBC, it has limited efficacy in PSC patients. It is challenging to develop effective therapeutic agents due to the limited understanding of disease pathogenesis. During the last decade, numerous studies have demonstrated that disruption of bile acid (BA) metabolism and intrahepatic circulation promotes the progression of cholestatic liver diseases. BAs not only play an essential role in nutrition absorption as detergents but also play an important role in regulating hepatic metabolism and modulating immune responses as key signaling molecules. Several excellent papers have recently reviewed the role of BAs in metabolic liver diseases. This review focuses on BA-mediated signaling in cholestatic liver disease.
Collapse
Affiliation(s)
- Jing Zeng
- Department of Microbiology and Immunology, Medical College of Virginia and Richmond VA Medical Center, Central Virginia Veterans Healthcare System, Virginia Commonwealth University, 1220 East Broad Street, MMRB-5044, Richmond, VA, 23298-0678, USA
- Department of Gastroenterology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China
| | - Jiangao Fan
- Department of Gastroenterology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China
| | - Huiping Zhou
- Department of Microbiology and Immunology, Medical College of Virginia and Richmond VA Medical Center, Central Virginia Veterans Healthcare System, Virginia Commonwealth University, 1220 East Broad Street, MMRB-5044, Richmond, VA, 23298-0678, USA.
| |
Collapse
|
|
11
|
Chen Q, Zhao L, Mei L, Zhao X, Han P, Liu J, Meng C, Li R, Zhong R, Wang K, Li J. Vitamin C and vitamin D3 alleviate metabolic-associated fatty liver disease by regulating the gut microbiota and bile acid metabolism via the gut-liver axis. Front Pharmacol 2023; 14:1163694. [PMID: 37089915 PMCID: PMC10113476 DOI: 10.3389/fphar.2023.1163694] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2023] [Accepted: 03/27/2023] [Indexed: 04/09/2023] Open
Abstract
Background: Previous studies have demonstrated that both vitamin C (VC) and vitamin D3 (VD3) have therapeutic potential against metabolic disorders, including obesity, diabetes, and metabolic-associated fatty liver disease (MAFLD). However, it is unclear whether VC supplementation is associated with improving the intestinal flora and regulating the metabolism of bile acids via the gut-liver axis in MAFLD. There is still no direct comparison or combination study of these two vitamins on these effects.Methods: In this study, we employed biochemical, histological, 16S rDNA-based microbiological, non-targeted liver metabolomic, and quantitative real-time polymerase chain reaction analyses to explore the intervening effect and mechanism of VC and VD3 on MAFLD by using a high-fat diet (HFD)-induced obese mouse model.Results: Treatment of mice with VC and VD3 efficiently reversed the characteristics of MAFLD, such as obesity, dyslipidemia, insulin resistance, hepatic steatosis, and inflammation. VC and VD3 showed similar beneficial effects as mentioned above in HFD-induced obese mice. Interestingly, VC and VD3 reshaped the gut microbiota composition; improved gut barrier integrity; ameliorated oxidative stress and inflammation in the gut-liver axis; inhibited bile acid salt reflux-related ASBT; activated bile acid synthesis-related CYP7A1, bile acid receptor FXR, and bile acid transportation-related BSEP in the gut-liver axis; and improved bile secretion, thus decreasing the expression of FAS in the liver and efficiently ameliorating MAFLD in mice.Conclusion: Together, the results indicate that the anti-MAFLD activities of VC and VD3 are linked to improved gut-liver interactions via regulation of the gut microbiota and bile acid metabolism, and they may therefore prove useful in treating MAFLD clinically.
Collapse
Affiliation(s)
- Qingling Chen
- Clinical School of the Second People’s Hospital, Tianjin Medical University, Tianjin, China
- Department of Gastroenterology and Hepatology, Tianjin Second People’s Hospital, Tianjin, China
| | - Lili Zhao
- Department of Gastroenterology and Hepatology, Tianjin Second People’s Hospital, Tianjin, China
| | - Ling Mei
- Clinical School of the Second People’s Hospital, Tianjin Medical University, Tianjin, China
- Department of Gastroenterology and Hepatology, Tianjin Second People’s Hospital, Tianjin, China
| | - Xiaotong Zhao
- Department of Clinical Laboratory, Tianjin Second People’s Hospital, Tianjin, China
| | - Ping Han
- Clinical School of the Second People’s Hospital, Tianjin Medical University, Tianjin, China
- Department of Gastroenterology and Hepatology, Tianjin Second People’s Hospital, Tianjin, China
| | - Jie Liu
- Department of Gastroenterology and Hepatology, Tianjin Second People’s Hospital, Tianjin, China
| | - Chao Meng
- Department of Clinical Laboratory, Tianjin Second People’s Hospital, Tianjin, China
| | - Ruifang Li
- School of Medicine, Nankai University, Tianjin, China
| | - Rui Zhong
- Department of Neurology, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Kai Wang
- Key Laboratory of Bioactive Materials for the Ministry of Education, College of Life Sciences, Nankai University, Tianjin, China
- *Correspondence: Kai Wang, ; Jia Li,
| | - Jia Li
- Department of Gastroenterology and Hepatology, Tianjin Second People’s Hospital, Tianjin, China
- *Correspondence: Kai Wang, ; Jia Li,
| |
Collapse
|
|
12
|
Collins SL, Stine JG, Bisanz JE, Okafor CD, Patterson AD. Bile acids and the gut microbiota: metabolic interactions and impacts on disease. Nat Rev Microbiol 2023; 21:236-247. [PMID: 36253479 DOI: 10.1038/s41579-022-00805-x] [Citation(s) in RCA: 400] [Impact Index Per Article: 200.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/13/2022] [Indexed: 11/08/2022]
Abstract
Despite decades of bile acid research, diverse biological roles for bile acids have been discovered recently due to developments in understanding the human microbiota. As additional bacterial enzymes are characterized, and the tools used for identifying new bile acids become increasingly more sensitive, the repertoire of bile acids metabolized and/or synthesized by bacteria continues to grow. Additionally, bile acids impact microbiome community structure and function. In this Review, we highlight how the bile acid pool is manipulated by the gut microbiota, how it is dependent on the metabolic capacity of the bacterial community and how external factors, such as antibiotics and diet, shape bile acid composition. It is increasingly important to understand how bile acid signalling networks are affected in distinct organs where the bile acid composition differs, and how these networks impact infectious, metabolic and neoplastic diseases. These advances have enabled the development of therapeutics that target imbalances in microbiota-associated bile acid profiles.
Collapse
Affiliation(s)
- Stephanie L Collins
- Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, PA, USA
| | - Jonathan G Stine
- Division of Gastroenterology and Hepatology, Department of Medicine, Penn State Health Milton S. Hershey Medical Center, Hershey, PA, USA
- Department of Public Health Sciences, Penn State Health Milton S. Hershey Medical Center, Hershey, PA, USA
- Penn State Health Liver Center, Penn State Health Milton S. Hershey Medical Center, Hershey, PA, USA
- Penn State Cancer Institute, Penn State Health Milton S. Hershey Medical Center, Hershey, PA, USA
| | - Jordan E Bisanz
- Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, PA, USA
| | - C Denise Okafor
- Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, PA, USA
- Department of Chemistry, The Pennsylvania State University, University Park, PA, USA
| | - Andrew D Patterson
- Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, PA, USA.
- Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, PA, USA.
- Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA, USA.
| |
Collapse
|
|
13
|
Vitamin D3 Supplementation: Comparison of 1000 IU and 2000 IU Dose in Healthy Individuals. Life (Basel) 2023; 13:life13030808. [PMID: 36983963 PMCID: PMC10053989 DOI: 10.3390/life13030808] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Revised: 03/10/2023] [Accepted: 03/13/2023] [Indexed: 03/18/2023] Open
Abstract
Background: Scientific studies point to a significant global vitamin D deficiency. The recommended dose of vitamin D for the adult population in Central Europe is 800–2000 IU/day. The aim of our study was to determine whether doses of 1000 IU or 2000 IU of vitamin D3 are adequate to achieve the sufficiency reference values of [25(OH)D]. Methods: Seventy-two healthy volunteers, average age twenty-two, took part in the study. The study was conducted from October to March in order to eliminate intra-dermal vitamin D production. Vitamin D3 in an oleaginous mixture was used. The participants used either 1000 IU or 2000 IU/daily for two 60-day periods with a 30-day break. Results: The dose of 1000 IU, taken for 60 days, increased vitamin D levels relatively little. Furthermore, serum vitamin D levels decreased in the 30 days following the cessation of supplementation. Taking 2000 IU daily led to a sharp increase in serum levels which plateaued 30 days after the subjects stopped using vitamin D3 drops. Conclusions: Both doses, taken daily, can help maintain adequate vitamin D levels during the winter months. A daily dose of 2000 IU, however, maintained the desired levels of vitamin D for a longer period.
Collapse
|
|
14
|
Tian H, Zhang S, Liu Y, Wu Y, Zhang D. Fibroblast Growth Factors for Nonalcoholic Fatty Liver Disease: Opportunities and Challenges. Int J Mol Sci 2023; 24:ijms24054583. [PMID: 36902015 PMCID: PMC10003526 DOI: 10.3390/ijms24054583] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2022] [Revised: 02/24/2023] [Accepted: 02/24/2023] [Indexed: 03/02/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD), a chronic condition associated with metabolic dysfunction and obesity, has reached epidemic proportions worldwide. Although early NAFLD can be treated with lifestyle changes, the treatment of advanced liver pathology, such as nonalcoholic steatohepatitis (NASH), remains a challenge. There are currently no FDA-approved drugs for NAFLD. Fibroblast growth factors (FGFs) play essential roles in lipid and carbohydrate metabolism and have recently emerged as promising therapeutic agents for metabolic diseases. Among them, endocrine members (FGF19 and FGF21) and classical members (FGF1 and FGF4) are key regulators of energy metabolism. FGF-based therapies have shown therapeutic benefits in patients with NAFLD, and substantial progress has recently been made in clinical trials. These FGF analogs are effective in alleviating steatosis, liver inflammation, and fibrosis. In this review, we describe the biology of four metabolism-related FGFs (FGF19, FGF21, FGF1, and FGF4) and their basic action mechanisms, and then summarize recent advances in the biopharmaceutical development of FGF-based therapies for patients with NAFLD.
Collapse
Affiliation(s)
- Haoyu Tian
- Department of Stem Cells and Regenerative Medicine, Key Laboratory of Cell Biology, National Health Commission of China, and Key Laboratory of Medical Cell Biology, Ministry of Education of China, China Medical University, Shenyang 110122, China
| | - Shuairan Zhang
- Department of Stem Cells and Regenerative Medicine, Key Laboratory of Cell Biology, National Health Commission of China, and Key Laboratory of Medical Cell Biology, Ministry of Education of China, China Medical University, Shenyang 110122, China
- Department of Gastroenterology, The First Affiliated Hospital of China Medical University, Shenyang 110001, China
| | - Ying Liu
- Department of Stem Cells and Regenerative Medicine, Key Laboratory of Cell Biology, National Health Commission of China, and Key Laboratory of Medical Cell Biology, Ministry of Education of China, China Medical University, Shenyang 110122, China
| | - Yifan Wu
- Department of Stem Cells and Regenerative Medicine, Key Laboratory of Cell Biology, National Health Commission of China, and Key Laboratory of Medical Cell Biology, Ministry of Education of China, China Medical University, Shenyang 110122, China
| | - Dianbao Zhang
- Department of Stem Cells and Regenerative Medicine, Key Laboratory of Cell Biology, National Health Commission of China, and Key Laboratory of Medical Cell Biology, Ministry of Education of China, China Medical University, Shenyang 110122, China
- Correspondence: or
| |
Collapse
|
|
15
|
Jin L, Yang R, Geng L, Xu A. Fibroblast Growth Factor-Based Pharmacotherapies for the Treatment of Obesity-Related Metabolic Complications. Annu Rev Pharmacol Toxicol 2023; 63:359-382. [PMID: 36100222 DOI: 10.1146/annurev-pharmtox-032322-093904] [Citation(s) in RCA: 35] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
The fibroblast growth factor (FGF) family, which comprises 22 structurally related proteins, plays diverse roles in cell proliferation, differentiation, development, and metabolism. Among them, two classical members (FGF1 and FGF4) and two endocrine members (FGF19 and FGF21) are important regulators of whole-body energy homeostasis, glucose/lipid metabolism, and insulin sensitivity. Preclinical studies have consistently demonstrated the therapeutic benefits of these FGFs for the treatment of obesity, diabetes, dyslipidemia, and nonalcoholic steatohepatitis (NASH). Several genetically engineered FGF19 and FGF21 analogs with improved pharmacodynamic and pharmacokinetic properties have been developed and progressed into various stages of clinical trials. These FGF analogs are effective in alleviating hepatic steatosis, steatohepatitis, and liver fibrosis in biopsy-confirmed NASH patients, whereas their antidiabetic and antiobesity effects are mildand vary greatly in different clinical trials. This review summarizes recent advances in biopharmaceutical development of FGF-based therapies against obesity-related metabolic complications, highlights major challenges in clinical implementation, and discusses possible strategies to overcome these hurdles.
Collapse
Affiliation(s)
- Leigang Jin
- State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong, China.,Department of Medicine, The University of Hong Kong, Hong Kong, China
| | - Ranyao Yang
- State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong, China.,Department of Medicine, The University of Hong Kong, Hong Kong, China
| | - Leiluo Geng
- State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong, China.,Department of Medicine, The University of Hong Kong, Hong Kong, China
| | - Aimin Xu
- State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong, China.,Department of Medicine, The University of Hong Kong, Hong Kong, China.,Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong, China;
| |
Collapse
|
|
16
|
Lopez-Carmona F, Toro-Ruiz A, Gomez-Guzman M, Valverde-Merino M, Piquer-Martinez C, Zarzuelo M. Community pharmacy is the key to improving vitamin D levels. EXPLORATORY RESEARCH IN CLINICAL AND SOCIAL PHARMACY 2023; 9:100224. [PMID: 36793797 PMCID: PMC9922955 DOI: 10.1016/j.rcsop.2023.100224] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Accepted: 01/17/2023] [Indexed: 01/19/2023] Open
Abstract
Introduction Vitamin D is an essential micronutrient that participates in the body's fundamental physiological processes. The pharmacist should involve the patient in his medication adherence, leading to a change in the patient's attitude towards his medication and towards his health problem, in order to achieve the pharmacological objective set. Methods Quasi-experimental multicenter study design with non-probabilistic convenience sampling. A pharmacist-led intervention in health education was carried out, divided in two groups, face-to-face interview and on-line survey, and the results were evaluated 3 months later to observe if there was any change in the patient's health status or in their vitamin D levels. Results The study was conducted in four pharmacies through face-to-face interviews (n = 49 patients) and online surveys (n = 23). Pharmaceutical intervention improved habits of exercise (0.81 ± 1.44 days/week face-to-face interviews vs -0.09 ± 2.35 days/week online surveys (p = 0.048)). In face-to-face interviews, consumption of vitamin D-rich foods was increased (0.55 unit of tuna/week; p = 0.035 and 0.56 unit of avocado/week; p = 0.001) and was improved correct intake of vitamin D supplements (32.5% baseline to 69.8% at 3 months). The increase in 25-hydroxyvitamin D levels (11.5 ng/mL after 3 months (p = 0.021)) was correlated to salmon consumption (0.951; p = 0.013) and the improvement of quality of life was correlated to avocado consumption (1; p < 0.001). Conclusion There are habits that improve vitamin D production such as increased physical activity, the correct use of vitamin D supplements and the consumption of foods with high vitamin D levels. The role of the pharmacist is crucial, involving the patient in the treatment making aware of the benefits for his/her health status of increasing vitamin D levels.
Collapse
Affiliation(s)
- F. Lopez-Carmona
- Pharmaceutical Care Research Group CTS-131, Faculty of Pharmacy, University of Granada, Spain
| | - A. Toro-Ruiz
- Pharmaceutical Care Research Group CTS-131, Faculty of Pharmacy, University of Granada, Spain
| | - M. Gomez-Guzman
- Department of Pharmacology, Faculty of Pharmacy, University of Granada, Spain
| | - M.I. Valverde-Merino
- Pharmaceutical Care Research Group CTS-131, Faculty of Pharmacy, University of Granada, Spain
| | - C. Piquer-Martinez
- Pharmaceutical Care Research Group CTS-131, Faculty of Pharmacy, University of Granada, Spain
| | - M.J. Zarzuelo
- Pharmaceutical Care Research Group CTS-131, Faculty of Pharmacy, University of Granada, Spain,Corresponding author at: Pharmaceutical Care Research Group CTS-131, Campus de Cartuja sn Faculty of Pharmacy, University of Granada, Spain.
| |
Collapse
|
|
17
|
Zheng Z, Xie J, Ma L, Hao Z, Zhang W, Li L. Vitamin D Receptor Activation Targets ROS-Mediated Crosstalk Between Autophagy and Apoptosis in Hepatocytes in Cholestasic Mice. Cell Mol Gastroenterol Hepatol 2023; 15:887-901. [PMID: 36280140 PMCID: PMC9972562 DOI: 10.1016/j.jcmgh.2022.10.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 10/17/2022] [Accepted: 10/17/2022] [Indexed: 12/10/2022]
Abstract
BACKGROUND & AIMS Observational epidemiologic studies have associated vitamin D deficiency with cholestasis. We reported previously that activation of the vitamin D/vitamin D receptor (VDR) axis in cholangiocytes mitigates cholestatic liver injury by remodeling the damaged bile duct. However, the function of VDR in hepatocytes during cholestasis remains unclear. METHODS Paricalcitol (VDR agonist, 200 ng/kg) was injected intraperitoneally into bile duct-ligated mice every other day for 5 days. Primary hepatocytes and HepG2 hepatoma cells were transfected with Vdr short hairpin RNA, control short hairpin RNA, Vdr plasmid, control vector, Atg5 small interfering RNA (siRNA), and control siRNA. Liver histology, cell proliferation, and autophagy were evaluated. RESULTS Treatment with the VDR agonist paricalcitol improved liver injury in bile duct-ligated mice by up-regulating VDR expression in hepatocytes, which in turn reduced hepatocyte apoptosis by inhibiting reactive oxygen species (ROS) generation via suppressing the Ras-related C3 botulinum toxin substrate 1/reduced nicotinamide adenine dinucleotide phosphate oxidase 1 pathway. Mechanistically, upon exposure to an ROS-inducing compound, Vdr siRNA contributed to apoptosis, whereas the Vdr overexpression caused resistance to apoptosis. Interestingly, up-regulated VDR expression also increased the generation of autophagosomes and macroautophagic/autophagic flux, which was the underlying mechanism for reduced apoptosis following VDR activation. Autophagy depletion impaired the positive effects of VDR overexpression, whereas autophagy induction was synergystic with VDR overexpression. Importantly, up-regulation of VDR promoted autophagy activation by suppressing the activation of the extracellular signal-regulated kinase (ERK)/p38 mitogen-activated protein kinase (p38MAPK) pathway. Thus, a p38MAPK inhibitor abrogated the Vdr siRNA-induced decrease in autophagy and the Vdr siRNA-induced increase in apoptosis. In contrast, a Mitogen-activated protein kinase kinase (MEK)/ERK activator prevented the enhancement of autophagy and decreased apoptosis following Vdr overexpression. Moreover, the ROS inhibitor N-acetylcystein (NAC) blocked Vdr siRNA-enhanced activation of the ERK/p38MAPK pathway. CONCLUSIONS VDR activation mitigated liver cholestatic injury by reducing autophagy-dependent hepatocyte apoptosis and suppressing the activation of the ROS-dependent ERK/p38MAPK pathway. Thus, VDR activation may be a potential target for the treatment of cholestatic liver disease.
Collapse
Affiliation(s)
- Zhijian Zheng
- Department of General Surgery, Affiliated Wenling First People's Hospital, Taizhou University, Taizhou, Zhejiang Province, P R China
| | - Jing Xie
- Department of Cell Biology, School of Medicine, Taizhou University, Taizhou, Zhejiang Province, P R China
| | - Liman Ma
- Department of Cell Biology, School of Medicine, Taizhou University, Taizhou, Zhejiang Province, P R China
| | - Zhiqing Hao
- Department of Pathophysiology, School of Basic Medicine, Shenyang Medical College, Shenyang, Liaoning Province, PR China
| | - Weiwei Zhang
- Department of Pathophysiology, School of Basic Medicine, Shenyang Medical College, Shenyang, Liaoning Province, PR China
| | - Lihua Li
- Department of General Surgery, Affiliated Wenling First People's Hospital, Taizhou University, Taizhou, Zhejiang Province, P R China.
| |
Collapse
|
|
18
|
Li C, Yu JL, Xu JJ, He YC, Qin KZ, Chen L, Huang HF, Wu YT. Interactive effects of ambient air pollution and sunshine duration on the risk of intrahepatic cholestasis of pregnancy. ENVIRONMENTAL RESEARCH 2022; 215:114345. [PMID: 36116502 DOI: 10.1016/j.envres.2022.114345] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Revised: 09/10/2022] [Accepted: 09/12/2022] [Indexed: 06/15/2023]
Abstract
INTRODUCTION While the associations among ambient pollutants and various pregnancy complications are well documented, the effect of ambient pollutants on intrahepatic cholestasis of pregnancy (ICP) has not been examined. This study aimed to explore the effects of ambient pollutants and sunshine duration on ICP. METHODS The study enrolled 169,971 pregnant women who delivered between 2015 and 2020 in two hospitals. The associations between ICP and exposure to ambient pollutants and sunshine duration, averaged throughout different periods (including the 3 months before conception, 1st trimester and 2nd trimester), were estimated using a generalized linear model. The interaction effects of ambient pollutants and sunshine duration on ICP were estimated. RESULTS The fitted curves for ICP incidence were similar to the temporal trends of PM2.5, PM10, SO2, CO and NO2 but not that of O3. The risk of ICP was significantly elevated following a 10-μg/m3 increase in PM2.5 (aOR [adjusted odds ratio] = 1.057, 95% CI [confidence interval]: 1.017-1.099) and PM10 (aOR = 1.043, 95% CI: 1.013-1.074) and a 1-h decrease in sunshine duration (aOR = 1.039, 95% CI: 1.011-1.068) during the 3 months before conception. In the second trimester, a 1-μg/m3 increase in the concentration of SO2 was associated with an increased risk of ICP (aOR = 1.011, 95% CI: 1.001-1.021). Increased concentrations of PM2.5 and PM10 had interactive effects with reduced sunshine duration during the 3 months before conception on increasing the risk of ICP. CONCLUSIONS Exposure to PM2.5 and PM10 during the 3 months before conception and exposure to SO2 in the second trimester were associated with an increased ICP risk. Reduced sunshine duration had an interactive effect with increased concentrations of PM2.5 and PM10 during the 3 months before conception on the occurrence of ICP.
Collapse
Affiliation(s)
- Cheng Li
- Obstetrics and Gynecology Hospital, Institute of Reproduction and Development, Fudan University, Shanghai, China
| | - Jia-Le Yu
- International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Jing-Jing Xu
- Obstetrics and Gynecology Hospital, Institute of Reproduction and Development, Fudan University, Shanghai, China
| | - Yi-Chen He
- Obstetrics and Gynecology Hospital, Institute of Reproduction and Development, Fudan University, Shanghai, China
| | - Kai-Zhou Qin
- Obstetrics and Gynecology Hospital, Institute of Reproduction and Development, Fudan University, Shanghai, China
| | - Lei Chen
- International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - He-Feng Huang
- Obstetrics and Gynecology Hospital, Institute of Reproduction and Development, Fudan University, Shanghai, China; International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
| | - Yan-Ting Wu
- Obstetrics and Gynecology Hospital, Institute of Reproduction and Development, Fudan University, Shanghai, China.
| |
Collapse
|
|
19
|
Hwang S, Hood RB, Hauser R, Schwartz J, Laden F, Jones D, Liang D, Gaskins AJ. Using follicular fluid metabolomics to investigate the association between air pollution and oocyte quality. ENVIRONMENT INTERNATIONAL 2022; 169:107552. [PMID: 36191487 PMCID: PMC9620437 DOI: 10.1016/j.envint.2022.107552] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Revised: 09/22/2022] [Accepted: 09/27/2022] [Indexed: 05/07/2023]
Abstract
BACKGROUND AND AIM Our objective was to use metabolomics in a toxicological-relevant target tissue to gain insight into the biological processes that may underlie the negative association between air pollution exposure and oocyte quality. METHODS Our study included 125 women undergoing in vitro fertilization at an academic fertility center in Massachusetts, US (2005-2015). A follicular fluid sample was collected during oocyte retrieval and untargeted metabolic profiling was conducted using liquid chromatography with ultra-high-resolution mass spectrometry and two chromatography columns (C18 and HILIC). Daily exposure to nitrogen dioxide (NO2), ozone, fine particulate matter, and black carbon was estimated at the women's residence using spatiotemporal models and averaged over the period of ovarian stimulation (2-weeks). Multivariable linear regression models were used to evaluate the associations between the air pollutants, number of mature oocytes, and metabolic feature intensities. A meet-in-the-middle approach was used to identify overlapping features and metabolic pathways. RESULTS Of the air pollutants, NO2 exposure had the largest number of overlapping metabolites (C18: 105; HILIC: 91) and biological pathways (C18: 3; HILIC: 6) with number of mature oocytes. Key pathways of overlap included vitamin D3 metabolism (both columns), bile acid biosynthesis (both columns), C21-steroid hormone metabolism (HILIC), androgen and estrogen metabolism (HILIC), vitamin A metabolism (HILIC), carnitine shuttle (HILIC), and prostaglandin formation (C18). Three overlapping metabolites were confirmed with level-1 or level-2 evidence. For example, hypoxanthine, a metabolite that protects against oxidant-induced cell injury, was positively associated with NO2 exposure and negatively associated with number of mature oocytes. Minimal overlap was observed between the other pollutants and the number of mature oocytes. CONCLUSIONS Higher exposure to NO2 during ovarian stimulation was associated with many metabolites and biologic pathways involved in endogenous vitamin metabolism, hormone synthesis, and oxidative stress that may mediate the observed associations with lower oocyte quality.
Collapse
Affiliation(s)
- Sueyoun Hwang
- Department of Epidemiology, Emory University Rollins School of Public Health, Atlanta, GA, United States
| | - Robert B Hood
- Department of Epidemiology, Emory University Rollins School of Public Health, Atlanta, GA, United States
| | - Russ Hauser
- Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, United States; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, United States
| | - Joel Schwartz
- Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, United States; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, United States; Channing Division of Network Medicine, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, United States
| | - Francine Laden
- Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, United States; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, United States; Channing Division of Network Medicine, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, United States
| | - Dean Jones
- Division of Pulmonary, Allergy, & Critical Care Medicine, Emory University School of Medicine, Atlanta, GA, United States
| | - Donghai Liang
- Gangarosa Department of Environmental Health, Emory University Rollins School of Public Health, Atlanta, GA, United States
| | - Audrey J Gaskins
- Department of Epidemiology, Emory University Rollins School of Public Health, Atlanta, GA, United States.
| |
Collapse
|
|
20
|
Chang MS, Hartman RI, Trepanowski N, Giovannucci EL, Nan H, Li X. Cumulative Erythemal Ultraviolet Radiation and Risk of Cancer in 3 Large US Prospective Cohorts. Am J Epidemiol 2022; 191:1742-1752. [PMID: 35671977 PMCID: PMC9991893 DOI: 10.1093/aje/kwac101] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Revised: 05/20/2022] [Accepted: 06/01/2022] [Indexed: 01/29/2023] Open
Abstract
Ultraviolet radiation (UVR) exposure is the major risk factor for melanoma. However, epidemiologic studies on UVR and noncutaneous cancers have reported inconsistent results, with some suggesting an inverse relationship potentially mediated by vitamin D. To address this, we examined 3 US prospective cohorts, the Health Professionals Follow-up Study (HPFS) (1986) and Nurses' Health Study (NHS) I and II (1976 and 1989), for associations between cumulative erythemal UVR and incident cancer risk, excluding nonmelanoma skin cancer. We used a validated spatiotemporal model to calculate erythemal UVR. Participants (47,714 men; 212,449 women) were stratified into quintiles by cumulative average erythemal UVR, using the first quintile as referent, for Cox proportional hazards regression analysis. In the multivariable-adjusted meta-analysis of all cohorts, compared with the lowest quintile, risk of any cancer was slightly increased across all other quintiles (highest quintile hazard ratio (HR) = 1.04, 95% confidence interval (CI): 1.01, 1.07; P for heterogeneity = 0.41). All UVR quintiles were associated with similarly increased risk of any cancer excluding melanoma. As expected, erythemal UVR was positively associated with risk of melanoma (highest quintile HR = 1.17, 95% CI: 1.04, 1.31; P for heterogeneity = 0.83). These findings suggest that elevated UVR is associated with increased risk of both melanoma and noncutaneous cancers.
Collapse
Affiliation(s)
| | | | | | | | | | - Xin Li
- Correspondence to Dr. Xin Li, Department of Epidemiology, Richard M. Fairbanks School of Public Health, Indiana University, Health Sciences Building, RG 5114, 1050 Wishard Boulevard., Indianapolis, IN 46202 (e-mail: )
| |
Collapse
|
|
21
|
Zhang YL, Li ZJ, Gou HZ, Song XJ, Zhang L. The gut microbiota–bile acid axis: A potential therapeutic target for liver fibrosis. Front Cell Infect Microbiol 2022; 12:945368. [PMID: 36189347 PMCID: PMC9519863 DOI: 10.3389/fcimb.2022.945368] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Accepted: 09/01/2022] [Indexed: 11/15/2022] Open
Abstract
Liver fibrosis involves the proliferation and deposition of extracellular matrix on liver tissues owing to various etiologies (including viral, alcohol, immune, and metabolic factors), ultimately leading to structural and functional abnormalities in the liver. If not effectively treated, liver fibrosis, a pivotal stage in the path to chronic liver disease, can progress to cirrhosis and eventually liver cancer; unfortunately, no specific clinical treatment for liver fibrosis has been established to date. In liver fibrosis cases, both the gut microbiota and bile acid metabolism are disrupted. As metabolites of the gut microbiota, bile acids have been linked to the progression of liver fibrosis via various pathways, thus implying that the gut microbiota–bile acid axis might play a critical role in the progression of liver fibrosis and could be a target for its reversal. Therefore, in this review, we examined the involvement of the gut microbiota–bile acid axis in liver fibrosis progression to the end of discovering new targets for the prevention, diagnosis, and therapy of chronic liver diseases, including liver fibrosis.
Collapse
Affiliation(s)
- Yu-Lin Zhang
- The First Clinical Medical College, Lanzhou University, Lanzhou, China
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, China
- Key Laboratory of Biotherapy and Regenerative Medicine of Gansu Province, The First Hospital of Lanzhou University, Lanzhou, China
| | - Zhen-Jiao Li
- The First Clinical Medical College, Lanzhou University, Lanzhou, China
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, China
- Key Laboratory of Biotherapy and Regenerative Medicine of Gansu Province, The First Hospital of Lanzhou University, Lanzhou, China
| | - Hong-Zhong Gou
- The First Clinical Medical College, Lanzhou University, Lanzhou, China
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, China
- Key Laboratory of Biotherapy and Regenerative Medicine of Gansu Province, The First Hospital of Lanzhou University, Lanzhou, China
| | - Xiao-Jing Song
- The First Clinical Medical College, Lanzhou University, Lanzhou, China
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, China
- Key Laboratory of Biotherapy and Regenerative Medicine of Gansu Province, The First Hospital of Lanzhou University, Lanzhou, China
| | - Lei Zhang
- The First Clinical Medical College, Lanzhou University, Lanzhou, China
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, China
- Key Laboratory of Biotherapy and Regenerative Medicine of Gansu Province, The First Hospital of Lanzhou University, Lanzhou, China
- *Correspondence: Lei Zhang,
| |
Collapse
|
|
22
|
Esan O, Viljoen A, Wierzbicki AS. Colesevelam - a bile acid sequestrant for treating hypercholesterolemia and improving hyperglycemia. Expert Opin Pharmacother 2022; 23:1363-1370. [PMID: 35968655 DOI: 10.1080/14656566.2022.2112945] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
INTRODUCTION Low density Lipoprotein cholesterol)LDL-C) levels show a clear relationship with cardiovascular disease (CVD). Statins are first line agents to reduce LDL-C and CVD risk. However, combination lipid-lowering therapy is often required to achieve large reductions in LDL-C. AREA COVERED Colesevelam HCl is a bile acid sequestrant (BAS), which reduces LDL-C by 16-22% in monotherapy and adds a further 12-14% reduction in LDL-C when combined with other lipid-lowering drugs. Like statins, colesevelam reduces C-reactive protein levels by 16% in monotherapy and additional 6% when added to statins. Colesevelam also reduced HbA1c by 4mmol/mol (0.5%) when used alone and added to other hypoglycaemic drugs in studies of patients with diabetes . EXPERT OPINION Bile acid sequestrants reduce LDL-C and HbA1c and have some CVD outcome evidence. The uses of these agents are limited in patients with gastrointestinal disease or high triglycerides due to adverse effects on gut function and raising triglycerides and they interfere with the absorption of lipid-soluble drugs. Colesevelam has a higher bile acid binding capacity, and fewer adverse effects than other BAS. Colesevelam may be useful as a third line agent for treatment of hypercholesterolemia with some additional specific benefits on glycemic control.
Collapse
Affiliation(s)
- Oluwayemisi Esan
- Metabolic Medicine/Chemical Pathology, Guy's & St Thomas Hospitals, London SE1 7EH, UK
| | - Adie Viljoen
- Metabolic Medicine/Chemical Pathology, East & North Hertfordshire Hospitals, Lister Hospital, Stevenage, Hertfordshire SG1 4AB, UK
| | - Anthony S Wierzbicki
- Metabolic Medicine/Chemical Pathology, Guy's & St Thomas Hospitals, London SE1 7EH, UK
| |
Collapse
|
|
23
|
Dai W, Liu J, Qiu Y, Teng Z, Li S, Yuan H, Huang J, Xiang H, Tang H, Wang B, Chen J, Wu H. Gut Microbial Dysbiosis and Cognitive Impairment in Bipolar Disorder: Current Evidence. Front Pharmacol 2022; 13:893567. [PMID: 35677440 PMCID: PMC9168430 DOI: 10.3389/fphar.2022.893567] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Accepted: 04/20/2022] [Indexed: 12/11/2022] Open
Abstract
Recent studies have reported that the gut microbiota influences mood and cognitive function through the gut-brain axis, which is involved in the pathophysiology of neurocognitive and mental disorders, including Parkinson’s disease, Alzheimer’s disease, and schizophrenia. These disorders have similar pathophysiology to that of cognitive dysfunction in bipolar disorder (BD), including neuroinflammation and dysregulation of various neurotransmitters (i.e., serotonin and dopamine). There is also emerging evidence of alterations in the gut microbial composition of patients with BD, suggesting that gut microbial dysbiosis contributes to disease progression and cognitive impairment in BD. Therefore, microbiota-centered treatment might be an effective adjuvant therapy for BD-related cognitive impairment. Given that studies focusing on connections between the gut microbiota and BD-related cognitive impairment are lagging behind those on other neurocognitive disorders, this review sought to explore the potential mechanisms of how gut microbial dysbiosis affects cognitive function in BD and identify potential microbiota-centered treatment.
Collapse
Affiliation(s)
- Wenyu Dai
- National Clinical Research Center for Mental Disorders, Department of Psychiatry, China National Technology Institute on Mental Disorders, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Jieyu Liu
- Department of Ultrasound Diagnostic, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Yan Qiu
- National Clinical Research Center for Mental Disorders, Department of Psychiatry, China National Technology Institute on Mental Disorders, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Ziwei Teng
- National Clinical Research Center for Mental Disorders, Department of Psychiatry, China National Technology Institute on Mental Disorders, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Sujuan Li
- National Clinical Research Center for Mental Disorders, Department of Psychiatry, China National Technology Institute on Mental Disorders, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Hui Yuan
- Department of Ultrasound Diagnostic, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Jing Huang
- National Clinical Research Center for Mental Disorders, Department of Psychiatry, China National Technology Institute on Mental Disorders, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Hui Xiang
- National Clinical Research Center for Mental Disorders, Department of Psychiatry, China National Technology Institute on Mental Disorders, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Hui Tang
- National Clinical Research Center for Mental Disorders, Department of Psychiatry, China National Technology Institute on Mental Disorders, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Bolun Wang
- Department of Radiology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Jindong Chen
- National Clinical Research Center for Mental Disorders, Department of Psychiatry, China National Technology Institute on Mental Disorders, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Haishan Wu
- National Clinical Research Center for Mental Disorders, Department of Psychiatry, China National Technology Institute on Mental Disorders, The Second Xiangya Hospital of Central South University, Changsha, China
| |
Collapse
|
|
24
|
Bauer KC, Littlejohn PT, Ayala V, Creus-Cuadros A, Finlay BB. Nonalcoholic Fatty Liver Disease and the Gut-Liver Axis: Exploring an Undernutrition Perspective. Gastroenterology 2022; 162:1858-1875.e2. [PMID: 35248539 DOI: 10.1053/j.gastro.2022.01.058] [Citation(s) in RCA: 61] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Revised: 12/31/2021] [Accepted: 01/07/2022] [Indexed: 02/08/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a chronic condition affecting one quarter of the global population. Although primarily linked to obesity and metabolic syndrome, undernutrition and the altered (dysbiotic) gut microbiome influence NAFLD progression. Both undernutrition and NAFLD prevalence are predicted to considerably increase, but how the undernourished gut microbiome contributes to hepatic pathophysiology remains far less studied. Here, we present undernutrition conditions with fatty liver features, including kwashiorkor and micronutrient deficiency. We then review the gut microbiota-liver axis, highlighting key pathways linked to NAFLD progression within both overnutrition and undernutrition. To conclude, we identify challenges and collaborative possibilities of emerging multiomic research addressing the pathology and treatment of undernourished NAFLD.
Collapse
Affiliation(s)
- Kylynda C Bauer
- Michael Smith Laboratories, University of British Columbia, Vancouver, British Columbia, Canada; Department of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia, Canada; Thoracic and Gastrointestinal Malignancies Branch, National Institutes of Health, National Cancer Institute, Center for Cancer Research, Bethesda, Maryland
| | - Paula T Littlejohn
- Michael Smith Laboratories, University of British Columbia, Vancouver, British Columbia, Canada; Department of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia, Canada
| | - Victoria Ayala
- Institut de Recerca Biomèdica de Lleida (IRB-Lleida), Lleida, Spain; Department of Experimental Medicine, Universitat de Lleida, Lleida, Spain
| | - Anna Creus-Cuadros
- Michael Smith Laboratories, University of British Columbia, Vancouver, British Columbia, Canada
| | - B Brett Finlay
- Michael Smith Laboratories, University of British Columbia, Vancouver, British Columbia, Canada; Department of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia, Canada; Biochemistry and Molecular Biology Department, University of British Columbia, Vancouver, British Columbia, Canada.
| |
Collapse
|
|
25
|
Noh K, Chow ECY, Quach HP, Groothuis GMM, Tirona RG, Pang KS. Significance of the Vitamin D Receptor on Crosstalk with Nuclear Receptors and Regulation of Enzymes and Transporters. AAPS J 2022; 24:71. [PMID: 35650371 DOI: 10.1208/s12248-022-00719-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Accepted: 05/16/2022] [Indexed: 11/30/2022] Open
Abstract
The vitamin D receptor (VDR), in addition to other nuclear receptors, the pregnane X receptor (PXR) and constitutive androstane receptor (CAR), is involved in the regulation of enzymes, transporters and receptors, and therefore intimately affects drug disposition, tissue health, and the handling of endogenous and exogenous compounds. This review examines the role of 1α,25-dihydroxyvitamin D3 or calcitriol, the natural VDR ligand, on activation of the VDR and its crosstalk with other nuclear receptors towards the regulation of enzymes and transporters, notably many of the cytochrome P450s including CYP3A4 and sulfotransferase 2A1 (SULT2A1) as well as cholesterol 7α-hydroxylase (CYP7A1). Moreover, the VDR upregulates the intestinal channel, TRPV6, for calcium absorption, LDL receptor-related protein 1 (LRP1) and receptor for advanced glycation end products (RAGE) in brain for β-amyloid peptide efflux and influx, the sodium phosphate transporters (NaPi), the apical sodium-dependent bile acid transporter (ASBT) and organic solute transporters (OSTα-OSTβ) for bile acid absorption and efflux, respectively, the renal organic anion transporter 3 (OAT3) and several of the ATP-binding cassette protein transporters-the multidrug resistance protein 1 (MDR1) and the multidrug resistance-associated proteins (MRPs). Hence, the role of the VDR is increasingly being recognized for its therapeutic potential and pharmacologic activity, giving rise to drug-drug interactions (DDI). Therapeutically, ligand-activated VDR shows anti-inflammatory effects towards the suppression of inflammatory mediators, improves cognition by upregulating amyloid-beta (Aβ) peptide clearance in brain, and maintains phosphate, calcium, and parathyroid hormone (PTH) balance and kidney function and bone health, demonstrating the crucial roles of the VDR in disease progression and treatment of diseases.
Collapse
Affiliation(s)
- Keumhan Noh
- Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, 144 College Street, Toronto, Ontario, M5S 3M2, Canada.,Drug Metabolism and Pharmacokinetics, Biogen, 225 Binney Street, Cambridge, Massachusetts, 02142, USA
| | - Edwin C Y Chow
- Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, 144 College Street, Toronto, Ontario, M5S 3M2, Canada.,Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland, USA
| | - Holly P Quach
- Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, 144 College Street, Toronto, Ontario, M5S 3M2, Canada
| | - Geny M M Groothuis
- Pharmacokinetics, Toxicology and Targeting, Department of Pharmacy, Groningen Research Institute of Pharmacy, University of Groningen, Groningen, The Netherlands
| | - Rommel G Tirona
- Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, N6A 5C1, Canada
| | - K Sandy Pang
- Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, 144 College Street, Toronto, Ontario, M5S 3M2, Canada.
| |
Collapse
|
|
26
|
Molecular Basis of Bile Acid-FXR-FGF15/19 Signaling Axis. Int J Mol Sci 2022; 23:ijms23116046. [PMID: 35682726 PMCID: PMC9181207 DOI: 10.3390/ijms23116046] [Citation(s) in RCA: 72] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Revised: 05/24/2022] [Accepted: 05/25/2022] [Indexed: 02/04/2023] Open
Abstract
Bile acids (BAs) are a group of amphiphilic molecules consisting of a rigid steroid core attached to a hydroxyl group with a varying number, position, and orientation, and a hydrophilic side chain. While BAs act as detergents to solubilize lipophilic nutrients in the small intestine during digestion and absorption, they also act as hormones. Farnesoid X receptor (FXR) is a nuclear receptor that forms a heterodimer with retinoid X receptor α (RXRα), is activated by BAs in the enterohepatic circulation reabsorbed via transporters in the ileum and the colon, and plays a critical role in regulating gene expression involved in cholesterol, BA, and lipid metabolism in the liver. The FXR/RXRα heterodimer also exists in the distal ileum and regulates production of fibroblast growth factor (FGF) 15/FGF19, a hormone traveling via the enterohepatic circulation that activates hepatic FGF receptor 4 (FGFR4)-β-klotho receptor complex and regulates gene expression involved in cholesterol, BA, and lipid metabolism, as well as those regulating cell proliferation. Agonists for FXR and analogs for FGF15/19 are currently recognized as a promising therapeutic target for metabolic syndrome and cholestatic diseases.
Collapse
|
|
27
|
Burchill L, Williams SJ. Chemistry and biology of the aminosulfonate cysteinolic acid: discovery, distribution, synthesis and metabolism. Org Biomol Chem 2022; 20:3043-3055. [PMID: 35354198 DOI: 10.1039/d2ob00362g] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
D-Cysteinolic acid is a zwitterionic aminosulfonate found in marine (and occasionally freshwater) environments. It is distributed in a wide range of algae (red, green and brown algae and diatoms), and some bacteria and sea animals. It was discovered in 1957 and in spite of its long history, its biosynthesis and degradation is poorly understood. Cysteinolic acid is found conjugated to steroids, lipids and arsenosugars, and the cysteinolic acid motif is found within the structures of various capnoid and sulfoceramide sulfonolipids. This review provides an historical account of the discovery of D-cysteinolic acid and related molecules, its distribution and occurrence within marine and freshwater organisms, routes for its chemical synthesis, and summarizes knowledge and speculations surrounding its biosynthesis, degradation and bioconversions.
Collapse
Affiliation(s)
- Laura Burchill
- School of Chemistry and Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Victoria 3010, Australia.
| | - Spencer J Williams
- School of Chemistry and Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Victoria 3010, Australia.
| |
Collapse
|
|
28
|
Endocrine Fibroblast Growth Factors in Relation to Stress Signaling. Cells 2022; 11:cells11030505. [PMID: 35159314 PMCID: PMC8834311 DOI: 10.3390/cells11030505] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Revised: 01/30/2022] [Accepted: 01/31/2022] [Indexed: 01/10/2023] Open
Abstract
Fibroblast growth factors (FGFs) play important roles in various growth signaling processes, including proliferation, development, and differentiation. Endocrine FGFs, i.e., atypical FGFs, including FGF15/19, FGF21, and FGF23, function as endocrine hormones that regulate energy metabolism. Nutritional status is known to regulate the expression of endocrine FGFs through nuclear hormone receptors. The increased expression of endocrine FGFs regulates energy metabolism processes, such as fatty acid metabolism and glucose metabolism. Recently, a relationship was found between the FGF19 subfamily and stress signaling during stresses such as endoplasmic reticulum stress and oxidative stress. This review focuses on endocrine FGFs and the recent progress in FGF studies in relation to stress signaling. In addition, the relevance of the stress-FGF pathway to disease and human health is discussed.
Collapse
|
|
29
|
Keely SJ, Urso A, Ilyaskin AV, Korbmacher C, Bunnett NW, Poole DP, Carbone SE. Contributions of bile acids to gastrointestinal physiology as receptor agonists and modifiers of ion channels. Am J Physiol Gastrointest Liver Physiol 2022; 322:G201-G222. [PMID: 34755536 PMCID: PMC8782647 DOI: 10.1152/ajpgi.00125.2021] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Revised: 10/28/2021] [Accepted: 11/08/2021] [Indexed: 02/03/2023]
Abstract
Bile acids (BAs) are known to be important regulators of intestinal motility and epithelial fluid and electrolyte transport. Over the past two decades, significant advances in identifying and characterizing the receptors, transporters, and ion channels targeted by BAs have led to exciting new insights into the molecular mechanisms involved in these processes. Our appreciation of BAs, their receptors, and BA-modulated ion channels as potential targets for the development of new approaches to treat intestinal motility and transport disorders is increasing. In the current review, we aim to summarize recent advances in our knowledge of the different BA receptors and BA-modulated ion channels present in the gastrointestinal system. We discuss how they regulate motility and epithelial transport, their roles in pathogenesis, and their therapeutic potential in a range of gastrointestinal diseases.
Collapse
Affiliation(s)
- Stephen J Keely
- Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital, Dublin, Ireland
| | - Andreacarola Urso
- Department of Surgery, Vagelos College of Physicians and Surgeons, Columbia University, New York, New York
- Department of Pharmacology, Columbia University, New York, New York
| | - Alexandr V Ilyaskin
- Institute of Cellular and Molecular Physiology, Friedrich-Alexander University Erlangen-Nürnberg, Bavaria, Germany
| | - Christoph Korbmacher
- Institute of Cellular and Molecular Physiology, Friedrich-Alexander University Erlangen-Nürnberg, Bavaria, Germany
| | - Nigel W Bunnett
- Department of Molecular Pathobiology, Neuroscience Institute, New York University, New York, New York
- Department of Neuroscience and Physiology, Neuroscience Institute, New York University, New York, New York
| | - Daniel P Poole
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia
- Australian Research Council, Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia
| | - Simona E Carbone
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia
- Australian Research Council, Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia
| |
Collapse
|
|
30
|
Warner ER, Aloor FZ, Satapathy SK. A narrative review of nutritional abnormalities, complications, and optimization in the cirrhotic patient. Transl Gastroenterol Hepatol 2022; 7:5. [PMID: 35243114 PMCID: PMC8826036 DOI: 10.21037/tgh-20-325] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Accepted: 04/08/2021] [Indexed: 08/10/2023] Open
Abstract
OBJECTIVE The purpose of this manuscript is to identify the pathophysiology of the metabolic abnormalities observed in cirrhosis and to uncover associations, if any, to its complications, such as sarcopenia and hepatic encephalopathy (HE). BACKGROUND Liver dysfunction in cirrhosis is known to be a precipitating factor in the disruption of many physiological pathways, specifically nutrient metabolism. As a result, affected patients are highly susceptible to derangements of processes affecting multiple classes of macro- and micronutrients, including proteins, carbohydrates, electrolytes, vitamins, and minerals. These disruptions are thought to be contributory to the pathogenesis of known complications of cirrhosis. METHODS Literature research of relevant topics was conducted for the above stated objective; sources were limited to articles from peer-reviewed journals published within the last 30 years. CONCLUSION This research established that there is positive correlation between nutrient derangements and the increased risk of complications of cirrhosis, which themselves carry significant morbidity and mortality risk. It also established that some nutrient and electrolyte abnormalities are independent indicators of prognosis and adverse outcomes, such as mortality. This also highlights the importance of comprehension of anomalous metabolism and its complications as it necessitates serious consideration in clinical care. In addition to medical management, cirrhotic patients also require ancillary assessment, such as comprehensive nutritional evaluation, to identify and treat reversible nutritional derangements. This consideration provides the best opportunity to achieve maximal health outcomes in the cirrhotic patient population.
Collapse
Affiliation(s)
- Edgewood R. Warner
- Department of Medicine, Donald and Barbara Zucker School of Medicine/Northwell Health, Manhasset, NY, USA
| | - Fuad Z. Aloor
- Department of Medicine, Donald and Barbara Zucker School of Medicine/Northwell Health, Manhasset, NY, USA
- Division of Hepatology and Sandra Atlas Bass Center for Liver Diseases and Transplantation, Department of Medicine, Donald and Barbara Zucker School of Medicine/Northwell Health, Manhasset, New York, USA
| | - Sanjaya K. Satapathy
- Division of Hepatology and Sandra Atlas Bass Center for Liver Diseases and Transplantation, Department of Medicine, Donald and Barbara Zucker School of Medicine/Northwell Health, Manhasset, New York, USA
| |
Collapse
|
|
31
|
Kim Y, Lee S, Kim S, Kim TY, Lee SH, Chang JH, Kweon MN. LKB1 in Intestinal Epithelial Cells Regulates Bile Acid Metabolism by Modulating FGF15/19 Production. Cell Mol Gastroenterol Hepatol 2021; 13:1121-1139. [PMID: 34973477 PMCID: PMC8873961 DOI: 10.1016/j.jcmgh.2021.12.017] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2021] [Revised: 12/22/2021] [Accepted: 12/27/2021] [Indexed: 12/17/2022]
Abstract
BACKGROUND & AIMS Liver kinase B1 (LKB1) is a master upstream protein kinase involved in nutrient sensing and glucose and lipid metabolism in many tissues; however, its metabolic role in intestinal epithelial cells (IEC) remains unclear. In this study, we investigated the regulatory role of LKB1 on bile acid (BA) homeostasis. METHODS We generated mice with IEC-specific deletion of LKB1 (LKB1ΔIEC) and analyzed the characteristics of IEC development and BA level. In vitro assays with small interfering RNA, liquid chromatography/mass spectrometry, metagenomics, and RNA-sequencing were used to elucidate the regulatory mechanisms underlying perturbed BA homeostasis. RESULTS LKB1 deletion resulted in abnormal differentiation of secretory cell lineages. Unexpectedly, BA pool size increased substantially in LKB1ΔIEC mice. A significant reduction of the farnesoid X receptor (FXR) target genes, including fibroblast growth factor 15/19 (FGF15/19), known to inhibit BA synthesis, was found in the small intestine (SI) ileum of LKB1ΔIEC mice. We observed that LKB1 depletion reduced FGF15/19 protein level in human IECs in vitro. Additionally, a lower abundance of bile salt hydrolase-producing bacteria and elevated levels of FXR antagonist (ie, T-βMCA) were observed in the SI of LKB1ΔIEC mice. Moreover, LKB1ΔIEC mice showed impaired conversion of retinol to retinoic acids in the SI ileum. Subsequently, vitamin A treatment failed to induce FGF15 production. Thus, LKB1ΔIEC mice fed with a high-fat diet showed improved glucose tolerance and increased energy expenditure. CONCLUSIONS LKB1 in IECs manages BA homeostasis by controlling FGF15/19 production.
Collapse
Affiliation(s)
- Yeji Kim
- Mucosal Immunology Laboratory, Department of Convergence Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Sohyeon Lee
- Mucosal Immunology Laboratory, Department of Convergence Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Seungil Kim
- Mucosal Immunology Laboratory, Department of Convergence Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea,Digestive Diseases Research Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Tae-Young Kim
- Mucosal Immunology Laboratory, Department of Convergence Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Su-Hyun Lee
- Mucosal Immunology Laboratory, Department of Convergence Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Jae-Hoon Chang
- College of Pharmacy, Yeungnam University, Gyeongsan, Republic of Korea
| | - Mi-Na Kweon
- Mucosal Immunology Laboratory, Department of Convergence Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea,Digestive Diseases Research Center, University of Ulsan College of Medicine, Seoul, Republic of Korea,Correspondence Address correspondence to: Dr Mi-Na Kweon, Asan Medical Center, Department of Convergence Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul 05505 Republic of Korea. tel: 82-2-3010-2096.
| |
Collapse
|
|
32
|
Colon cancer checks in when bile acids check out: the bile acid-nuclear receptor axis in colon cancer. Essays Biochem 2021; 65:1015-1024. [PMID: 34414429 PMCID: PMC8628182 DOI: 10.1042/ebc20210038] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Revised: 08/03/2021] [Accepted: 08/06/2021] [Indexed: 02/06/2023]
Abstract
Bile acids (BAs) are a class of hepatically derived metabolite-hormones with prominent roles in nutrient absorption, metabolic and immune homeostasis in the intestine. BAs are ligands for multiple nuclear receptors (NRs), through which they confer transcriptional regulation on target genes that form an enterohepatic hormonal feedback loop to regulate BA synthesis and maintain lipid homeostasis. Endogenous BAs made by the host undergo significant biotransformation by the gut microbiota in the intestine, which diversifies the intestinal BA pool and facilitate host–microbiota cross-talk through BA-mediated signaling. BAs dysregulation contributes to development of metabolic diseases, pathological inflammation and colon cancer. This review provides a brief historic perspective of the study of NR-mediated BA signaling transduction, with a focus on recent advancements in understanding the active role the gut microbiome plays in reshaping intestinal BA landscape, and the implications of novel microbially derived BAs in modulating immune homeostasis and cancer development in the host. Targeting the BA–NR signaling axis for pharmacological intervention provides ample opportunities in the prevention and treatment of intestinal diseases.
Collapse
|
|
33
|
Liechtenstein GR. Highlights From the 2021 Advances in Inflammatory Bowel Diseases Conference: Commentary. Gastroenterol Hepatol (N Y) 2021; 17:14-19. [PMID: 35611126 PMCID: PMC9122055] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
|
|
34
|
Kenna JE, Chua EG, Bakeberg M, Tay A, McGregor S, Gorecki A, Horne M, Marshall B, Mastaglia FL, Anderton RS. Changes in the Gut Microbiome and Predicted Functional Metabolic Effects in an Australian Parkinson's Disease Cohort. Front Neurosci 2021; 15:756951. [PMID: 34776854 PMCID: PMC8588830 DOI: 10.3389/fnins.2021.756951] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Accepted: 10/01/2021] [Indexed: 01/03/2023] Open
Abstract
Background: There has been increasing recognition of the importance of the gut microbiome in Parkinson's disease (PD), but the influence of geographic location has received little attention. The present study characterized the gut microbiota and associated changes in host metabolic pathways in an Australian cohort of people with PD (PwP). Methods: The study involved recruitment and assessment of 87 PwP from multiple Movement Disorders Clinics in Australia and 47 healthy controls. Illumina sequencing of the V3 and V4 regions of the 16S rRNA gene was used to distinguish inter-cohort differences in gut microbiota; KEGG analysis was subsequently performed to predict functional changes in host metabolic pathways. Results: The current findings identified significant differences in relative abundance and diversity of microbial operational taxonomic units (OTUs), and specific bacterial taxa between PwP and control groups. Alpha diversity was significantly reduced in PwP when compared to controls. Differences were found in two phyla (Synergistetes and Proteobacteria; both increased in PwP), and five genera (Colidextribacter, Intestinibacter, Kineothrix, Agathobaculum, and Roseburia; all decreased in PwP). Within the PD cohort, there was no association identified between microbial composition and gender, constipation or use of gastrointestinal medication. Furthermore, KEGG analysis identified 15 upregulated and 11 downregulated metabolic pathways which were predicted to be significantly altered in PwP. Conclusion: This study provides the first comprehensive characterization of the gut microbiome and predicted functional metabolic effects in a southern hemisphere PD population, further exploring the possible mechanisms whereby the gut microbiota may exert their influence on this disease, and providing evidence for the incorporation of such data in future individualized therapeutic strategies.
Collapse
Affiliation(s)
- Jade E Kenna
- School of Medicine, The University of Western Australia, Nedlands, WA, Australia.,Centre for Neuromuscular and Neurological Disorders, The University of Western Australia, Nedlands, WA, Australia.,Centre for Clinical Neurosciences and Neurological Research, St. Vincent's Hospital Melbourne, Fitzroy, VIC, Australia.,Perron Institute for Neurological and Translational Science, Nedlands, WA, Australia
| | - Eng Guan Chua
- School of Biological Sciences, The University of Western Australia, Crawley, WA, Australia.,Marshall Centre for Infectious Diseases Research and Training, The University of Western Australia, Nedlands, WA, Australia
| | - Megan Bakeberg
- Centre for Neuromuscular and Neurological Disorders, The University of Western Australia, Nedlands, WA, Australia.,School of Medicine, University of Notre Dame Australia, Fremantle, WA, Australia
| | - Alfred Tay
- School of Biological Sciences, The University of Western Australia, Crawley, WA, Australia.,Marshall Centre for Infectious Diseases Research and Training, The University of Western Australia, Nedlands, WA, Australia
| | - Sarah McGregor
- Centre for Clinical Neurosciences and Neurological Research, St. Vincent's Hospital Melbourne, Fitzroy, VIC, Australia
| | - Anastazja Gorecki
- Perron Institute for Neurological and Translational Science, Nedlands, WA, Australia.,School of Biological Sciences, The University of Western Australia, Crawley, WA, Australia
| | - Malcolm Horne
- Centre for Clinical Neurosciences and Neurological Research, St. Vincent's Hospital Melbourne, Fitzroy, VIC, Australia.,Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, Australia
| | - Barry Marshall
- School of Biological Sciences, The University of Western Australia, Crawley, WA, Australia.,Marshall Centre for Infectious Diseases Research and Training, The University of Western Australia, Nedlands, WA, Australia
| | - Frank L Mastaglia
- Centre for Neuromuscular and Neurological Disorders, The University of Western Australia, Nedlands, WA, Australia.,Perron Institute for Neurological and Translational Science, Nedlands, WA, Australia
| | - Ryan S Anderton
- Centre for Neuromuscular and Neurological Disorders, The University of Western Australia, Nedlands, WA, Australia.,Institute for Health Research, University of Notre Dame Australia, Fremantle, WA, Australia.,School of Nursing, Midwifery, Health Sciences and Physiotherapy, The University of Notre Dame Australia, Fremantle, WA, Australia
| |
Collapse
|
|
35
|
Tian S, Chen M, Wang B, Han Y, Shang H, Chen J. Salvianolic acid B blocks hepatic stellate cell activation via FGF19/FGFR4 signaling. Ann Hepatol 2021; 20:100259. [PMID: 32980439 DOI: 10.1016/j.aohep.2020.07.013] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2020] [Revised: 07/27/2020] [Accepted: 07/27/2020] [Indexed: 02/04/2023]
Abstract
INTRODUCTION AND OBJECTIVES The activation of hepatic stellate cells (HSCs) is the main cause of liver fibrosis. The beneficial effects of fibroblast growth factor (FGF) 19 on liver fibrosis were recently reported. The S. miltiorrhiza as well as S. miltiorrhiza derived bioactive chemical components has shown prominent antifibrotic effects in liver fibrosis but the mechanism is still not fully understood. We aimed to investigate the bioactive compounds derived from S. miltiorrhiza which exerts antifibrotic effects in HSCs via regulating FGF19. MATERIALS AND METHODS FGF19 level in culture media was determined by enzyme-linked immunosorbent assay. Cell proliferation was measured by Cell Counting Kit-8 assay. Further, mRNA and protein expressions were assessed by quantitative polymerase chain reaction and western blotting, respectively. Knocking down of FGF receptor 4 (FGFR4) by transfection with siRNA was used to confirm the role of FGF19/FGFR4 signaling. RESULTS Using the human HSC cell line LX-2, we screened several natural products and found that bioactive compounds isolated from Salvia miltiorrhiza, particularly salvianolic acid B, strongly upregulated FGF19 secretion by LX-2 cells. We further showed that salvianolic acid B inhibited lipopolysaccharide (LPS)-induced HSC proliferation and activation. LPS treatment may also reduce the mRNA and protein levels of FGF19 and its receptor FGFR4. Salvianolic acid B treatment restored the impaired expressions of FGF19 and FGFR4. Finally, FGFR4 knockdown abolished the antifibrotic effects of salvianolic acid B in the LPS-induced HSC activation model. CONCLUSIONS Salvianolic acid B prevented LPS-induced HSC proliferation and activation by enhancing antifibrotic FGF19/FGFR4 signaling.
Collapse
Affiliation(s)
- Shuxia Tian
- Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, China
| | - Min Chen
- Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, China
| | - Bing Wang
- Shanghai Jiaotong University Affiliated Sixth People's Hospital, China
| | - Yonglong Han
- Shanghai Jiaotong University Affiliated Sixth People's Hospital, China
| | - Haonan Shang
- Shanghai Jiaotong University Affiliated Sixth People's Hospital, China
| | - Junming Chen
- Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, China; Shanghai Jiaotong University Affiliated Sixth People's Hospital, China.
| |
Collapse
|
|
36
|
Fortea M, Albert-Bayo M, Abril-Gil M, Ganda Mall JP, Serra-Ruiz X, Henao-Paez A, Expósito E, González-Castro AM, Guagnozzi D, Lobo B, Alonso-Cotoner C, Santos J. Present and Future Therapeutic Approaches to Barrier Dysfunction. Front Nutr 2021; 8:718093. [PMID: 34778332 PMCID: PMC8582318 DOI: 10.3389/fnut.2021.718093] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Accepted: 09/29/2021] [Indexed: 12/12/2022] Open
Abstract
There is converging and increasing evidence, but also uncertainty, for the role of abnormal intestinal epithelial barrier function in the origin and development of a growing number of human gastrointestinal and extraintestinal inflammatory disorders, and their related complaints. Despite a vast literature addressing factors and mechanisms underlying changes in intestinal permeability in humans, and its connection to the appearance and severity of clinical symptoms, the ultimate link remains to be established in many cases. Accordingly, there are no directives or clinical guidelines related to the therapeutic management of intestinal permeability disorders that allow health professionals involved in the management of these patients to carry out a consensus treatment based on clinical evidence. Instead, there are multiple pseudoscientific approaches and commercial propaganda scattered on the internet that confuse those affected and health professionals and that often lack scientific rigor. Therefore, in this review we aim to shed light on the different therapeutic options, which include, among others, dietary management, nutraceuticals and medical devices, microbiota and drugs, and epigenetic and exosomes-manipulation, through an objective evaluation of the scientific publications in this field. Advances in the knowledge and management of intestinal permeability will sure enable better options of dealing with this group of common disorders to enhance quality of life of those affected.
Collapse
Affiliation(s)
- Marina Fortea
- Laboratory for Enteric NeuroScience, Translational Research Center for GastroIntestinal Disorders, University of Leuven, Leuven, Belgium
| | - Mercé Albert-Bayo
- Laboratory of Neuro-Immuno-Gastroenterology, Digestive System Research Unit, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Hospital Universitari, Barcelona, Spain
| | - Mar Abril-Gil
- Laboratory of Neuro-Immuno-Gastroenterology, Digestive System Research Unit, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Hospital Universitari, Barcelona, Spain
| | - John-Peter Ganda Mall
- Laboratory of Neuro-Immuno-Gastroenterology, Digestive System Research Unit, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Hospital Universitari, Barcelona, Spain
- Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
| | - Xavier Serra-Ruiz
- Department of Gastroenterology, Vall d'Hebron Hospital Universitari, Barcelona, Spain
| | - Alejandro Henao-Paez
- Department of Gastroenterology, Vall d'Hebron Hospital Universitari, Barcelona, Spain
| | - Elba Expósito
- Laboratory of Neuro-Immuno-Gastroenterology, Digestive System Research Unit, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Hospital Universitari, Barcelona, Spain
| | - Ana María González-Castro
- Laboratory of Neuro-Immuno-Gastroenterology, Digestive System Research Unit, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Hospital Universitari, Barcelona, Spain
| | - Danila Guagnozzi
- Laboratory of Neuro-Immuno-Gastroenterology, Digestive System Research Unit, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Hospital Universitari, Barcelona, Spain
- Department of Gastroenterology, Vall d'Hebron Hospital Universitari, Barcelona, Spain
- Facultad de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERHED), Instituto de Salud Carlos III, Madrid, Spain
| | - Beatriz Lobo
- Laboratory of Neuro-Immuno-Gastroenterology, Digestive System Research Unit, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Hospital Universitari, Barcelona, Spain
- Department of Gastroenterology, Vall d'Hebron Hospital Universitari, Barcelona, Spain
- Facultad de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Spain
| | - Carmen Alonso-Cotoner
- Laboratory of Neuro-Immuno-Gastroenterology, Digestive System Research Unit, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Hospital Universitari, Barcelona, Spain
- Department of Gastroenterology, Vall d'Hebron Hospital Universitari, Barcelona, Spain
- Facultad de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERHED), Instituto de Salud Carlos III, Madrid, Spain
| | - Javier Santos
- Laboratory of Neuro-Immuno-Gastroenterology, Digestive System Research Unit, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Hospital Universitari, Barcelona, Spain
- Department of Gastroenterology, Vall d'Hebron Hospital Universitari, Barcelona, Spain
- Facultad de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERHED), Instituto de Salud Carlos III, Madrid, Spain
| |
Collapse
|
|
37
|
Travica N, Ried K, Hudson I, Scholey A, Pipingas A, Sali A. The effects of cardiovascular and orthopaedic surgery on vitamin concentrations: a narrative review of the literature and mechanisms of action. Crit Rev Food Sci Nutr 2021:1-31. [PMID: 34619992 DOI: 10.1080/10408398.2021.1983762] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
Given the rise in worldwide chronic diseases, supplemented by an aging population, the volume of global major surgeries, encompassing cardiac and orthopedic procedures is anticipated to surge significantly. Surgical trauma can be accompanied by numerous postoperative complications and metabolic changes. The present review summarized the results from studies assessing the effects of orthopedic and cardiovascular surgery on vitamin concentrations, in addition to exploring the possible mechanisms associated with changes in concentrations. Studies have revealed a potentially severe depletion in plasma/serum concentrations of numerous vitamins following these surgeries acutely. Vitamins C, D and B1 appear particularly vulnerable to significant depletions, with vitamin C and D depletions consistently transpiring into inadequate and deficient concentrations, respectively. The possible multifactorial mechanisms impacting postoperative vitamin concentrations include changes in hemodilution and vitamin utilization, redistribution, circulatory transport and absorption. For a majority of vitamins, there has been a lack of investigation into the effects of both, cardiac and orthopedic surgery. Additionally, studies were predominantly restricted to short-term postoperative investigations, primarily performed within the first postoperative week of surgery. Overall, results indicated that further examination is necessary to determine the severity and clinical significance of the possible depletions in vitamin concentrations that ensue cardiovascular and orthopedic surgery.
Collapse
Affiliation(s)
- Nikolaj Travica
- Food & Mood Centre, School of Medicine, Barwon Health, Deakin University, the Institute for Mental and Physical Health and Clinical Translation (IMPACT), Geelong, Australia.,Centre for Human Psychopharmacology, Swinburne University of Technology, Melbourne, Australia.,The National Institute of Integrative Medicine, Melbourne, Australia
| | - Karin Ried
- The National Institute of Integrative Medicine, Melbourne, Australia.,Honorary Associate Professor, Discipline of General Practice, University of Adelaide, South Australia, Australia.,Torrens University, Melbourne, Australia
| | - Irene Hudson
- Centre for Human Psychopharmacology, Swinburne University of Technology, Melbourne, Australia.,Digital Health, CRC, College of STEM, Mathematical Sciences, Royal Melbourne Institute of Technology (RMIT), Melbourne, Australia.,School of Mathematical and Physical Science, University of Newcastle, Newcastle, Australia
| | - Andrew Scholey
- Centre for Human Psychopharmacology, Swinburne University of Technology, Melbourne, Australia
| | - Andrew Pipingas
- Centre for Human Psychopharmacology, Swinburne University of Technology, Melbourne, Australia
| | - Avni Sali
- The National Institute of Integrative Medicine, Melbourne, Australia
| |
Collapse
|
|
38
|
Xie J, Fan Y, Jia R, Yang F, Ma L, Li L. Yes-associated protein regulates the hepatoprotective effect of vitamin D receptor activation through promoting adaptive bile duct remodeling in cholestatic mice. J Pathol 2021; 255:95-106. [PMID: 34156701 DOI: 10.1002/path.5750] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Revised: 05/13/2021] [Accepted: 06/19/2021] [Indexed: 12/31/2022]
Abstract
Mounting clinical evidence has revealed that the vitamin D receptor (VDR) is associated with cholestatic liver injury, although the functions of VDR in this condition remain largely unexplored. Here, we investigated the effects of VDR activation on bile duct ligation (BDL) mice, and the underlying mechanisms were further investigated. A low-calcemic VDR agonist, paricalcitol (PAL, 200 ng/kg), was intraperitoneally injected into BDL mice every other day for 5 days or 28 days. Liver histology, liver function indicators, cholangiocyte proliferation, fibrosis scores, and inflammation were evaluated. Mice treated with PAL were rescued from the decreased survival rate induced by BDL and liver damage was reduced. Mechanistically, PAL promoted cholangiocyte proliferation, which was likely conducive to proliferating bile duct maturation and increased branching of bile ducts. PAL treatment also increased the expression of Yes-associated protein (YAP) and its target protein epithelial cell adhesion molecule (EpCam) and decreased the level of inactive cytoplasmic phosphorylated YAP. YAP knockdown abrogated PAL-induced primary bile duct epithelial cell proliferation, confirmed with YAP inhibitor administration. In addition, BDL-induced liver fibrosis and inflammatory cell infiltration were reduced by PAL treatment at both day 5 and day 28 post-BDL. In conclusion, VDR activation mitigates cholestatic liver injury by promoting adaptive bile duct remodeling through cholangiocytic YAP upregulation. Because PAL is an approved clinical drug, it may be useful for treatment of cholestatic liver disease. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Collapse
Affiliation(s)
- Jing Xie
- Department of Cell Biology, School of Medicine, Taizhou University, Taizhou, PR China
| | - Yonggang Fan
- Institute of Health Sciences, Key Laboratory of Medical Cell Biology of the Ministry of Education, China Medical University, Shenyang, PR China
| | - Rongjun Jia
- Department of Cell Biology, Jinzhou Medical University, Jinzhou, PR China
| | - Fan Yang
- Department of Cell Biology, Jinzhou Medical University, Jinzhou, PR China
| | - Liman Ma
- Department of Cell Biology, School of Medicine, Taizhou University, Taizhou, PR China
| | - Lihua Li
- Department of Cell Biology, School of Medicine, Taizhou University, Taizhou, PR China
| |
Collapse
|
|
39
|
Kaur H, Seeger D, Golovko S, Golovko M, Combs CK. Liver Bile Acid Changes in Mouse Models of Alzheimer's Disease. Int J Mol Sci 2021; 22:ijms22147451. [PMID: 34299071 PMCID: PMC8303891 DOI: 10.3390/ijms22147451] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2021] [Revised: 06/23/2021] [Accepted: 06/24/2021] [Indexed: 12/28/2022] Open
Abstract
Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive cognitive impairment. It is hypothesized to develop due to the dysfunction of two major proteins, amyloid-β (Aβ) and microtubule-associated protein, tau. Evidence supports the involvement of cholesterol changes in both the generation and deposition of Aβ. This study was performed to better understand the role of liver cholesterol and bile acid metabolism in the pathophysiology of AD. We used male and female wild-type control (C57BL/6J) mice to compare to two well-characterized amyloidosis models of AD, APP/PS1, and AppNL-G-F. Both conjugated and unconjugated primary and secondary bile acids were quantified using UPLC-MS/MS from livers of control and AD mice. We also measured cholesterol and its metabolites and identified changes in levels of proteins associated with bile acid synthesis and signaling. We observed sex differences in liver cholesterol levels accompanied by differences in levels of synthesis intermediates and conjugated and unconjugated liver primary bile acids in both APP/PS1 and AppNL-G-F mice when compared to controls. Our data revealed fundamental deficiencies in cholesterol metabolism and bile acid synthesis in the livers of two different AD mouse lines. These findings strengthen the involvement of liver metabolism in the pathophysiology of AD.
Collapse
|
|
40
|
Abstract
Bile acids (BAs) are a family of hydroxylated steroids secreted by the liver that aid in the breakdown and absorption of dietary fats. BAs also function as nutrient and inflammatory signaling molecules, acting through cognate receptors, to coordinate host metabolism. Commensal bacteria in the gastrointestinal tract are functional modifiers of the BA pool, affecting composition and abundance. Deconjugation of host BAs creates a molecular network that inextricably links gut microtia with their host. In this review we highlight the roles of BAs in mediating this mutualistic relationship with a focus on those events that impact host physiology and metabolism.
Collapse
Affiliation(s)
- James C Poland
- Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
| | - C Robb Flynn
- Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
| |
Collapse
|
|
41
|
Li J, Witonsky D, Sprague E, Alleyne D, Bielski MC, Lawrence KM, Kupfer SS. Genomic and epigenomic active vitamin D responses in human colonic organoids. Physiol Genomics 2021; 53:235-248. [PMID: 33900108 DOI: 10.1152/physiolgenomics.00150.2020] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Active vitamin D, 1α,25(OH)2D3, is a nuclear hormone with roles in colonic homeostasis and carcinogenesis; yet, mechanisms underlying these effects are incompletely understood. Human organoids are an ideal system to study genomic and epigenomic host-environment interactions. Here, we use human colonic organoids to measure 1α,25(OH)2D3 responses on genome-wide gene expression and chromatin accessibility over time. Human colonic organoids were cultured and treated in triplicate with 100 nM 1α,25(OH)2D3 or vehicle control for 4 h and 18 h for chromatin accessibility, and 6 h and 24 h for gene expression. ATAC- and RNA-sequencing were performed. Differentially accessible peaks were analyzed using DiffBind and edgeR; differentially expressed genes were analyzed using DESeq2. Motif enrichment was determined using HOMER. At 6 h and 24 h, 2,870 and 2,721 differentially expressed genes, respectively (false discovery rate, FDR < 5%), were identified with overall stronger responses with 1α,25(OH)2D3. Similarly, 1α,25(OH)2D3 treatment led to stronger chromatin accessibility especially at 4 h. The vitamin D receptor (VDR) motif was strongly enriched among accessible chromatin peaks with 1α,25(OH)2D3 treatment accounting for 30.5% and 11% of target sequences at 4 h and 18 h, respectively (FDR < 1%). A number of genes such as CYP24A1, FGF19, MYC, FOS, and TGFBR2 showed significant transcriptional and chromatin accessibility responses to 1α,25(OH)2D3 treatment with accessible chromatin located distant from promoters for some gene regions. Assessment of chromatin accessibility and transcriptional responses to 1α,25(OH)2D3 yielded new observations about vitamin D genome-wide effects in the colon facilitated by application of human colonic organoids. This framework can be applied to study host-environment interactions between individuals and populations in the future.
Collapse
Affiliation(s)
- Jinchao Li
- Section of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Chicago, Chicago, Illinois
| | - David Witonsky
- Section of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Chicago, Chicago, Illinois
| | - Emily Sprague
- Section of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Chicago, Chicago, Illinois
| | - Dereck Alleyne
- Section of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Chicago, Chicago, Illinois
| | - Maggie C Bielski
- Section of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Chicago, Chicago, Illinois
| | - Kristi M Lawrence
- Section of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Chicago, Chicago, Illinois
| | - Sonia S Kupfer
- Section of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Chicago, Chicago, Illinois
| |
Collapse
|
|
42
|
Miura K, Oshima T, Ito C, Horikawa T, Yamada M, Tomita T, Fukui H, Miwa H. Vitamin D receptor is overexpressed in the duodenum of patients with irritable bowel syndrome. J Gastroenterol Hepatol 2021; 36:951-958. [PMID: 32839988 DOI: 10.1111/jgh.15225] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2020] [Revised: 07/21/2020] [Accepted: 08/16/2020] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIM Irritable bowel syndrome (IBS) is one of the most common functional gastrointestinal disorders, and bile acids are thought to be associated with the pathogenesis of IBS. Bile acid receptors are expressed on intestinal epithelial cells. However, no study has assessed bile acid receptor proteins in IBS. Therefore, we examined the intestinal mucosal expression of bile acid receptors in patients with IBS. METHODS Intestinal biopsies were performed in patients with IBS and controls. Mast cells, vitamin D receptor (VDR), and somatostatin were stained with specific antibodies. Levels of VDR, farnesoid X receptor (FXR), takeda-G-protein-receptor-5 (TGR5), claudins, and transient-receptor-potential-cation-channel-subfamily-V-member 6 (TRPV6) were assessed by western blotting. RESULTS 3Mast cell counts in the second part of the duodenum were significantly higher in patients with IBS than in controls. VDR protein levels were significantly elevated in the duodenum and terminal ileum of patients with IBS compared with controls, although this difference was not seen in the cecum or rectum. FXR and TGR5 protein levels did not differ in any part of the intestine. VDR-positive cryptal epithelia in IBS were distributed not only at basal crypt but also along the upper part of the basal crypt epithelial cells. In contrast, the pattern of gut somatostatin-positive cells, claudins, and TRPV6 levels did not differ. CONCLUSIONS The number of mast cells in the duodenum was significantly increased, and the protein expression levels of VDR, but not those of FXR or TGR5, were elevated in the duodenal epithelial crypt in patients with IBS.
Collapse
Affiliation(s)
- Ko Miura
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
| | - Tadayuki Oshima
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
| | - Chiyomi Ito
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
| | - Tomoki Horikawa
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
| | - Mayumi Yamada
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
| | - Toshihiko Tomita
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
| | - Hirokazu Fukui
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
| | - Hiroto Miwa
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
| |
Collapse
|
|
43
|
Sun H, Sherrier M, Li H. Skeletal Muscle and Bone - Emerging Targets of Fibroblast Growth Factor-21. Front Physiol 2021; 12:625287. [PMID: 33762965 PMCID: PMC7982600 DOI: 10.3389/fphys.2021.625287] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Accepted: 02/16/2021] [Indexed: 12/13/2022] Open
Abstract
Fibroblast growth factor 21 (FGF21) is an atypical member of the FGF family, which functions as a powerful endocrine and paracrine regulator of glucose and lipid metabolism. In addition to liver and adipose tissue, recent studies have shown that FGF21 can also be produced in skeletal muscle. As the most abundant tissue in the human body, skeletal muscle has become increasingly recognized as a major site of metabolic activity and an important modulator of systemic metabolic homeostasis. The function and mechanism of action of muscle-derived FGF21 have recently gained attention due to the findings of considerably increased expression and secretion of FGF21 from skeletal muscle under certain pathological conditions. Recent reports regarding the ectopic expression of FGF21 from skeletal muscle and its potential effects on the musculoskeletal system unfolds a new chapter in the story of FGF21. In this review, we summarize the current knowledge base of muscle-derived FGF21 and the possible functions of FGF21 on homeostasis of the musculoskeletal system with a focus on skeletal muscle and bone.
Collapse
Affiliation(s)
- Hui Sun
- Musculoskeletal Growth & Regeneration Laboratory, Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, PA, United States.,Department of Orthopaedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Matthew Sherrier
- Musculoskeletal Growth & Regeneration Laboratory, Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, PA, United States.,Department of Physical Medicine and Rehabilitation, University of Pittsburgh Medical Center, Pittsburgh, PA, United States
| | - Hongshuai Li
- Musculoskeletal Growth & Regeneration Laboratory, Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, PA, United States
| |
Collapse
|
|
44
|
Jia C, Bai Y, Liu J, Cai W, Liu L, He Y, Song J. Metabolic Regulations by lncRNA, miRNA, and ceRNA Under Grass-Fed and Grain-Fed Regimens in Angus Beef Cattle. Front Genet 2021; 12:579393. [PMID: 33747033 PMCID: PMC7969984 DOI: 10.3389/fgene.2021.579393] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Accepted: 02/03/2021] [Indexed: 12/13/2022] Open
Abstract
Beef cattle raised under grass-fed and grain-fed have many differences, including metabolic efficiency and meat quality. To investigate these two regimens' intrinsic influence on beef cattle, we used high-throughput sequencing and metabolomics analyses to explore differentially expressed genes (DEGs) and metabolimic networks in the liver. A total of 200 DEGs, 76 differentially expressed miRNAs (DEmiRNAs), and two differentially expressed lncRNAs (DElncRNAs) were detected between regimen groups. Metabolic processes and pathways enriched functional genes including target genes of miRNAs and lncRNAs. We found that many genes were involved in energy, retinol and cholesterol metabolism, and bile acid synthesis. Combined with metabolites such as low glucose concentration, high cholesterol concentration, and increased primary bile acid concentration, these genes were mainly responsible for lowering intramuscular fat, low cholesterol, and yellow meat in grass-fed cattle. Additionally, we identified two lncRNAs and eight DEGs as potential competing endogenous RNAs (ceRNAs) to bind miRNAs by the interaction network analysis. These results revealed that the effects of two feeding regimens on beef cattle were mainly induced by gene expression changes in metabolic pathways mediated via lncRNAs, miRNAs, and ceRNAs, and contents of metabolites in the liver. It may provide a clue on feeding regimens inducing the metabolic regulations.
Collapse
Affiliation(s)
- Cunling Jia
- College of Animal Science and Technology, Northwest A&F University, Yangling, China.,Department of Animal & Avian Science, University of Maryland, College Park, MD, United States
| | - Ying Bai
- Department of Animal & Avian Science, University of Maryland, College Park, MD, United States
| | - Jianan Liu
- Department of Animal & Avian Science, University of Maryland, College Park, MD, United States
| | - Wentao Cai
- Department of Animal & Avian Science, University of Maryland, College Park, MD, United States
| | - Lei Liu
- Department of Animal & Avian Science, University of Maryland, College Park, MD, United States.,Research Centre for Animal Genome, Agricultural Genome Institute at Shenzhen, Chinese Academy of Agricultural Science, Shenzhen, China
| | - Yanghua He
- Department of Human Nutrition, Food and Animal Sciences, College of Tropical Agriculture and Human Resources, University of Hawaii, Manoa, HI, United States
| | - Jiuzhou Song
- Department of Animal & Avian Science, University of Maryland, College Park, MD, United States
| |
Collapse
|
|
45
|
Rozmus D, Ciesielska A, Płomiński J, Grzybowski R, Fiedorowicz E, Kordulewska N, Savelkoul H, Kostyra E, Cieślińska A. Vitamin D Binding Protein (VDBP) and Its Gene Polymorphisms-The Risk of Malignant Tumors and Other Diseases. Int J Mol Sci 2020; 21:E7822. [PMID: 33105665 PMCID: PMC7659952 DOI: 10.3390/ijms21217822] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Revised: 10/17/2020] [Accepted: 10/20/2020] [Indexed: 02/06/2023] Open
Abstract
Vitamin D is an important component of the endocrine system that controls calcium homeostasis and bone mineralization. Because of the very short half-life of free serum vitamin D it is stabilized and transported to target tissues by being bound to the vitamin D binding protein (VDBP). The most common polymorphisms: rs4588 and rs7041 in the vitamin D binding protein gene may correlate with differences in vitamin D status in the serum. This review presents data that relate to the presence of genetic variants in the VDBP gene in correlation with certain diseases, mostly concerning cancers (breast, prostate, pancreatic, lung, colorectal, basal cell carcinoma cancer and cutaneous melanoma) or other related diseases (thyroid autoimmunity disorders, obesity, diabetes mellitus, bone metabolism, rheumatoid arthritis, ankylosing spondylitis, asthma, chronic obstructive pulmonary disease, tuberculosis and coronary artery diseases).
Collapse
Affiliation(s)
- Dominika Rozmus
- Faculty of Biology and Biotechnology, University of Warmia and Mazury, 10-719 Olsztyn, Poland; (D.R.); (A.C.); (E.F.); (N.K.); (E.K.)
| | - Alicja Ciesielska
- Faculty of Biology and Biotechnology, University of Warmia and Mazury, 10-719 Olsztyn, Poland; (D.R.); (A.C.); (E.F.); (N.K.); (E.K.)
| | - Janusz Płomiński
- Clinical Department of Trauma-Orthopedic Surgery and Spine Surgery of the Provincial Specialist Hospital in Olsztyn, 10-561 Olsztyn, Poland; (J.P.); (R.G.)
- Department and Clinic of Orthopaedics and Traumatology, Collegium Medicum, University of Warmia and Mazury, 10-719 Olsztyn, Poland
| | - Roman Grzybowski
- Clinical Department of Trauma-Orthopedic Surgery and Spine Surgery of the Provincial Specialist Hospital in Olsztyn, 10-561 Olsztyn, Poland; (J.P.); (R.G.)
- Department and Clinic of Orthopaedics and Traumatology, Collegium Medicum, University of Warmia and Mazury, 10-719 Olsztyn, Poland
| | - Ewa Fiedorowicz
- Faculty of Biology and Biotechnology, University of Warmia and Mazury, 10-719 Olsztyn, Poland; (D.R.); (A.C.); (E.F.); (N.K.); (E.K.)
| | - Natalia Kordulewska
- Faculty of Biology and Biotechnology, University of Warmia and Mazury, 10-719 Olsztyn, Poland; (D.R.); (A.C.); (E.F.); (N.K.); (E.K.)
| | - Huub Savelkoul
- Cell Biology and Immunology Group, Department of Animal Sciences, Wageningen University and Research, 6700 AG Wageningen, The Netherlands;
| | - Elżbieta Kostyra
- Faculty of Biology and Biotechnology, University of Warmia and Mazury, 10-719 Olsztyn, Poland; (D.R.); (A.C.); (E.F.); (N.K.); (E.K.)
| | - Anna Cieślińska
- Faculty of Biology and Biotechnology, University of Warmia and Mazury, 10-719 Olsztyn, Poland; (D.R.); (A.C.); (E.F.); (N.K.); (E.K.)
| |
Collapse
|
|
46
|
La Frano MR, Brito A, Johnson CM, Wilhelmson B, Gannon B, Fanter RK, Pedersen TL, Tanumihardjo SA, Newman JW. Metabolomics Reveals Altered Hepatic Bile Acids, Gut Microbiome Metabolites, and Cell Membrane Lipids Associated with Marginal Vitamin A Deficiency in a Mongolian Gerbil Model. Mol Nutr Food Res 2020; 64:e1901319. [PMID: 32453876 DOI: 10.1002/mnfr.201901319] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2019] [Revised: 05/19/2020] [Indexed: 12/17/2022]
Abstract
SCOPE This study is designed to provide a broad evaluation of the impacts of vitamin A (VA) deficiency on hepatic metabolism in a gerbil model. METHODS AND RESULTS After 28 days of VA depletion, male Mongolian gerbils (Meriones unguiculatus) are randomly assigned to experimental diets for 28 days. Groups are fed a white-maize-based diet with ≈50 µL cottonseed oil vehicle either alone (VA-, n = 10) or containing 40 µg retinyl acetate (VA+, n = 10) for 28 days. Liver retinol is measured by high-performance liquid chromatography. Primary metabolomics, aminomics, lipidomics, bile acids, oxylipins, ceramides, and endocannabinoids are analyzed in post-mortem liver samples by liquid chromatography-mass spectrometry. RESULTS Liver retinol is lower (p < 0.001) in the VA- versus VA+ group, with concentrations indicating marginal VA deficiency. A total of 300 metabolites are identified. Marginal VA deficiency is associated with lower bile acids, trimethylamine N-oxide, and a variety of acylcarnitines, phospholipids and sphingomyelins (p < 0.05). Components of DNA, including deoxyguanosine, cytidine, and N-carbomoyl-beta-alanine (p < 0.05), are differentially altered. CONCLUSIONS Hepatic metabolomics in a marginally VA-deficient gerbil model revealed alterations in markers of the gut microbiome, fatty acid and nucleotide metabolism, and cellular structure and signaling.
Collapse
Affiliation(s)
- Michael R La Frano
- Department of Food Science and Nutrition, California Polytechnic State University, San Luis Obispo, CA, 93407, USA.,Center for Health Research, California Polytechnic State University, San Luis Obispo, CA, 93407, USA.,West Coast Metabolomics Center, University of California, Davis, CA, USA.,Department of Nutrition, University of California Davis, Davis, CA, USA
| | - Alex Brito
- Laboratory of Pharmacokinetics and Metabolomic Analysis, Institute of Translational Medicine and Biotechnology, I. M. Sechenov First Moscow State Medical University, Moscow, 119991, Russia.,Luxembourg Institute of Health, Department of Population Health, Nutrition and Health Research Group, 1A-B, rue Thomas Edison, Strassen, 1445, Luxembourg
| | - Catherine M Johnson
- Department of Food Science and Nutrition, California Polytechnic State University, San Luis Obispo, CA, 93407, USA
| | - Baylee Wilhelmson
- Department of Food Science and Nutrition, California Polytechnic State University, San Luis Obispo, CA, 93407, USA
| | - Bryan Gannon
- University of Wisconsin-Madison, Department of Nutritional Sciences, Madison, WI, USA.,Division of Nutritional Sciences, Cornell University, Ithaca, NY, USA
| | - Rob K Fanter
- College of Agriculture, Food and Environmental Sciences, California Polytechnic State University, San Luis Obispo, CA, USA
| | - Theresa L Pedersen
- Department of Food Science and Technology, University of California Davis, Davis, CA, USA
| | - Sherry A Tanumihardjo
- University of Wisconsin-Madison, Department of Nutritional Sciences, Madison, WI, USA
| | - John W Newman
- West Coast Metabolomics Center, University of California, Davis, CA, USA.,Department of Nutrition, University of California Davis, Davis, CA, USA.,Obesity and Metabolism Research Unit, United States Department of Agriculture, Agricultural Research Service, Western Human Nutrition Research Center, Davis, CA, USA
| |
Collapse
|
|
47
|
Zhang YG, Lu R, Wu S, Chatterjee I, Zhou D, Xia Y, Sun J. Vitamin D Receptor Protects Against Dysbiosis and Tumorigenesis via the JAK/STAT Pathway in Intestine. Cell Mol Gastroenterol Hepatol 2020; 10:729-746. [PMID: 32497792 PMCID: PMC7498955 DOI: 10.1016/j.jcmgh.2020.05.010] [Citation(s) in RCA: 53] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2020] [Revised: 05/22/2020] [Accepted: 05/22/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS Vitamin D exerts regulatory roles via vitamin D receptor (VDR) in mucosal immunity, host defense, and inflammation involving host factors and microbiome. Human Vdr gene variation shapes the microbiome and VDR deletion leads to dysbiosis. Low VDR expression and diminished vitamin D/VDR signaling are observed in colon cancer. Nevertheless, how intestinal epithelial VDR is involved in tumorigenesis through gut microbiota remains unknown. We hypothesized that intestinal VDR protects mice against dysbiosis via modulating the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway in tumorigenesis. METHODS To test our hypothesis, we used an azoxymethane/dextran sulfate sodium-induced cancer model in intestinal VDR conditional knockout (VDRΔIEC) mice, cell cultures, stem cell-derived colonoids, and human colon cancer samples. RESULTS VDRΔIEC mice have higher numbers of tumors, with the location shifted from the distal to proximal colon. Fecal microbiota analysis showed that VDR deletion leads to a bacterial profile shift from normal to susceptible carcinogenesis. We found enhanced bacterial staining in mouse and human tumors. Microbial metabolites from VDRΔIEC mice showed increased secondary bile acids, consistent with observations in human CRC. We further identified that VDR protein bound to the Jak2 promoter, suggesting that VDR transcriptionally regulated Jak2. The JAK/STAT pathway is critical in intestinal and microbial homeostasis. Fecal samples from VDRΔIEC mice activate the STAT3 signaling in human and mouse organoids. Lack of VDR led to hyperfunction of Jak2 in response to intestinal dysbiosis. A JAK/STAT inhibitor abolished the microbiome-induced activation of STAT3. CONCLUSIONS We provide insights into the mechanism of VDR dysfunction leading to dysbiosis and tumorigenesis. It indicates a new target: microbiome and VDR for the prevention of cancer.
Collapse
Affiliation(s)
- Yong-Guo Zhang
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois
| | - Rong Lu
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois
| | - Shaoping Wu
- Department of Biochemistry, Rush University, Chicago, Illinois
| | - Ishita Chatterjee
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois
| | - David Zhou
- Department of Pathology and Immunology, Washington University in St. Louis, St. Louis, Missouri
| | - Yinglin Xia
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois
| | - Jun Sun
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois,University of Illinois at Chicago Cancer Center, University of Illinois at Chicago, Chicago, Illinois,Correspondence Address correspondence to: Jun Sun, PhD, AGAF, FAPS, Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois at Chicago, 840 S Wood Street, Room 704 CSB, MC716 Chicago, Illinois 60612. fax: (312) 996-6010.
| |
Collapse
|
|
48
|
Golonka RM, San Yeoh B, Li Y, Saha P, Abokor AA, Cheng X, Xiao X, Chandrashekar DS, Varambally S, Gonzalez DJ, Ross AC, Vijay-Kumar M. Fermentable fibers induce rapid macro- and micronutrient depletion in Toll-like receptor 5-deficient mice. Am J Physiol Gastrointest Liver Physiol 2020; 318:G955-G965. [PMID: 32200644 PMCID: PMC7276927 DOI: 10.1152/ajpgi.00349.2019] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Functional fermentable fibers are considered essential for a healthy diet. Recently, we demonstrated that gut microbiota dysbiotic mice fed an inulin-containing diet (ICD) developed hepatocellular carcinoma (HCC) within 6 mo. In particular, a subset of Toll-like receptor 5-deficient (T5KO) mice prone to HCC exhibited rapid onset of hyperbilirubinemia (HB) and cholemia; these symptoms provide rationale that ICD induces cholestasis. Our objective in the present study was to determine whether inulin-fed T5KO-HB mice exhibit other known consequences of cholestasis, including essential fatty acid and fat-soluble vitamin deficiencies. Here, we measured hepatic fatty acids and serum vitamin A and D levels from wild-type (WT), T5KO low bilirubin (LB) and T5KO-HB mice fed ICD for 4 wk. Additionally, hepatic RNAseq and proteomics were performed to ascertain other metabolic alterations. Compared with WT and T5KO-LB, T5KO-HB mice exhibited steatorrhea, i.e., ~50% increase in fecal lipids. This could contribute to the significant reduction of linoleate in hepatic neutral lipids in T5KO-HB mice. Additionally, serum vitamins A and D were ~50% reduced in T5KO-HB mice, which was associated with metabolic compromises. Overall, our study highlights that fermentable fiber-induced cholestasis is further characterized by depletion of macro-and micronutrients.NEW & NOTEWORTHY Feeding a dietary, fermentable fiber diet to a subset of Toll-like receptor 5 deficient (T5KO) mice induces early onset hyperbilirubinemia and cholemia that later manifests to hepatocellular carcinoma (HCC). Our study highlights that fermentable fiber-induced cholestasis is characterized with modest macro- and micronutrient deficiencies that may further contribute to hepatic biliary disease. Compared with chemical induction, immunization, surgery, or genetic manipulation, these findings provide a novel approach to study the cholestatic subtype of HCC.
Collapse
Affiliation(s)
- Rachel M. Golonka
- 1Department of Physiology and Pharmacology, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio
| | - Beng San Yeoh
- 1Department of Physiology and Pharmacology, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio
| | - Yaqi Li
- 2Department of Nutritional Sciences, Pennsylvania State University, University Park, Pennsylvania
| | - Piu Saha
- 1Department of Physiology and Pharmacology, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio
| | - Ahmed A. Abokor
- 1Department of Physiology and Pharmacology, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio
| | - Xi Cheng
- 1Department of Physiology and Pharmacology, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio
| | - Xia Xiao
- 3Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
| | | | - Sooryanarayana Varambally
- 4Department of Pathology, University of Alabama, Birmingham, Alabama,5Comprehensive Cancer Center, University of Alabama, Birmingham, Alabama,6Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan
| | - David J. Gonzalez
- 7Department of Pharmacology, School of Medicine, and the School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, California
| | - A. Catharine Ross
- 2Department of Nutritional Sciences, Pennsylvania State University, University Park, Pennsylvania
| | - Matam Vijay-Kumar
- 1Department of Physiology and Pharmacology, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio,8Department of Medical Microbiology and Immunology, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio
| |
Collapse
|
|
49
|
Chatterjee I, Lu R, Zhang Y, Zhang J, Dai Y, Xia Y, Sun J. Vitamin D receptor promotes healthy microbial metabolites and microbiome. Sci Rep 2020; 10:7340. [PMID: 32355205 PMCID: PMC7192915 DOI: 10.1038/s41598-020-64226-7] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2019] [Accepted: 01/03/2020] [Indexed: 02/06/2023] Open
Abstract
Microbiota derived metabolites act as chemical messengers that elicit a profound impact on host physiology. Vitamin D receptor (VDR) is a key genetic factor for shaping the host microbiome. However, it remains unclear how microbial metabolites are altered in the absence of VDR. We investigated metabolites from mice with tissue-specific deletion of VDR in intestinal epithelial cells or myeloid cells. Conditional VDR deletion severely changed metabolites specifically produced from carbohydrate, protein, lipid, and bile acid metabolism. Eighty-four out of 765 biochemicals were significantly altered due to the Vdr status, and 530 significant changes were due to the high-fat diet intervention. The impact of diet was more prominent due to loss of VDR as indicated by the differences in metabolites generated from energy expenditure, tri-carboxylic acid cycle, tocopherol, polyamine metabolism, and bile acids. The effect of HFD was more pronounced in female mice after VDR deletion. Interestingly, the expression levels of farnesoid X receptor in liver and intestine were significantly increased after intestinal epithelial VDR deletion and were further increased by the high-fat diet. Our study highlights the gender differences, tissue specificity, and potential gut-liver-microbiome axis mediated by VDR that might trigger downstream metabolic disorders.
Collapse
Affiliation(s)
- Ishita Chatterjee
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois at Chicago, Chicago, USA
| | - Rong Lu
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois at Chicago, Chicago, USA
| | - Yongguo Zhang
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois at Chicago, Chicago, USA
| | - Jilei Zhang
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois at Chicago, Chicago, USA
| | - Yang Dai
- Department of Bioengineering, University of Illinois at Chicago, Chicago, USA
| | - Yinglin Xia
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois at Chicago, Chicago, USA.
| | - Jun Sun
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois at Chicago, Chicago, USA.
| |
Collapse
|
|
50
|
Lang L, Shull AY, Teng Y. Interrupting the FGF19-FGFR4 Axis to Therapeutically Disrupt Cancer Progression. Curr Cancer Drug Targets 2020; 19:17-25. [PMID: 29557750 DOI: 10.2174/1568009618666180319091731] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2017] [Revised: 09/01/2017] [Accepted: 10/10/2017] [Indexed: 02/07/2023]
Abstract
Coordination between the amplification of the fibroblast growth factor FGF19, overexpression of its corresponding receptor FGFR4, and hyperactivation of the downstream transmembrane enzyme β-klotho has been found to play pivotal roles in mediating tumor development and progression. Aberrant FGF19-FGFR4 signaling has been implicated in driving specific tumorigenic events including cancer cell proliferation, apoptosis resistance, and metastasis by activating a myriad of downstream signaling cascades. As an attractive target, several strategies implemented to disrupt the FGF19-FGFR4 axis have been developed in recent years, and FGF19-FGFR4 binding inhibitors are being intensely evaluated for their clinical use in treating FGF19-FGFR4 implicated cancers. Based on the established work, this review aims to detail how the FGF19-FGFR4 signaling pathway plays a vital role in cancer progression and why disrupting communication between FGF19 and FGFR4 serves as a promising therapeutic strategy for disrupting cancer progression.
Collapse
Affiliation(s)
- Liwei Lang
- Department of Oral Biology, Augusta University, Augusta, GA 30912, United States
| | - Austin Y Shull
- Department of Biology, Presbyterian College, Clinton, SC 29325, United States
| | - Yong Teng
- Department of Oral Biology, Augusta University, Augusta, GA 30912, United States.,Georgia Cancer Center, Augusta University, Augusta, GA 30912, United States.,Department of Biochemistry & Molecular Biology, Augusta University, Augusta, GA 30912, United States
| |
Collapse
|