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1
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Shen H, Liangpunsakul S, Iwakiri Y, Szabo G, Wang H. Immunological mechanisms and emerging therapeutic targets in alcohol-associated liver disease. Cell Mol Immunol 2025:10.1038/s41423-025-01291-w. [PMID: 40399593 DOI: 10.1038/s41423-025-01291-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2025] [Accepted: 04/19/2025] [Indexed: 05/23/2025] Open
Abstract
Alcohol-associated liver disease (ALD) is a major global health challenge, with inflammation playing a central role in its progression. As inflammation emerges as a critical therapeutic target, ongoing research aims to unravel its underlying mechanisms. This review explores the immunological pathways of ALD, highlighting the roles of immune cells and their inflammatory mediators in disease onset and progression. We also examine the complex interactions between inflammatory cells and non-parenchymal liver cells, as well as their crosstalk with extra-hepatic organs, including the gut, adipose tissue, and nervous system. Furthermore, we summarize current clinical research on anti-inflammatory therapies and discuss promising therapeutic targets. Given the heterogeneity of ALD-associated inflammation, we emphasize the need for precision medicine to optimize treatment strategies and improve patient outcomes.
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Affiliation(s)
- Haiyuan Shen
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
- The Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Medical University, Hefei, China
| | - Suthat Liangpunsakul
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA
- Roudebush Veterans Administration Medical Center, Indianapolis, IN, USA
| | - Yasuko Iwakiri
- Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA
| | - Gyongyi Szabo
- Department of Medicine, Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Hua Wang
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, China.
- The Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Medical University, Hefei, China.
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2
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Li W, Gao W, Yan S, Yang L, Zhu Q, Chu H. Gut Microbiota as Emerging Players in the Development of Alcohol-Related Liver Disease. Biomedicines 2024; 13:74. [PMID: 39857657 PMCID: PMC11761646 DOI: 10.3390/biomedicines13010074] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2024] [Revised: 12/23/2024] [Accepted: 12/29/2024] [Indexed: 01/27/2025] Open
Abstract
The global incidence and mortality rates of alcohol-related liver disease are on the rise, reflecting a growing health concern worldwide. Alcohol-related liver disease develops due to a complex interplay of multiple reasons, including oxidative stress generated during the metabolism of ethanol, immune response activated by immunogenic substances, and subsequent inflammatory processes. Recent research highlights the gut microbiota's significant role in the progression of alcohol-related liver disease. In patients with alcohol-related liver disease, the relative abundance of pathogenic bacteria, including Enterococcus faecalis, increases and is positively correlated with the level of severity exhibited by alcohol-related liver disease. Supplement probiotics like Lactobacillus, as well as Bifidobacterium, have been found to alleviate alcohol-related liver disease. The gut microbiota is speculated to trigger specific signaling pathways, influence metabolite profiles, and modulate immune responses in the gut and liver. This research aimed to investigate the role of gut microorganisms in the onset and advancement of alcohol-related liver disease, as well as to uncover the underlying mechanisms by which the gut microbiota may contribute to its development. This review outlines current treatments for reversing gut dysbiosis, including probiotics, fecal microbiota transplantation, and targeted phage therapy. Particularly, targeted therapy will be a vital aspect of future alcohol-related liver disease treatment. It is to be hoped that this article will prove beneficial for the treatment of alcohol-related liver disease.
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Affiliation(s)
- Wei Li
- Wuhan Jinyintan Hospital, Tongji Medical College of Huazhong University of Science and Technology, Hubei Clinical Research Center for Infectious Diseases, Wuhan Research Center for Communicable Disease Diagnosis and Treatment, Chinese Academy of Medical Sciences, Joint Laboratory of Infectious Diseases and Health, Wuhan Institute of Virology and Wuhan Jinyintan Hospital, Chinese Academy of Sciences, Wuhan 430023, China;
| | - Wenkang Gao
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; (W.G.); (S.Y.); (L.Y.)
| | - Shengqi Yan
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; (W.G.); (S.Y.); (L.Y.)
| | - Ling Yang
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; (W.G.); (S.Y.); (L.Y.)
| | - Qingjing Zhu
- Wuhan Jinyintan Hospital, Tongji Medical College of Huazhong University of Science and Technology, Hubei Clinical Research Center for Infectious Diseases, Wuhan Research Center for Communicable Disease Diagnosis and Treatment, Chinese Academy of Medical Sciences, Joint Laboratory of Infectious Diseases and Health, Wuhan Institute of Virology and Wuhan Jinyintan Hospital, Chinese Academy of Sciences, Wuhan 430023, China;
| | - Huikuan Chu
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; (W.G.); (S.Y.); (L.Y.)
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3
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Sun Y, Men Q, Ren X, Yan C, Song S, Ai C. Low molecular fucoidan alleviated alcohol-induced liver injury in BALB/c mice by regulating the gut microbiota-bile acid-liver axis. Int J Biol Macromol 2024; 282:136930. [PMID: 39490864 DOI: 10.1016/j.ijbiomac.2024.136930] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2024] [Revised: 09/24/2024] [Accepted: 10/24/2024] [Indexed: 11/05/2024]
Abstract
Fucoidan has attracted significant attention owing to its remarkable bioactivities, but the effect of molecular weight (Mw) on its activities in the context of alcoholic liver diseases (ALD) is poorly understood. In this study, low Mw fucoidan (OSLF) was prepared, and its protective effect against alcohol-induced liver injury was assessed in a mouse model. OSLF increased weight gain and colon length, improved lipid disorders, and reduced oxidative stress in mice exposed to alcohol, alleviating liver injury. OSLF alleviated inflammation in the liver by inhibiting alcohol-activated NF-κB and MAPK pathways. The underlying mechanism can be attributed to the improvement of alcohol-induced dysbiosis of the gut microbiota, including a decrease in Proteobacteria and Bacteroidetes and an increase in microbiota diversity, as well as the abundances of Parabacteroides, Bacteroides, and Faecalibaculum. Metabolomics results showed that OSLF improved alcohol-induced abnormalities of microbiota metabolites, primarily involving amino acid metabolism and short chain fatty acids production. In addition, OSLF ameliorated bile acid metabolism in the gut and regulated the expression of bile acid-associated genes in the liver, affecting bile acid synthesis, regulation, and transport. It suggested that OSLF had the potential for the management of ALD by regulating the gut microbiota-bile acid-liver axis.
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Affiliation(s)
- Yiyun Sun
- School of Food Science and Technology, National Engineering Research Center of Seafood, Dalian Polytechnic University, Dalian 116034, PR China
| | - Qiuyue Men
- School of Food Science and Technology, National Engineering Research Center of Seafood, Dalian Polytechnic University, Dalian 116034, PR China
| | - Xiaomeng Ren
- School of Food Science and Technology, National Engineering Research Center of Seafood, Dalian Polytechnic University, Dalian 116034, PR China
| | - Chunhong Yan
- School of Food Science and Technology, National Engineering Research Center of Seafood, Dalian Polytechnic University, Dalian 116034, PR China
| | - Shuang Song
- School of Food Science and Technology, National Engineering Research Center of Seafood, Dalian Polytechnic University, Dalian 116034, PR China
| | - Chunqing Ai
- School of Food Science and Technology, National Engineering Research Center of Seafood, Dalian Polytechnic University, Dalian 116034, PR China; National & Local Joint Engineering Laboratory for Marine Bioactive Polysaccharide Development and Application, Dalian Polytechnic University, Dalian 116034, PR China.
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4
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Wu Y, He X, Chen H, Lin Y, Zheng C, Zheng B. Extraction and characterization of hepatoprotective polysaccharides from Anoectochilus roxburghii against CCl 4-induced liver injury via regulating lipid metabolism and the gut microbiota. Int J Biol Macromol 2024; 277:134305. [PMID: 39094884 DOI: 10.1016/j.ijbiomac.2024.134305] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2024] [Revised: 07/11/2024] [Accepted: 07/28/2024] [Indexed: 08/04/2024]
Abstract
Anoectochilus roxburghii polysaccharides exhibit notable hepatoprotective effects, but the underlying substance basis and mechanisms remain unknown. In this study, four new polysaccharides named ARP-1a, ARP-1b, ARP-2a and ARP-2b, were isolated from A. roxburghii. Their structural characteristics were systematically analyzed using HPGPC, HPLC, GC-MS, IR and NMR analysis. ARP-1a, the leading polysaccharide isolated from A. roxburghii, was further evaluated for its hepatoprotective effects on acute liver injury mice induced by CCl4. ARP-1a significantly reduced the serum ALT, AST, TNF-α, IL-1β and IL-6 levels, liver MDA content, and increased the SOD and CAT activities and GSH level in liver. H&E staining revealed that ARP-1a pretreatment could markedly relieve liver injury. Further mechanism exploration indicated that ARP-1a could relieve CCl4-induced oxidative damage through activating the Nrf2 signaling. In addition, metabolomics, lipidomics and 16S rRNA amplicon sequencing were used to elucidate the underlying mechanisms of ARP-1a. Multi-omics analysis indicated that ARP-1a exerted hepatoprotective effect against CCl4-induced acute liver injury by regulating lipid metabolism and modulating the gut microbiota. In conclusion, the above results suggest that ARP-1a can be considered a promising and safe candidate for hepatoprotective drug, as well as a potential prebiotic for maintaining intestinal homeostasis and promoting human intestinal health.
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Affiliation(s)
- Yanbin Wu
- College of Food Science, Fujian Agriculture and Forestry University, Fuzhou 350002, China; College of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, China
| | - Xuhui He
- Department of Chinese Medicine Authentication, School of Pharmacy, Naval Medical University, Shanghai 200433, China
| | - Huiling Chen
- College of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, China
| | - Yan Lin
- College of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, China
| | - Chengjian Zheng
- Department of Chinese Medicine Authentication, School of Pharmacy, Naval Medical University, Shanghai 200433, China.
| | - Baodong Zheng
- College of Food Science, Fujian Agriculture and Forestry University, Fuzhou 350002, China.
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5
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Leclercq S. Involvement of the gut microbiome-brain axis in alcohol use disorder. Alcohol Alcohol 2024; 59:agae050. [PMID: 39042929 DOI: 10.1093/alcalc/agae050] [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: 04/18/2024] [Revised: 06/06/2024] [Accepted: 07/10/2024] [Indexed: 07/25/2024] Open
Abstract
The human intestine is colonized by a variety of microorganisms that influence the immune system, the metabolic response, and the nervous system, with consequences for brain function and behavior. Unbalance in this microbial ecosystem has been shown to be associated with psychiatric disorders, and altered gut microbiome composition related to bacteria, viruses, and fungi has been well established in patients with alcohol use disorder. This review describes the gut microbiome-brain communication pathways, including the ones related to the vagus nerve, the inflammatory cytokines, and the gut-derived metabolites. Finally, the potential benefits of microbiota-based therapies for the management of alcohol use disorder, such as probiotics, prebiotics, and fecal microbiota transplantation, are also discussed.
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Affiliation(s)
- Sophie Leclercq
- Laboratory of Nutritional Psychiatry, Institute of Neuroscience, Université Catholique de Louvain, 1200 Brussels, Belgium
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Zhang X, Wang J, Zhang T, Li S, Liu J, Li M, Lu J, Zhang M, Chen H. Updated Progress on Polysaccharides with Anti-Diabetic Effects through the Regulation of Gut Microbiota: Sources, Mechanisms, and Structure-Activity Relationships. Pharmaceuticals (Basel) 2024; 17:456. [PMID: 38675416 PMCID: PMC11053653 DOI: 10.3390/ph17040456] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2024] [Revised: 03/28/2024] [Accepted: 03/29/2024] [Indexed: 04/28/2024] Open
Abstract
Diabetes mellitus (DM) is a common chronic metabolic disease worldwide. The disturbance of the gut microbiota has a complex influence on the development of DM. Polysaccharides are one type of the most important natural components with anti-diabetic effects. Gut microbiota can participate in the fermentation of polysaccharides, and through this, polysaccharides regulate the gut microbiota and improve DM. This review begins by a summary of the sources, anti-diabetic effects and the gut microbiota regulation functions of natural polysaccharides. Then, the mechanisms of polysaccharides in regulating the gut microbiota to exert anti-diabetic effects and the structure-activity relationship are summarized. It is found that polysaccharides from plants, fungi, and marine organisms show great hypoglycemic activities and the gut microbiota regulation functions. The mechanisms mainly include repairing the gut burrier, reshaping gut microbiota composition, changing the metabolites, regulating anti-inflammatory activity and immune function, and regulating the signal pathways. Structural characteristics of polysaccharides, such as monosaccharide composition, molecular weight, and type of glycosidic linkage, show great influence on the anti-diabetic activity of polysaccharides. This review provides a reference for the exploration and development of the anti-diabetic effects of polysaccharides.
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Affiliation(s)
- Xiaoyu Zhang
- Tianjin Key Laboratory for Modern Drug Delivery and High-Efficiency, School of Pharmaceutical Science and Technology, Faculty of Medicine, Tianjin University, Tianjin 300072, China; (X.Z.); (J.W.); (T.Z.); (S.L.); (J.L.); (M.L.); (J.L.)
| | - Jia Wang
- Tianjin Key Laboratory for Modern Drug Delivery and High-Efficiency, School of Pharmaceutical Science and Technology, Faculty of Medicine, Tianjin University, Tianjin 300072, China; (X.Z.); (J.W.); (T.Z.); (S.L.); (J.L.); (M.L.); (J.L.)
| | - Tingting Zhang
- Tianjin Key Laboratory for Modern Drug Delivery and High-Efficiency, School of Pharmaceutical Science and Technology, Faculty of Medicine, Tianjin University, Tianjin 300072, China; (X.Z.); (J.W.); (T.Z.); (S.L.); (J.L.); (M.L.); (J.L.)
| | - Shuqin Li
- Tianjin Key Laboratory for Modern Drug Delivery and High-Efficiency, School of Pharmaceutical Science and Technology, Faculty of Medicine, Tianjin University, Tianjin 300072, China; (X.Z.); (J.W.); (T.Z.); (S.L.); (J.L.); (M.L.); (J.L.)
| | - Junyu Liu
- Tianjin Key Laboratory for Modern Drug Delivery and High-Efficiency, School of Pharmaceutical Science and Technology, Faculty of Medicine, Tianjin University, Tianjin 300072, China; (X.Z.); (J.W.); (T.Z.); (S.L.); (J.L.); (M.L.); (J.L.)
| | - Mingyue Li
- Tianjin Key Laboratory for Modern Drug Delivery and High-Efficiency, School of Pharmaceutical Science and Technology, Faculty of Medicine, Tianjin University, Tianjin 300072, China; (X.Z.); (J.W.); (T.Z.); (S.L.); (J.L.); (M.L.); (J.L.)
| | - Jingyang Lu
- Tianjin Key Laboratory for Modern Drug Delivery and High-Efficiency, School of Pharmaceutical Science and Technology, Faculty of Medicine, Tianjin University, Tianjin 300072, China; (X.Z.); (J.W.); (T.Z.); (S.L.); (J.L.); (M.L.); (J.L.)
| | - Min Zhang
- China-Russia Agricultural Processing Joint Laboratory, Tianjin Agricultural University, Tianjin 300384, China;
- State Key Laboratory of Nutrition and Safety, Tianjin University of Science & Technology, Tianjin 300457, China
| | - Haixia Chen
- Tianjin Key Laboratory for Modern Drug Delivery and High-Efficiency, School of Pharmaceutical Science and Technology, Faculty of Medicine, Tianjin University, Tianjin 300072, China; (X.Z.); (J.W.); (T.Z.); (S.L.); (J.L.); (M.L.); (J.L.)
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Scarlata GGM, Colaci C, Scarcella M, Dallio M, Federico A, Boccuto L, Abenavoli L. The Role of Cytokines in the Pathogenesis and Treatment of Alcoholic Liver Disease. Diseases 2024; 12:69. [PMID: 38667527 PMCID: PMC11048950 DOI: 10.3390/diseases12040069] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Revised: 03/27/2024] [Accepted: 03/29/2024] [Indexed: 04/28/2024] Open
Abstract
Alcoholic liver disease (ALD) is a major cause of chronic liver disease. This term covers a broad spectrum of liver lesions, from simple steatosis to alcoholic hepatitis and cirrhosis. The pathogenesis of ALD is multifactorial and not fully elucidated due to complex mechanisms related to direct ethanol toxicity with subsequent hepatic and systemic inflammation. The accumulation of pro-inflammatory cytokines and the reduction of anti-inflammatory cytokines promote the development and progression of ALD. To date, there are no targeted therapies to counter the progression of chronic alcohol-related liver disease and prevent acute liver failure. Corticosteroids reduce mortality by acting on the hepatic-systemic inflammation. On the other hand, several studies analyzed the effect of inhibiting pro-inflammatory cytokines and stimulating anti-inflammatory cytokines as potential therapeutic targets in ALD. This narrative review aims to clarify the role of the main cytokines involved in the pathogenesis and treatment of ALD.
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Affiliation(s)
| | - Carmen Colaci
- Department of Health Sciences, University “Magna Græcia”, Viale Europa, 88100 Catanzaro, Italy; (G.G.M.S.); (C.C.)
| | - Marialaura Scarcella
- Anesthesia, Intensive Care and Nutritional Science, Azienda Ospedaliera “Santa Maria”, Via Tristano di Joannuccio, 05100 Terni, Italy;
| | - Marcello Dallio
- Hepatogastroenterology Division, Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Piazza Miraglia 2, 80138 Naples, Italy; (M.D.); (A.F.)
| | - Alessandro Federico
- Hepatogastroenterology Division, Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Piazza Miraglia 2, 80138 Naples, Italy; (M.D.); (A.F.)
| | - Luigi Boccuto
- Healthcare Genetics and Genomics Doctoral Program, School of Nursing, College of Behavioral, Social and Health Sciences, Clemson University, Clemson, SC 29634, USA;
| | - Ludovico Abenavoli
- Department of Health Sciences, University “Magna Græcia”, Viale Europa, 88100 Catanzaro, Italy; (G.G.M.S.); (C.C.)
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Shen M, Zhao H, Han M, Su L, Cui X, Li D, Liu L, Wang C, Yang F. Alcohol-induced gut microbiome dysbiosis enhances the colonization of Klebsiella pneumoniae on the mouse intestinal tract. mSystems 2024; 9:e0005224. [PMID: 38345382 PMCID: PMC10949497 DOI: 10.1128/msystems.00052-24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Accepted: 01/12/2024] [Indexed: 03/20/2024] Open
Abstract
Chronic alcohol consumption, an important risk factor for diseases and deaths, can cause intestinal microbiota dysbiosis and increase the infection of some opportunistic pathogens. However, the current studies on the effects of alcohol-induced intestinal microbiota dysbiosis on gut colonization of Klebsiella pneumoniae are still scarce. In the present study, we established a binge-on-chronic alcohol model in mice to identify the characteristics of alcohol-induced intestinal microbiome and metabolite dysbiosis using multi-omics and explored the effects and potential mechanisms of these dysbioses on the intestinal colonization of K. pneumoniae. The results show that chronic alcohol consumption alters the diversity and composition of gut microbiota (including bacteria and fungi), decreases the complexity of the interaction between intestinal bacteria and fungi, disturbs the gut metabolites, and promotes the colonization of K. pneumoniae on the gut of mice. The relevance analyses find that alcohol-induced gut microbiome dysbiosis has a strong correlation with the alteration of secondary bile acids. In vitro results suggest that the high concentration of lithocholic acid, a secondary bile acid, could significantly inhibit the proliferation of K. pneumoniae, and the adhesion of K. pneumoniae to Caco-2 cells. Our results indicate that alcohol-induced microbiome dysbiosis contributes to decreased levels of secondary bile acids, which was one of the main reasons affecting the colonization of K. pneumoniae in mice's intestines. Some secondary bile acids (e.g., lithocholic acid) might be a potential drug to prevent the colonization and spread of K. pneumoniae.IMPORTANCEAlcohol is one of the most commonly misused substances in our lives. However, long-term heavy drinking will increase the colonization of some opportunistic pathogens (e.g., Klebsiella pneumoniae) in the body. Here, we revealed that binge-on-chronic alcohol consumption disrupted the balance between gut bacteria and fungi, induced the gut microbiome and metabolites dysbiosis, and promoted the colonization of K. pneumoniae in the intestine of mice. In particular, alcohol-taking disrupted intestinal bile acid metabolism and reduced the lithocholic acid concentration. However, a high concentration of lithocholic acid can protect against intestinal colonization of K. pneumoniae by inhabiting the bacterial growth and adhesion to the host cell. Hence, regulating the balance of gut microbiota and intestinal bile acid metabolism may be a potential strategy for reducing the risk of K. pneumoniae infection and spread.
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Affiliation(s)
- Mengke Shen
- Department of Pathogenic Biology, School of Basic Medical Science, Xinxiang Medical University, Xinxiang, China
- Department of Pathogenic Biology and Immunology, Sanquan College of Xinxiang Medical University, Xinxiang, China
| | - Huajie Zhao
- Department of Pathogenic Biology, School of Basic Medical Science, Xinxiang Medical University, Xinxiang, China
| | - Meiqing Han
- Department of Pathogenic Biology, School of Basic Medical Science, Xinxiang Medical University, Xinxiang, China
| | - Lin Su
- Department of Pathogenic Biology, School of Basic Medical Science, Xinxiang Medical University, Xinxiang, China
| | - Xiaojian Cui
- Department of Pathogenic Biology, School of Basic Medical Science, Xinxiang Medical University, Xinxiang, China
| | - Duan Li
- Department of Pathogenic Biology, School of Basic Medical Science, Xinxiang Medical University, Xinxiang, China
| | - Liang Liu
- Department of Pathogenic Biology, School of Basic Medical Science, Xinxiang Medical University, Xinxiang, China
| | - Chuansheng Wang
- The Second Affiliated Hospital of Xinxiang Medical University, Henan Key Laboratory of Biological Psychiatry, Xinxiang Medical University, Xinxiang, China
| | - Fan Yang
- Department of Pathogenic Biology, School of Basic Medical Science, Xinxiang Medical University, Xinxiang, China
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Siddiqui MT, Han Y, Shapiro D, West G, Fiocchi C, Cresci GAM. The Postbiotic Butyrate Mitigates Gut Mucosal Disruption Caused by Acute Ethanol Exposure. Int J Mol Sci 2024; 25:1665. [PMID: 38338944 PMCID: PMC10855591 DOI: 10.3390/ijms25031665] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Revised: 01/03/2024] [Accepted: 01/11/2024] [Indexed: 02/12/2024] Open
Abstract
We aimed to test how the postbiotic butyrate impacts select gut bacteria, small intestinal epithelial integrity, and microvascular endothelial activation during acute ethanol exposure in mice and primary human intestinal microvascular endothelial cells (HIMECs). Supplementation during an acute ethanol challenge with or without tributyrin, a butyrate prodrug, was delivered to C57BL/6 mice. A separate group of mice received 3 days of clindamycin prior to the acute ethanol challenge. Upon euthanasia, blood endotoxin, cecal bacteria, jejunal barrier integrity, and small intestinal lamina propria dendritic cells were assessed. HIMECs were tested for activation following exposure to ethanol ± lipopolysaccharide (LPS) and sodium butyrate. Tributyrin supplementation protected a butyrate-generating microbe during ethanol and antibiotic exposure. Tributyrin rescued ethanol-induced disruption in jejunal epithelial barrier, elevated plasma endotoxin, and increased mucosal vascular addressin cell-adhesion molecule-1 (MAdCAM-1) expression in intestinal microvascular endothelium. These protective effects of tributyrin coincided with a tolerogenic dendritic response in the intestinal lamina propria. Lastly, sodium butyrate pre- and co-treatment attenuated the direct effects of ethanol and LPS on MAdCAM-1 induction in the HIMECs from a patient with ulcerative colitis. Tributyrin supplementation protects small intestinal epithelial and microvascular barrier integrity and modulates microvascular endothelial activation and dendritic tolerizing function during a state of gut dysbiosis and acute ethanol challenge.
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Affiliation(s)
- Mohamed Tausif Siddiqui
- Department of Gastroenterology, Hepatology and Nutrition, Digestive Disease Institute, Cleveland Clinic, Cleveland, OH 44195, USA; (M.T.S.); (C.F.)
- Department of Inflammation & Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
| | - Yingchun Han
- Department of Inflammation & Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
| | - David Shapiro
- Department of Inflammation & Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
| | - Gail West
- Department of Inflammation & Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
| | - Claudio Fiocchi
- Department of Gastroenterology, Hepatology and Nutrition, Digestive Disease Institute, Cleveland Clinic, Cleveland, OH 44195, USA; (M.T.S.); (C.F.)
- Department of Inflammation & Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
| | - Gail A. M. Cresci
- Department of Gastroenterology, Hepatology and Nutrition, Digestive Disease Institute, Cleveland Clinic, Cleveland, OH 44195, USA; (M.T.S.); (C.F.)
- Department of Inflammation & Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Cleveland Clinic Children’s Hospital, Cleveland, OH 44195, USA
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10
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Sosnowski K, Przybyłkowski A. Ethanol-induced changes to the gut microbiome compromise the intestinal homeostasis: a review. Gut Microbes 2024; 16:2393272. [PMID: 39224006 PMCID: PMC11376419 DOI: 10.1080/19490976.2024.2393272] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2024] [Revised: 08/06/2024] [Accepted: 08/12/2024] [Indexed: 09/04/2024] Open
Abstract
The intestine is the largest organ in terms of surface area in the human body. It is responsible not only for absorbing nutrients but also for protection against the external world. The gut microbiota is essential in maintaining a properly functioning intestinal barrier, primarily through producing its metabolites: short-chain fatty acids, bile acids, and tryptophan derivatives. Ethanol overconsumption poses a significant threat to intestinal health. Not only does it damage the intestinal epithelium, but, maybe foremostly, it changes the gut microbiome. Those ethanol-driven changes shift its metabolome, depriving the host of the protective effect the physiological gut microbiota has. This literature review discusses the impact of ethanol consumption on the gut, the gut microbiota, and its metabolome, providing a comprehensive overview of the mechanisms through which ethanol disrupts intestinal homeostasis and discussing potential avenues for new therapeutic intervention.
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Affiliation(s)
- Konrad Sosnowski
- Department of Gastroenterology and Internal Medicine, Medical University of Warsaw, Warsaw, Poland
| | - Adam Przybyłkowski
- Department of Gastroenterology and Internal Medicine, Medical University of Warsaw, Warsaw, Poland
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11
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Fonseca-Pereira D, Bae S, Michaud M, Glickman JN, Garrett WS. Chronic binge drinking-induced susceptibility to colonic inflammation is microbiome-dependent. Gut Microbes 2024; 16:2392874. [PMID: 39163515 PMCID: PMC11340762 DOI: 10.1080/19490976.2024.2392874] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 08/22/2024] Open
Abstract
Alterations in intestinal permeability and the gut microbiome caused by alcohol abuse are associated with alcoholic liver disease and with worsening of inflammatory bowel diseases (IBD) symptoms. To resolve the direct effects of chronic ethanol consumption on the colon and its microbiome in the absence of acute or chronic alcohol-induced liver disease, we developed a mouse model of chronic binge drinking that uncovers how alcohol may enhance susceptibility to colitis via the microbiota. Employing daily ethanol gavage, we recapitulate key features of binge ethanol consumption. We found that binge ethanol drinking worsens intestinal infection, colonic injury and inflammation, and this effect persists beyond the drinking period. Using gnotobiotics, we showed that alcohol-driven susceptibility to colitis is microbiota-dependent and transferable to ethanol-naïve mice by microbiome transplantation. Allobaculum spp. expanded in binge drinking mice, and administration of Allobaculum fili was sufficient to enhance colitis in non-drinking mice. Our study provides a model to study binge drinking-microbiota interactions and their effects on host disease and reinforces the pathogenic function of Allobaculum spp. as colitogenic bacteria. Our findings illustrate how chronic binge drinking-induced alterations of the microbiome may affect susceptibility to IBD onset or flares.
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Affiliation(s)
- Diogo Fonseca-Pereira
- Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA
- Harvard T.H. Chan Microbiome in Public Health Center, Boston, MA, USA
| | - Sena Bae
- Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA
- Harvard T.H. Chan Microbiome in Public Health Center, Boston, MA, USA
| | - Monia Michaud
- Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA
- Harvard T.H. Chan Microbiome in Public Health Center, Boston, MA, USA
| | - Jonathan N. Glickman
- Gastrointestinal Pathology, Massachusetts General Hospital, Boston, MA, USA
- Department of Pathology, Harvard Medical School, Boston, MA, USA
| | - Wendy S. Garrett
- Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA
- Harvard T.H. Chan Microbiome in Public Health Center, Boston, MA, USA
- Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, MA, USA
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Division of Medical Sciences, Harvard Medical School, Boston, MA, USA
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
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12
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Zhang H, Li C, Han L, Xiao Y, Bian J, Liu C, Gong L, Liu Z, Wang M. MUP1 mediates urolithin A alleviation of chronic alcohol-related liver disease via gut-microbiota-liver axis. Gut Microbes 2024; 16:2367342. [PMID: 38889450 PMCID: PMC11188796 DOI: 10.1080/19490976.2024.2367342] [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: 01/23/2024] [Accepted: 06/07/2024] [Indexed: 06/20/2024] Open
Abstract
Alcohol-related liver disease (ALD) is recognized as a global health crisis, contributing to approximately 20% of liver cancer-associated fatalities. Dysbiosis of the gut microbiome is associated with the development of ALD, with the gut microbial metabolite urolithin A (UA) exhibiting a potential for alleviating liver symptoms. However, the protective efficacy of UA against ALD and its underlying mechanism mediated by microbiota remain elusive. In this study, we provide evidence demonstrating that UA effectively ameliorates alcohol-induced metabolic disorders and hepatic endoplasmic reticulum (ER) stress through a specific gut-microbiota-liver axis mediated by major urinary protein 1 (MUP1). Moreover, UA exhibited the potential to restore alcohol-induced dysbiosis of the intestinal microbiota by enriching the abundance of Bacteroides sartorii (B. sartorii), Parabacteroides distasonis (P. distasonis), and Akkermansia muciniphila (A. muciniphila), along with their derived metabolite propionic acid. Partial attenuation of the hepatoprotective effects exerted by UA was observed upon depletion of gut microbiota using antibiotics. Subsequently, a fecal microbiota transplantation (FMT) experiment was conducted to evaluate the microbiota-dependent effects of UA in ALD. FMT derived from mice treated with UA exhibited comparable efficacy to direct UA treatment, as it effectively attenuated ER stress through modulation of MUP1. It was noteworthy that strong associations were observed among the hepatic MUP1, gut microbiome, and metabolome profiles affected by UA. Intriguingly, oral administration of UA-enriched B. sartorii, P. distasonis, and A. muciniphila can enhance propionic acid production to effectively suppress ER stress via MUP1, mimicking UA treatment. Collectively, these findings elucidate the causal mechanism that UA alleviated ALD through the gut-microbiota-liver axis. This unique mechanism sheds light on developing novel microbiome-targeted therapeutic strategies against ALD.
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Affiliation(s)
- Hongbo Zhang
- College of Food Science and Engineering, Northwest A&F University, Yang ling, Shaanxi, China
| | - Chaoyue Li
- College of Food Science and Engineering, Northwest A&F University, Yang ling, Shaanxi, China
| | - Lin Han
- College of Food Science and Engineering, Northwest A&F University, Yang ling, Shaanxi, China
| | - Yao Xiao
- College of Food Science and Engineering, Northwest A&F University, Yang ling, Shaanxi, China
| | - Ji Bian
- Kolling Institute, Sydney Medical School, Royal North Shore Hospital, University of Sydney, Sydney, Australia
| | - Chao Liu
- Key Laboratory of Novel Food Resources Processing, Ministry of Agriculture and Rural Affairs/Institute of Agro-Food Science and Technology, Shandong Academy of Agricultural Sciences, Jinan, P.R. China
| | - Lan Gong
- UNSW Microbiome Research Centre, St George and Sutherland Clinical Campus, University of New South Wales, Sydney, Australia
| | - Zhigang Liu
- College of Food Science and Engineering, Northwest A&F University, Yang ling, Shaanxi, China
| | - Min Wang
- College of Food Science and Engineering, Northwest A&F University, Yang ling, Shaanxi, China
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13
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Zhang B, Zhang R, Deng H, Cui P, Li C, Yang F, Leong Bin Abdullah MFI. Research protocol of the efficacy of probiotics for the treatment of alcohol use disorder among adult males: A comparison with placebo and acceptance and commitment therapy in a randomized controlled trial. PLoS One 2023; 18:e0294768. [PMID: 38051740 PMCID: PMC10697511 DOI: 10.1371/journal.pone.0294768] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Accepted: 10/30/2023] [Indexed: 12/07/2023] Open
Abstract
BACKGROUND AND AIM Primarily, this study compares the efficacy of probiotic and acceptance and commitment therapy (ACT) in alleviating the severity of alcohol craving and alcohol use disorder (AUD) among patients who had undergo two weeks of in-patient detoxification. Secondarily, this study compares the efficacy of probiotic and ACT in mitigating the severity of comorbid depression and anxiety symptoms; decreasing serum level of pro-inflammatory cytokines, such as interleukin 1β (IL-1β), interleukin 6 (IL-6), and tumor necrosis factor α (TNF-α); changing the event-related potential in electroencephalogram (EEG) and restoring microbiota flora in the gut of AUD patients. METHODS AND ANALYSIS Initially, during Phase I of the study, the serum level of IL-1β, IL-6 and TNF-α; ERP changes in the EEG and fecal microbiota content will be compared between 120 AUD patients and 120 healthy controls. Subsequently in Phase II of the study, 120 AUD patients will be randomized by stratified permuted block randomization into the probiotic, ACT and placebo groups in a 1:1:1 ratio. Participants in the probiotic and placebo groups will be administered one sachet per day of Lactobacillus spp. probiotic and placebo, respectively for 12 weeks. While those in the ACT group will receive one session per week of ACT for 8 weeks. Outcome measures will be administered at four timepoints, such as t0 = baseline assessment prior to intervention, t1 = 8 weeks after intervention began, t2 = 12 weeks after intervention and t3 = 24 weeks after intervention. Primary outcomes are the degrees of alcohol craving, alcohol withdrawal during abstinence and AUD. Secondary outcomes to be assessed are the severity of co-morbid depression and anxiety symptoms; the serum levels of IL-1β, IL-6 and TNF-α; changes in ERP and fecal microbiota content. TRIAL REGISTRATION NUMBER NCT05830708 (ClinicalTrials.gov). Registered on April 25, 2023.
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Affiliation(s)
- Bingyu Zhang
- Department of Community Health, Advanced Medical and Dental Institute, Universiti Sains Malaysia, Kepala Batas, Pulau Pinang, Malaysia
- Department of Psychiatry, 2 Affiliated Hospital, Xinxiang Medical University, Xinxiang, Henan, China
| | - Ruiling Zhang
- Department of Psychiatry, 2 Affiliated Hospital, Xinxiang Medical University, Xinxiang, Henan, China
| | - Hongdu Deng
- Department of Community Health, Advanced Medical and Dental Institute, Universiti Sains Malaysia, Kepala Batas, Pulau Pinang, Malaysia
- Department of Psychiatry, 2 Affiliated Hospital, Xinxiang Medical University, Xinxiang, Henan, China
| | - Ping Cui
- Department of Psychiatry, 2 Affiliated Hospital, Xinxiang Medical University, Xinxiang, Henan, China
| | - Chunyan Li
- Department of Psychiatry, 2 Affiliated Hospital, Xinxiang Medical University, Xinxiang, Henan, China
| | - Fan Yang
- Department of Psychiatry, 2 Affiliated Hospital, Xinxiang Medical University, Xinxiang, Henan, China
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14
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Renu K, Myakala H, Chakraborty R, Bhattacharya S, Abuwani A, Lokhandwala M, Vellingiri B, Gopalakrishnan AV. Molecular mechanisms of alcohol's effects on the human body: A review and update. J Biochem Mol Toxicol 2023; 37:e23502. [PMID: 37578200 DOI: 10.1002/jbt.23502] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2022] [Revised: 07/18/2023] [Accepted: 07/31/2023] [Indexed: 08/15/2023]
Abstract
Alcohol consumption has been linked to numerous negative health outcomes although it has some beneficial effects on moderate dosages, the most severe of which being alcohol-induced hepatitis. The number of people dying from this liver illness has been shown to climb steadily over time, and its prevalence has been increasing. Researchers have found that alcohol consumption primarily affects the brain, leading to a wide range of neurological and psychological diseases. High-alcohol-consumption addicts not only experienced seizures, but also ataxia, aggression, social anxiety, and variceal hemorrhage that ultimately resulted in death, ascites, and schizophrenia. Drugs treating this liver condition are limited and can cause serious side effects like depression. Serine-threonine kinases, cAMP protein kinases, protein kinase C, ERK, RACK 1, Homer 2, and more have all been observed to have their signaling pathways disrupted by alcohol, and alcohol has also been linked to epigenetic changes. In addition, alcohol consumption induces dysbiosis by changing the composition of the microbiome found in the gastrointestinal tract. Although more studies are needed, those that have been done suggest that probiotics aid in keeping the various microbiota concentrations stable. It has been argued that reducing one's alcohol intake may seem less harmful because excessive drinking is a lifestyle disorder.
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Affiliation(s)
- Kaviyarasi Renu
- Department of Biochemistry, Centre of Molecular Medicine and Diagnostics (COMManD), Saveetha Dental College & Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, Tamil Nadu, India
| | - Haritha Myakala
- Department of Biomedical Sciences, School of Biosciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, India
| | - Rituraj Chakraborty
- Department of Biomedical Sciences, School of Biosciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, India
| | - Sharmishtha Bhattacharya
- Department of Biomedical Sciences, School of Biosciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, India
| | - Asmita Abuwani
- Department of Biomedical Sciences, School of Biosciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, India
| | - Mariyam Lokhandwala
- Department of Biomedical Sciences, School of Biosciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, India
| | - Balachandar Vellingiri
- Department of Zoology, Stem Cell and Regenerative Medicine/Translational Research, School of Basic Sciences, Central University of Punjab (CUPB), Bathinda, Punjab, India
| | - Abilash Valsala Gopalakrishnan
- Department of Biomedical Sciences, School of Biosciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, India
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15
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Ghare SS, Charpentier BT, Ghooray DT, Zhang J, Vadhanam MV, Reddy S, Joshi-Barve S, McClain CJ, Barve SS. Tributyrin Mitigates Ethanol-Induced Lysine Acetylation of Histone-H3 and p65-NFκB Downregulating CCL2 Expression and Consequent Liver Inflammation and Injury. Nutrients 2023; 15:4397. [PMID: 37892472 PMCID: PMC10610222 DOI: 10.3390/nu15204397] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Revised: 09/27/2023] [Accepted: 10/12/2023] [Indexed: 10/29/2023] Open
Abstract
PURPOSE Chemokine-driven leukocyte infiltration and sustained inflammation contribute to alcohol-associated liver disease (ALD). Elevated hepatic CCL2 expression, seen in ALD, is associated with disease severity. However, mechanisms of CCL2 regulation are not completely elucidated. Post-translational modifications (PTMs) of proteins, particularly acetylation, modulate gene expression. This study examined the acetylation changes of promoter-associated histone-H3 and key transcription factor-NFκB in regulating hepatic CCL2 expression and subsequent inflammation and injury. Further, the effect of therapeutic modulation of the acetylation state by tributyrin (TB), a butyrate prodrug, was assessed. METHODS Hepatic CCL2 expression was assessed in mice fed control (PF) or an ethanol-containing Lieber-DeCarli (5% v/v, EF) diet for 7 weeks with or without oral administration of tributyrin (TB, 2 g/kg, 5 days/week). A chromatin immunoprecipitation (ChIP) assay evaluated promoter-associated modifications. Nuclear association between SIRT1, p300, and NFκB-p65 and acetylation changes of p65 were determined using immunoprecipitation and Western blot analyses. A Student's t-test and one-way ANOVA determined the significance. RESULTS Ethanol significantly increased promoter-associated histone-H3-lysine-9 acetylation (H3K9Ac), reflecting a transcriptionally permissive state with a resultant increase in hepatic CCL2 mRNA and protein expression. Moreover, increased lysine-310-acetylation of nuclear RelA/p65 decreased its association with SIRT1, a class III HDAC, but concomitantly increased with p300, a histone acetyltransferase. This further led to enhanced recruitment of NF-κB/p65 and RNA polymerase-II to the CCL2 promoter. Oral TB administration prevented ethanol-associated acetylation changes, thus downregulating CCL2 expression, hepatic neutrophil infiltration, and inflammation/ injury. CONCLUSION The modulation of a protein acetylation state via ethanol or TB mechanistically regulates hepatic CCL2 upregulation in ALD.
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Affiliation(s)
- Smita S. Ghare
- Department of Medicine, University of Louisville, Louisville, KY 40202, USA
- UofL Alcohol Center, University of Louisville, Louisville, KY 40202, USA
- UofL Hepatobiology COBRE, University of Louisville, Louisville, KY 40202, USA
| | - Benjamin T. Charpentier
- UofL Alcohol Center, University of Louisville, Louisville, KY 40202, USA
- Department of Anatomical Science and Neurobiology, University of Louisville, Louisville, KY 40202, USA
| | - Dushan T. Ghooray
- Department of Medicine, University of Louisville, Louisville, KY 40202, USA
- UofL Alcohol Center, University of Louisville, Louisville, KY 40202, USA
- UofL Hepatobiology COBRE, University of Louisville, Louisville, KY 40202, USA
| | - Jingwen Zhang
- Department of Medicine, University of Louisville, Louisville, KY 40202, USA
- UofL Alcohol Center, University of Louisville, Louisville, KY 40202, USA
- UofL Hepatobiology COBRE, University of Louisville, Louisville, KY 40202, USA
| | - Manicka V. Vadhanam
- Department of Medicine, University of Louisville, Louisville, KY 40202, USA
- UofL Alcohol Center, University of Louisville, Louisville, KY 40202, USA
- UofL Hepatobiology COBRE, University of Louisville, Louisville, KY 40202, USA
| | - Sreelatha Reddy
- Department of Medicine, University of Louisville, Louisville, KY 40202, USA
- UofL Alcohol Center, University of Louisville, Louisville, KY 40202, USA
- UofL Hepatobiology COBRE, University of Louisville, Louisville, KY 40202, USA
| | - Swati Joshi-Barve
- Department of Medicine, University of Louisville, Louisville, KY 40202, USA
- UofL Alcohol Center, University of Louisville, Louisville, KY 40202, USA
- UofL Hepatobiology COBRE, University of Louisville, Louisville, KY 40202, USA
| | - Craig J. McClain
- Department of Medicine, University of Louisville, Louisville, KY 40202, USA
- UofL Alcohol Center, University of Louisville, Louisville, KY 40202, USA
- UofL Hepatobiology COBRE, University of Louisville, Louisville, KY 40202, USA
- Robley Rex VA Medical Center, University of Louisville, Louisville, KY 40202, USA
| | - Shirish S. Barve
- Department of Medicine, University of Louisville, Louisville, KY 40202, USA
- UofL Alcohol Center, University of Louisville, Louisville, KY 40202, USA
- UofL Hepatobiology COBRE, University of Louisville, Louisville, KY 40202, USA
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16
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Liu Y, Zhang P, Sheng H, Xu D, Li D, An L. 16S rRNA gene sequencing and machine learning reveal correlation between drug abuse and human host gut microbiota. Addict Biol 2023; 28:e13311. [PMID: 37753568 DOI: 10.1111/adb.13311] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Revised: 06/08/2023] [Accepted: 06/09/2023] [Indexed: 09/28/2023]
Abstract
Over the past few years, there has been increasing evidence highlighting the strong connection between gut microbiota and overall well-being of the host. This has led to a renewed emphasis on studying and addressing substance use disorder from the perspective of brain-gut axis. Previous studies have suggested that alcohol, food, and cigarette addictions are strongly linked to gut microbiota and faecal microbiota transplantation or the use of probiotics achieved significant efficacy. Unfortunately, little is known about the relationship between drug abuse and gut microbiota. This paper aims to reveal the potential correlation between gut microbiota and drug abuse and to develop an accurate identification model for drug-related faeces samples by machine learning. Faecal samples were collected from 476 participants from three regions in China (Shanghai, Yunnan, and Shandong). Their gut microbiota information was obtained using 16S rRNA gene sequencing, and a substance use disorder identification model was developed by machine learning. Analysis revealed a lower diversity and a more homogeneous gut microbiota community structure among participants with substance use disorder. Bacteroides, Prevotella_9, Faecalibacterium, and Blautia were identified as important biomarkers associated with substance use disorder. The function prediction analysis revealed that the citrate and reductive citrate cycles were significantly upregulated in the substance use disorder group, while the shikimate pathway was downregulated. In addition, the machine learning model could distinguish faecal samples between substance users and nonsubstance users with an AUC = 0.9, indicating its potential use in predicting and screening individuals with substance use disorder within the community in the future.
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Affiliation(s)
| | - Pei Zhang
- Zaozhuang University, Zaozhuang, China
| | | | - Ding Xu
- Shanghai Administration of Drug Rehabilitation, Shanghai, China
| | - Daixi Li
- University of Shanghai for Science and Technology, Shanghai, China
| | - Lizhe An
- Lanzhou University, Lanzhou, China
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17
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Yang K, Song M. New Insights into the Pathogenesis of Metabolic-Associated Fatty Liver Disease (MAFLD): Gut-Liver-Heart Crosstalk. Nutrients 2023; 15:3970. [PMID: 37764755 PMCID: PMC10534946 DOI: 10.3390/nu15183970] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2023] [Revised: 09/11/2023] [Accepted: 09/13/2023] [Indexed: 09/29/2023] Open
Abstract
Metabolism-associated fatty liver disease (MAFLD) is a multifaceted disease that involves complex interactions between various organs, including the gut and heart. It is defined by hepatic lipid accumulation and is related to metabolic dysfunction, obesity, and diabetes. Understanding the intricate interplay of the gut-liver-heart crosstalk is crucial for unraveling the complexities of MAFLD and developing effective treatment and prevention strategies. The gut-liver crosstalk participates in the regulation of the metabolic and inflammatory processes through host-microbiome interactions. Gut microbiota have been associated with the development and progression of MAFLD, and its dysbiosis contributes to insulin resistance, inflammation, and oxidative stress. Metabolites derived from the gut microbiota enter the systemic circulation and influence both the liver and heart, resulting in the gut-liver-heart axis playing an important role in MAFLD. Furthermore, growing evidence suggests that insulin resistance, endothelial dysfunction, and systemic inflammation in MAFLD may contribute to an increased risk of cardiovascular disease (CVD). Additionally, the dysregulation of lipid metabolism in MAFLD may also lead to cardiac dysfunction and heart failure. Overall, the crosstalk between the liver and heart involves a complex interplay of molecular pathways that contribute to the development of CVD in patients with MAFLD. This review emphasizes the current understanding of the gut-liver-heart crosstalk as a foundation for optimizing patient outcomes with MAFLD.
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Affiliation(s)
| | - Myeongjun Song
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea;
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18
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Zhang D, Liu Z, Bai F. Roles of Gut Microbiota in Alcoholic Liver Disease. Int J Gen Med 2023; 16:3735-3746. [PMID: 37641627 PMCID: PMC10460590 DOI: 10.2147/ijgm.s420195] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2023] [Accepted: 08/10/2023] [Indexed: 08/31/2023] Open
Abstract
Alcoholic liver disease (ALD)-one of the most common liver diseases - involves a wide range of disorders, including asymptomatic hepatic steatosis, alcoholic hepatitis (AH), liver fibrosis, and cirrhosis. Alcohol consumption induces a weakened gut barrier and changes in the composition of the gut microbiota. The presence of CYP2E1 and its elevated levels in the gastrointestinal tract after alcohol exposure lead to elevated levels of ROS and acetaldehyde, inducing inflammation and oxidative damage in the gut. At the same time, the influx of harmful molecules such as the bacterial endotoxin LPS and peptidogly from gut dysbiosis can induce intestinal inflammation and oxidative damage, further compromising the intestinal mucosal barrier. In this process, various oxidative stress-mediated post-translational modifications (PTMs) play an important role in the integrity of the barrier, eg, the presence of acetaldehyde will result in the sustained phosphorylation of several paracellular proteins (occludin and zona occludens-1), which can lead to intestinal leakage. Eventually, persistent oxidative stress, LPS infiltration and hepatocyte damage through the enterohepatic circulation will lead to hepatic stellate cell activation and hepatic fibrosis. In addition, probiotics, prebiotics, synbiotics, fecal microbial transplantation (FMT), bioengineered bacteria, gut-restricted FXR agonists and others are promising therapeutic approaches that can alter gut microbiota composition to improve ALD. In the future, there will be new challenges to study the interactions between the genetics of individuals with ALD and their gut microbiome, to provide personalized interventions targeting the gut-liver axis, and to develop better techniques to measure microbial communities and metabolites in the body.
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Affiliation(s)
- Daya Zhang
- Graduate School, Hainan Medical University, Haikou, People’s Republic of China
| | - ZhengJin Liu
- Department of Gastroenterology, The Second Affiliated Hospital of Hainan Medical University, Haikou, People’s Republic of China
| | - Feihu Bai
- Department of Gastroenterology, The Second Affiliated Hospital of Hainan Medical University, Haikou, People’s Republic of China
- The Gastroenterology Clinical Medical Center of Hainan Province, Haikou, People’s Republic of China
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19
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Kaufmann B, Seyfried N, Hartmann D, Hartmann P. Probiotics, prebiotics, and synbiotics in nonalcoholic fatty liver disease and alcohol-associated liver disease. Am J Physiol Gastrointest Liver Physiol 2023; 325:G42-G61. [PMID: 37129252 PMCID: PMC10312326 DOI: 10.1152/ajpgi.00017.2023] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Revised: 04/26/2023] [Accepted: 04/26/2023] [Indexed: 05/03/2023]
Abstract
The use of probiotics, prebiotics, and synbiotics has become an important therapy in numerous gastrointestinal diseases in recent years. Modifying the gut microbiota, this therapeutic approach helps to restore a healthy microbiome. Nonalcoholic fatty liver disease and alcohol-associated liver disease are among the leading causes of chronic liver disease worldwide. A disrupted intestinal barrier, microbial translocation, and an altered gut microbiome metabolism, or metabolome, are crucial in the pathogenesis of these chronic liver diseases. As pro-, pre-, and synbiotics modulate these targets, they were identified as possible new treatment options for liver disease. In this review, we highlight the current findings on clinical and mechanistic effects of this therapeutic approach in nonalcoholic fatty liver disease and alcohol-associated liver disease.
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Affiliation(s)
- Benedikt Kaufmann
- Department of Surgery, Klinikum rechts der Isar, Technical University Munich, Munich, Germany
| | - Nick Seyfried
- Department of Surgery, Klinikum rechts der Isar, Technical University Munich, Munich, Germany
| | - Daniel Hartmann
- Department of Surgery, Klinikum rechts der Isar, Technical University Munich, Munich, Germany
| | - Phillipp Hartmann
- Department of Surgery, Klinikum rechts der Isar, Technical University Munich, Munich, Germany
- Department of Pediatrics, University of California San Diego, La Jolla, California, United States
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20
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Fang Q, Lai Y, Zhang D, Lei H, Wang F, Guo X, Song C. Gut microbiota regulation and prebiotic properties of polysaccharides from Oudemansiella raphanipes mushroom. World J Microbiol Biotechnol 2023; 39:167. [PMID: 37076579 DOI: 10.1007/s11274-023-03616-1] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Accepted: 04/11/2023] [Indexed: 04/21/2023]
Abstract
Oudemansiella raphanipes is a type of fungus used as both medicine and food. Fungal polysaccharides have demonstrated various bioactivities, involving the adjust and control of gut microbiota, but no such studies on O. raphanipes polysaccharides (OrPs) have been reported. It is by extracting and purifying that OrPs was obtained from O. raphanipes crude polysaccharide and study their effects in mice. The sample contents of total sugar was 97.26%, and the monosaccharide content comprised mannose, rhamnose, glucose, and xylose in a molar ratio of 35.2:2.8:21.2:40.8. The effects of OrPs on body weight (BW), gut microbiota, fecal short-chain fatty acids (SCFAs), and the correlation between fecal SCFAs and gut microbes, in mice were investigated. The results of the experiment found that OrPs significantly (P < 0.01) inhibited the increase in BW, altered the constitution of the gut microbiota, and significantly (P < 0.05) enhanced the content of fecal SCFAs in mice. Moreover, among the top ten bacteria in terms of relative abundance, the Lachnospiraceae and Lachnospiraceae NK4A136 groups were positively associated with the increased production of SCFAs. Other bacteria, such as Atopobiaceae and Bifidobacterium of Actinobacteriota, and Faecalibaculum, Dubosiella, and Clostridium sensu stricto 5 of Firmicutes, were also positively associated with higher content of fecal SCFAs. The results of the experiment suggest that OrPs have a potential prebiotic effect on gut microbiota and may prevent BW gain. Furthermore, the major producers of SCFAs were Firmicutes and Actinobacteriota.
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Affiliation(s)
- Qi Fang
- School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646000, China
| | - Yong Lai
- School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646000, China
| | - Dan Zhang
- School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646000, China
| | - Hui Lei
- School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646000, China
| | - Fang Wang
- School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646000, China
| | - Xiurong Guo
- School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646000, China
| | - Can Song
- School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646000, China.
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21
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Jochum SB, Engen PA, Shaikh M, Naqib A, Wilber S, Raeisi S, Zhang L, Song S, Sanzo G, Chouhan V, Ko F, Post Z, Tran L, Ramirez V, Green SJ, Khazaie K, Hayden DM, Brown MJ, Voigt RM, Forsyth CB, Keshavarzian A, Swanson GR. Colonic Epithelial Circadian Disruption Worsens Dextran Sulfate Sodium-Induced Colitis. Inflamm Bowel Dis 2023; 29:444-457. [PMID: 36287037 PMCID: PMC9977234 DOI: 10.1093/ibd/izac219] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Indexed: 12/09/2022]
Abstract
BACKGROUND Disruption of central circadian rhythms likely mediated by changes in microbiota and a decrease in gut-derived metabolites like short chain fatty acids (SCFAs) negatively impacts colonic barrier homeostasis. We aimed to explore the effects of isolated peripheral colonic circadian disruption on the colonic barrier in a mouse model of colitis and explore the mechanisms, including intestinal microbiota community structure and function. METHODS Colon epithelial cell circadian rhythms were conditionally genetically disrupted in mice: TS4Cre-BMAL1lox (cBMAL1KO) with TS4Cre as control animals. Colitis was induced through 5 days of 2% dextran sulfate sodium (DSS). Disease activity index and intestinal barrier were assessed, as were fecal microbiota and metabolites. RESULTS Colitis symptoms were worse in mice with peripheral circadian disruption (cBMAL1KO). Specifically, the disease activity index and intestinal permeability were significantly higher in circadian-disrupted mice compared with control animals (TS4Cre) (P < .05). The worsening of colitis appears to be mediated, in part, through JAK (Janus kinase)-mediated STAT3 (signal transducer and activator of transcription 3), which was significantly elevated in circadian-disrupted (cBMAL1KO) mice treated with DSS (P < .05). Circadian-disrupted (cBMAL1KO) mice also had decreased SCFA metabolite concentrations and decreased relative abundances of SCFA-producing bacteria in their stool when compared with control animals (TS4Cre). CONCLUSIONS Disruption of intestinal circadian rhythms in colonic epithelial cells promoted more severe colitis, increased inflammatory mediators (STAT3 [signal transducer and activator of transcription 3]), and decreased gut microbiota-derived SCFAs compared with DSS alone. Further investigation elucidating the molecular mechanisms behind these findings could provide novel circadian directed targets and strategies in the treatment of inflammatory bowel disease.
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Affiliation(s)
- Sarah B Jochum
- Department of Surgery, Rush University Medical Center, Chicago, IL, USA
| | - Phillip A Engen
- Rush Center for Integrated Microbiome and Chronobiology Research, Rush Medical College, Rush University Medical Center, Chicago, IL, USA
| | - Maliha Shaikh
- Rush Center for Integrated Microbiome and Chronobiology Research, Rush Medical College, Rush University Medical Center, Chicago, IL, USA
| | - Ankur Naqib
- Rush Center for Integrated Microbiome and Chronobiology Research, Rush Medical College, Rush University Medical Center, Chicago, IL, USA
| | - Sherry Wilber
- Rush Center for Integrated Microbiome and Chronobiology Research, Rush Medical College, Rush University Medical Center, Chicago, IL, USA
| | - Shohreh Raeisi
- Rush Center for Integrated Microbiome and Chronobiology Research, Rush Medical College, Rush University Medical Center, Chicago, IL, USA
| | - Lijuan Zhang
- Rush Center for Integrated Microbiome and Chronobiology Research, Rush Medical College, Rush University Medical Center, Chicago, IL, USA
| | - Shiwen Song
- Department of Pathology, GoPath Global Pathology Service, Buffalo Grove, IL, USA
| | - Gabriella Sanzo
- Rush Center for Integrated Microbiome and Chronobiology Research, Rush Medical College, Rush University Medical Center, Chicago, IL, USA
| | - Vijit Chouhan
- Rush Center for Integrated Microbiome and Chronobiology Research, Rush Medical College, Rush University Medical Center, Chicago, IL, USA
| | - Frank Ko
- Department of Cell and Molecular Medicine, Rush University Medical Center, Chicago, IL, USA
| | - Zoe Post
- Rush Center for Integrated Microbiome and Chronobiology Research, Rush Medical College, Rush University Medical Center, Chicago, IL, USA
- Department of Medicine, Rush University Medical Center, Chicago, IL, USA
| | - Laura Tran
- Rush Center for Integrated Microbiome and Chronobiology Research, Rush Medical College, Rush University Medical Center, Chicago, IL, USA
| | - Vivian Ramirez
- Rush Center for Integrated Microbiome and Chronobiology Research, Rush Medical College, Rush University Medical Center, Chicago, IL, USA
| | - Stefan J Green
- Genomics and Microbiome Core Facility, Rush University Medical Center, Chicago, IL, USA
| | | | - Dana M Hayden
- Division of Colon and Rectal Surgery, Department of Surgery, Rush University Medical Center, Chicago, IL, USA
| | - Mark J Brown
- Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, OH, USA
| | - Robin M Voigt
- Rush Center for Integrated Microbiome and Chronobiology Research, Rush Medical College, Rush University Medical Center, Chicago, IL, USA
- Department of Medicine, Rush University Medical Center, Chicago, IL, USA
| | - Christopher B Forsyth
- Rush Center for Integrated Microbiome and Chronobiology Research, Rush Medical College, Rush University Medical Center, Chicago, IL, USA
- Department of Medicine, Rush University Medical Center, Chicago, IL, USA
| | - Ali Keshavarzian
- Rush Center for Integrated Microbiome and Chronobiology Research, Rush Medical College, Rush University Medical Center, Chicago, IL, USA
- Department of Medicine, Rush University Medical Center, Chicago, IL, USA
- Department of Physiology, Rush University Medical Center, Chicago, IL, USA
| | - Garth R Swanson
- Rush Center for Integrated Microbiome and Chronobiology Research, Rush Medical College, Rush University Medical Center, Chicago, IL, USA
- Department of Medicine, Rush University Medical Center, Chicago, IL, USA
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22
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Yi S, Zhang G, Liu M, Yu W, Cheng G, Luo L, Ning F. Citrus Honey Ameliorates Liver Disease and Restores Gut Microbiota in Alcohol-Feeding Mice. Nutrients 2023; 15:nu15051078. [PMID: 36904078 PMCID: PMC10005585 DOI: 10.3390/nu15051078] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Revised: 02/09/2023] [Accepted: 02/13/2023] [Indexed: 02/25/2023] Open
Abstract
Citrus honey (CH) is rich in nutrients that have a wide variety of biological functions, such as antibacterial, anti-inflammatory, and antioxidant activities, and which demonstrate therapeutic properties, such as anti-cancer and wound-healing abilities. However, the effects of CH on alcohol-related liver disease (ALD) and the intestinal microbiota remain unknown. This study aimed to determine the alleviating effects of CH on ALD and its regulatory effects on the gut microbiota in mice. In total, 26 metabolites were identified and quantified in CH, and the results suggested that the primary metabolites were abscisic acid, 3,4-dimethoxycinnamic acid, rutin, and two markers of CH, hesperetin and hesperidin. CH lowered the levels of aspartate aminotransferase, glutamate aminotransferase, and alcohol-induced hepatic edema. CH could promote the proliferation of Bacteroidetes while reducing the abundance of Firmicutes. Additionally, CH also showed some inhibitory effects on the growth of Campylobacterota and Turicibacter. CH enhanced the secretion of short-chain fatty acids (SCFAs), such as acetic acid, propionic acid, butyric acid, and valeric acid. Given its alleviating functions in liver tissue damage and its regulatory effects on the gut microbiota and SCFAs, CH could be a promising candidate for the therapeutic treatment of ALD.
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Affiliation(s)
- Shengxiang Yi
- School of Life Sciences, Nanchang University, Nanchang 330031, China
| | - Gaowei Zhang
- School of Life Sciences, Nanchang University, Nanchang 330031, China
| | - Mingyan Liu
- School of Life Sciences, Nanchang University, Nanchang 330031, China
| | - Wenjie Yu
- School of Life Sciences, Nanchang University, Nanchang 330031, China
- College of Food and Health, Beijing Technology and Business University (BTBU), Beijing 100048, China
| | - Guohua Cheng
- Agriculture and Rural Affairs Bureau of Nanfeng County, Fuzhou 344500, China
| | - Liping Luo
- School of Life Sciences, Nanchang University, Nanchang 330031, China
- College of Food and Health, Beijing Technology and Business University (BTBU), Beijing 100048, China
- Correspondence: (L.L.); (F.N.); Tel./Fax: +86-0791-83969519 (L.L.)
| | - Fangjian Ning
- School of Life Sciences, Nanchang University, Nanchang 330031, China
- College of Food and Health, Beijing Technology and Business University (BTBU), Beijing 100048, China
- Correspondence: (L.L.); (F.N.); Tel./Fax: +86-0791-83969519 (L.L.)
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23
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Chen L, Yang P, Hu L, Yang L, Chu H, Hou X. Modulating phenylalanine metabolism by L. acidophilus alleviates alcohol-related liver disease through enhancing intestinal barrier function. Cell Biosci 2023; 13:24. [PMID: 36739426 PMCID: PMC9899391 DOI: 10.1186/s13578-023-00974-z] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2022] [Accepted: 01/27/2023] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Impaired metabolic functions of gut microbiota have been demonstrated in alcohol-related liver disease (ALD), but little is known about changes in phenylalanine metabolism. METHODS Bacterial genomics and fecal metabolomics analysis were used to recognize the changes of phenylalanine metabolism and its relationship with intestinal flora. Intestinal barrier function was detected by intestinal alkaline phosphatase (IAP) activity, levels of tight junction protein expression, colonic inflammation and levels of serum LPS. Lactobacillus acidophilus was chosen to correct phenylalanine metabolism of ALD mice by redundancy analysis and Pearson correlation analysis. RESULTS Using 16S rRNA sequencing and ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) methods, we identified elevated levels of phenylalanine and its' metabolites in the gut of alcohol-fed mice compared to control mice and were negatively correlated with the abundance of Lactobacillus, which mainly metabolized phenylalanine. The intestinal phenylalanine level was positively correlated with the colon inflammatory factors TNF-α and IL-6, and negatively correlated with ZO-1 and Occludin. While intestinal alkaline phosphatase (IAP) activity was negatively correlated with the colon inflammatory factors TNF-α, IL-6 and MCP-1, and positively correlated with ZO-1 and Occludin. Increased phenylalanine inhibited IAP activity, blocked LPS dephosphorylation, increased colonic inflammation and bacterial translocation. Phenylalanine supplementation aggravated alcohol-induced liver injury and intestinal barrier dysfunction. Among the 37 Lactobacillus species, the abundance of Lactobacillus acidophilus was most significantly decreased in ALD mice. Supplementation with L. acidophilus recovered phenylalanine metabolism and protected mice from alcohol-induced steatohepatitis. CONCLUSIONS Recovery of phenylalanine metabolism through the oral supplementation of L. acidophilus boosted intestinal barrier integrity and ameliorated experimental ALD.
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Affiliation(s)
- Liuying Chen
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022, China
| | - Pengcheng Yang
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022, China
| | - Lilin Hu
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022, China
| | - Ling Yang
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022, China
| | - Huikuan Chu
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022, China.
| | - Xiaohua Hou
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022, China.
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24
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Wang K, Zhao Y, Xu L, Liao X, Xu Z. Health outcomes of 100% orange juice and orange flavored beverage: A comparative analysis of gut microbiota and metabolomics in rats. Curr Res Food Sci 2023; 6:100454. [PMID: 36815996 PMCID: PMC9932342 DOI: 10.1016/j.crfs.2023.100454] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2022] [Revised: 01/08/2023] [Accepted: 02/01/2023] [Indexed: 02/05/2023] Open
Abstract
A high intake of sugar-sweetened fruity beverage (FB) is associated with a higher risk of metabolic syndromes, but the health outcome of 100% fruit juice (FJ) intake remains unclear. We aim to reveal health outcomes of diet intervention (FJ or FB) with system profiling via interaction of gut microbiota and metabolomics in a rat (Rattus norvegicus) model. Firstly, the glucose, sucrose, fructose, and bioactive metabolites of FJ and FB were analyzed, and FJ possessed higher sucrose and flavonoids, while FB showed higher glucose and fructose. Secondly, C0 was set as the control group on Day 0, and a 4-week diet invention was performed to control, FJ-intake, and FB-intake groups with normal saline, FJ, and FB, respectively. The results showed that FJ improved alpha diversity and decreased the Firmicutes/Bacteroidota ratio (F/B ratio) of gut microbiota and prevented insulin resistance. However, FB possessed unchanged microbial diversity and enhanced F/B ratio, causing insulin resistance with renal triglyceride accumulation. In summary, FJ, although naturally containing similar amounts of total free sugars as FB, could be a healthier drink choice.
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Affiliation(s)
- Kewen Wang
- College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, 100083, China
- Institute of Quality Standard & Testing Technology for Agro-Products, Key Laboratory of Agro-food Safety and Quality, Ministry of Agriculture and Rural Affairs, Chinese Academy of Agricultural Sciences, Beijing, 100081, China
| | - Yang Zhao
- College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, 100083, China
| | - Lei Xu
- College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, 100083, China
- Institute of Quality Standard & Testing Technology for Agro-Products, Key Laboratory of Agro-food Safety and Quality, Ministry of Agriculture and Rural Affairs, Chinese Academy of Agricultural Sciences, Beijing, 100081, China
| | - Xiaojun Liao
- College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, 100083, China
- Corresponding author.
| | - Zhenzhen Xu
- College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, 100083, China
- Institute of Quality Standard & Testing Technology for Agro-Products, Key Laboratory of Agro-food Safety and Quality, Ministry of Agriculture and Rural Affairs, Chinese Academy of Agricultural Sciences, Beijing, 100081, China
- Corresponding author. College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, 100083, China.
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25
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Liu H, Meng W, Zhao D, Ma Z, Zhang W, Chen Z, Li Z, Zhao P. Study on mechanism of action of total flavonoids from Cortex Juglandis Mandshuricae against alcoholic liver disease based on "gut-liver axis". Front Pharmacol 2023; 13:1074286. [PMID: 36712682 PMCID: PMC9873969 DOI: 10.3389/fphar.2022.1074286] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2022] [Accepted: 12/28/2022] [Indexed: 01/12/2023] Open
Abstract
The objective of this study was to investigate the effects and molecular mechanisms of total flavonoids from Cortex Juglandis Mandshuricae (TFC) on preventing alcohol-induced chronic liver injury and regulating gut microbiota in mice. The results showed that oral administration of TFC significantly attenuated alcoholic liver injury in mice. TFC improved lipid accumulation in mice with chronic alcoholic liver injury through activation of the AMPK/PPARα pathway. In addition, TFC maintained the integrity of the intestinal barrier in alcoholic mice, reducing endotoxin leakage from the intestine and further inhibiting the TLR4/NF-κB inflammatory pathway. More importantly, TFC regulated the intestinal microbiota composition and certain bacteria, including Akkermansia muciniphila, Lactobacillus and others. At the same time, reduced levels of short-chain fatty acids due to alcohol consumption were restored. In summary, TFC upregulated AMPK/PPARα signaling pathway to improve hepatic fat accumulation and oxidative stress; TFC positively regulated intestinal flora composition to reduce intestinal disorders caused by alcohol consumption, and further inhibited alcohol-induced inflammatory responses through the intestinal-liver axis. The above findings may be the mechanism of TFC's pharmacological effects against alcoholic liver injury.
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Affiliation(s)
- Huiru Liu
- College of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China
| | - Wenwen Meng
- College of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China
| | - Dongsheng Zhao
- College of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China
| | - Zhihui Ma
- College of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China
| | - Wenguang Zhang
- College of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China
| | - Zhi Chen
- College of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China
| | - Zhengguo Li
- College of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China,Jining Food and Drug Inspection and Testing Research Institute, Jining, Shandong, China
| | - Pan Zhao
- College of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China,*Correspondence: Pan Zhao,
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26
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Patel D, Desai C, Singh D, Soppina V, Parwani K, Patel F, Mandal P. Synbiotic Intervention Ameliorates Oxidative Stress and Gut Permeability in an In Vitro and In Vivo Model of Ethanol-Induced Intestinal Dysbiosis. Biomedicines 2022; 10:3285. [PMID: 36552041 PMCID: PMC9816946 DOI: 10.3390/biomedicines10123285] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Accepted: 12/13/2022] [Indexed: 12/24/2022] Open
Abstract
Alcoholic liver disease (ALD) alters gut microbiota and tight junctions, causing bacterial components to enter the portal vein and induce oxidative stress-induced inflammation in the liver. Only corticosteroids and liver transplants are treatment options for severe alcoholic hepatitis. ALD's pathophysiology is unknown. However, acetaldehyde's toxic effects cause oxidative stress and intestinal permeability. This study investigates the influence of a synbiotic (a combination of aged garlic extract (AGE) and Lactobacillus rhamnosus MTCC1423) on colonic oxidative stress and inflammation in ALD male Wistar rats and Caco2 cells. MDA measurement by HPLC in CaCo2 cells, blood serum, and colon tissue demonstrated that synbiotic treatment in the ALD model reduces oxidative stress. Further, fecal high-throughput 16S rRNA gene sequencing revealed the microbiome's shift towards Firmicutes in the synbiotic group compared to ethanol. In addition, DCFDA labeling and H/E staining demonstrate that the synbiotic is beneficial in inhibiting the development of ALD. In the colon, the synbiotic reduces the activation of CYP2E1 and the inflammatory markers TNF-a and IL-6 while elevating the mRNA expression of ZO-1, occludin, and IL-10. Synbiotics colonize Lactobacillus to restore barrier function and microbiota and reduce colon oxidative stress. Thus, a synbiotic combination can be used in ALD treatment.
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Affiliation(s)
- Dhara Patel
- P. D. Patel Institute of Applied Sciences, Charotar University of Science and Technology, Nadiad 388421, Gujarat, India; (D.P.); (K.P.); (F.P.)
| | - Chirayu Desai
- Department of Environmental Biotechnology, Gujarat Biotechnology University, Gandhinagar 382355, Gujarat, India;
| | - Deepmala Singh
- Indian Institute of Technology, Gandhinagar 382355, Gujarat, India; (D.S.); (V.S.)
| | - Virupakshi Soppina
- Indian Institute of Technology, Gandhinagar 382355, Gujarat, India; (D.S.); (V.S.)
| | - Kirti Parwani
- P. D. Patel Institute of Applied Sciences, Charotar University of Science and Technology, Nadiad 388421, Gujarat, India; (D.P.); (K.P.); (F.P.)
| | - Farhin Patel
- P. D. Patel Institute of Applied Sciences, Charotar University of Science and Technology, Nadiad 388421, Gujarat, India; (D.P.); (K.P.); (F.P.)
| | - Palash Mandal
- P. D. Patel Institute of Applied Sciences, Charotar University of Science and Technology, Nadiad 388421, Gujarat, India; (D.P.); (K.P.); (F.P.)
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27
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Corriero A, Gadaleta RM, Puntillo F, Inchingolo F, Moschetta A, Brienza N. The central role of the gut in intensive care. Crit Care 2022; 26:379. [PMID: 36476497 PMCID: PMC9730662 DOI: 10.1186/s13054-022-04259-8] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Accepted: 11/29/2022] [Indexed: 12/12/2022] Open
Abstract
Critically ill patients undergo early impairment of their gut microbiota (GM) due to routine antibiotic therapies and other environmental factors leading to intestinal dysbiosis. The GM establishes connections with the rest of the human body along several axes representing critical inter-organ crosstalks that, once disrupted, play a major role in the pathophysiology of numerous diseases and their complications. Key players in this communication are GM metabolites such as short-chain fatty acids and bile acids, neurotransmitters, hormones, interleukins, and toxins. Intensivists juggle at the crossroad of multiple connections between the intestine and the rest of the body. Harnessing the GM in ICU could improve the management of several challenges, such as infections, traumatic brain injury, heart failure, kidney injury, and liver dysfunction. The study of molecular pathways affected by the GM in different clinical conditions is still at an early stage, and evidence in critically ill patients is lacking. This review aims to describe dysbiosis in critical illness and provide intensivists with a perspective on the potential as adjuvant strategies (e.g., nutrition, probiotics, prebiotics and synbiotics supplementation, adsorbent charcoal, beta-lactamase, and fecal microbiota transplantation) to modulate the GM in ICU patients and attempt to restore eubiosis.
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Affiliation(s)
- Alberto Corriero
- Department of Interdisciplinary Medicine - ICU Section, University of Bari “Aldo Moro”, Piazza Giulio Cesare 11, 70124 Bari, Italy
| | - Raffaella Maria Gadaleta
- Department of Interdisciplinary Medicine, University of Bari “Aldo Moro”, Piazza Giulio Cesare 11, 70124 Bari, Italy
| | - Filomena Puntillo
- Department of Interdisciplinary Medicine - ICU Section, University of Bari “Aldo Moro”, Piazza Giulio Cesare 11, 70124 Bari, Italy
| | - Francesco Inchingolo
- Dental Medicine Section, Department of Interdisciplinary Medicine, University of Bari “Aldo Moro”, 70124 Bari, Italy
| | - Antonio Moschetta
- Department of Interdisciplinary Medicine, University of Bari “Aldo Moro”, Piazza Giulio Cesare 11, 70124 Bari, Italy
| | - Nicola Brienza
- Department of Interdisciplinary Medicine - ICU Section, University of Bari “Aldo Moro”, Piazza Giulio Cesare 11, 70124 Bari, Italy
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28
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Garbuzenko DV. Pathophysiological Prerequisites and Therapeutic Potential of Fecal Microbiota Transplantation in Severe Alcoholic Hepatitis. THE RUSSIAN ARCHIVES OF INTERNAL MEDICINE 2022; 12:352-362. [DOI: 10.20514/2226-6704-2022-12-5-352-362] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/26/2024]
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29
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Hou X, Rong C, Zhang Q, Song S, Cong Y, Zhang HT. Cyclic Nucleotide Phosphodiesterases in Alcohol Use Disorders: Involving Gut Microbiota. Int J Neuropsychopharmacol 2022; 26:70-79. [PMID: 36087271 PMCID: PMC9850663 DOI: 10.1093/ijnp/pyac060] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2021] [Revised: 08/18/2022] [Accepted: 09/09/2022] [Indexed: 01/22/2023] Open
Abstract
Alcohol abuse is 1 of the most significant public health problems in the world. Chronic, excessive alcohol consumption not only causes alcohol use disorder (AUD) but also changes the gut and lung microbiota, including bacterial and nonbacterial types. Both types of microbiota can release toxins, further damaging the gastrointestinal and respiratory tracts; causing inflammation; and impairing the functions of the liver, lung, and brain, which in turn deteriorate AUD. Phosphodiesterases (PDEs) are critical in the control of intracellular cyclic nucleotides, including cyclic adenosine monophosphate and cyclic guanosine monophosphate. Inhibition of certain host PDEs reduces alcohol consumption and attenuates alcohol-related impairment. These PDEs are also expressed in the microbiota and may play a role in controlling microbiota-associated inflammation. Here, we summarize the influences of alcohol on gut/lung bacterial and nonbacterial microbiota as well as on the gut-liver/brain/lung axis. We then discuss the relationship between gut and lung microbiota-mediated PDE signaling and AUD consequences in addition to highlighting PDEs as potential targets for treatment of AUD.
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Affiliation(s)
- Xueqin Hou
- Correspondence: Xueqin Hou, PhD, Institute of Pharmacology, Shandong First Medical University & Shandong Academy of Medical Sciences, Taian, Shandong 271016, P.R. China ()
| | | | - Qiwei Zhang
- Institute of Pharmacology, Shandong First Medical University and Shandong Academy of Medical Sciences, Taian, Shandong 271016, P.R. China
| | - Shuangshuang Song
- Institute of Pharmacology, Shandong First Medical University and Shandong Academy of Medical Sciences, Taian, Shandong 271016, P.R. China
| | - Yifan Cong
- Institute of Pharmacology, Shandong First Medical University and Shandong Academy of Medical Sciences, Taian, Shandong 271016, P.R. China
| | - Han-Ting Zhang
- Han-Ting Zhang, MD, PhD, Department of Pharmacology, School of Pharmacy, Qingdao University, Qingdao, Shandong 266073, P.R. China ()
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30
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Impact of Clarified Apple Juices with Different Processing Methods on Gut Microbiota and Metabolomics of Rats. Nutrients 2022; 14:nu14173488. [PMID: 36079746 PMCID: PMC9460580 DOI: 10.3390/nu14173488] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2022] [Revised: 08/09/2022] [Accepted: 08/12/2022] [Indexed: 11/16/2022] Open
Abstract
The consumption of processed foods has increased compared to that of fresh foods in recent years, especially due to the coronavirus disease 2019 pandemic. Here, we evaluated the health effects of clarified apple juices (CAJs, devoid of pectin and additives) processed to different degrees, including not-from-concentrate (NFC) and from-concentrate (FC) CAJs. A 56-day experiment including a juice-switch after 28 days was designed. An integrated analysis of 16S rRNA sequencing and untargeted metabolomics of cecal content were performed. In addition, differences in the CAJs tested with respect to nutritional indices and composition of small-molecule compounds were analyzed. The NFC CAJ, which showed a higher phenolic content resulting from the lower processing degree, could improve microbiota diversity and influence its structure. It also reduced bile acid and bilirubin contents, as well as inhibited the microbial metabolism of tryptophan in the gut. However, we found that these effects diminished with time by performing experiment extension and undertaking juice-switching. Our study provides evidence regarding the health effects of processed foods that can potentially be applied to public health policy decision making. We believe that NFC juices with a lower processing degree could potentially be healthier than FC juice.
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31
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Kim J, Ahn SW, Kim JY, Whon TW, Lim SK, Ryu BH, Han NS, Choi HJ, Roh SW, Lee SH. Probiotic Lactobacilli ameliorate alcohol-induced hepatic damage via gut microbial alteration. Front Microbiol 2022; 13:869250. [PMID: 36081800 PMCID: PMC9446534 DOI: 10.3389/fmicb.2022.869250] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Accepted: 07/20/2022] [Indexed: 11/13/2022] Open
Abstract
Alcoholic liver disease (ALD), which includes fatty liver, cirrhosis, steatosis, fibrosis, and hepatocellular carcinoma, is a global health problem. The probiotic effects of lactic acid bacteria (LAB) are well-known; however, their protective effect against ALD remains unclear. Therefore, in this study, our objective was to assess the protective effects of LAB on ALD. To this end, mice were fed either a normal diet or an alcohol diet for 10 days (to induce ALD) accompanied by vehicle treatment (the NC and AC groups) or kimchi-derived LAB (Lactiplantibacillus plantarum DSR J266 and Levilactobacillus brevis DSR J301, the AL group; or Lacticaseibacillus rhamnosus GG, the AG group). Our results showed that mice in the AC group showed significantly higher serum aspartate aminotransferase and alanine aminotransferase levels than those in the normal diet groups; however, their levels in the AL and AG groups were relatively lower. We also observed that the AL and AG groups showed relatively lower interleukin-6 levels than the AC group. Additionally, AC group showed the accumulation of several fat vesicles in the liver, while the AL and AG groups showed remarkably lower numbers of fat vesicles. The relative abundance of Enterococcus feacalis, which showed association with liver injury, significantly increased in the AC group compared with its levels in the normal diet groups. However, the AG group showed a decreased relative abundance in this regard, confirming that LAB exerted an improvement effect on gut microbial community. These findings suggested that via gut microbiota alteration, the ingestion of LAB can alleviate the ill effects of alcohol consumption, including inflammation, liver damage, gut dysbiosis, and abnormal intestinal nutrient metabolism.
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Affiliation(s)
- Juseok Kim
- Kimchi Functionality Research Group, World Institute of Kimchi, Gwangju, South Korea
- Microbiome Research Team, LISCure Biosciences Inc., Seongnam, South Korea
| | - Seong Woo Ahn
- Kimchi Functionality Research Group, World Institute of Kimchi, Gwangju, South Korea
- Microbiome Research Team, LISCure Biosciences Inc., Seongnam, South Korea
| | - Joon Yong Kim
- Kimchi Functionality Research Group, World Institute of Kimchi, Gwangju, South Korea
- Microbiome Research Team, LISCure Biosciences Inc., Seongnam, South Korea
| | - Tae Woong Whon
- Kimchi Functionality Research Group, World Institute of Kimchi, Gwangju, South Korea
| | - Seul Ki Lim
- Fermentation Regulation Technology Research Group, World Institute of Kimchi, Gwangju, South Korea
| | - Byung Hee Ryu
- Food Research Division, Food BU, Daesang Corporation Research Institute, Icheon, South Korea
| | - Nam Soo Han
- Department of Food Science and Biotechnology, Brain Korea 21 Center for Bio-Health Industry, Chungbuk National University, Cheongju, South Korea
| | - Hak-Jong Choi
- Kimchi Functionality Research Group, World Institute of Kimchi, Gwangju, South Korea
| | - Seong Woon Roh
- Kimchi Functionality Research Group, World Institute of Kimchi, Gwangju, South Korea
- Microbiome Research Team, LISCure Biosciences Inc., Seongnam, South Korea
| | - Se Hee Lee
- Kimchi Functionality Research Group, World Institute of Kimchi, Gwangju, South Korea
- *Correspondence: Se Hee Lee,
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Jung JH, Kim SE, Suk KT, Kim DJ. Gut microbiota-modulating agents in alcoholic liver disease: Links between host metabolism and gut microbiota. Front Med (Lausanne) 2022; 9:913842. [PMID: 35935787 PMCID: PMC9354621 DOI: 10.3389/fmed.2022.913842] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Accepted: 07/04/2022] [Indexed: 11/13/2022] Open
Abstract
Alcoholic liver disease (ALD) involves a wide spectrum of diseases, including asymptomatic hepatic steatosis, alcoholic hepatitis, hepatic fibrosis, and cirrhosis, which leads to morbidity and mortality and is responsible for 0.9% of global deaths. Alcohol consumption induces bacterial translocation and alteration of the gut microbiota composition. These changes in gut microbiota aggravate hepatic inflammation and fibrosis. Alteration of the gut microbiota leads to a weakened gut barrier and changes host immunity and metabolic function, especially related to bile acid metabolism. Modulation and treatment for the gut microbiota in ALD has been studied using probiotics, prebiotics, synbiotics, and fecal microbial transplantation with meaningful results. In this review, we focused on the interaction between alcohol and gut dysbiosis in ALD. Additionally, treatment approaches for gut dysbiosis, such as abstinence, diet, pro-, pre-, and synbiotics, antibiotics, and fecal microbial transplantation, are covered here under ALD. However, further research through human clinical trials is warranted to evaluate the appropriate gut microbiota-modulating agents for each condition related to ALD.
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Affiliation(s)
- Jang Han Jung
- Department of Internal Medicine, Hallym University College of Medicine, Chuncheon, South Korea
| | - Sung-Eun Kim
- Department of Internal Medicine, Hallym University College of Medicine, Chuncheon, South Korea
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon, South Korea
| | - Ki Tae Suk
- Department of Internal Medicine, Hallym University College of Medicine, Chuncheon, South Korea
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon, South Korea
| | - Dong Joon Kim
- Department of Internal Medicine, Hallym University College of Medicine, Chuncheon, South Korea
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon, South Korea
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Guo L, Guan Q, Duan W, Ren Y, Zhang XJ, Xu HY, Shi JS, Wang FZ, Lu R, Zhang HL, Xu ZH, Li H, Geng Y. Dietary Goji Shapes the Gut Microbiota to Prevent the Liver Injury Induced by Acute Alcohol Intake. Front Nutr 2022; 9:929776. [PMID: 35898713 PMCID: PMC9309278 DOI: 10.3389/fnut.2022.929776] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Accepted: 06/08/2022] [Indexed: 11/25/2022] Open
Abstract
Diet is a major driver of the structure and function of the gut microbiota, which influences the host physiology. Alcohol abuse can induce liver disease and gut microbiota dysbiosis. Here, we aim to elucidate whether the well-known traditional health food Goji berry targets gut microbiota to prevent liver injury induced by acute alcohol intake. The results showed that Goji supplementation for 14 days alleviated acute liver injury as indicated by lowering serum aspartate aminotransferase, alanine aminotransferase, pro-inflammatory cytokines, as well as lipopolysaccharide content in the liver tissue. Goji maintained the integrity of the epithelial barrier and increased the levels of butyric acid in cecum contents. Furthermore, we established the causal relationship between gut microbiota and liver protection effects of Goji with the help of antibiotics treatment and fecal microbiota transplantation (FMT) experiments. Both Goji and FMT-Goji increased glutathione (GSH) in the liver and selectively enriched the butyric acid-producing gut bacterium Akkermansia and Ruminococcaceae by using 16S rRNA gene sequencing. Metabolomics analysis of cecum samples revealed that Goji and its trained microbiota could regulate retinoyl β-glucuronide, vanillic acid, and increase the level of glutamate and pyroglutamic acid, which are involved in GSH metabolism. Our study highlights the communication among Goji, gut microbiota, and liver homeostasis.
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Affiliation(s)
- Lin Guo
- The Key Laboratory of Industrial Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, Wuxi, China
| | - Qijie Guan
- National Engineering Research Center for Cereal Fermentation and Food Biomanufacturing, Jiangnan University, Wuxi, China
- Jiangsu Provincial Engineering Research Center for Bioactive Product Processing, Jiangnan University, Wuxi, China
| | - Wenhui Duan
- The Key Laboratory of Industrial Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, Wuxi, China
| | - Yilin Ren
- Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Life Sciences and Health Engineering, Jiangnan University, Wuxi, China
- Department of Gastroenterology, Affiliated Hospital of Jiangnan University, Wuxi, China
| | - Xiao-Juan Zhang
- National Engineering Research Center for Cereal Fermentation and Food Biomanufacturing, Jiangnan University, Wuxi, China
- Jiangsu Provincial Engineering Research Center for Bioactive Product Processing, Jiangnan University, Wuxi, China
| | - Hong-Yu Xu
- National Engineering Research Center for Cereal Fermentation and Food Biomanufacturing, Jiangnan University, Wuxi, China
- Jiangsu Provincial Engineering Research Center for Bioactive Product Processing, Jiangnan University, Wuxi, China
| | - Jin-Song Shi
- Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Life Sciences and Health Engineering, Jiangnan University, Wuxi, China
| | | | - Ran Lu
- Ningxia Red Power Goji Co., Ltd, Zhongwei, China
| | - Hui-Ling Zhang
- Ningxia Key Laboratory for Food Microbial-Applications Technology and Safety Control, Ningxia University, Yinchuan, China
| | - Zheng-Hong Xu
- The Key Laboratory of Industrial Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, Wuxi, China
- National Engineering Research Center for Cereal Fermentation and Food Biomanufacturing, Jiangnan University, Wuxi, China
- Jiangsu Provincial Engineering Research Center for Bioactive Product Processing, Jiangnan University, Wuxi, China
| | - Huazhong Li
- The Key Laboratory of Industrial Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, Wuxi, China
- *Correspondence: Huazhong Li
| | - Yan Geng
- Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Life Sciences and Health Engineering, Jiangnan University, Wuxi, China
- Yan Geng
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Cheng C, Zhou MX, He X, Liu Y, Huang Y, Niu M, Liu YX, Gao Y, Lu YW, Song XH, Li HF, Xiao XH, Wang JB, Ma ZT. Metabolomic Analysis Uncovers Lipid and Amino Acid Metabolism Disturbance During the Development of Ascites in Alcoholic Liver Disease. Front Med (Lausanne) 2022; 9:815467. [PMID: 35770013 PMCID: PMC9234647 DOI: 10.3389/fmed.2022.815467] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Accepted: 05/19/2022] [Indexed: 12/20/2022] Open
Abstract
Ascites is one of the most common complications of cirrhosis, and there is a dearth of knowledge about ascites-related pathologic metabolism. In this study, 122 alcoholic liver disease (ALD) patients, including 49 cases without ascites, 18 cases with mild-ascites, and 55 cases with large-ascites (1) were established according to the International Ascites Club (2), and untargeted metabolomics coupled with pattern recognition approaches were performed to profile and extract metabolite signatures. A total of 553 metabolites were uniquely discovered in patients with ascites, of which 136 metabolites had been annotated in the human metabolome database. Principal component analysis (PCA) analysis was used to further identify 21 ascites-related fingerprints. The eigenmetabolite calculated by reducing the dimensions of the 21 metabolites could be used to effectively identify those ALD patients with or without ascites. The eigenmetabolite showed a decreasing trend during ascites production and accumulation and was negatively related to the disease progress. These metabolic fingerprints mainly belong to the metabolites in lipid metabolism and the amino acid pathway. The results imply that lipid and amino acid metabolism disturbance may play a critical role in the development of ascites in ALD patients and could be a potent prognosis marker.
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Affiliation(s)
- Cheng Cheng
- College of Chinese Medicine and Food Engineering, Shanxi University of Traditional Chinese Medicine, Jinzhong, China
- Department of Hepatology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Ming-xi Zhou
- Department of Hepatology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Xian He
- Department of Hepatology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Yao Liu
- School of Traditional Chinese Medicine, Capital Medical University, Beijing, China
| | - Ying Huang
- Department of Hepatology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Ming Niu
- Department of Hepatology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Yi-xuan Liu
- College of Chinese Medicine and Food Engineering, Shanxi University of Traditional Chinese Medicine, Jinzhong, China
| | - Yuan Gao
- School of Traditional Chinese Medicine, Capital Medical University, Beijing, China
| | - Ya-wen Lu
- School of Traditional Chinese Medicine, Capital Medical University, Beijing, China
| | - Xin-hua Song
- School of Traditional Chinese Medicine, Capital Medical University, Beijing, China
| | - Hui-fang Li
- College of Chinese Medicine and Food Engineering, Shanxi University of Traditional Chinese Medicine, Jinzhong, China
| | - Xiao-he Xiao
- Department of Hepatology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Jia-bo Wang
- School of Traditional Chinese Medicine, Capital Medical University, Beijing, China
- *Correspondence: Jia-bo Wang,
| | - Zhi-tao Ma
- School of Traditional Chinese Medicine, Capital Medical University, Beijing, China
- Zhi-tao Ma,
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Zhu H, Jiang W, Liu C, Wang C, Hu B, Guo Y, Cheng Y, Qian H. Ameliorative effects of chlorogenic acid on alcoholic liver injury in mice via gut microbiota informatics. Eur J Pharmacol 2022; 928:175096. [PMID: 35697148 DOI: 10.1016/j.ejphar.2022.175096] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2022] [Revised: 05/22/2022] [Accepted: 06/08/2022] [Indexed: 11/19/2022]
Abstract
Chlorogenic acid (CGA) is a functional phenolic acid widely used in food and medicine-related fields. It has been proved to be effective in the treatment of alcoholic liver disease (ALD). However, the exact mechanism by which CGA prevents ALD, especially from the crosstalk between gut and liver, has not been previously reported. This work was aimed to explore the protective effects of CGA against ALD and its relationships to gut-liver axis abnormalities. Experimental results showed the increased (p < 0.05) serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), low density lipoprotein (LDL), total cholesterol (TC) and triglyceride (TG) levels of mice fed with ethanol were ameliorated by supplementing with CGA. Moreover, CGA promoted the production of n-butyric acid by nearly 3 times (1.78 vs 0.62 nM, p < 0.01), a short-chain fatty acid that helps maintain the integrity of the intestinal barrier. Furthermore, CGA alleviated microbial dysbiosis, evidenced by the increased relative abundances of beneficial bacteria Muribaculaceae, Bacteroides, Alloprevotella, and Parabacteroides, and decreased that of opportunistic pathogens Eubacterium_nodatum, Eubacterium_ruminantium, and Anaerotruncus. Correlation analysis further elucidated the microbiota altered after CGA intervention was positively correlated with short-chain fatty acids and antioxidant indexes, while negatively correlated with inflammatory cytokines. In summary, these findings suggested the hepatoprotective effect of CGA was ascribed to the modulation of gut-liver axis homeostasis.
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Affiliation(s)
- Hongkang Zhu
- State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, Wuxi, 214122, China; Synergetic Innovation Center for Food Safety and Nutrition, Jiangnan University, Wuxi, 214122, China
| | - Wenhao Jiang
- State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, Wuxi, 214122, China; Synergetic Innovation Center for Food Safety and Nutrition, Jiangnan University, Wuxi, 214122, China
| | - Chang Liu
- State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, Wuxi, 214122, China; Synergetic Innovation Center for Food Safety and Nutrition, Jiangnan University, Wuxi, 214122, China
| | - Cheng Wang
- State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, Wuxi, 214122, China; Synergetic Innovation Center for Food Safety and Nutrition, Jiangnan University, Wuxi, 214122, China
| | - Bin Hu
- School of Biotechnology, Jiangnan University, Wuxi, 214122, China
| | - Yahui Guo
- State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, Wuxi, 214122, China; Synergetic Innovation Center for Food Safety and Nutrition, Jiangnan University, Wuxi, 214122, China
| | - Yuliang Cheng
- State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, Wuxi, 214122, China; Synergetic Innovation Center for Food Safety and Nutrition, Jiangnan University, Wuxi, 214122, China.
| | - He Qian
- State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, Wuxi, 214122, China; Synergetic Innovation Center for Food Safety and Nutrition, Jiangnan University, Wuxi, 214122, China.
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In-depth investigation of the mechanisms of Echinacea purpurea polysaccharide mitigating alcoholic liver injury in mice via gut microbiota informatics and liver metabolomics. Int J Biol Macromol 2022; 209:1327-1338. [PMID: 35461865 DOI: 10.1016/j.ijbiomac.2022.04.131] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Revised: 04/12/2022] [Accepted: 04/17/2022] [Indexed: 12/12/2022]
Abstract
Accumulating evidence suggests that the pathogenesis of alcoholic liver disease (ALD) is strongly correlated with abnormalities of the gut-liver axis. Echinacea purpurea polysaccharide (EPP) is a homogeneous polysaccharide, which has been shown to mitigate ALD. However, the effects of EPP on gut microbiome and consequently on hepatic metabolism have yet to be explored. In this study, the microbiome and metabolomics were combined to explore the effects of EPP on gut microbiota and hepatic metabolism, and the relationship between both was further revealed by Spearman correlation analysis. Results exhibited EPP reversed alcohol-induced disturbances in gut microbiota, evidenced by increased abundance of Muribaculaceae, Lactobacillus, and Bacteroides and decreased abundance of Escherichia_Shigella and Enterococcus. Besides, EPP promoted the production of n-butyric acid, a short-chain fatty acid that maintains the integrity of the intestinal barrier. Moreover, EPP improved alterations in hepatic metabolites, and characteristic metabolites such as Berberine and Ponasterone as well as key metabolic pathways, particularly Nitrogen metabolism, were identified. Furthermore, correlation analysis suggested significant associations between gut microbes and hepatic metabolites, which in turn confirmed EPP alleviated ALD via the gut-liver axis. Therefore, these findings elucidated in-depth mechanisms of EPP against ALD and provided a new target for intervention in alcohol-related diseases.
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Xu Q, Zhang R, Mu Y, Song Y, Hao N, Wei Y, Wang Q, Mackay CR. Propionate Ameliorates Alcohol-Induced Liver Injury in Mice via the Gut-Liver Axis: Focus on the Improvement of Intestinal Permeability. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2022; 70:6084-6096. [PMID: 35549256 DOI: 10.1021/acs.jafc.2c00633] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
Alcohol-related liver disease (ALD) is a major cause of chronic liver disease worldwide with limited therapeutic options. Here, we first revealed the promising beneficial effect of gut microbiota-derived propionate on alcoholic liver injury in mice. This effect was dependent on the modulation of homeostasis of the gut-liver axis, especially the improvement of intestinal permeability. Dietary supplementation with propionate protected against ethanol-induced loss of hepatic function and hepatic steatosis in mice. Meanwhile, propionate treatment attenuated intestinal epithelial barrier dysfunction, restored the expression of intestinal mucus layer components, suppressed intestinal inflammation, and altered intestinal microbiota dysbiosis, which inhibited the intestinal hyperpermeability and subsequently reduced lipopolysaccharide leakage in ALD mice. Furthermore, as a consequence of endotoxemia amelioration, the liver inflammation-related TLR4-NF-κB pathway was inhibited. Collectively, our results suggested that propionate supplementation may be a promising option for the prevention and treatment of ALD.
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Affiliation(s)
- Qi Xu
- School of Pharmaceutical Sciences, Laboratory of Immunology for Environment and Health, Shandong Analysis and Test Center, Qilu University of Technology (Shandong Academy of Sciences), Jinan 250353, China
| | - Renshuai Zhang
- The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao 266071, China
| | - Yan Mu
- School of Pharmaceutical Sciences, Laboratory of Immunology for Environment and Health, Shandong Analysis and Test Center, Qilu University of Technology (Shandong Academy of Sciences), Jinan 250353, China
| | - Yue Song
- School of Pharmaceutical Sciences, Laboratory of Immunology for Environment and Health, Shandong Analysis and Test Center, Qilu University of Technology (Shandong Academy of Sciences), Jinan 250353, China
| | - Na Hao
- School of Pharmaceutical Sciences, Laboratory of Immunology for Environment and Health, Shandong Analysis and Test Center, Qilu University of Technology (Shandong Academy of Sciences), Jinan 250353, China
| | - Yunbo Wei
- School of Pharmaceutical Sciences, Laboratory of Immunology for Environment and Health, Shandong Analysis and Test Center, Qilu University of Technology (Shandong Academy of Sciences), Jinan 250353, China
| | - Quanbo Wang
- School of Pharmaceutical Sciences, Laboratory of Immunology for Environment and Health, Shandong Analysis and Test Center, Qilu University of Technology (Shandong Academy of Sciences), Jinan 250353, China
| | - Charles R Mackay
- School of Pharmaceutical Sciences, Laboratory of Immunology for Environment and Health, Shandong Analysis and Test Center, Qilu University of Technology (Shandong Academy of Sciences), Jinan 250353, China
- Department of Microbiology, Infection and Immunity Program, Biomedicine Discovery Institute, Monash University, Melbourne 3800, Australia
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Non-Alcoholic Components in Huangjiu as Potential Factors Regulating the Intestinal Barrier and Gut Microbiota in Mouse Model of Alcoholic Liver Injury. Foods 2022; 11:foods11111537. [PMID: 35681289 PMCID: PMC9180658 DOI: 10.3390/foods11111537] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Revised: 05/06/2022] [Accepted: 05/16/2022] [Indexed: 11/17/2022] Open
Abstract
Different alcoholic beverages and drinking patterns might exert divergent impacts on alcoholic liver disease (ALD) progression. Whether the abundant non-alcoholic components (NAC) in fermented wine could alleviate ethanol (EtOH)-induced adverse influences on the liver remains unknown. Hence, the chronic ALD mouse model was established to compare the effects of Huangjiu (a typical fermented wine) and EtOH feeding on the liver, intestinal barrier, gut microbiota, and intestinal short-chain fatty acids (SCFAs) content. Although Huangjiu intake led to slight hepatic steatosis, it mitigated oxidative stress, inflammation, and intestinal damage relative to EtOH intake. In comparison with EtOH feeding, Huangjiu significantly improved the intestinal barrier integrity and reduced hepatic lipopolysaccharide levels by up-regulating the expression of intestinal tight junction proteins (ZO-1 and occludin) and antimicrobial activity peptides (Reg3β and Reg3γ). The administration of Huangjiu NAC partially restored alcohol-induced gut microbiota dysbiosis via recovering the abundance of Lactobacillus, Faecalibaculum, and Akkermansia. Moreover, mice receiving Huangjiu showed higher SCFAs levels (such as acetic acid and butyric acid) than those receiving EtOH. Huangjiu consumption resulted in lower hepatotoxicity than pure EtOH, at the same alcohol dose. The NAC in Huangjiu might attenuate the progression of ALD by regulating intestinal barrier function and microbiota-meditated gut ecology.
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Identification of a protective Bacteroides strain of alcoholic liver disease and its synergistic effect with pectin. Appl Microbiol Biotechnol 2022; 106:3735-3749. [PMID: 35554627 DOI: 10.1007/s00253-022-11946-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Revised: 04/25/2022] [Accepted: 04/27/2022] [Indexed: 12/15/2022]
Abstract
The depletion of Bacteroides in the gut is closely correlated with the progression of alcoholic liver disease (ALD). This study aimed to identify Bacteroides strains with protective effects against ALD and evaluate the synergistic effects of Bacteroides and pectin in this disease. Mice were fed Lieber-DeCarli alcohol diet to establish an experimental ALD model and pre-treated with 4 Bacteroides strains. The severity of the liver injury, hepatic steatosis, and inflammation was evaluated through histological and biochemical assays. We found that Bacteroides fragilis ATCC25285 had the best protective effects against ALD strains by alleviating both ethanol-induced liver injury and steatosis. B. fragilis ATCC25285 could counteract inflammatory reactions in ALD by producing short-chain fat acids (SCFAs) and enhancing the intestinal barrier. In the subsequent experiment, the synbiotic combination of B. fragilis ATCC25285 and pectin was evaluated and the underlying mechanisms were investigated by metabolomic and microbiome analyses. The combination elicited superior anti-ALD effects than the individual agents used alone. The synergistic effects of B. fragilis ATCC25285 and pectin were driven by modulating gut microbiota, improving tryptophan metabolism, and regulating intestinal immune function. Based on our findings, the combination of B. fragilis ATCC25285 and pectin can be considered a potential treatment for ALD. KEY POINTS: • B. fragilis ATCC25285 was identified as a protective Bacteroides strain against ALD. • The synbiotic combination of B. fragilis and pectin has better anti-ALD effects. • The synbiotic combination modulates gut microbiota and tryptophan metabolism.
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Liu Z, Gomez CR, Espinoza I, Le TPT, Shenoy V, Zhou X. Correlation of cholesteryl ester metabolism to pathogenesis, progression and disparities in colorectal Cancer. Lipids Health Dis 2022; 21:22. [PMID: 35172832 PMCID: PMC8851778 DOI: 10.1186/s12944-022-01629-7] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Accepted: 01/24/2022] [Indexed: 12/20/2022] Open
Abstract
Background Colorectal cancer (CRC) is one of the most common cancers worldwide characterized by disparities in age, gender, race and anatomic sites. The mechanism underlying pathogenesis, progression and disparities of CRC remains unclear. This study aims to reveal the association of expression levels of enzymes related to cholesteryl ester (CE) metabolism with pathogenesis, progression and disparities of CRC. Methods The differences in gene expression levels were analyzed for enzymes in CE synthesis (acyl CoA: cholesterol acyltransferase 1 and 2, ACAT1, and ACAT2), and in CE hydrolysis (neutral cholesterol ester hydrolase, NCEH1 and lysosomal acid lipase, LAL) on TNMplot platform between CRC and normal colorectal tissues (NCT) in a large cohort. The differences in protein expression levels for these enzymes were determined by Immunochemistry (IHC) performed on tissue microarray containing 96 pairs of CRC and benign colorectal tissues (BCT) from different patient populations. The expression level represented as IHC score of each enzyme was compared between CRC and BCT in entire population and populations stratified by race, gender and anatomic sites. Student’s t-test, Fisher exact test and ANOVA were used for data analysis. Significant p value was set at P<0.05. Results The gene expression level of ACAT1 was significantly lower in CRC than in NCT (P = 2.15e-119). The gene expression level of ACAT2 was not statistically different between CRC and NCT. The gene expression level of LIPA (encoding LAL) was significantly higher in CRC than in NCT (P = 2.01e-14). No data was found for the gene expression level of NCEH1. The IHC score of ACAT1was significantly lower in CRC than in BCT in all studied populations and in sub site of colon, but not in that of rectum. The IHC score of ACAT2 was not statistically different between CRC and BCT. IHC score of NCEH1 was significantly higher in CRC than in BCT only in African American (AA) population. The IHC score of LAL was significantly higher in CRC than in BCT in all studied populations and in all sub sites. In addition, decreased ACAT1 in CRC significantly correlated to progression of CRC: the lower IHC score of ACAT1, the more advanced clinical stage of CRC will be. Conclusions This study revealed that altered expression levels in enzymes related to CE metabolism highly correlate to the pathogenesis, clinical progression and disparities of CRC. The results will add revenue in elucidating mechanisms underlying progression of CRC, and shed light on seeking biomarkers and exploring therapeutic targets for CRC in a new direction.
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Affiliation(s)
- Zhirong Liu
- Department of Biochemistry, Shanxi Medical University, Taiyuan, 030001, Shanxi Province, China.,Department of Pathology, University of Mississippi Medical Center, Jackson, MS, 39216, USA
| | - Christian R Gomez
- Department of Pathology, University of Mississippi Medical Center, Jackson, MS, 39216, USA
| | - Ingrid Espinoza
- Department of Preventive Medicine, University of Mississippi Medical Center, Jackson, MS, 39216, USA
| | - Thuy Phuong T Le
- School of Medicine, University of Mississippi Medical Center, Jackson, MS, 39216, USA
| | - Veena Shenoy
- Department of Pathology, University of Mississippi Medical Center, Jackson, MS, 39216, USA
| | - Xinchun Zhou
- Department of Pathology, University of Mississippi Medical Center, Jackson, MS, 39216, USA.
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Portincasa P, Bonfrate L, Khalil M, Angelis MD, Calabrese FM, D’Amato M, Wang DQH, Di Ciaula A. Intestinal Barrier and Permeability in Health, Obesity and NAFLD. Biomedicines 2021; 10:83. [PMID: 35052763 PMCID: PMC8773010 DOI: 10.3390/biomedicines10010083] [Citation(s) in RCA: 107] [Impact Index Per Article: 26.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Revised: 12/20/2021] [Accepted: 12/28/2021] [Indexed: 02/07/2023] Open
Abstract
The largest surface of the human body exposed to the external environment is the gut. At this level, the intestinal barrier includes luminal microbes, the mucin layer, gastrointestinal motility and secretion, enterocytes, immune cells, gut vascular barrier, and liver barrier. A healthy intestinal barrier is characterized by the selective permeability of nutrients, metabolites, water, and bacterial products, and processes are governed by cellular, neural, immune, and hormonal factors. Disrupted gut permeability (leaky gut syndrome) can represent a predisposing or aggravating condition in obesity and the metabolically associated liver steatosis (nonalcoholic fatty liver disease, NAFLD). In what follows, we describe the morphological-functional features of the intestinal barrier, the role of major modifiers of the intestinal barrier, and discuss the recent evidence pointing to the key role of intestinal permeability in obesity/NAFLD.
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Affiliation(s)
- Piero Portincasa
- Clinica Medica “A. Murri”, Department of Biomedical Sciences & Human Oncology, University of Bari Medical School, 70124 Bari, Italy; (L.B.); (M.K.); (A.D.C.)
| | - Leonilde Bonfrate
- Clinica Medica “A. Murri”, Department of Biomedical Sciences & Human Oncology, University of Bari Medical School, 70124 Bari, Italy; (L.B.); (M.K.); (A.D.C.)
| | - Mohamad Khalil
- Clinica Medica “A. Murri”, Department of Biomedical Sciences & Human Oncology, University of Bari Medical School, 70124 Bari, Italy; (L.B.); (M.K.); (A.D.C.)
- Department of Soil, Plant and Food Sciences, University of Bari Aldo Moro, Via Amendola 165/a, 70126 Bari, Italy; (M.D.A.); (F.M.C.)
| | - Maria De Angelis
- Department of Soil, Plant and Food Sciences, University of Bari Aldo Moro, Via Amendola 165/a, 70126 Bari, Italy; (M.D.A.); (F.M.C.)
| | - Francesco Maria Calabrese
- Department of Soil, Plant and Food Sciences, University of Bari Aldo Moro, Via Amendola 165/a, 70126 Bari, Italy; (M.D.A.); (F.M.C.)
| | - Mauro D’Amato
- Gastrointestinal Genetics Lab, CIC bioGUNE-BRTA, 48160 Derio, Spain;
- Ikerbasque, Basque Foundation for Science, 48009 Bilbao, Spain
| | - David Q.-H. Wang
- Department of Medicine and Genetics, Division of Gastroenterology and Liver Diseases, Marion Bessin Liver Research Center, Einstein-Mount Sinai Diabetes Research Center, Albert Einstein College of Medicine, New York, NY 10461, USA;
| | - Agostino Di Ciaula
- Clinica Medica “A. Murri”, Department of Biomedical Sciences & Human Oncology, University of Bari Medical School, 70124 Bari, Italy; (L.B.); (M.K.); (A.D.C.)
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Singhal R, Donde H, Ghare S, Stocke K, Zhang J, Vadhanam M, Reddy S, Gobejishvili L, Chilton P, Joshi-Barve S, Feng W, McClain C, Hoffman K, Petrosino J, Vital M, Barve S. Decrease in acetyl-CoA pathway utilizing butyrate-producing bacteria is a key pathogenic feature of alcohol-induced functional gut microbial dysbiosis and development of liver disease in mice. Gut Microbes 2021; 13:1946367. [PMID: 34369304 PMCID: PMC8354657 DOI: 10.1080/19490976.2021.1946367] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Emerging research evidence has established the critical role of the gut-liver axis in the development of alcohol-associated liver disease (ALD). The present study employed 16S rRNA gene and whole genome shotgun (WGS) metagenomic analysis in combination with a revised microbial dataset to comprehensively detail the butyrate-producing microbial communities and the associated butyrate metabolic pathways affected by chronic ethanol feeding. Specifically, the data demonstrated that a decrease in several butyrate-producing bacterial genera belonging to distinct families within the Firmicutes phyla was a significant component of ethanol-induced dysbiosis. WGS analysis of total bacterial genomes encompassing butyrate synthesizing pathways provided the functional characteristics of the microbiome associated with butyrate synthesis. The data revealed that in control mice microbiome, the acetyl-coenzyme A (CoA) butyrate synthesizing pathway was the most prevalent and was significantly and maximally decreased by chronic ethanol feeding. Further WGS analysis i) validated the ethanol-induced decrease in the acetyl-CoA pathway by identifying the decrease in two critical genes but - (butyryl-CoA: acetate CoA transferase) and buk - (butyrate kinase) that encode the terminal condensing enzymes required for converting butyryl-CoA to butyrate and ii) detection of specific taxa of butyrate-producing bacteria containing but and buk genes. Notably, the administration of tributyrin (Tb) - a butyrate prodrug - significantly prevented ethanol-induced decrease in butyrate-producing bacteria, hepatic steatosis, inflammation, and injury. Taken together, our findings strongly suggest that the loss of butyrate-producing bacteria using the acetyl-CoA pathway is a significant pathogenic feature of ethanol-induced microbial dysbiosis and ALD and can be targeted for therapy.
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Affiliation(s)
- Richa Singhal
- University of Louisville Department of Medicine,University of Louisville Alcohol Research Center
| | - Hridgandh Donde
- University of Louisville Department of Medicine,University of Louisville Alcohol Research Center
| | - Smita Ghare
- University of Louisville Department of Medicine,University of Louisville Alcohol Research Center
| | - Kendall Stocke
- University of Louisville Department of Environmental and Occupational Health Science
| | - Jingwein Zhang
- University of Louisville Department of Medicine,University of Louisville Alcohol Research Center
| | - Manicka Vadhanam
- University of Louisville Department of Medicine,University of Louisville Alcohol Research Center
| | - Sreelatha Reddy
- University of Louisville Department of Medicine,University of Louisville Alcohol Research Center
| | - Leila Gobejishvili
- University of Louisville Department of Medicine,University of Louisville Alcohol Research Center
| | - Paula Chilton
- University of Louisville Department of Medicine,University of Louisville Alcohol Research Center
| | - Swati Joshi-Barve
- University of Louisville Department of Medicine,University of Louisville Alcohol Research Center
| | - Wenke Feng
- University of Louisville Department of Medicine,University of Louisville Alcohol Research Center
| | - Craig McClain
- University of Louisville Department of Medicine,University of Louisville Alcohol Research Center
| | - Kristi Hoffman
- Baylor College of Medicine Department of Molecular Virology and Microbiology,Baylor College of Medicine Center for Metagenomics and Microbiome Research
| | - Joseph Petrosino
- Baylor College of Medicine Department of Molecular Virology and Microbiology,Baylor College of Medicine Center for Metagenomics and Microbiome Research
| | - Marius Vital
- Hannover Medical School, Hanover, Germany,Helmholtz Center for Infection Research,Helmholtz Association of German Research Centers
| | - Shirish Barve
- University of Louisville Department of Medicine,University of Louisville Alcohol Research Center,University of Louisville Department of Pharmacology and Toxicology,CONTACT Dr. Shirish Barve Departments of Medicine and Pharmacology and Toxicology, University of Louisville Health Sciences Center, 505 S. Hancock St. CTR Bldg., Room 515, Louisville, KY40202, USA
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Yan J, Ouyang J, Isnard S, Zhou X, Harypursat V, Routy JP, Chen Y. Alcohol Use and Abuse Conspires With HIV Infection to Aggravate Intestinal Dysbiosis and Increase Microbial Translocation in People Living With HIV: A Review. Front Immunol 2021; 12:741658. [PMID: 34975838 PMCID: PMC8718428 DOI: 10.3389/fimmu.2021.741658] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Accepted: 11/30/2021] [Indexed: 12/12/2022] Open
Abstract
The intestinal microbiome is an essential so-called human "organ", vital for the induction of innate immunity, for metabolizing nutrients, and for maintenance of the structural integrity of the intestinal barrier. HIV infection adversely influences the richness and diversity of the intestinal microbiome, resulting in structural and functional impairment of the intestinal barrier and an increased intestinal permeability. Pathogens and metabolites may thus cross the "leaky" intestinal barrier and enter the systemic circulation, which is a significant factor accounting for the persistent underlying chronic inflammatory state present in people living with HIV (PLWH). Additionally, alcohol use and abuse has been found to be prevalent in PLWH and has been strongly associated with the incidence and progression of HIV/AIDS. Recently, converging evidence has indicated that the mechanism underlying this phenomenon is related to intestinal microbiome and barrier function through numerous pathways. Alcohol acts as a "partner" with HIV in disrupting microbiome ecology, and thus impairing of the intestinal barrier. Optimizing the microbiome and restoring the integrity of the intestinal barrier is likely to be an effective adjunctive therapeutic strategy for PLWH. We herein critically review the interplay among HIV, alcohol, and the gut barrier, thus setting the scene with regards to development of effective strategies to counteract the dysregulated gut microbiome and the reduction of microbial translocation and inflammation in PLWH.
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Affiliation(s)
- Jiangyu Yan
- Clinical Research Center, Chongqing Public Health Medical Center, Chongqing, China
| | - Jing Ouyang
- Clinical Research Center, Chongqing Public Health Medical Center, Chongqing, China
| | - Stéphane Isnard
- Infectious Diseases and Immunity in Global Health Program, Research Institute, McGill University Health Centre, Montréal, QC, Canada
- Chronic Viral Illness Service, McGill University Health Centre, Montréal, QC, Canada
- Canadian HIV Trials Network (CTN), Canadian Institutes of Health Research (CIHR), Vancouver, BC, Canada
| | - Xin Zhou
- Clinical Research Center, Chongqing Public Health Medical Center, Chongqing, China
| | - Vijay Harypursat
- Clinical Research Center, Chongqing Public Health Medical Center, Chongqing, China
| | - Jean-Pierre Routy
- Infectious Diseases and Immunity in Global Health Program, Research Institute, McGill University Health Centre, Montréal, QC, Canada
- Chronic Viral Illness Service, McGill University Health Centre, Montréal, QC, Canada
- Division of Hematology, McGill University Health Centre, Montréal, QC, Canada
| | - Yaokai Chen
- Clinical Research Center, Chongqing Public Health Medical Center, Chongqing, China
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Pizarro N, Kossatz E, González P, Gamero A, Veza E, Fernández C, Gabaldón T, de la Torre R, Robledo P. Sex-Specific Effects of Synbiotic Exposure in Mice on Addictive-Like Behavioral Alterations Induced by Chronic Alcohol Intake Are Associated With Changes in Specific Gut Bacterial Taxa and Brain Tryptophan Metabolism. Front Nutr 2021; 8:750333. [PMID: 34901109 PMCID: PMC8662823 DOI: 10.3389/fnut.2021.750333] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Accepted: 10/11/2021] [Indexed: 12/12/2022] Open
Abstract
Chronic alcohol intake has been shown to disrupt gut microbiota homeostasis, but whether microbiota modulation could prevent behavioral alterations associated with chronic alcohol intake remains unknown. We investigated the effects of synbiotic dietary supplementation on the development of alcohol-related addictive behavior in female and male mice and evaluated whether these effects were associated with changes in bacterial species abundance, short-chain fatty acids, tryptophan metabolism, and neurotransmitter levels in the prefrontal cortex and hippocampus. Chronic intermittent exposure to alcohol during 20 days induced escalation of intake in both female and male mice. Following alcohol deprivation, relapse-like behavior was observed in both sexes, but anxiogenic and cognitive deficits were present only in females. Synbiotic treatment reduced escalation and relapse to alcohol intake in females and males. In addition, the anxiogenic-like state and cognitive deficits observed in females following alcohol deprivation were abolished in mice exposed to synbiotic. Alcohol-induced differential alterations in microbial diversity and abundance in both sexes. In females, synbiotic exposure abrogated the alterations provoked by alcohol in Prevotellaceae UCG-001 and Ruminococcaceae UCG-014 abundance. In males, synbiotic exposure restored the changes induced by alcohol in Akkermansia and Muribaculum uncultured bacterium abundance. Following alcohol withdrawal, tryptophan metabolites, noradrenaline, dopamine, and γ-aminobutyric acid concentrations in the prefrontal cortex and the hippocampus were correlated with bacterial abundance and behavioral alterations in a sex-dependent manner. These results suggested that a dietary intervention with a synbiotic to reduce gut dysbiosis during chronic alcohol intake may impact differently the gut-brain-axis in females and males.
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Affiliation(s)
- Nieves Pizarro
- Integrative Pharmacology and Systems Neuroscience Research Group, Neurosciences Research Program, IMIM-Hospital del Mar Medical Research Institute, Barcelona, Spain.,Department of Experimental and Health Sciences, Pompeu Fabra University (CEXS-UPF), Barcelona, Spain
| | - Elk Kossatz
- Integrative Pharmacology and Systems Neuroscience Research Group, Neurosciences Research Program, IMIM-Hospital del Mar Medical Research Institute, Barcelona, Spain
| | | | - Alba Gamero
- Integrative Pharmacology and Systems Neuroscience Research Group, Neurosciences Research Program, IMIM-Hospital del Mar Medical Research Institute, Barcelona, Spain.,Department of Experimental and Health Sciences, Pompeu Fabra University (CEXS-UPF), Barcelona, Spain
| | - Emma Veza
- Integrative Pharmacology and Systems Neuroscience Research Group, Neurosciences Research Program, IMIM-Hospital del Mar Medical Research Institute, Barcelona, Spain
| | - Cristina Fernández
- Department of Experimental and Health Sciences, Pompeu Fabra University (CEXS-UPF), Barcelona, Spain
| | - Toni Gabaldón
- Barcelona Supercomputing Centre (BSC-CNS), Barcelona, Spain.,Institute for Research in Biomedicine, The Barcelona Institute of Science and Technology, Barcelona, Spain.,Catalan Institution for Research and Advanced Studies (ICREA), Barcelona, Spain
| | - Rafael de la Torre
- Integrative Pharmacology and Systems Neuroscience Research Group, Neurosciences Research Program, IMIM-Hospital del Mar Medical Research Institute, Barcelona, Spain.,Department of Experimental and Health Sciences, Pompeu Fabra University (CEXS-UPF), Barcelona, Spain.,CIBER Fisiopatología Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain
| | - Patricia Robledo
- Integrative Pharmacology and Systems Neuroscience Research Group, Neurosciences Research Program, IMIM-Hospital del Mar Medical Research Institute, Barcelona, Spain.,Department of Experimental and Health Sciences, Pompeu Fabra University (CEXS-UPF), Barcelona, Spain
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Piacentino D, Grant-Beurmann S, Vizioli C, Li X, Moore CF, Ruiz-Rodado V, Lee MR, Joseph PV, Fraser CM, Weerts EM, Leggio L. Gut microbiome and metabolome in a non-human primate model of chronic excessive alcohol drinking. Transl Psychiatry 2021; 11:609. [PMID: 34853299 PMCID: PMC8636625 DOI: 10.1038/s41398-021-01728-6] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Revised: 10/27/2021] [Accepted: 11/05/2021] [Indexed: 02/08/2023] Open
Abstract
A relationship between the gut microbiome and alcohol use disorder has been suggested. Excessive alcohol use produces changes in the fecal microbiome and metabolome in both rodents and humans. Yet, these changes can be observed only in a subgroup of the studied populations, and reversal does not always occur after abstinence. We aimed to analyze fecal microbial composition and function in a translationally relevant baboon model of chronic heavy drinking that also meets binge criteria (drinking too much, too fast, and too often), i.e., alcohol ~1 g/kg and blood alcohol levels (BALs) ≥ 0.08 g/dL in a 2-hour period, daily, for years. We compared three groups of male baboons (Papio anubis): L = Long-term alcohol drinking group (12.1 years); S = Short-term alcohol drinking group (2.7 years); and C = Control group, drinking a non-alcoholic reinforcer (Tang®) (8.2 years). Fecal collection took place during 3 days of Drinking (D), followed by a short period (3 days) of Abstinence (A). Fecal microbial alpha- and beta-diversity were significantly lower in L vs. S and C (p's < 0.05). Members of the commensal families Lachnospiraceae and Prevotellaceae showed a relative decrease, whereas the opportunistic pathogen Streptococcus genus showed a relative increase in L vs. S and C (p's < 0.05). Microbiota-related metabolites of aromatic amino acids, tricarboxylic acid cycle, and pentose increased in L vs. S and C (FDR-corrected p < 0.01), with the latter two suggesting high energy metabolism and enhanced glycolysis in the gut lumen in response to alcohol. Consistent with the long-term alcohol exposure, mucosal damage and oxidative stress markers (N-acetylated amino acids, 2-hydroxybutyrate, and metabolites of the methionine cycle) increased in L vs. S and C (FDR-corrected p < 0.01). Overall, S showed few differences vs. C, possibly due to the long-term, chronic alcohol exposure needed to alter the normal gut microbiota. In the three groups, the fecal microbiome barely differed between conditions D and A, whereas the metabolome shifted in the transition from condition D to A. In conclusion, changes in the fecal microbiome and metabolome occur after significant long-term excessive drinking and are only partially affected by acute forced abstinence from alcohol. These results provide novel information on the relationship between the fecal microbiome and metabolome in a controlled experimental setting and using a unique non-human primate model of chronic excessive alcohol drinking.
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Affiliation(s)
- Daria Piacentino
- grid.94365.3d0000 0001 2297 5165Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, Translational Addiction Medicine Branch, National Institute on Drug Abuse Intramural Research Program and National Institute on Alcohol Abuse and Alcoholism Division of Intramural Clinical and Biological Research, National Institutes of Health, 251 Bayview Blvd, Baltimore, MD 21224 USA ,grid.94365.3d0000 0001 2297 5165Center on Compulsive Behaviors, National Institutes of Health, 10 Center Dr, Bethesda, MD 20892 USA
| | - Silvia Grant-Beurmann
- grid.411024.20000 0001 2175 4264Institute for Genome Sciences, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD USA
| | - Carlotta Vizioli
- grid.420085.b0000 0004 0481 4802Sensory Science and Metabolism Unit, National Institute on Alcohol Abuse and Alcoholism Division of Intramural Clinical and Biological Research and National Institute of Nursing Research Division of Intramural Research, 10 Center Dr, Bethesda, MD 20892 USA
| | - Xiaobai Li
- grid.94365.3d0000 0001 2297 5165Biostatistics and Clinical Epidemiology Services, National Institutes of Health, Bethesda, MD USA
| | - Catherine F. Moore
- grid.21107.350000 0001 2171 9311Division of Behavioral Biology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Nathan Shock Drive, Baltimore, MD 21224 USA
| | - Victor Ruiz-Rodado
- grid.94365.3d0000 0001 2297 5165Neuro-Oncology Branch, National Cancer Institute, National Institutes of Health, 10 Center Dr, Bethesda, MD 20892 USA
| | - Mary R. Lee
- grid.94365.3d0000 0001 2297 5165Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, Translational Addiction Medicine Branch, National Institute on Drug Abuse Intramural Research Program and National Institute on Alcohol Abuse and Alcoholism Division of Intramural Clinical and Biological Research, National Institutes of Health, 251 Bayview Blvd, Baltimore, MD 21224 USA
| | - Paule V. Joseph
- grid.420085.b0000 0004 0481 4802Sensory Science and Metabolism Unit, National Institute on Alcohol Abuse and Alcoholism Division of Intramural Clinical and Biological Research and National Institute of Nursing Research Division of Intramural Research, 10 Center Dr, Bethesda, MD 20892 USA
| | - Claire M. Fraser
- grid.411024.20000 0001 2175 4264Institute for Genome Sciences, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD USA
| | - Elise M. Weerts
- grid.21107.350000 0001 2171 9311Division of Behavioral Biology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Nathan Shock Drive, Baltimore, MD 21224 USA
| | - Lorenzo Leggio
- Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, Translational Addiction Medicine Branch, National Institute on Drug Abuse Intramural Research Program and National Institute on Alcohol Abuse and Alcoholism Division of Intramural Clinical and Biological Research, National Institutes of Health, 251 Bayview Blvd, Baltimore, MD, 21224, USA. .,Center on Compulsive Behaviors, National Institutes of Health, 10 Center Dr, Bethesda, MD, 20892, USA. .,Medication Development Program, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, 251 Bayview Blvd, Baltimore, MD, 21224, USA. .,Center for Alcohol and Addiction Studies, Department of Behavioral and Social Sciences, Brown University School of Public Health, 121 South Main Street, Providence, RI, USA. .,Division of Addiction Medicine, Department of Medicine, Johns Hopkins University School of Medicine, 733 N Broadway, Baltimore, MD, 21205, USA. .,Department of Neuroscience, Georgetown University Medical Center, 3970 Reservoir Rd NW, Washington, DC, 20007, USA.
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Yadav M, Chauhan NS. Microbiome therapeutics: exploring the present scenario and challenges. Gastroenterol Rep (Oxf) 2021; 10:goab046. [PMID: 35382166 PMCID: PMC8972995 DOI: 10.1093/gastro/goab046] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Revised: 09/24/2021] [Accepted: 09/25/2021] [Indexed: 12/11/2022] Open
Abstract
Human gut-microbiome explorations have enriched our understanding of microbial colonization, maturation, and dysbiosis in health-and-disease subsets. The enormous metabolic potential of gut microbes and their role in the maintenance of human health is emerging, with new avenues to use them as therapeutic agents to overcome human disorders. Microbiome therapeutics are aimed at engineering the gut microbiome using additive, subtractive, or modulatory therapy with an application of native or engineered microbes, antibiotics, bacteriophages, and bacteriocins. This approach could overcome the limitation of conventional therapeutics by providing personalized, harmonized, reliable, and sustainable treatment. Its huge economic potential has been shown in the global therapeutics market. Despite the therapeutic and economical potential, microbiome therapeutics is still in the developing stage and is facing various technical and administrative issues that require research attention. This review aims to address the current knowledge and landscape of microbiome therapeutics, provides an overview of existing health-and-disease applications, and discusses the potential future directions of microbiome modulations.
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Affiliation(s)
- Monika Yadav
- Department of Biochemistry, Maharshi Dayanand University, Rohtak, Haryana, India
| | - Nar Singh Chauhan
- Department of Biochemistry, Maharshi Dayanand University, Rohtak, Haryana, India
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Patel F, Parwani K, Rao P, Patel D, Rawal R, Mandal P. Prophylactic Treatment of Probiotic and Metformin Mitigates Ethanol-Induced Intestinal Barrier Injury: In Vitro, In Vivo, and In Silico Approaches. Mediators Inflamm 2021; 2021:5245197. [PMID: 34616233 PMCID: PMC8490080 DOI: 10.1155/2021/5245197] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Accepted: 08/09/2021] [Indexed: 02/07/2023] Open
Abstract
Ethanol depletes intestinal integrity and promotes gut dysbiosis. Studies have suggested the individual role of probiotics and metformin Met in protecting intestinal barrier function from injuries induced by ethanol. The objective of the current study is to investigate the potential mechanism by which coadministration of probiotic Visbiome® (V) and Met blocks the ethanol-induced intestinal barrier dysfunction/gut leakiness utilizing Caco-2 monolayers, a rat model with chronic ethanol injury, and in silico docking interaction models. In Caco-2 monolayers, exposure to ethanol significantly disrupted tight junction (TJ) localization, elevated monolayer permeability, and oxidative stress compared with controls. However, cotreatment with probiotic V and Met largely ameliorated the ethanol-induced mucosal barrier dysfunction, TJ disruption, and gut oxidative stress compared with ethanol-exposed monolayers and individual treatment of either agent. Rats fed with ethanol-containing Lieber-DeCarli liquid diet showed decreased expression of TJ proteins, and increased intestinal barrier injury resulting in pro-inflammatory response and oxidative stress in the colon. We found that co-administration of probiotic V and Met improved the expression of intestinal TJ proteins (ZO-1 and occludin) and upregulated the anti-inflammatory response, leading to reduced ER stress. Moreover, co-administration of probiotic V and Met inhibited the CYP2E1 and NOX gene expression, and increase the translocation of Nrf-2 as well as anti-oxidative genes (SOD, catalase, Gpx, and HO-1), leading to reduced colonic ROS content and malondialdehyde levels. The combined treatment of probiotic V and Met also improved their binding affinities towards HO-1, Nrf-2, SLC5A8, and GPR109A, which could be attributed to their synergistic effect. Our findings based on in-vitro, in-vivo, and in-silico analyses suggest that the combination of probiotic V and Met potentially acts in synergism, attributable to their property of inhibition of inflammation and oxidative stress against ethanol-induced intestinal barrier injury.
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Affiliation(s)
- Farhin Patel
- Department of Biological Sciences, P.D. Patel Institute of Applied Sciences, Charotar University of Science and Technology, Changa, 388421 Anand, Gujarat, India
| | - Kirti Parwani
- Department of Biological Sciences, P.D. Patel Institute of Applied Sciences, Charotar University of Science and Technology, Changa, 388421 Anand, Gujarat, India
| | - Priyashi Rao
- Department of Biochemistry & Forensic Science, University School of Sciences, Gujarat University, Ahmedabad, 380009 Gujarat, India
| | - Dhara Patel
- Department of Biological Sciences, P.D. Patel Institute of Applied Sciences, Charotar University of Science and Technology, Changa, 388421 Anand, Gujarat, India
| | - Rakesh Rawal
- Department of Biochemistry & Forensic Science, University School of Sciences, Gujarat University, Ahmedabad, 380009 Gujarat, India
| | - Palash Mandal
- Department of Biological Sciences, P.D. Patel Institute of Applied Sciences, Charotar University of Science and Technology, Changa, 388421 Anand, Gujarat, India
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Samuelson DR, Gu M, Shellito JE, Molina PE, Taylor CM, Luo M, Welsh DA. Pulmonary immune cell trafficking promotes host defense against alcohol-associated Klebsiella pneumonia. Commun Biol 2021; 4:997. [PMID: 34426641 PMCID: PMC8382828 DOI: 10.1038/s42003-021-02524-0] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Accepted: 08/05/2021] [Indexed: 12/15/2022] Open
Abstract
The intestinal microbiota generates many different metabolites which are critical for the regulation of host signaling pathways. In fact, a wide-range of diseases are associated with increased levels of local or systemic microbe-derived metabolites. In contrast, certain bacterial metabolites, such as tryptophan metabolites, are known to contribute to both local and systemic homeostasis. Chronic alcohol consumption is accompanied by alterations to intestinal microbial communities, and their functional capacities. However, little is known about the role of alcohol-associated dysbiosis on host defense against bacterial pneumonia. Our previous work using fecal transplantation demonstrated that alcohol-associated intestinal dysbiosis, independent of ethanol consumption, increased susceptibility to Klebsiella pneumonia. Here, we demonstrate that intestinal microbiota treatments mitigate the increased risk of alcohol-associated pneumonia. Treatment with the microbial metabolite indole or with probiotics reduced pulmonary and extrapulmonary bacterial burden, restored immune responses, and improved cellular trafficking required for host defense. Protective effects were, in part, mediated by aryl hydrocarbon receptors (AhR), as inhibition of AhR diminished the protective effects. Thus, alcohol appears to impair the production/processing of tryptophan catabolites resulting in immune dysregulation and impaired cellular trafficking. These data support microbiota therapeutics as novel strategies to mitigate the increased risk for alcohol-associated bacterial pneumonia. Samuelson et al show that alcohol impairs the production/processing of microbial metabolites, specifically tryptophan catabolites, resulting in immune dysregulation and impaired cellular trafficking for optimal host defense. The metabolite, indole, or probiotics making indole metabolites mitigate alcohol-induced susceptibility to Klebsiella-associated pneumonia, and that the mechanisms are partially dependent on AhR.
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Affiliation(s)
- Derrick R Samuelson
- Department of Internal Medicine, Section of Pulmonary/Critical Care & Allergy/Immunology, Louisiana State University Health Sciences Center, New Orleans, LA, USA. .,Department of Internal Medicine, Division of Pulmonary, Critical Care, & Sleep, University of Nebraska Medical Center, Omaha, NE, USA.
| | - Min Gu
- Department of Internal Medicine, Section of Pulmonary/Critical Care & Allergy/Immunology, Louisiana State University Health Sciences Center, New Orleans, LA, USA
| | - Judd E Shellito
- Department of Internal Medicine, Section of Pulmonary/Critical Care & Allergy/Immunology, Louisiana State University Health Sciences Center, New Orleans, LA, USA.,Department of Microbiology, Immunology and Parasitology, Louisiana State University Health Sciences Center, New Orleans, LA, USA
| | - Patricia E Molina
- Department of Physiology, Louisiana State University Health Sciences Center, New Orleans, LA, USA
| | - Christopher M Taylor
- Department of Microbiology, Immunology and Parasitology, Louisiana State University Health Sciences Center, New Orleans, LA, USA
| | - Meng Luo
- Department of Microbiology, Immunology and Parasitology, Louisiana State University Health Sciences Center, New Orleans, LA, USA
| | - David A Welsh
- Department of Internal Medicine, Section of Pulmonary/Critical Care & Allergy/Immunology, Louisiana State University Health Sciences Center, New Orleans, LA, USA.,Department of Microbiology, Immunology and Parasitology, Louisiana State University Health Sciences Center, New Orleans, LA, USA
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Liu C, Hu B, Cheng Y, Guo Y, Yao W, Qian H. In-depth analysis of the mechanisms of aloe polysaccharides on mitigating subacute colitis in mice via microbiota informatics. Carbohydr Polym 2021; 265:118041. [PMID: 33966825 DOI: 10.1016/j.carbpol.2021.118041] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Accepted: 04/03/2021] [Indexed: 12/23/2022]
Abstract
Aloe polysaccharides (APs) are indigestible bioactive polysaccharides, while can be fermented by colonic microbiota. Although plant polysaccharides can alleviate subacute ulcerative colitis (SUC), the mechanisms APs regulated SUC via colonic microbiota have not been fully explored. Hence, to elucidate the complex interactions between the novel APs, colonic microbiota, SCFAs, and inflammation, the SUC mouse model and in-depth analysis were performed, including multiple bioinformatics analysis and structural equation modeling (SEM). After APs intervention, SCFAs and SCFAs-producing genus, including Akkermansia and Blautia, were increased in colon, and the colonic inflammation and barrier dysfunction were alleviated significantly in SUC mice. Spearman analysis found positive correlations between microbiota and SCFAs. PICRUSt2 and KEGG analysis revealed 6-pyruvoyltetra hydropterin synthase in folate biosynthesis metabolism pathway was activated, while phosphotransferase system was inhibited. SEM results further proved APs was beneficial to gut micro-ecological balance in mice via SCFAs metabolism and anti-inflammatory functions. Together, APs could be exploited to alleviate SUC as dietary therapeutics.
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Affiliation(s)
- Chang Liu
- State Key Laboratory of Food Science and Technology, Jiangnan University, No.1800 Lihu Avenue, Wuxi, Jiangsu Province, 214122, China; School of Food Science and Technology, Jiangnan University, No.1800 Lihu Avenue, Wuxi, Jiangsu Province, 214122, China; International Joint Laboratory on Food Safety, Jiangnan University, No.1800 Lihu Avenue, Wuxi, Jiangsu Province, 214122, China
| | - Bin Hu
- School of Biotechnology, Jiangnan University, Jiangnan University, No.1800 Lihu Avenue, Wuxi, Jiangsu Province, 214122, China
| | - Yuliang Cheng
- State Key Laboratory of Food Science and Technology, Jiangnan University, No.1800 Lihu Avenue, Wuxi, Jiangsu Province, 214122, China; School of Food Science and Technology, Jiangnan University, No.1800 Lihu Avenue, Wuxi, Jiangsu Province, 214122, China; International Joint Laboratory on Food Safety, Jiangnan University, No.1800 Lihu Avenue, Wuxi, Jiangsu Province, 214122, China
| | - Yahui Guo
- State Key Laboratory of Food Science and Technology, Jiangnan University, No.1800 Lihu Avenue, Wuxi, Jiangsu Province, 214122, China; School of Food Science and Technology, Jiangnan University, No.1800 Lihu Avenue, Wuxi, Jiangsu Province, 214122, China; International Joint Laboratory on Food Safety, Jiangnan University, No.1800 Lihu Avenue, Wuxi, Jiangsu Province, 214122, China
| | - Weirong Yao
- State Key Laboratory of Food Science and Technology, Jiangnan University, No.1800 Lihu Avenue, Wuxi, Jiangsu Province, 214122, China; School of Food Science and Technology, Jiangnan University, No.1800 Lihu Avenue, Wuxi, Jiangsu Province, 214122, China; International Joint Laboratory on Food Safety, Jiangnan University, No.1800 Lihu Avenue, Wuxi, Jiangsu Province, 214122, China
| | - He Qian
- State Key Laboratory of Food Science and Technology, Jiangnan University, No.1800 Lihu Avenue, Wuxi, Jiangsu Province, 214122, China; School of Food Science and Technology, Jiangnan University, No.1800 Lihu Avenue, Wuxi, Jiangsu Province, 214122, China; International Joint Laboratory on Food Safety, Jiangnan University, No.1800 Lihu Avenue, Wuxi, Jiangsu Province, 214122, China.
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Silva CBP, Elias-Oliveira J, McCarthy CG, Wenceslau CF, Carlos D, Tostes RC. Ethanol: striking the cardiovascular system by harming the gut microbiota. Am J Physiol Heart Circ Physiol 2021; 321:H275-H291. [PMID: 34142885 DOI: 10.1152/ajpheart.00225.2021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Ethanol consumption represents a significant public health problem, and excessive ethanol intake is a risk factor for cardiovascular disease (CVD), one of the leading causes of death and disability worldwide. The mechanisms underlying the effects of ethanol on the cardiovascular system are complex and not fully comprehended. The gut microbiota and their metabolites are indispensable symbionts essential for health and homeostasis and therefore, have emerged as potential contributors to ethanol-induced cardiovascular system dysfunction. By mechanisms that are not completely understood, the gut microbiota modulates the immune system and activates several signaling pathways that stimulate inflammatory responses, which in turn, contribute to the development and progression of CVD. This review summarizes preclinical and clinical evidence on the effects of ethanol in the gut microbiota and discusses the mechanisms by which ethanol-induced gut dysbiosis leads to the activation of the immune system and cardiovascular dysfunction. The cross talk between ethanol consumption and the gut microbiota and its implications are detailed. In summary, an imbalance in the symbiotic relationship between the host and the commensal microbiota in a holobiont, as seen with ethanol consumption, may contribute to CVD. Therefore, manipulating the gut microbiota, by using antibiotics, probiotics, prebiotics, and fecal microbiota transplantation might prove a valuable opportunity to prevent/mitigate the deleterious effects of ethanol and improve cardiovascular health and risk prevention.
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Affiliation(s)
- Carla B P Silva
- Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil.,Department of Biochemistry and Immunology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
| | - Jefferson Elias-Oliveira
- Department of Biochemistry and Immunology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
| | - Cameron G McCarthy
- Department of Physiology and Pharmacology, The University of Toledo College of Medicine and Life Sciences, Toledo, Ohio
| | - Camilla F Wenceslau
- Department of Physiology and Pharmacology, The University of Toledo College of Medicine and Life Sciences, Toledo, Ohio
| | - Daniela Carlos
- Department of Biochemistry and Immunology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
| | - Rita C Tostes
- Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
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