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Kreimeyer H, Llorente C, Schnabl B. Influence of Alcohol on the Intestinal Immune System. Alcohol Res 2025; 45:03. [PMID: 40151622 PMCID: PMC11913448 DOI: 10.35946/arcr.v45.1.03] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/29/2025] Open
Abstract
PURPOSE Alcohol misuse is associated with disruption of the microbial homeostasis (dysbiosis) and microbial overgrowth in the gut, gut barrier disruption, and translocation of microbes into the systemic circulation. It also induces changes in regulatory mechanisms of the gut, which is the largest peripheral immune organ. The gut-liver axis is important for health and disease, and alterations in the intestinal immune system contribute to alcohol-associated liver disease (ALD). Understanding these changes might help discover new targets for drugs and therapeutic approaches. SEARCH METHODS A systematic literature search was conducted in PubMed, Medline, and Embase of manuscripts published between January 2000 and November 2023 using the terms ("alcohol" or "ethanol") AND ("immune" or "immunol") AND ("intestine," "colon," or "gut"). Eligible manuscripts included studies and reviews that discussed the effects of ethanol on immune cells in the intestine. SEARCH RESULTS A total of 506 publications were found in the databases on November 20, 2023. After excluding duplicates and research not covering ALD (415 articles), 91 studies were reviewed. Also included were manuscripts covering specific immune cells in the context of ALD. DISCUSSION AND CONCLUSIONS Balancing immune tolerance vs. initiating an immune response challenges the intestinal immune system. Alcohol induces disruption of the intestinal barrier, which is accompanied by a thicker mucus layer and reduced anti-microbial peptides. This leads to longer attachment of bacteria to epithelial cells and consequently greater translocation into the circulation. Bacterial translocation activates the immune system, reducing the activity of regulatory T cells and inducing T helper 17 response via a variety of pathways. The role of innate immune cells, especially Type 3 innate lymphoid cells, and of specific B- and T-cell subsets in ALD remains elusive. Gut dysbiosis, translocation of viable bacteria and bacterial products into the circulation, and changes in the intestinal barrier have been linked to immune deficiency and infections in patients with cirrhosis. Modifying the intestinal immune system could reduce intestinal inflammation and alcohol-induced liver injury. Understanding the underlying pathophysiology can help to detect new targets for drugs and design therapeutic strategies.
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Affiliation(s)
- Henriette Kreimeyer
- Department of Medicine, University of California San Diego, La Jolla, California
| | - Cristina Llorente
- Department of Medicine, University of California San Diego, La Jolla, California
| | - Bernd Schnabl
- Department of Medicine, University of California San Diego, La Jolla, California
- Department of Medicine, U.S. Department of Veterans Affairs San Diego Healthcare System, San Diego, California
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Mak KM, Shekhar AC. Lipopolysaccharide, arbiter of the gut-liver axis, modulates hepatic cell pathophysiology in alcoholism. Anat Rec (Hoboken) 2025; 308:975-1004. [PMID: 39166429 DOI: 10.1002/ar.25562] [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: 04/22/2024] [Revised: 07/18/2024] [Accepted: 08/06/2024] [Indexed: 08/22/2024]
Abstract
Over the last four decades, clinical research and experimental studies have established that lipopolysaccharide (LPS)-a component of the outer membrane of gram-negative bacteria-is a potent hepatotoxic molecule in humans and animals. Alcohol abuse is commonly associated with LPS endotoxemia. This review highlights LPS molecular structures and modes of release from bacteria, plasma LPS concentrations, induction of microbiota dysbiosis, disruption of gut epithelial barrier, and translocation of LPS into the portal circulation impacting the pathophysiology of hepatic cells via the gut-liver axis. We describe and illustrate the portal vein circulation and its distributaries draining the gastrointestinal tract. We also elaborate on the gut-liver axis coupled with enterohepatic circulation that represents a bidirectional communication between the gut and liver. The review also updates the data on how circulating LPS is cleared in a coordinated effort between Kupffer cells, hepatocytes, and liver sinusoidal endothelial cells. Significantly, the article reviews and updates the modes/mechanisms of action by which LPS mediates the diverse pathophysiology of Kupffer cells, hepatocytes, sinusoidal endothelial cells, and hepatic stellate cells primarily in association with alcohol consumption. Specifically, we review the intricate linkages between ethanol, microbiota dysbiosis, LPS production, gut-liver axis, and pathophysiology of various hepatic cells. The maintenance of the gut barrier structural and functional integrity and microbiome homeostasis is essential in mitigating alcoholic liver disease and improving liver health.
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Affiliation(s)
- Ki M Mak
- Department of Medical Education, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Aditya C Shekhar
- Department of Medical Education, Icahn School of Medicine at Mount Sinai, New York, New York, USA
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3
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Yang W, Guo G, Sun C. Therapeutic potential of rifaximin in liver diseases. Biomed Pharmacother 2024; 178:117283. [PMID: 39126775 DOI: 10.1016/j.biopha.2024.117283] [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: 06/14/2024] [Revised: 08/05/2024] [Accepted: 08/08/2024] [Indexed: 08/12/2024] Open
Abstract
Rifaximin, derived from rifamycin, is a broad-spectrum antibiotic by inhibiting bacterial RNA synthesis. Rifaximin has a very low intestinal absorption and exerts its antimicrobial activity primarily in the intestinal tract. It regulates the gut microbiota with limited side effects systemically. Rifaximin has been recommended for the treatment of hepatic encephalopathy but some studies shed light on its medicinal effects in many other diseases. For instance, rifaximin may suppress the progression of liver fibrosis and its related complications, and ameliorate metabolic dysfunction-associated steatotic liver disease and alcohol-associated liver disease, etc. Rifaximin can also mediate anti-inflammation, antiproliferation, and proapoptotic events by activating pregnane X receptor, which is efficious in cancers such as colon cancer. In addition, some investigations have shown rifaximin may play a therapeutic role in various autoimmune and neurological disorders. However, these findings still need more real-world practices and in-depth investigations to obtain more precise indications and fully elucidate the multifaceted potentials of rifaximin.
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Affiliation(s)
- Wanting Yang
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin 300052, China; Department of Gastroenterology, Tianjin Medical University General Hospital Airport Hospital, East Street 6, Tianjin Airport Economic Area, Tianjin 300308, China
| | - Gaoyue Guo
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin 300052, China; Department of Gastroenterology, Tianjin Medical University General Hospital Airport Hospital, East Street 6, Tianjin Airport Economic Area, Tianjin 300308, China
| | - Chao Sun
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin 300052, China; Department of Gastroenterology, Tianjin Medical University General Hospital Airport Hospital, East Street 6, Tianjin Airport Economic Area, Tianjin 300308, China.
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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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Xia N, Ding Z, Dong M, Li S, Liu J, Xue H, Wang Z, Lu J, Chen X. Protective Effects of Lycium ruthenicum Murray against Acute Alcoholic Liver Disease in Mice via the Nrf2/HO-1/NF-κB Signaling Pathway. Pharmaceuticals (Basel) 2024; 17:497. [PMID: 38675458 PMCID: PMC11054480 DOI: 10.3390/ph17040497] [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: 03/15/2024] [Revised: 04/07/2024] [Accepted: 04/10/2024] [Indexed: 04/28/2024] Open
Abstract
Acute alcoholic liver disease (ALD) resulting from short-term heavy alcohol consumption has become a global health concern. Moreover, anthocyanins have attracted much attention for their ability to prevent oxidation and inflammation. The present work evaluates the protective effects of Lycium ruthenicum Murray (LRM) against ALD and explores the possible underlying mechanism involved. The total anthocyanin content in LRM was 43.64 ± 9.28 Pt g/100 g dry weight. Mice were orally administered 50, 125, or 375 mg LRM/kg body weight (BW) for 21 days. On days 18-21, mice were orally administered 15 mL of ethanol/kg BW. Markers of liver damage, oxidative stress, and inflammation were examined. Furthermore, the modulatory effect of LRM on Nrf2/HO-1/NF-κB pathway molecules was evaluated through quantitative reverse transcription polymerase chain reaction (RT‒qPCR) and immunohistochemistry analyses. The difference between the groups indicated that LRM improved liver histopathology and the liver index, decreased aspartate transaminase, alanine transaminase, malondialdehyde, reactive oxygen species, IL-6, TNF-α, and IL-1β expression, but elevated superoxide dismutase, catalase, and glutathione-s-transferase levels. Moreover, LRM upregulated Nrf2 and Ho-1 but downregulated Nf-κb and Tnf-α genes at the transcript level. In summary, LRM alleviated ethanol-induced ALD in mice by reducing oxidative damage and associated inflammatory responses. LRM protects against ALD by reducing damage factors and enhancing defense factors, especially via the Nrf2/HO-1/NF-κB pathway. Thus, LRM has application potential in ALD prophylaxis and treatment.
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Affiliation(s)
- Niantong Xia
- State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100193, China; (N.X.); (Z.D.); (M.D.); (S.L.); (J.L.); (H.X.)
- Department of Pharmaceutical Analysis, Heilongjiang University of Chinese Medicine, Harbin 150040, China;
| | - Zimian Ding
- State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100193, China; (N.X.); (Z.D.); (M.D.); (S.L.); (J.L.); (H.X.)
| | - Mingran Dong
- State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100193, China; (N.X.); (Z.D.); (M.D.); (S.L.); (J.L.); (H.X.)
| | - Shuyang Li
- State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100193, China; (N.X.); (Z.D.); (M.D.); (S.L.); (J.L.); (H.X.)
| | - Jia Liu
- State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100193, China; (N.X.); (Z.D.); (M.D.); (S.L.); (J.L.); (H.X.)
- Department of Pharmaceutical Analysis, Heilongjiang University of Chinese Medicine, Harbin 150040, China;
| | - Hongwei Xue
- State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100193, China; (N.X.); (Z.D.); (M.D.); (S.L.); (J.L.); (H.X.)
| | - Zhigang Wang
- Department of Pharmaceutical Analysis, Heilongjiang University of Chinese Medicine, Harbin 150040, China;
| | - Juan Lu
- State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100193, China; (N.X.); (Z.D.); (M.D.); (S.L.); (J.L.); (H.X.)
| | - Xi Chen
- State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100193, China; (N.X.); (Z.D.); (M.D.); (S.L.); (J.L.); (H.X.)
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Chen J, Yang W, Liu H, Niu J, Liu Y, Cheng Q. Protective effect of Macleaya cordata isoquinoline alkaloids on lipopolysaccharide-induced liver injury in broilers. Anim Biosci 2024; 37:131-141. [PMID: 37946426 PMCID: PMC10766460 DOI: 10.5713/ab.23.0267] [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: 07/14/2023] [Revised: 08/29/2023] [Accepted: 09/18/2023] [Indexed: 11/12/2023] Open
Abstract
OBJECTIVE This experiment aimed to explore the protective action of dietary supplementation with isoquinoline alkaloids (IA) from Macleaya cordata on lipopolysaccharide (LPS)-induced liver injury in broilers. METHODS Total 216 healthy broilers were selected in a 21-d trial and assigned randomly to the following 3 treatments: control (CON) group, LPS group, and LPS+IA group. The CON and LPS groups were provided with a basal diet, whereas the LPS+IA group received the basal diet supplemented with 0.6 mg/kg Macleaya cordata IA. Broilers in LPS and LPS+IA groups were intraperitoneally injected with LPS (1 mg/kg body weight) at 17, 19, and 21 days of age, while those in CON group were injected with equivalent amount of saline solution. RESULTS Results showed LPS injection caused systemic and liver inflammation in broilers, inhibited immune function, and ultimately lead to liver injury. By contrast, supplementation of IA ameliorated LPS-induced adverse change in serum parameters, boosted immunity in LPS+IA group. Furthermore, IA suppressed the elevation of hepatic inflammatory cytokines and caspases levels induced by LPS, as well as the expressions of genes related to the tolllike receptor 4 (TLR4)/myeloid differentiation primary response 88 (MyD88)/nuclear factorkappa B (NF-κB) pathway. CONCLUSION Dietary inclusion of 0.6 mg/kg Macleaya cordata IA could enhance immune function of body and inhibit liver damage via inactivating TLR4/MyD88/NF-κB signaling pathway in broilers.
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Affiliation(s)
- Jiaxin Chen
- Department of Animal Science, Qingdao Agricultural University, Qingdao 266109,
China
| | - Weiren Yang
- Key Laboratory of Efficient Utilization of Non-grain Feed Resources (Co-construction by Ministry and Province), Ministry of Agriculture and Rural Affairs, Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Department of Animal Science and Veterinary Medicine, Shandong Agricultural University, Tai’an 271018,
China
| | - Hua Liu
- College of Animal Science and Technology, Hunan Agriculture University, Changsha 410128,
China
| | - Jiaxing Niu
- Key Laboratory of Efficient Utilization of Non-grain Feed Resources (Co-construction by Ministry and Province), Ministry of Agriculture and Rural Affairs, Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Department of Animal Science and Veterinary Medicine, Shandong Agricultural University, Tai’an 271018,
China
| | - Yang Liu
- Key Laboratory of Efficient Utilization of Non-grain Feed Resources (Co-construction by Ministry and Province), Ministry of Agriculture and Rural Affairs, Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Department of Animal Science and Veterinary Medicine, Shandong Agricultural University, Tai’an 271018,
China
| | - Qun Cheng
- Department of Animal Science, Qingdao Agricultural University, Qingdao 266109,
China
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Sato S, Nakaji S, Sawada K, Akimoto N, Tateda T, Kaizuka M, Sasada T, Nomiya H, Igarashi G, Iino C, Chinda D, Mikami T, Sakuraba H, Fukuda S. Association between reactive oxygen species production in neutrophils and liver fibrosis in the general population. J Clin Biochem Nutr 2023; 73:214-220. [PMID: 37970548 PMCID: PMC10636577 DOI: 10.3164/jcbn.23-46] [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: 06/19/2023] [Accepted: 07/22/2023] [Indexed: 11/17/2023] Open
Abstract
Fibrosis, induced by reactive oxygen species (ROS) production in neutrophils, has harmful effects on the liver and various other organs. However, little is known about the association between liver fibrosis and ROS levels in neutrophils in the general population. This large-scale epidemiological study aimed to determine the association between liver fibrosis and neutrophil-generated ROS levels according to age and sex in the general population. This cross-sectional study included 1,000 participants from a district health promotion project. Participants were grouped based on sex (male; female) and age (young, <65 years; old, ≥65 years). The four groups were as follows: male, young (n = 289); male, old (n = 100); female, young (n = 425); and female, old (n = 186). Liver fibrosis was assessed using the fibrosis 4 (FIB-4) index, aspartate aminotransferase-to-platelet ratio index (APRI), and non-alcoholic fatty liver disease (NAFLD) fibrosis score (NFS). Basal and stimulated ROS were considered in the analysis. Multiple linear analyses showed (1) significant positive correlations between all liver fibrosis scores and basal ROS in the young groups, and (2) significant negative correlations between NFS and stimulated ROS in females. Preventing liver fibrosis through neutrophil-related immune system enhancement may avert the development of lifestyle-related diseases and infections.
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Affiliation(s)
- Satoshi Sato
- Department of Gastroenterology and Hematology, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori 036-8562, Japan
| | - Shigeyuki Nakaji
- Center of Healthy Aging Innovation, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori 036-8562, Japan
| | - Kaori Sawada
- Center of Healthy Aging Innovation, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori 036-8562, Japan
| | - Naoki Akimoto
- Department of Gastroenterology and Hematology, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori 036-8562, Japan
| | - Tetsuyuki Tateda
- Department of Gastroenterology and Hematology, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori 036-8562, Japan
| | - Masatoshi Kaizuka
- Department of Gastroenterology and Hematology, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori 036-8562, Japan
| | - Takafumi Sasada
- Department of Gastroenterology and Hematology, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori 036-8562, Japan
| | - Hiroki Nomiya
- Department of Gastroenterology and Hematology, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori 036-8562, Japan
| | - Go Igarashi
- Department of Gastroenterology and Hematology, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori 036-8562, Japan
| | - Chikara Iino
- Department of Gastroenterology and Hematology, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori 036-8562, Japan
| | - Daisuke Chinda
- Department of Gastroenterology and Hematology, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori 036-8562, Japan
| | - Tatsuya Mikami
- Center of Healthy Aging Innovation, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori 036-8562, Japan
| | - Hirotake Sakuraba
- Department of Gastroenterology and Hematology, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori 036-8562, Japan
| | - Shinsaku Fukuda
- Department of Gastroenterology and Hematology, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori 036-8562, Japan
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Safari F, Sharifi M, Talebi A, Mehranfard N, Ghasemi M. Alleviation of cholestatic liver injury and intestinal permeability by lubiprostone treatment in bile duct ligated rats: role of intestinal FXR and tight junction proteins claudin-1, claudin-2, and occludin. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2023; 396:2009-2022. [PMID: 36897372 DOI: 10.1007/s00210-023-02455-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Accepted: 02/28/2023] [Indexed: 03/11/2023]
Abstract
Gut barrier disintegrity and endotoxin translocation to the liver and systemic circulation are serious clinical complications associated with the stoppage of intestinal bile flow. There is no precise pharmacological option to prevent increased intestinal permeability after bile duct ligation (BDL). Lubiprostone, a chloride channel-2 agonist, has been shown to accelerate restoration of epithelial barrier dysfunction caused by injury, but the exact mechanisms underlying the beneficial effects of lubiprostone on intestine barrier integrity remain unknown. Here, we assessed the beneficial effect of lubiprostone on cholestasis caused by BDL and relevant mechanisms. Male rats were subjected to BDL for 21 days. Seven days after BDL induction, lubiprostone was administered twice daily (10 µg/kg of body weight). Intestinal permeability was assessed through measurements of serum lipopolysaccharide (LPS) concentration. Real-time PCR was conducted to assess expression of intestinal claudin-1 occludin and FXR genes, which are important in preserving the intestinal epithelial barrier integrity, as well as claudin-2 being involved in a leaky gut barrier. Histopathological alterations were also monitored for liver injury. Lubiprostone significantly decreased BDL-induced systemic LPS elevation in rats. BDL induced a significant reduction in FXR, occludin, and claudin-1 genes expression, while increased claudin-2 expression in rat colon. Treatment with lubiprostone significantly restored expression of these genes to the control values. BDL also increased the level of hepatic enzymes ALT, ALP, AST, and total bilirubin, while lubiprostone could preserve the hepatic enzymes and total bilirubin in the treated BDL rats. Lubiprostone also caused a significant reduction in BDL-induced liver fibrosis and intestinal damage in rats. Our results suggest that lubiprostone favorably prevents BDL-induced alterations in intestinal epithelial barrier integrity possibly via modulating intestinal FXRs and tight junction gene expression.
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Affiliation(s)
- Fereydoon Safari
- Department of Physiology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mohammadreza Sharifi
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Ardeshir Talebi
- Department of Pathology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Nasrin Mehranfard
- Neurophysiology Research Center, Cellular and Molecular Medicine Research Institute, Urmia University of Medical Sciences, Urmia, Iran
| | - Maedeh Ghasemi
- Department of Physiology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.
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Sato S, Iino C, Chinda D, Sasada T, Tateda T, Kaizuka M, Nomiya H, Igarashi G, Sawada K, Mikami T, Nakaji S, Sakuraba H, Fukuda S. Effect of Liver Fibrosis on Oral and Gut Microbiota in the Japanese General Population Determined by Evaluating the FibroScan-Aspartate Aminotransferase Score. Int J Mol Sci 2023; 24:13470. [PMID: 37686272 PMCID: PMC10487682 DOI: 10.3390/ijms241713470] [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: 07/26/2023] [Revised: 08/18/2023] [Accepted: 08/28/2023] [Indexed: 09/10/2023] Open
Abstract
The association between liver fibrosis and oral or gut microbiota has been studied before. However, epidemiological studies in the general population are limited owing to the difficulty of noninvasive liver-fibrosis assessment. FibroScan-asparate aminotransferase (FAST) scores can be used to accurately and non-invasively evaluate liver fibrosis. This study aimed to determine the association between liver fibrosis and oral or gut microbiota using the FAST score in the general population. After propensity score matching of 1059 participants based on sex, age, body mass index, homeostasis model assessment of insulin resistance, and triglyceride levels, 125 (non-liver-fibrosis group, 100; liver fibrosis group, 25) were included. The diversity of gut microbiota differed significantly between the two groups; however, no significant differences were noted in their oral microbiota. The liver fibrosis group showed an increase in the relative abundance of Fusobacteria strains and a decrease in the relative abundance of Faecalibacterium, with the presence of Fusicatenibacter in the gut microbiota. Feacalibacterium was not identified as an independent factor of liver fibrosis in adjusting the fatty liver index. In the general population, gut microbiota may be more involved in liver fibrosis than oral microbiota.
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Affiliation(s)
- Satoshi Sato
- Department of Gastroenterology and Hematology, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan; (S.S.); (T.S.); (T.T.); (M.K.); (H.N.); (G.I.); (H.S.); (S.F.)
| | - Chikara Iino
- Department of Gastroenterology and Hematology, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan; (S.S.); (T.S.); (T.T.); (M.K.); (H.N.); (G.I.); (H.S.); (S.F.)
| | - Daisuke Chinda
- Division of Endoscopy, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan
| | - Takafumi Sasada
- Department of Gastroenterology and Hematology, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan; (S.S.); (T.S.); (T.T.); (M.K.); (H.N.); (G.I.); (H.S.); (S.F.)
| | - Tetsuyuki Tateda
- Department of Gastroenterology and Hematology, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan; (S.S.); (T.S.); (T.T.); (M.K.); (H.N.); (G.I.); (H.S.); (S.F.)
| | - Masatoshi Kaizuka
- Department of Gastroenterology and Hematology, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan; (S.S.); (T.S.); (T.T.); (M.K.); (H.N.); (G.I.); (H.S.); (S.F.)
| | - Hiroki Nomiya
- Department of Gastroenterology and Hematology, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan; (S.S.); (T.S.); (T.T.); (M.K.); (H.N.); (G.I.); (H.S.); (S.F.)
| | - Go Igarashi
- Department of Gastroenterology and Hematology, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan; (S.S.); (T.S.); (T.T.); (M.K.); (H.N.); (G.I.); (H.S.); (S.F.)
| | - Kaori Sawada
- Department of Preemptive Medicine, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan; (K.S.); (T.M.)
| | - Tatsuya Mikami
- Department of Preemptive Medicine, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan; (K.S.); (T.M.)
| | - Shigeyuki Nakaji
- Center of Healthy Aging Innovation, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan;
| | - Hirotake Sakuraba
- Department of Gastroenterology and Hematology, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan; (S.S.); (T.S.); (T.T.); (M.K.); (H.N.); (G.I.); (H.S.); (S.F.)
| | - Shinsaku Fukuda
- Department of Gastroenterology and Hematology, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan; (S.S.); (T.S.); (T.T.); (M.K.); (H.N.); (G.I.); (H.S.); (S.F.)
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10
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Louvet A, Labreuche J, Dao T, Thévenot T, Oberti F, Bureau C, Paupard T, Nguyen-Khac E, Minello A, Bernard-Chabert B, Anty R, Wartel F, Carbonell N, Pageaux GP, Hilleret MN, Moirand R, Nahon P, Potey C, Duhamel A, Mathurin P. Effect of Prophylactic Antibiotics on Mortality in Severe Alcohol-Related Hepatitis: A Randomized Clinical Trial. JAMA 2023; 329:1558-1566. [PMID: 37159035 PMCID: PMC10170332 DOI: 10.1001/jama.2023.4902] [Citation(s) in RCA: 28] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Accepted: 03/14/2023] [Indexed: 05/10/2023]
Abstract
Importance The benefits of prophylactic antibiotics for hospitalized patients with severe alcohol-related hepatitis are unclear. Objective To determine the efficacy of amoxicillin-clavulanate, compared with placebo, on mortality in patients hospitalized with severe alcohol-related hepatitis and treated with prednisolone. Design, Setting, and Participants Multicenter, randomized, double-blind clinical trial among patients with biopsy-proven severe alcohol-related hepatitis (Maddrey function score ≥32 and Model for End-stage Liver Disease [MELD] score ≥21) from June 13, 2015, to May 24, 2019, in 25 centers in France and Belgium. All patients were followed up for 180 days. Final follow-up occurred on November 19, 2019. Intervention Patients were randomly assigned (1:1 allocation) to receive prednisolone combined with amoxicillin-clavulanate (n = 145) or prednisolone combined with placebo (n = 147). Main Outcome and Measures The primary outcome was all-cause mortality at 60 days. Secondary outcomes were all-cause mortality at 90 and 180 days; incidence of infection, incidence of hepatorenal syndrome, and proportion of participants with a MELD score less than 17 at 60 days; and proportion of patients with a Lille score less than 0.45 at 7 days. Results Among 292 randomized patients (mean age, 52.8 [SD, 9.2] years; 80 [27.4%] women) 284 (97%) were analyzed. There was no significant difference in 60-day mortality between participants randomized to amoxicillin-clavulanate and those randomized to placebo (17.3% in the amoxicillin-clavulanate group and 21.3% in the placebo group [P = .33]; between-group difference, -4.7% [95% CI, -14.0% to 4.7%]; hazard ratio, 0.77 [95% CI, 0.45-1.31]). Infection rates at 60 days were significantly lower in the amoxicillin-clavulanate group (29.7% vs 41.5%; mean difference, -11.8% [95% CI, -23.0% to -0.7%]; subhazard ratio, 0.62; [95% CI, 0.41-0.91]; P = .02). There were no significant differences in any of the remaining 3 secondary outcomes. The most common serious adverse events were related to liver failure (25 in the amoxicillin-clavulanate group and 20 in the placebo group), infections (23 in the amoxicillin-clavulanate group and 46 in the placebo group), and gastrointestinal disorders (15 in the amoxicillin-clavulanate group and 21 in the placebo group). Conclusion and Relevance In patients hospitalized with severe alcohol-related hepatitis, amoxicillin-clavulanate combined with prednisolone did not improve 2-month survival compared with prednisolone alone. These results do not support prophylactic antibiotics to improve survival in patients hospitalized with severe alcohol-related hepatitis. Trial Registration ClinicalTrials.gov Identifier: NCT02281929.
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Affiliation(s)
- Alexandre Louvet
- Université Lille, CHU de Lille, Service des maladies de l’appareil digestif, Hôpital Huriez, INFINITE–U1286, Lille, France
| | | | - Thong Dao
- Service d’hépato-gastroentérologie, CHU de Caen, Caen, France
| | - Thierry Thévenot
- Service d’hépatologie, Hôpital Jean-Minjoz, CHU de Besançon, Besançon, France
| | - Frédéric Oberti
- Service d’hépato-gastroentérologie, CHU d’Angers, Angers, France
| | | | - Thierry Paupard
- Service d’hépato-gastroentérologie, Hôpital de Dunkerque, Dunkerque, France
| | - Eric Nguyen-Khac
- Service d’hépato-gastroentérologie, CHU d’Amiens, Amiens, France
| | - Anne Minello
- Service d’hépato-gastroentérologie, CHU de Dijon, Dijon, France
| | | | - Rodolphe Anty
- Service d’hépato-gastroentérologie, CHU de Nice, Nice, France
| | - Faustine Wartel
- Service d’hépato-gastroentérologie, Hôpital de Valenciennes, Valenciennes, France
| | | | | | | | - Romain Moirand
- Service des maladies du foie, Hôpital Pontchaillou, Rennes, Rennes, France
| | - Pierre Nahon
- Service d’hépato-gastroentérologie, Hôpital Jean-Verdier, Bondy, France
| | - Camille Potey
- Unité de pharmacovigilance, CHU de Lille, Lille, France
| | - Alain Duhamel
- Unité de biostatistiques, CHU de Lille, Lille, France
| | - Philippe Mathurin
- Université Lille, CHU de Lille, Service des maladies de l’appareil digestif, Hôpital Huriez, INFINITE–U1286, Lille, France
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11
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Rodríguez-Zapata M, Galán-Llario M, Cañeque-Rufo H, Sevillano J, Sánchez-Alonso MG, Zapico JM, Ferrer-Alcón M, Uribarri M, Pascual-Teresa BD, Ramos-Álvarez MDP, Herradón G, Pérez-García C, Gramage E. Implication of the PTN/RPTPβ/ζ Signaling Pathway in Acute Ethanol Neuroinflammation in Both Sexes: A Comparative Study with LPS. Biomedicines 2023; 11:biomedicines11051318. [PMID: 37238989 DOI: 10.3390/biomedicines11051318] [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: 12/31/2022] [Revised: 03/16/2023] [Accepted: 04/26/2023] [Indexed: 05/28/2023] Open
Abstract
Binge drinking during adolescence increases the risk of alcohol use disorder, possibly by involving alterations of neuroimmune responses. Pleiotrophin (PTN) is a cytokine that inhibits Receptor Protein Tyrosine Phosphatase (RPTP) β/ζ. PTN and MY10, an RPTPβ/ζ pharmacological inhibitor, modulate ethanol behavioral and microglial responses in adult mice. Now, to study the contribution of endogenous PTN and the implication of its receptor RPTPβ/ζ in the neuroinflammatory response in the prefrontal cortex (PFC) after acute ethanol exposure in adolescence, we used MY10 (60 mg/kg) treatment and mice with transgenic PTN overexpression in the brain. Cytokine levels by X-MAP technology and gene expression of neuroinflammatory markers were determined 18 h after ethanol administration (6 g/kg) and compared with determinations performed 18 h after LPS administration (5 g/kg). Our data indicate that Ccl2, Il6, and Tnfa play important roles as mediators of PTN modulatory actions on the effects of ethanol in the adolescent PFC. The data suggest PTN and RPTPβ/ζ as targets to differentially modulate neuroinflammation in different contexts. In this regard, we identified for the first time important sex differences that affect the ability of the PTN/RPTPβ/ζ signaling pathway to modulate ethanol and LPS actions in the adolescent mouse brain.
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Affiliation(s)
- María Rodríguez-Zapata
- Departamento de Ciencias Farmacéuticas y de la Salud, Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Urbanización Montepríncipe, Boadilla del Monte, 28660 Madrid, Spain
| | - Milagros Galán-Llario
- Departamento de Ciencias Farmacéuticas y de la Salud, Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Urbanización Montepríncipe, Boadilla del Monte, 28660 Madrid, Spain
| | - Héctor Cañeque-Rufo
- Departamento de Ciencias Farmacéuticas y de la Salud, Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Urbanización Montepríncipe, Boadilla del Monte, 28660 Madrid, Spain
- Departamento de Química y Bioquímica, Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Urbanización Montepríncipe, Boadilla del Monte, 28660 Madrid, Spain
| | - Julio Sevillano
- Departamento de Química y Bioquímica, Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Urbanización Montepríncipe, Boadilla del Monte, 28660 Madrid, Spain
| | - María Gracia Sánchez-Alonso
- Departamento de Química y Bioquímica, Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Urbanización Montepríncipe, Boadilla del Monte, 28660 Madrid, Spain
| | - José M Zapico
- Departamento de Química y Bioquímica, Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Urbanización Montepríncipe, Boadilla del Monte, 28660 Madrid, Spain
| | - Marcel Ferrer-Alcón
- BRAINco Biopharma, S.L., Bizkaia Technology Park, Zamudio, 48170 Vizcaya, Spain
| | - María Uribarri
- BRAINco Biopharma, S.L., Bizkaia Technology Park, Zamudio, 48170 Vizcaya, Spain
| | - Beatriz de Pascual-Teresa
- Departamento de Química y Bioquímica, Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Urbanización Montepríncipe, Boadilla del Monte, 28660 Madrid, Spain
| | - María Del Pilar Ramos-Álvarez
- Departamento de Química y Bioquímica, Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Urbanización Montepríncipe, Boadilla del Monte, 28660 Madrid, Spain
| | - Gonzalo Herradón
- Departamento de Ciencias Farmacéuticas y de la Salud, Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Urbanización Montepríncipe, Boadilla del Monte, 28660 Madrid, Spain
- Instituto de Estudios de las Adicciones, Universidad San Pablo-CEU, CEU Universities, Urbanización Montepríncipe, Boadilla del Monte, 28660 Madrid, Spain
| | - Carmen Pérez-García
- Departamento de Ciencias Farmacéuticas y de la Salud, Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Urbanización Montepríncipe, Boadilla del Monte, 28660 Madrid, Spain
- Instituto de Estudios de las Adicciones, Universidad San Pablo-CEU, CEU Universities, Urbanización Montepríncipe, Boadilla del Monte, 28660 Madrid, Spain
| | - Esther Gramage
- Departamento de Ciencias Farmacéuticas y de la Salud, Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Urbanización Montepríncipe, Boadilla del Monte, 28660 Madrid, Spain
- Instituto de Estudios de las Adicciones, Universidad San Pablo-CEU, CEU Universities, Urbanización Montepríncipe, Boadilla del Monte, 28660 Madrid, Spain
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12
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Wickramasinghe PB, Qian S, Langley LE, Liu C, Jia L. Hepatocyte Toll-Like Receptor 4 Mediates Alcohol-Induced Insulin Resistance in Mice. Biomolecules 2023; 13:454. [PMID: 36979389 PMCID: PMC10046504 DOI: 10.3390/biom13030454] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Revised: 02/20/2023] [Accepted: 02/25/2023] [Indexed: 03/06/2023] Open
Abstract
Accumulating evidence has demonstrated the association between alcohol overconsumption and the development of insulin resistance. However, the underlying mechanisms are not completely understood. To investigate the requirement and sufficiency of hepatocyte toll-like receptor 4 (TLR4) in alcohol-induced insulin resistance, we used two mouse models (Tlr4fl/fl and Tlr4LoxTB) that allow ablation of TLR4 only in hepatocytes (Tlr4LKO) and restoration of endogenous TLR4 expression in hepatocytes on a TLR4-null background (Tlr4LoxTB × Alb-Cre), respectively. A Lieber-DeCarli feeding model was used to induce glucose intolerance and insulin resistance in mice. Glucose tolerance test, insulin tolerance test, and insulin signaling experiments were performed to examine systemic and tissue-specific insulin sensitivity. We found that alcohol-fed hepatocyte TLR4 deficient mice (Tlr4LKO) had lower blood glucose levels in response to intraperitoneal injection of insulin. Moreover, increased phosphorylation of glycogen synthase kinase-3β (GSK3β) was observed in the liver of Tlr4LKO mice after chronic alcohol intake. In contrast, when hepatic TLR4 was reactivated in mice (Tlr4LoxTB × Alb-Cre), alcohol feeding caused glucose intolerance in these mice compared with littermate controls (Tlr4LoxTB). In addition, AKT phosphorylation was dramatically reduced in the liver and epididymal white adipose tissue (eWAT) of alcohol-fed Tlr4LoxTB × Alb-Cre mice, which was similar to that of mice with whole-body TLR4 reactivation (Tlr4LoxTB × Zp3-Cre). Collectively, these findings suggest that hepatocyte TLR4 is both required and sufficient in the development of insulin resistance induced by alcohol overconsumption.
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Affiliation(s)
- Piumi B. Wickramasinghe
- Department of Biological Sciences, The University of Texas at Dallas, Richardson, TX 75080, USA
| | - Shuwen Qian
- Center for Hypothalamic Research, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Lyndsey E. Langley
- Department of Biological Sciences, The University of Texas at Dallas, Richardson, TX 75080, USA
| | - Chen Liu
- Center for Hypothalamic Research, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Lin Jia
- Department of Biological Sciences, The University of Texas at Dallas, Richardson, TX 75080, USA
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13
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Wang Z, Wang X, Wang Y, Liu Y, Wang X, Song Y, Xu J, Xue C. Lipidomics approach in alcoholic liver disease mice with sphingolipid metabolism disorder: Alleviation using sea cucumber phospholipids. FOOD BIOSCI 2023. [DOI: 10.1016/j.fbio.2023.102601] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/31/2023]
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14
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Zhang J, Zao X, Zhang J, Guo Z, Jin Q, Chen G, Gan D, Du H, Ye Y. Is it possible to intervene early cirrhosis by targeting toll-like receptors to rebalance the intestinal microbiome? Int Immunopharmacol 2023; 115:109627. [PMID: 36577151 DOI: 10.1016/j.intimp.2022.109627] [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: 11/01/2022] [Revised: 12/13/2022] [Accepted: 12/19/2022] [Indexed: 12/27/2022]
Abstract
Cirrhosis is a progressive chronic liver disease caused by one or more causes and characterized by diffuse fibrosis, pseudolobules, and regenerated nodules. Once progression to hepatic decompensation, the function of the liver and other organs is impaired and almost impossible to reverse and recover, which often results in hospitalization, impaired quality of life, and high mortality. However, in the early stage of cirrhosis, there seems to be a possibility of cirrhosis reversal. The development of cirrhosis is related to the intestinal microbiota and activation of toll-like receptors (TLRs) pathways, which could regulate cell proliferation, apoptosis, expression of the hepatomitogen epiregulin, and liver inflammation. Targeting regulation of intestinal microbiota and TLRs pathways could affect the occurrence and development of cirrhosis and its complications. In this paper, we first reviewed the dynamic change of intestinal microbiota and TLRs during cirrhosis progression. And further discussed the interaction between them and potential therapeutic targets to reverse early staged cirrhosis.
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Affiliation(s)
- Jiaxin Zhang
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China; Institute of Liver Diseases, Beijing University of Chinese Medicine, Beijing, China
| | - Xiaobin Zao
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China; Institute of Liver Diseases, Beijing University of Chinese Medicine, Beijing, China
| | - Jiaying Zhang
- School of Mechanical Engineering and Automation, Beihang University, Beijing, China
| | - Ziwei Guo
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Qian Jin
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Guang Chen
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China; Institute of Liver Diseases, Beijing University of Chinese Medicine, Beijing, China
| | - Da'nan Gan
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China; Institute of Liver Diseases, Beijing University of Chinese Medicine, Beijing, China
| | - Hongbo Du
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China; Institute of Liver Diseases, Beijing University of Chinese Medicine, Beijing, China
| | - Yong'an Ye
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China; Institute of Liver Diseases, Beijing University of Chinese Medicine, Beijing, China.
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15
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Saifi S, Swaminathan A, Devi P, Chattopadhyay P, Gupta S, Garg A, Saxena S, Parveen S, Pandey R. A Tour-d’Horizon of microbiota therapeutics for metabolic disorders. MICROBIOME THERAPEUTICS 2023:231-253. [DOI: 10.1016/b978-0-323-99336-4.00006-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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16
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Osna NA, Rasineni K, Ganesan M, Donohue TM, Kharbanda KK. Pathogenesis of Alcohol-Associated Liver Disease. J Clin Exp Hepatol 2022; 12:1492-1513. [PMID: 36340300 PMCID: PMC9630031 DOI: 10.1016/j.jceh.2022.05.004] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Accepted: 05/25/2022] [Indexed: 12/12/2022] Open
Abstract
Excessive alcohol consumption is a global healthcare problem with enormous social, economic, and clinical consequences. While chronic, heavy alcohol consumption causes structural damage and/or disrupts normal organ function in virtually every tissue of the body, the liver sustains the greatest damage. This is primarily because the liver is the first to see alcohol absorbed from the gastrointestinal tract via the portal circulation and second, because the liver is the principal site of ethanol metabolism. Alcohol-induced damage remains one of the most prevalent disorders of the liver and a leading cause of death or transplantation from liver disease. Despite extensive research on the pathophysiology of this disease, there are still no targeted therapies available. Given the multifactorial mechanisms for alcohol-associated liver disease pathogenesis, it is conceivable that a multitherapeutic regimen is needed to treat different stages in the spectrum of this disease.
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Key Words
- AA, Arachidonic acid
- ADH, Alcohol dehydrogenase
- AH, Alcoholic hepatitis
- ALD, Alcohol-associated liver disease
- ALDH, Aldehyde dehydrogenase
- ALT, Alanine transaminase
- ASH, Alcohol-associated steatohepatitis
- AST, Aspartate transaminase
- AUD, Alcohol use disorder
- BHMT, Betaine-homocysteine-methyltransferase
- CD, Cluster of differentiation
- COX, Cycloxygenase
- CTLs, Cytotoxic T-lymphocytes
- CYP, Cytochrome P450
- CYP2E1, Cytochrome P450 2E1
- Cu/Zn SOD, Copper/zinc superoxide dismutase
- DAMPs, Damage-associated molecular patterns
- DC, Dendritic cells
- EDN1, Endothelin 1
- ER, Endoplasmic reticulum
- ETOH, Ethanol
- EVs, Extracellular vesicles
- FABP4, Fatty acid-binding protein 4
- FAF2, Fas-associated factor family member 2
- FMT, Fecal microbiota transplant
- Fn14, Fibroblast growth factor-inducible 14
- GHS-R1a, Growth hormone secretagogue receptor type 1a
- GI, GOsteopontinastrointestinal tract
- GSH Px, Glutathione peroxidase
- GSSG Rdx, Glutathione reductase
- GST, Glutathione-S-transferase
- GWAS, Genome-wide association studies
- H2O2, Hydrogen peroxide
- HA, Hyaluronan
- HCC, Hepatocellular carcinoma
- HNE, 4-hydroxynonenal
- HPMA, 3-hydroxypropylmercapturic acid
- HSC, Hepatic stellate cells
- HSD17B13, 17 beta hydroxy steroid dehydrogenase 13
- HSP 90, Heat shock protein 90
- IFN, Interferon
- IL, Interleukin
- IRF3, Interferon regulatory factor 3
- JAK, Janus kinase
- KC, Kupffer cells
- LCN2, Lipocalin 2
- M-D, Mallory–Denk
- MAA, Malondialdehyde-acetaldehyde protein adducts
- MAT, Methionine adenosyltransferase
- MCP, Macrophage chemotactic protein
- MDA, Malondialdehyde
- MIF, Macrophage migration inhibitory factor
- Mn SOD, Manganese superoxide dismutase
- Mt, Mitochondrial
- NK, Natural killer
- NKT, Natural killer T-lymphocytes
- OPN, Osteopontin
- PAMP, Pathogen-associated molecular patterns
- PNPLA3, Patatin-like phospholipase domain containing 3
- PUFA, Polyunsaturated fatty acid
- RIG1, Retinoic acid inducible gene 1
- SAH, S-adenosylhomocysteine
- SAM, S-adenosylmethionine
- SCD, Stearoyl-CoA desaturase
- STAT, Signal transduction and activator of transcription
- TIMP1, Tissue inhibitor matrix metalloproteinase 1
- TLR, Toll-like receptor
- TNF, Tumor necrosis factor-α
- alcohol
- alcohol-associated liver disease
- ethanol metabolism
- liver
- miRNA, MicroRNA
- p90RSK, 90 kDa ribosomal S6 kinase
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Affiliation(s)
- Natalia A. Osna
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE, 68105, USA
- Department of Internal Medicine, Omaha, NE, 68198, USA
| | - Karuna Rasineni
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE, 68105, USA
- Department of Internal Medicine, Omaha, NE, 68198, USA
| | - Murali Ganesan
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE, 68105, USA
- Department of Internal Medicine, Omaha, NE, 68198, USA
| | - Terrence M. Donohue
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE, 68105, USA
- Department of Internal Medicine, Omaha, NE, 68198, USA
- Department of Biochemistry & Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Kusum K. Kharbanda
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE, 68105, USA
- Department of Internal Medicine, Omaha, NE, 68198, USA
- Department of Biochemistry & Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
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17
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Philips CA, Schnabl B, Bajaj JS. Gut Microbiome and Alcohol-associated Liver Disease. J Clin Exp Hepatol 2022; 12:1349-1359. [PMID: 36157139 PMCID: PMC9499847 DOI: 10.1016/j.jceh.2021.12.016] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Accepted: 12/28/2021] [Indexed: 02/07/2023] Open
Abstract
Changes in gut microbiota (GM) may be associated with the causation and progression of multiple liver diseases such as metabolic-associated liver disease, alcohol-associated liver disease (ALD), alcohol-associated hepatitis (AH), primary biliary cholangitis, primary sclerosing cholangitis, autoimmune liver disease, and most importantly, complications of cirrhosis and portal hypertension such as hepatic encephalopathy (HE), infection, and hepatocellular carcinoma. ALD includes simple steatosis, steatohepatitis, AH, cirrhosis, and acute-on-chronic liver failure. Alcohol consumption is associated with GM changes even before ALD development, and continued alcohol intake results in progressive dysbiosis and development of clinical events such as AH, infection, and HE. The composition and function of GM, specific changes in bacterial communities, and the functional metabolism of GM are affected in the spectrum of ALD, as revealed using high-throughput sequencing. It was reported in preliminary studies that modulation of disrupted GM improves adverse clinical events and ameliorates disease progression in ALD. In this review, we exhaustively discuss the preclinical and clinical studies on GM in ALD and critically discuss GM modulation and its effects based on various human and animal models of ALD.
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Key Words
- ACLF
- ACLF, acute on chronic liver failure
- AH, alcohol-associated hepatitis
- ALD
- ALD, alcohol-associated liver disease
- AUD, alcohol use disorder
- FMT
- FMT, fecal microbiota transplantation
- GM, gut microbiota
- HE, hepatic encephalopathy
- IL, interleukin
- MAFLD, metabolic-associated fatty liver disease
- SCFA, short chain fatty acids
- cirrhosis
- microbiome
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Affiliation(s)
- Cyriac A. Philips
- Department of Clinical and Translational Hepatology and The Monarch Liver Laboratory, The Liver Institute, Center for Excellence in Gastrointestinal Sciences, Rajagiri Hospital, Aluva, Kerala, India
| | - Bernd Schnabl
- Department of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Jasmohan S. Bajaj
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Internal Medicine, Virginia Commonwealth University and Central Virginia Veterans Healthcare System, Richmond, VA, USA
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18
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Microbiome-Based Metabolic Therapeutic Approaches in Alcoholic Liver Disease. Int J Mol Sci 2022; 23:ijms23158749. [PMID: 35955885 PMCID: PMC9368757 DOI: 10.3390/ijms23158749] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Revised: 07/21/2022] [Accepted: 08/03/2022] [Indexed: 11/21/2022] Open
Abstract
Alcohol consumption is a global healthcare problem. Chronic alcohol consumption generates a wide spectrum of hepatic lesions, the most characteristic of which are steatosis, hepatitis, fibrosis, and cirrhosis. Alcoholic liver diseases (ALD) refer to liver damage and metabolomic changes caused by excessive alcohol intake. ALD present several clinical stages of severity found in liver metabolisms. With increased alcohol consumption, the gut microbiome promotes a leaky gut, metabolic dysfunction, oxidative stress, liver inflammation, and hepatocellular injury. Much attention has focused on ALD, such as alcoholic fatty liver (AFL), alcoholic steatohepatitis (ASH), alcoholic cirrhosis (AC), hepatocellular carcinoma (HCC), a partnership that reflects the metabolomic significance. Here, we report on the global function of inflammation, inhibition, oxidative stress, and reactive oxygen species (ROS) mechanisms in the liver biology framework. In this tutorial review, we hypothetically revisit therapeutic gut microbiota-derived alcoholic oxidative stress, liver inflammation, inflammatory cytokines, and metabolic regulation. We summarize the perspective of microbial therapy of genes, gut microbes, and metabolic role in ALD. The end stage is liver transplantation or death. This review may inspire a summary of the gut microbial genes, critical inflammatory molecules, oxidative stress, and metabolic routes, which will offer future promising therapeutic compounds in ALD.
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19
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Spanu D, Pretta A, Lai E, Persano M, Donisi C, Mariani S, Dubois M, Migliari M, Saba G, Ziranu P, Pusceddu V, Puzzoni M, Astara G, Scartozzi M. Hepatocellular carcinoma and microbiota: Implications for clinical management and treatment. World J Hepatol 2022; 14:1319-1332. [PMID: 36158925 PMCID: PMC9376771 DOI: 10.4254/wjh.v14.i7.1319] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Revised: 04/11/2022] [Accepted: 07/11/2022] [Indexed: 02/06/2023] Open
Abstract
Gut microbiota plays an essential role in host homeostasis. It is involved in several physiological processes such as nutrients digestion and absorption, maintenance of intestinal epithelial barrier integrity and immune system self-tolerance. Especially the gut microbiota is assumed to play a crucial role in many gastrointestinal, pancreatic and liver disorders. Its role in hepatic carcinogenesis is also gaining increasing interest, especially regarding the development of therapeutic strategies. Different studies are highlighting a link between some bacterial strains and liver disease, including hepatocellular carcinoma (HCC). Indeed, HCC represents an interesting field of research in this perspective, due to the gut-liver axis, to the implication of microbiota in the immune system and to the increasing number of immunotherapy agents investigated in this tumour. Thus, the assessment of the role of microbiota in influencing clinical outcome for patients treated with these drugs is becoming of increasing importance. Our review aims to give an overview on the relationship between microbiota and HCC development/progression and treatment. We focus on potential implications on the available treatment strategies and those under study in the various stages of disease. We highlight the pathogenic mechanisms and investigate the underlying molecular pathways involved. Moreover, we investigate the potential prognostic and/or predictive role of microbiota for target therapies, immune checkpoint inhibitors and loco-regional treatment. Finally, given the limitation of current treatments, we analyze the gut microbiota-mediated therapies and its potential options for HCC treatment focusing on fecal microbiota transplantation.
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Affiliation(s)
- Dario Spanu
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato 09042, Cagliari, Italy
| | - Andrea Pretta
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato 09042, Cagliari, Italy
| | - Eleonora Lai
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato 09042, Cagliari, Italy
| | - Mara Persano
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato 09042, Cagliari, Italy
| | - Clelia Donisi
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato 09042, Cagliari, Italy
| | - Stefano Mariani
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato 09042, Cagliari, Italy
| | - Marco Dubois
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato 09042, Cagliari, Italy
| | - Marco Migliari
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato 09042, Cagliari, Italy
| | - Giorgio Saba
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato 09042, Cagliari, Italy
| | - Pina Ziranu
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato 09042, Cagliari, Italy
| | - Valeria Pusceddu
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato 09042, Cagliari, Italy
| | - Marco Puzzoni
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato 09042, Cagliari, Italy
| | - Giorgio Astara
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato 09042, Cagliari, Italy
| | - Mario Scartozzi
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato 09042, Cagliari, Italy
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20
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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] [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
- *Correspondence: Dong Joon Kim,
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21
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Lutein Can Alleviate Oxidative Stress, Inflammation, and Apoptosis Induced by Excessive Alcohol to Ameliorate Reproductive Damage in Male Rats. Nutrients 2022; 14:nu14122385. [PMID: 35745115 PMCID: PMC9228221 DOI: 10.3390/nu14122385] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Revised: 06/02/2022] [Accepted: 06/05/2022] [Indexed: 12/18/2022] Open
Abstract
Chronic excessive alcohol intake may lead to male reproductive damage. Lutein is a carotenoid compound with antioxidant activity. The purpose of this study was to observe the effect of lutein supplementation on male reproductive damage caused by excessive alcohol intake. In this study, an animal model of excessive drinking (12 mL/(kg.bw.d)) for 12 weeks was established and supplemented with different doses of lutein (12, 24, 48 mg/(kg.bw.d)). The results showed that the body weight, sperm quality, sex hormones (FSH, testosterone), and antioxidant markers (GSH-Px) decreased significantly, while MDA and inflammatory factors (IL-6, TNF-α) increased significantly in the alcohol model group when compared to the normal control group. After 12 weeks of high-dose lutein supplementation with 48mg/(kg.bw.d), the spermatogenic ability, testosterone level, and the activity of marker enzymes reflecting testicular injury were improved. In addition, high-dose lutein supplementation downregulated the NF-κB and the pro-apoptosis biomarkers (Bax, Cytc and caspase-3), whereas it upregulated the expression of Nrf2/HO-1 and the anti-apoptotic molecule Bcl-2. These findings were fully supported by analyzing the testicular histopathology and by measuring germ cell apoptosis. In conclusion, lutein protects against reproductive injury induced by excessive alcohol through its antioxidant, anti-inflammatory, and anti-apoptotic properties.
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22
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Leinwand JC, Paul B, Chen R, Xu F, Sierra MA, Paluru MM, Nanduri S, Alcantara CG, Shadaloey SA, Yang F, Adam SA, Li Q, Bandel M, Gakhal I, Appiah L, Guo Y, Vardhan M, Flaminio Z, Grodman ER, Mermelstein A, Wang W, Diskin B, Aykut B, Khan M, Werba G, Pushalkar S, McKinstry M, Kluger Z, Park JJ, Hsieh B, Dancel-Manning K, Liang FX, Park JS, Saxena A, Li X, Theise ND, Saxena D, Miller G. Intrahepatic microbes govern liver immunity by programming NKT cells. J Clin Invest 2022; 132:e151725. [PMID: 35175938 PMCID: PMC9012289 DOI: 10.1172/jci151725] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Accepted: 02/16/2022] [Indexed: 11/17/2022] Open
Abstract
The gut microbiome shapes local and systemic immunity. The liver is presumed to be a protected sterile site. As such, a hepatic microbiome has not been examined. Here, we showed a liver microbiome in mice and humans that is distinct from that of the gut and is enriched in Proteobacteria. It undergoes dynamic alterations with age and is influenced by the environment and host physiology. Fecal microbial transfer experiments revealed that the liver microbiome is populated from the gut in a highly selective manner. Hepatic immunity is dependent on the microbiome, specifically the bacteroidetes species. Targeting bacteroidetes with oral antibiotics reduced hepatic immune cells by approximately 90%, prevented antigen-presenting cell (APC) maturation, and mitigated adaptive immunity. Mechanistically, our findings are consistent with presentation of bacteroidetes-derived glycosphingolipids to NKT cells promoting CCL5 signaling, which drives hepatic leukocyte expansion and activation, among other possible host-microbe interactions. Collectively, we reveal a microbial/glycosphingolipid/NKT/CCL5 axis that underlies hepatic immunity.
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Affiliation(s)
- Joshua C. Leinwand
- S.A. Localio Laboratory, Department of Surgery, New York University (NYU) Langone Health, New York, New York, USA
| | - Bidisha Paul
- Department of Molecular Pathobiology, NYU College of Dentistry, New York, New York, USA
| | - Ruonan Chen
- S.A. Localio Laboratory, Department of Surgery, New York University (NYU) Langone Health, New York, New York, USA
| | - Fangxi Xu
- Department of Molecular Pathobiology, NYU College of Dentistry, New York, New York, USA
| | - Maria A. Sierra
- Department of Molecular Pathobiology, NYU College of Dentistry, New York, New York, USA
| | - Madan M. Paluru
- S.A. Localio Laboratory, Department of Surgery, New York University (NYU) Langone Health, New York, New York, USA
| | - Sumant Nanduri
- S.A. Localio Laboratory, Department of Surgery, New York University (NYU) Langone Health, New York, New York, USA
| | - Carolina G. Alcantara
- S.A. Localio Laboratory, Department of Surgery, New York University (NYU) Langone Health, New York, New York, USA
| | - Sorin A.A. Shadaloey
- S.A. Localio Laboratory, Department of Surgery, New York University (NYU) Langone Health, New York, New York, USA
| | - Fan Yang
- S.A. Localio Laboratory, Department of Surgery, New York University (NYU) Langone Health, New York, New York, USA
| | - Salma A. Adam
- S.A. Localio Laboratory, Department of Surgery, New York University (NYU) Langone Health, New York, New York, USA
| | - Qianhao Li
- Department of Molecular Pathobiology, NYU College of Dentistry, New York, New York, USA
| | - Michelle Bandel
- S.A. Localio Laboratory, Department of Surgery, New York University (NYU) Langone Health, New York, New York, USA
| | - Inderdeep Gakhal
- S.A. Localio Laboratory, Department of Surgery, New York University (NYU) Langone Health, New York, New York, USA
| | - Lara Appiah
- S.A. Localio Laboratory, Department of Surgery, New York University (NYU) Langone Health, New York, New York, USA
| | - Yuqi Guo
- Department of Molecular Pathobiology, NYU College of Dentistry, New York, New York, USA
| | - Mridula Vardhan
- Department of Molecular Pathobiology, NYU College of Dentistry, New York, New York, USA
| | - Zia Flaminio
- Department of Molecular Pathobiology, NYU College of Dentistry, New York, New York, USA
| | - Emilie R. Grodman
- Department of Molecular Pathobiology, NYU College of Dentistry, New York, New York, USA
| | - Ari Mermelstein
- S.A. Localio Laboratory, Department of Surgery, New York University (NYU) Langone Health, New York, New York, USA
| | - Wei Wang
- S.A. Localio Laboratory, Department of Surgery, New York University (NYU) Langone Health, New York, New York, USA
| | - Brian Diskin
- S.A. Localio Laboratory, Department of Surgery, New York University (NYU) Langone Health, New York, New York, USA
| | - Berk Aykut
- S.A. Localio Laboratory, Department of Surgery, New York University (NYU) Langone Health, New York, New York, USA
| | - Mohammad Khan
- S.A. Localio Laboratory, Department of Surgery, New York University (NYU) Langone Health, New York, New York, USA
| | - Gregor Werba
- S.A. Localio Laboratory, Department of Surgery, New York University (NYU) Langone Health, New York, New York, USA
| | - Smruti Pushalkar
- Department of Molecular Pathobiology, NYU College of Dentistry, New York, New York, USA
| | - Mia McKinstry
- S.A. Localio Laboratory, Department of Surgery, New York University (NYU) Langone Health, New York, New York, USA
| | - Zachary Kluger
- S.A. Localio Laboratory, Department of Surgery, New York University (NYU) Langone Health, New York, New York, USA
| | - Jaimie J. Park
- S.A. Localio Laboratory, Department of Surgery, New York University (NYU) Langone Health, New York, New York, USA
| | - Brandon Hsieh
- Department of Pathology
- Department of Medicine
- Ronald O. Perelman Department of Dermatology, and
| | | | - Feng-Xia Liang
- Department of Cell Biology, NYU Langone Health, New York, New York, USA
| | | | - Anjana Saxena
- Biology Department, Brooklyn College and Biology/Biochemistry Programs, Graduate Center (CUNY), New York, New York, USA
| | - Xin Li
- Department of Molecular Pathobiology, NYU College of Dentistry, New York, New York, USA
| | | | - Deepak Saxena
- Department of Molecular Pathobiology, NYU College of Dentistry, New York, New York, USA
| | - George Miller
- S.A. Localio Laboratory, Department of Surgery, New York University (NYU) Langone Health, New York, New York, USA
- Department of Cell Biology, NYU Langone Health, New York, New York, USA
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23
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León BE, Kang S, Franca-Solomon G, Shang P, Choi DS. Alcohol-Induced Neuroinflammatory Response and Mitochondrial Dysfunction on Aging and Alzheimer's Disease. Front Behav Neurosci 2022; 15:778456. [PMID: 35221939 PMCID: PMC8866940 DOI: 10.3389/fnbeh.2021.778456] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Accepted: 12/07/2021] [Indexed: 12/27/2022] Open
Abstract
Mitochondria are essential organelles central to various cellular functions such as energy production, metabolic pathways, signaling transduction, lipid biogenesis, and apoptosis. In the central nervous system, neurons depend on mitochondria for energy homeostasis to maintain optimal synaptic transmission and integrity. Deficiencies in mitochondrial function, including perturbations in energy homeostasis and mitochondrial dynamics, contribute to aging, and Alzheimer's disease. Chronic and heavy alcohol use is associated with accelerated brain aging, and increased risk for dementia, especially Alzheimer's disease. Furthermore, through neuroimmune responses, including pro-inflammatory cytokines, excessive alcohol use induces mitochondrial dysfunction. The direct and indirect alcohol-induced neuroimmune responses, including pro-inflammatory cytokines, are critical for the relationship between alcohol-induced mitochondrial dysfunction. In the brain, alcohol activates microglia and increases inflammatory mediators that can impair mitochondrial energy production, dynamics, and initiate cell death pathways. Also, alcohol-induced cytokines in the peripheral organs indirectly, but synergistically exacerbate alcohol's effects on brain function. This review will provide recent and advanced findings focusing on how alcohol alters the aging process and aggravates Alzheimer's disease with a focus on mitochondrial function. Finally, we will contextualize these findings to inform clinical and therapeutic approaches towards Alzheimer's disease.
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Affiliation(s)
- Brandon Emanuel León
- Regenerative Sciences Program, Center for Regenerative Medicine, Mayo Clinic, Rochester, MN, United States
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, United States
| | - Shinwoo Kang
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, United States
| | - Gabriela Franca-Solomon
- Neuroscience Program, Mayo Clinic College of Medicine and Science, Rochester, MN, United States
| | - Pei Shang
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, United States
| | - Doo-Sup Choi
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, United States
- Neuroscience Program, Mayo Clinic College of Medicine and Science, Rochester, MN, United States
- Department of Psychiatry and Psychology, Mayo Clinic College of Medicine and Science, Rochester, MN, United States
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24
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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: 96] [Impact Index Per Article: 24.0] [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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25
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Zheng Z, Wang B. The Gut-Liver Axis in Health and Disease: The Role of Gut Microbiota-Derived Signals in Liver Injury and Regeneration. Front Immunol 2021; 12:775526. [PMID: 34956204 PMCID: PMC8703161 DOI: 10.3389/fimmu.2021.775526] [Citation(s) in RCA: 75] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Accepted: 11/19/2021] [Indexed: 12/12/2022] Open
Abstract
Diverse liver diseases undergo a similar pathophysiological process in which liver regeneration follows a liver injury. Given the important role of the gut-liver axis in health and diseases, the role of gut microbiota-derived signals in liver injury and regeneration has attracted much attention. It has been observed that the composition of gut microbiota dynamically changes in the process of liver regeneration after partial hepatectomy, and gut microbiota modulation by antibiotics or probiotics affects both liver injury and regeneration. Mechanically, through the portal vein, the liver is constantly exposed to gut microbial components and metabolites, which have immense effects on the immunity and metabolism of the host. Emerging data demonstrate that gut-derived lipopolysaccharide, gut microbiota-associated bile acids, and other bacterial metabolites, such as short-chain fatty acids and tryptophan metabolites, may play multifaceted roles in liver injury and regeneration. In this perspective, we provide an overview of the possible molecular mechanisms by which gut microbiota-derived signals modulate liver injury and regeneration, highlighting the potential roles of gut microbiota in the development of gut microbiota-based therapies to alleviate liver injury and promote liver regeneration.
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Affiliation(s)
- Zhipeng Zheng
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Baohong Wang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
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26
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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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27
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Sun Y, Kang K, Li YL, Sang LX, Chang B. Tea polyphenols protect mice from acute ethanol-Induced liver injury by modulating the gut microbiota and short-chain fatty acids. J Funct Foods 2021. [DOI: 10.1016/j.jff.2021.104865] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
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28
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Bou Saleh M, Louvet A, Ntandja-Wandji LC, Boleslawski E, Gnemmi V, Lassailly G, Truant S, Maggiotto F, Ningarhari M, Artru F, Anglo E, Sancho-Bru P, Corlu A, Argemi J, Dubois-Chevalier J, Dharancy S, Eeckhoute J, Bataller R, Mathurin P, Dubuquoy L. Loss of hepatocyte identity following aberrant YAP activation: A key mechanism in alcoholic hepatitis. J Hepatol 2021; 75:912-923. [PMID: 34129887 DOI: 10.1016/j.jhep.2021.05.041] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Revised: 04/30/2021] [Accepted: 05/18/2021] [Indexed: 12/19/2022]
Abstract
BACKGROUND & AIMS Alcoholic hepatitis (AH) is a life-threatening disease with limited therapeutic options, as the molecular mechanisms leading to death are not well understood. This study evaluates the Hippo/Yes-associated protein (YAP) pathway which has been shown to play a role in liver regeneration. METHOD The Hippo/YAP pathway was dissected in explants of patients transplanted for AH or alcohol-related cirrhosis and in control livers, using RNA-seq, real-time PCR, western blot, immunohistochemistry and transcriptome analysis after laser microdissection. We transfected primary human hepatocytes with constitutively active YAP (YAPS127A) and treated HepaRG cells and primary hepatocytes isolated from AH livers with a YAP inhibitor. We also used mouse models of ethanol exposure (Lieber de Carli) and liver regeneration (carbon tetrachloride) after hepatocyte transduction of YAPS127A. RESULTS In AH samples, RNA-seq analysis and immunohistochemistry of total liver and microdissected hepatocytes revealed marked downregulation of the Hippo pathway, demonstrated by lower levels of active MST1 kinase and abnormal activation of YAP in hepatocytes. Overactivation of YAP in hepatocytes in vitro and in vivo led to biliary differentiation and loss of key biological functions such as regeneration capacity. Conversely, a YAP inhibitor restored the mature hepatocyte phenotype in abnormal hepatocytes taken from patients with AH. In ethanol-fed mice, YAP activation using YAPS127A resulted in a loss of hepatocyte differentiation. Hepatocyte proliferation was hampered by YAPS127A after carbon tetrachloride intoxication. CONCLUSION Aberrant activation of YAP plays an important role in hepatocyte transdifferentiation in AH, through a loss of hepatocyte identity and impaired regeneration. Thus, targeting YAP is a promising strategy for the treatment of patients with AH. LAY SUMMARY Alcoholic hepatitis is characterized by inflammation and a life-threatening alteration of liver regeneration, although the mechanisms behind this have not been identified. Herein, we show that liver samples from patients with alcoholic hepatitis are characterized by profound deregulation of the Hippo/YAP pathway with uncontrolled activation of YAP in hepatocytes. We used human cell and mouse models to show that inhibition of YAP reverts this hepatocyte defect and could be a novel therapeutic strategy for alcoholic hepatitis.
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Affiliation(s)
- Mohamed Bou Saleh
- Univ. Lille, Inserm, CHU Lille, U1286 - INFINITE - Institute for Translational Research in Inflammation, F-59000 Lille, France
| | - Alexandre Louvet
- Univ. Lille, Inserm, CHU Lille, U1286 - INFINITE - Institute for Translational Research in Inflammation, F-59000 Lille, France
| | - Line Carolle Ntandja-Wandji
- Univ. Lille, Inserm, CHU Lille, U1286 - INFINITE - Institute for Translational Research in Inflammation, F-59000 Lille, France
| | - Emmanuel Boleslawski
- Univ. Lille, Inserm, CHU Lille, U1189 - ONCO-THAI - Image Assisted Laser Therapy for Oncology, F-59000 Lille, France
| | - Viviane Gnemmi
- CHU Lille, Service d'Anatomopathologie, F-59000 Lille, France
| | - Guillaume Lassailly
- Univ. Lille, Inserm, CHU Lille, U1286 - INFINITE - Institute for Translational Research in Inflammation, F-59000 Lille, France
| | - Stéphanie Truant
- CHU Lille, Service de Chirurgie Digestive et Transplantations, F-59000 Lille, France
| | - François Maggiotto
- Univ. Lille, Inserm, CHU Lille, U1286 - INFINITE - Institute for Translational Research in Inflammation, F-59000 Lille, France
| | - Massih Ningarhari
- Univ. Lille, Inserm, CHU Lille, U1286 - INFINITE - Institute for Translational Research in Inflammation, F-59000 Lille, France
| | - Florent Artru
- Univ. Lille, Inserm, CHU Lille, U1286 - INFINITE - Institute for Translational Research in Inflammation, F-59000 Lille, France
| | - Emilie Anglo
- Univ. Lille, Inserm, CHU Lille, U1286 - INFINITE - Institute for Translational Research in Inflammation, F-59000 Lille, France
| | - Pau Sancho-Bru
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
| | - Anne Corlu
- INSERM, Univ Rennes, INRAE, Institut NuMeCan (Nutrition, Metabolisms and Cancer), F-35043, Rennes, France
| | - Josepmaria Argemi
- Division of Gastroenterology, Hepatology and Nutrition. Pittsburgh Liver Research Center. University of Pittsburgh Medical Center (UPMC), Pittsburgh, PA, USA
| | - Julie Dubois-Chevalier
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, F-59000 Lille, France
| | - Sébastien Dharancy
- Univ. Lille, Inserm, CHU Lille, U1286 - INFINITE - Institute for Translational Research in Inflammation, F-59000 Lille, France
| | - Jérôme Eeckhoute
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, F-59000 Lille, France
| | - Ramon Bataller
- Division of Gastroenterology, Hepatology and Nutrition. Pittsburgh Liver Research Center. University of Pittsburgh Medical Center (UPMC), Pittsburgh, PA, USA
| | - Philippe Mathurin
- Univ. Lille, Inserm, CHU Lille, U1286 - INFINITE - Institute for Translational Research in Inflammation, F-59000 Lille, France.
| | - Laurent Dubuquoy
- Univ. Lille, Inserm, CHU Lille, U1286 - INFINITE - Institute for Translational Research in Inflammation, F-59000 Lille, France.
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Caraceni P, Vargas V, Solà E, Alessandria C, de Wit K, Trebicka J, Angeli P, Mookerjee RP, Durand F, Pose E, Krag A, Bajaj JS, Beuers U, Ginès P, Napoleone L, Carol M, Avitabile E, Thu AM, Cervera M, Pérez M, Belén Rubio‐Garcia A, Ardiaca A, Vives A, Pich J, Fabrellas N, Zaccherini G, Chiappa MT, Jiménez C, Palacio E, Campion D, Lanzillotti T, Piano S, Nicolao G, Uschner F, Graf_Dirmeier S, Francoz C, Roux O, Esnault V, Helder J, Aban M, Kazankov K, Korenjak M, Kamath P, Abraldes JG, Watson H. The Use of Rifaximin in Patients With Cirrhosis. Hepatology 2021; 74:1660-1673. [PMID: 33421158 PMCID: PMC8518409 DOI: 10.1002/hep.31708] [Citation(s) in RCA: 76] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Revised: 11/10/2020] [Accepted: 12/02/2020] [Indexed: 12/12/2022]
Abstract
Rifaximin is an oral nonsystemic antibiotic with minimal gastrointestinal absorption and broad-spectrum antibacterial activity covering both gram-positive and gram-negative organisms. Rifaximin is currently used worldwide in patients with cirrhosis for preventing recurrent HE because its efficacy and safety have been proven by large randomized clinical trials. In the last decade, experimental and clinical evidence suggest that rifaximin could have other beneficial effects on the course of cirrhosis by modulating the gut microbiome and affecting the gut-liver axis, which in turn can interfere with major events of the pathophysiological cascade underlying decompensated cirrhosis, such as systemic inflammatory syndrome, portal hypertension, and bacterial infections. However, the use of rifaximin for prevention or treatment of other complications, including spontaneous bacterial peritonitis or other bacterial infections, is not accepted because evidence by clinical trials is still very weak. The present review deals in the first part with the potential impact of rifaximin on pathogenic mechanisms in liver diseases, whereas in the second part, its clinical effects are critically discussed. It clearly emerges that, because of its potential activity on multiple pathogenic events, the efficacy of rifaximin in the prevention or management of complications other than HE deserves to be investigated extensively. The results of double-blinded, adequately powered randomized clinical trials assessing the effect of rifaximin, alone or in combination with other drugs, on hard clinical endpoints, such as decompensation of cirrhosis, acute-on-chronic liver failure, and mortality, are therefore eagerly awaited.
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Affiliation(s)
- Paolo Caraceni
- University of BolognaUniversity Hospital S. Orsola‐Malpighi di BolognaBolognaItaly
| | - Victor Vargas
- Hospital Vall d’HebronUniversitat Autònoma de BarcelonaCIEREHDBarcelonaCataloniaSpain
| | - Elsa Solà
- Hospital Clinic of BarcelonaUniversity of BarcelonaIDIBAPSCIBEReHDBarcelonaCataloniaSpain
| | - Carlo Alessandria
- Division of Gastroenterology and HepatologyCittà della Salute e della Scienza HospitalUniversity of TorinoTurinItaly
| | - Koos de Wit
- Amsterdam University Medical CentersAmsterdamthe Netherlands
| | - Jonel Trebicka
- Goethe‐University ‐ Frankfurt am MainFrankfurt am MainGermany,EF‐CLIFBarcelonaCataloniaSpain
| | | | | | | | - Elisa Pose
- Hospital Clinic of BarcelonaUniversity of BarcelonaIDIBAPSCIBEReHDBarcelonaCataloniaSpain
| | - Aleksander Krag
- Department of Gastroenterology and HepatologyOdense University HospitalOdenseDenmark,Institute of Clinical ResearchUniversity of Southern DenmarkOdenseDenmark
| | | | - Ulrich Beuers
- Amsterdam University Medical CentersAmsterdamthe Netherlands
| | - Pere Ginès
- Hospital Clinic of BarcelonaUniversity of BarcelonaIDIBAPSCIBEReHDBarcelonaCataloniaSpain
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30
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The Gut Microbiota-Derived Immune Response in Chronic Liver Disease. Int J Mol Sci 2021; 22:ijms22158309. [PMID: 34361075 PMCID: PMC8347749 DOI: 10.3390/ijms22158309] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Revised: 07/29/2021] [Accepted: 07/30/2021] [Indexed: 02/06/2023] Open
Abstract
In chronic liver disease, the causative factor is important; however, recently, the intestinal microbiome has been associated with the progression of chronic liver disease and the occurrence of side effects. The immune system is affected by the metabolites of the microbiome, and diet is the primary regulator of the microbiota composition and function in the gut–liver axis. These metabolites can be used as therapeutic material, and postbiotics, in the future, can increase or decrease human immunity by modulating inflammation and immune reactions. Therefore, the excessive intake of nutrients and the lack of nutrition have important effects on immunity and inflammation. Evidence has been published indicating that microbiome-induced chronic inflammation and the consequent immune dysregulation affect the development of chronic liver disease. In this research paper, we discuss the overall trend of microbiome-derived substances related to immunity and the future research directions.
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Abstract
Malnutrition is common in alcohol-associated hepatitis (AH); almost all patients with severe AH have some component of malnutrition. The classic phenotype of malnutrition in AH is sarcopenia, but this has become more difficult to discern clinically as patients have become more obese. Patients with AH are often drinking 10 to 15 standard drinks per day. This substantial alcohol consumption becomes a major source of calories, but these are considered "empty" calories that contain little nutritional value. Malnutrition is associated with liver complications, such as hepatic encephalopathy, and worse liver outcomes. Nutrition support can improve nutrition status and reduce complications.
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Affiliation(s)
- Craig J. McClain
- Division of Gastroenterology, Hepatology and Nutrition, University of Louisville, Louisville, KY;,UofL Alcohol Research Center, University of Louisville, Louisville, KY;,Department of Medicine, University of Louisville, Louisville, KY;,Hepatobiology and Toxicology Center, University of Louisville, Louisville, KY;,Robely Rex Veterans Affairs Medical Center, Louisville, KY 40207
| | - Cristian D. Rios
- Division of Gastroenterology, Hepatology and Nutrition, University of Louisville, Louisville, KY
| | - Sally Condon
- Division of Gastroenterology, Hepatology and Nutrition, University of Louisville, Louisville, KY
| | - Luis S. Marsano
- Division of Gastroenterology, Hepatology and Nutrition, University of Louisville, Louisville, KY;,Department of Medicine, University of Louisville, Louisville, KY
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Ezquer F, Quintanilla ME, Moya‐Flores F, Morales P, Munita JM, Olivares B, Landskron G, Hermoso MA, Ezquer M, Herrera‐Marschitz M, Israel Y. Innate gut microbiota predisposes to high alcohol consumption. Addict Biol 2021; 26:e13018. [PMID: 33508889 DOI: 10.1111/adb.13018] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Revised: 12/14/2020] [Accepted: 01/19/2021] [Indexed: 02/06/2023]
Abstract
Gut microbiota is known to be transferred from the mother to their offspring. This study determines whether the innate microbiota of rats selectively bred for generations as high alcohol drinkers play a role in their alcohol intake. Wistar-derived high-drinker UChB rats (intake 10-g ethanol/kg/day) administered nonabsorbable oral antibiotics before allowing access to alcohol, reducing their voluntary ethanol intake by 70%, an inhibition that remained after the antibiotic administration was discontinued. Oral administration of Lactobacillus rhamnosus Gorbach-Goldin (GG) induced the synthesis of FGF21, a vagal β-Klotho receptor agonist, and partially re-invoked a mechanism that reduces alcohol intake. The vagus nerve constitutes the main axis transferring gut microbiota information to the brain ("microbiota-gut-brain" axis). Bilateral vagotomy inhibited rat alcohol intake by 75%. Neither antibiotic treatment nor vagotomy affected total fluid intake. A microbiota-mediated marked inflammatory environment was observed in the gut of ethanol-naïve high-drinker rats, as gene expression of proinflammatory cytokines (TNF-α; IL-6; IL-1β) was significantly reduced by nonabsorbable antibiotic administration. Gut cytokines are known to activate the vagus nerve, while vagal activation induces pro-rewarding effects in nucleus accumbens. Both alcoholics and alcohol-preferring rats share a marked preference for sweet tastes-likely an evolutionary trait to seek sweet fermented fruits. Saccharin intake by UChB rats was inhibited by 75%-85% by vagotomy or oral antibiotic administration, despite saccharin-induced polydipsia. Overall, data indicate that the mechanisms that normally curtail heavy drinking are inhibited in alcohol-preferring animals and inform a gut microbiota origin. Whether it applies to other mammals and humans merits further investigation.
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Affiliation(s)
- Fernando Ezquer
- Center for Regenerative Medicine, School of Medicine Clínica Alemana‐Universidad del Desarrollo Santiago Chile
| | - Maria Elena Quintanilla
- Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine Universidad de Chile Santiago Chile
| | - Francisco Moya‐Flores
- Millennium Initiative for Collaborative Research on Bacterial Resistance (MICROB‐R) Santiago Chile
- Genomics and Resistant Microbes Group, School of Medicine Clínica Alemana‐Universidad del Desarrollo Santiago Chile
| | - Paola Morales
- Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine Universidad de Chile Santiago Chile
- Department of Neuroscience, School of Medicine Universidad de Chile Santiago Chile
| | - José Manuel Munita
- Millennium Initiative for Collaborative Research on Bacterial Resistance (MICROB‐R) Santiago Chile
- Genomics and Resistant Microbes Group, School of Medicine Clínica Alemana‐Universidad del Desarrollo Santiago Chile
| | - Belén Olivares
- Center for Medical Chemistry, School of Medicine Clínica Alemana‐Universidad del Desarrollo Santiago Chile
| | - Glauben Landskron
- Laboratory of Innate Immunity, Program of Immunology, Institute of Biomedical Science, Faculty of Medicine Universidad de Chile Santiago Chile
| | - Marcela A. Hermoso
- Laboratory of Innate Immunity, Program of Immunology, Institute of Biomedical Science, Faculty of Medicine Universidad de Chile Santiago Chile
| | - Marcelo Ezquer
- Center for Regenerative Medicine, School of Medicine Clínica Alemana‐Universidad del Desarrollo Santiago Chile
| | - Mario Herrera‐Marschitz
- Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine Universidad de Chile Santiago Chile
| | - Yedy Israel
- Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine Universidad de Chile Santiago Chile
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Jiang L, Schnabl B. Gut Microbiota in Liver Disease: What Do We Know and What Do We Not Know? Physiology (Bethesda) 2021; 35:261-274. [PMID: 32490750 DOI: 10.1152/physiol.00005.2020] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
The gut and the liver have a bidirectional communication via the biliary system and the portal vein. The intestinal microbiota and microbial products play an important role for modulating liver diseases such as alcohol-associated liver disease, non-alcoholic fatty liver disease and steatohepatitis, and cholestatic liver diseases. Here, we review the role of the gut microbiota and its products for the pathogenesis and therapy of chronic liver diseases.
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Affiliation(s)
- Lu Jiang
- Department of Medicine, University of California San Diego, La Jolla, California; and Department of Medicine, VA San Diego Healthcare System, San Diego, California
| | - Bernd Schnabl
- Department of Medicine, University of California San Diego, La Jolla, California; and Department of Medicine, VA San Diego Healthcare System, San Diego, California
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34
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Moreno-Gonzalez M, Beraza N. The Role of the Microbiome in Liver Cancer. Cancers (Basel) 2021; 13:2330. [PMID: 34066064 PMCID: PMC8150469 DOI: 10.3390/cancers13102330] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Revised: 04/30/2021] [Accepted: 05/03/2021] [Indexed: 12/11/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common malignancy occuring in the context of chronic liver disease and is one of the main causes of cancer-derived death worldwide. The lack of effective treatments, together with the poor prognosis, underlines the urge to develop novel and multidisciplinary therapeutics. An increasing body of evidence shows that HCC associates with changes in intestinal microbiota abundance and composition as well as with impaired barrier function, leading to the release of bacteria and their metabolites to the liver. These factors trigger a cascade of inflammatory responses contributing to liver cirrhosis and constituting an ideal environment for the progression of HCC. Interestingly, the use of bacteriotherapy in human and preclinical studies of chronic liver disease and HCC has been shown to successfully modify the microbiota composition, reducing overall inflammation and fibrosis. In this review, we explore the existing knowledge on the characterisation of the intestinal microbial composition in humans and experimental murine chronic liver disease and HCC, as well as the use of antibiotics and bacteriotherapy as therapeutic options.
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Affiliation(s)
- Mar Moreno-Gonzalez
- Gut Microbes and Health Institute Strategic Programme, Quadram Institute Bioscience, Norwich Research Park, Norwich NR4 7UQ, UK;
| | - Naiara Beraza
- Gut Microbes and Health Institute Strategic Programme, Quadram Institute Bioscience, Norwich Research Park, Norwich NR4 7UQ, UK;
- Food Innovation and Health Institute Strategic Programme, Quadram Institute Bioscience, Norwich Research Park, Norwich NR4 7UQ, UK
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35
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Li R, Mao Z, Ye X, Zuo T. Human Gut Microbiome and Liver Diseases: From Correlation to Causation. Microorganisms 2021; 9:1017. [PMID: 34066850 PMCID: PMC8151257 DOI: 10.3390/microorganisms9051017] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Revised: 04/25/2021] [Accepted: 04/30/2021] [Indexed: 02/06/2023] Open
Abstract
The important role of human gut microbiota in liver diseases has long been recognized as dysbiosis and the translocation of certain microbes from the gut to liver. With the development of high-throughput DNA sequencing, the complexity and integrity of the gut microbiome in the whole spectrum of liver diseases is emerging. Specific patterns of gut microbiota have been identified in liver diseases with different causes, including alcoholic, non-alcoholic, and virus induced liver diseases, or even at different stages, ranging from steatohepatitis, fibrosis, cirrhosis, to hepatocellular carcinoma. At the same time, the mechanism of how microbiota contributes to liver diseases goes beyond the traditional function of the gut-liver axis which could lead to liver injury and inflammation. With the application of proteomics, metabolomics, and modern molecular technologies, more microbial metabolites and the complicated interaction of microbiota with host immunity come into our understanding in the liver pathogenesis. Germ-free animal models serve as a workhorse to test the function of microbiota and their derivatives in liver disease models. Here, we review the current evidence on the relationship between gut microbiota and liver diseases, and the mechanisms underlying this phenotype. In addition to original liver diseases, gut microbiota might also affect liver injury in systemic disorders involving multiple organs, as in the case of COVID-19 at a severe state. A better understanding of the gut microbial contribution to liver diseases might help us better benefit from this guest-host relationship and pave the way for novel therapies.
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Affiliation(s)
- Rui Li
- Department of Geriatrics, Zhongnan Hospital of Wuhan University, Wuhan 430070, China;
| | - Zhengsheng Mao
- Department of Neurology, Wuhan Fourth Hospital, Puai Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430074, China;
| | - Xujun Ye
- Department of Geriatrics, Zhongnan Hospital of Wuhan University, Wuhan 430070, China;
| | - Tao Zuo
- Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital of Sun Yat-Sen University, Sun Yat-Sen University, Guangzhou 510000, China
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Tranah TH, Edwards LA, Schnabl B, Shawcross DL. Targeting the gut-liver-immune axis to treat cirrhosis. Gut 2021; 70:982-994. [PMID: 33060124 DOI: 10.1136/gutjnl-2020-320786] [Citation(s) in RCA: 106] [Impact Index Per Article: 26.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Revised: 08/12/2020] [Accepted: 08/26/2020] [Indexed: 12/11/2022]
Abstract
Cirrhotic portal hypertension is characterised by development of the decompensating events of ascites, encephalopathy, portal hypertensive bleeding and hepatorenal syndrome, which arise in a setting of cirrhosis-associated immune dysfunction (CAID) and define morbidity and prognosis. CAID describes the dichotomous observations that systemic immune cells are primed and display an inflammatory phenotype, while failing to mount robust responses to pathogen challenge. Bacterial infections including spontaneous bacterial peritonitis are common complications of advanced chronic liver disease and can precipitate variceal haemorrhage, hepatorenal syndrome and acute-on-chronic liver failure; they frequently arise from gut-derived organisms and are closely linked with dysbiosis of the commensal intestinal microbiota in advanced chronic liver disease.Here, we review the links between cirrhotic dysbiosis, intestinal barrier dysfunction and deficits of host-microbiome compartmentalisation and mucosal immune homoeostasis that occur in settings of advanced chronic liver disease. We discuss established and emerging therapeutic strategies targeted at restoring intestinal eubiosis, augmenting gut barrier function and ameliorating the mucosal and systemic immune deficits that characterise and define the course of decompensated cirrhosis.
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Affiliation(s)
- Thomas Henry Tranah
- Institute of Liver Studies, Department of Inflammation Biology, School of Immunology and Microbial Sciences, FoLSM, King's College London, London, UK
| | - Lindsey A Edwards
- Institute of Liver Studies, Department of Inflammation Biology, School of Immunology and Microbial Sciences, FoLSM, King's College London, London, UK
| | - Bernd Schnabl
- Medicine, University of California San Diego, San Diego, California, USA
| | - Debbie Lindsay Shawcross
- Institute of Liver Studies, Department of Inflammation Biology, School of Immunology and Microbial Sciences, FoLSM, King's College London, London, UK
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Lee JS, O’Connell EM, Pacher P, Lohoff FW. PCSK9 and the Gut-Liver-Brain Axis: A Novel Therapeutic Target for Immune Regulation in Alcohol Use Disorder. J Clin Med 2021; 10:1758. [PMID: 33919550 PMCID: PMC8074019 DOI: 10.3390/jcm10081758] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 04/14/2021] [Accepted: 04/16/2021] [Indexed: 02/06/2023] Open
Abstract
Alcohol use disorder (AUD) is a chronic relapsing disorder characterized by an impaired ability to control or stop alcohol intake and is associated with organ damage including alcohol-associated liver disease (ALD) and progressive neurodegeneration. The etiology of AUD is complex, but organ injury due to chronic alcohol use can be partially attributed to systemic and local inflammation along the gut-liver-brain axis. Excessive alcohol use can result in translocation of bacterial products into circulation, increased expression of pro-inflammatory cytokines, and activation of immune cells, including macrophages and/or microglia in the liver and brain. One potential mediator of this alcohol-induced inflammation is proprotein convertase subtilisin/kexin type 9 (PCSK9). PCSK9 is primarily known for its regulation of plasma low-density lipoprotein cholesterol but has more recently been shown to influence inflammatory responses in the liver and brain. In rodent and post-mortem brain studies, chronic alcohol use altered methylation of the PCSK9 gene and increased expression of PCSK9 in the liver and cerebral spinal fluid. Additionally, PCSK9 inhibition in a rat model of ALD attenuated liver inflammation and steatosis. PCSK9 may play an important role in alcohol-induced pathologies along the gut-liver-brain axis and may be a novel therapeutic target for AUD-related liver and brain inflammation.
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Affiliation(s)
- Ji Soo Lee
- Section on Clinical Genomics and Experimental Therapeutics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA; (J.S.L.)
| | - Emma M. O’Connell
- Section on Clinical Genomics and Experimental Therapeutics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA; (J.S.L.)
| | - Pal Pacher
- Laboratory of Cardiovascular Physiology and Tissue Injury, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20852, USA;
| | - Falk W. Lohoff
- Section on Clinical Genomics and Experimental Therapeutics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA; (J.S.L.)
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Translational Approaches with Antioxidant Phytochemicals against Alcohol-Mediated Oxidative Stress, Gut Dysbiosis, Intestinal Barrier Dysfunction, and Fatty Liver Disease. Antioxidants (Basel) 2021; 10:antiox10030384. [PMID: 33806556 PMCID: PMC8000766 DOI: 10.3390/antiox10030384] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Revised: 02/25/2021] [Accepted: 02/25/2021] [Indexed: 12/12/2022] Open
Abstract
Emerging data demonstrate the important roles of altered gut microbiomes (dysbiosis) in many disease states in the peripheral tissues and the central nervous system. Gut dysbiosis with decreased ratios of Bacteroidetes/Firmicutes and other changes are reported to be caused by many disease states and various environmental factors, such as ethanol (e.g., alcohol drinking), Western-style high-fat diets, high fructose, etc. It is also caused by genetic factors, including genetic polymorphisms and epigenetic changes in different individuals. Gut dysbiosis, impaired intestinal barrier function, and elevated serum endotoxin levels can be observed in human patients and/or experimental rodent models exposed to these factors or with certain disease states. However, gut dysbiosis and leaky gut can be normalized through lifestyle alterations such as increased consumption of healthy diets with various fruits and vegetables containing many different kinds of antioxidant phytochemicals. In this review, we describe the mechanisms of gut dysbiosis, leaky gut, endotoxemia, and fatty liver disease with a specific focus on the alcohol-associated pathways. We also mention translational approaches by discussing the benefits of many antioxidant phytochemicals and/or their metabolites against alcohol-mediated oxidative stress, gut dysbiosis, intestinal barrier dysfunction, and fatty liver disease.
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39
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Labib HMA. Alteration of CYP2E1, DBN1, DNMT1, miRNA-335, miRNA-21, c-Fos and Cox-2 gene expression in prefrontal cortex of rats' offspring submitted to prenatal ethanol exposure during their neurodevelopment and the preventive role of nancocurcumin administration: A histological, ultrastructural and molecular study. J Chem Neuroanat 2021; 113:101940. [PMID: 33657396 DOI: 10.1016/j.jchemneu.2021.101940] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2020] [Revised: 01/05/2021] [Accepted: 02/21/2021] [Indexed: 12/27/2022]
Abstract
Ethanol (EtOH) has been linked to neurotoxic effects on the fetus and prenatal alcohol exposure (PAE) has a negative impact on brain neurodevelopment. Therefore, the present study was aimed to focus on the underlying mechanisms of alcohol-induced oxidative stress and apoptotic cell death in addition to shedding the light on the modulatory effect of nanocurcumin in rats' offspring prefrontal cortices. The current study investigated the effects of prenatal maternal exposure to EtOH intragastric (i.g.) administration of 0.015 mL/g of a 10 % v/v ethanol solution throughout gestation and the concomitant use of nanocurcumin, on 21-day-old offspring Wistar rat prefrontal cortex parameters. CYP2E1, DBN1, DNMT1, miRNA-335, miRNA-21, c-Fos and Cox-2 gene expression as well as the accompanying histological and ultrastructural alterations were assessed. The implemented experimental setting has revealed that ethanol exposure caused significant alterations in the above mentioned parameters. Changes observed in nanocurcumin-treated animals were significantly different to the ethanol-treated group when nanocurcumin was concomitantly administered.
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Affiliation(s)
- Heba Mohamed Ali Labib
- Department of Anatomy and Embryology, Faculty of Medicine, Kasr Alainy, Cairo University, 71 El Kasr Al Ainy. Sector, Greater Cairo, 11562, Cairo, Egypt.
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Hartmann P, Schnabl B. New Developments in Microbiome in Alcohol-Associated and Nonalcoholic Fatty Liver Disease. Semin Liver Dis 2021; 41:87-102. [PMID: 33957682 PMCID: PMC8163568 DOI: 10.1055/s-0040-1719174] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Alcohol-associated liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD) are important causes of morbidity and mortality worldwide. The intestinal microbiota is involved in the development and progression of both ALD and NAFLD. Here we describe associated changes in the intestinal microbiota, and we detail randomized clinical trials in ALD and NAFLD which evaluate treatments modulating the intestinal microbiome including fecal microbiota transplantation, probiotics, prebiotics, synbiotics, and antibiotics. Finally, we discuss precision medicine approaches targeting the intestinal microbiome to ameliorate ALD and NAFLD.
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Affiliation(s)
- Phillipp Hartmann
- Department of Pediatrics, University of California San Diego, La Jolla, CA 92093, USA;,Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA
| | - Bernd Schnabl
- Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA;,Department of Medicine, VA San Diego Healthcare System, San Diego, CA 92161, USA.,Corresponding Author: Bernd Schnabl, MD, Department of Medicine, University of California, San Diego, Biomedical Research Facility 2 (BRF2), Room 4A22, 9500 Gilman Drive, MC0063, La Jolla, CA 92093, Phone: +1 858-822-5311, Fax: +1 858-822-5370,
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41
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Bruellman R, Llorente C. A Perspective Of Intestinal Immune-Microbiome Interactions In Alcohol-Associated Liver Disease. Int J Biol Sci 2021; 17:307-327. [PMID: 33390852 PMCID: PMC7757023 DOI: 10.7150/ijbs.53589] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Accepted: 11/13/2020] [Indexed: 02/07/2023] Open
Abstract
Uncovering the intricacies of the gut microbiome and how it interacts with the host immune system has opened up pathways in the search for the treatment of disease conditions. Alcohol-associated liver disease is a major cause of death worldwide. Research has shed light on the breakdown of the protective gut barriers, translocation of gut microbes to the liver and inflammatory immune response to microbes all contributing to alcohol-associated liver disease. This knowledge has opened up avenues for alternative therapies to alleviate alcohol-associated liver disease based on the interaction of the commensal gut microbiome as a key player in the regulation of the immune response. This review describes the relevance of the intestinal immune system, the gut microbiota, and specialized and non-specialized intestinal cells in the regulation of intestinal homeostasis. It also reflects how these components are altered during alcohol-associated liver disease and discusses new approaches for potential future therapies in alcohol-associated liver disease.
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Affiliation(s)
- Ryan Bruellman
- Department of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Cristina Llorente
- Department of Medicine, University of California San Diego, La Jolla, CA, USA
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Liu Y, Cavallaro PM, Kim BM, Liu T, Wang H, Kühn F, Adiliaghdam F, Liu E, Vasan R, Samarbafzadeh E, Farber MZ, Li J, Xu M, Mohad V, Choi M, Hodin RA. A role for intestinal alkaline phosphatase in preventing liver fibrosis. Theranostics 2021; 11:14-26. [PMID: 33391458 PMCID: PMC7681079 DOI: 10.7150/thno.48468] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2020] [Accepted: 07/27/2020] [Indexed: 12/12/2022] Open
Abstract
Rationale: Liver fibrosis is frequently associated with gut barrier dysfunction, and the lipopolysaccharides (LPS) -TLR4 pathway is common to the development of both. Intestinal alkaline phosphatase (IAP) has the ability to detoxify LPS, as well as maintain intestinal tight junction proteins and gut barrier integrity. Therefore, we hypothesized that IAP may function as a novel therapy to prevent liver fibrosis. Methods: Stool IAP activity from cirrhotic patients were determined. Common bile duct ligation (CBDL) and Carbon Tetrachloride-4 (CCl4)-induced liver fibrosis models were used in WT, IAP knockout (KO), and TLR4 KO mice supplemented with or without exogenous IAP in their drinking water. The gut barrier function and liver fibrosis markers were tested. Results: Human stool IAP activity was decreased in the setting of liver cirrhosis. In mice, IAP activity and genes expression decreased after CBDL and CCl4 exposure. Intestinal tight junction related genes and gut barrier function were impaired in both models of liver fibrosis. Oral IAP supplementation attenuated the decrease in small intestine tight junction protein gene expression and gut barrier function. Liver fibrosis markers were significantly higher in IAP KO compared to WT mice in both models, while oral IAP rescued liver fibrosis in both WT and IAP KO mice. In contrast, IAP supplementation did not attenuate fibrosis in TLR4 KO mice in either model. Conclusions: Endogenous IAP is decreased during liver fibrosis, perhaps contributing to the gut barrier dysfunction and worsening fibrosis. Oral IAP protects the gut barrier and further prevents the development of liver fibrosis via a TLR4-mediated mechanism.
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Affiliation(s)
- Yang Liu
- Department of General Surgery, Xi'an Jiaotong University Second Affiliated Hospital, Xi'an, China
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, US
| | - Paul M. Cavallaro
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, US
| | - Byeong-Moo Kim
- Division of Gastroenterology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, US
| | - Tao Liu
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, US
- Department of Gastroenterological Surgery, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Hongyan Wang
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, US
- Department of Gastroenterological Surgery, People's Hospital of Liaoning Province, Shenyang, China
| | - Florian Kühn
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, US
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Fatemeh Adiliaghdam
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, US
| | - Enyu Liu
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, US
- Department of Hepatobiliary Surgery, Qilu Hospital of Shandong University, Jian, China
| | - Robin Vasan
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, US
- Department of Surgery, University-Pittsburgh Medical Center, Pittsburgh, PA, US
| | - Ehsan Samarbafzadeh
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, US
| | - Matthew Z. Farber
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, US
| | - Junhui Li
- Department of General Surgery, Xi'an Jiaotong University Second Affiliated Hospital, Xi'an, China
| | - Meng Xu
- Department of General Surgery, Xi'an Jiaotong University Second Affiliated Hospital, Xi'an, China
| | - Vidisha Mohad
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, US
| | - Michael Choi
- Division of Gastroenterology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, US
| | - Richard A. Hodin
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, US
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Microbiota reprogramming for treatment of alcohol-related liver disease. Transl Res 2020; 226:26-38. [PMID: 32687975 PMCID: PMC7572584 DOI: 10.1016/j.trsl.2020.07.004] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Revised: 07/01/2020] [Accepted: 07/13/2020] [Indexed: 02/08/2023]
Abstract
In the past decade knowledge has expanded regarding the importance of the gut microbiota in maintaining intestinal homeostasis and overall health. During this same time, we have also gained appreciation for the role of the gut-liver axis in the development of liver diseases. Alcohol overconsumption is one of the leading causes of liver failure globally. However, not all people with alcohol use disorder progress to advanced stages of liver disease. With advances in technology to investigate the gut microbiome and metabolome, we are now beginning to delineate alcohol's effects on the gut microbiome in relation to liver disease. This review presents our current understanding on the role of the gut microbiota during alcohol exposure, and various therapeutic attempts that have been made to reprogram the gut microbiota with the goal of alleviating alcoholic-related liver disease.
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Maccioni L, Gao B, Leclercq S, Pirlot B, Horsmans Y, De Timary P, Leclercq I, Fouts D, Schnabl B, Stärkel P. Intestinal permeability, microbial translocation, changes in duodenal and fecal microbiota, and their associations with alcoholic liver disease progression in humans. Gut Microbes 2020; 12:1782157. [PMID: 32588725 PMCID: PMC7524402 DOI: 10.1080/19490976.2020.1782157] [Citation(s) in RCA: 98] [Impact Index Per Article: 19.6] [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
BACKGROUND Animal data suggest a role of the gut-liver axis in progression of alcoholic liver disease (ALD), but human data are scarce especially for early disease stages. METHODS We included patients with alcohol use disorder (AUD) who follow a rehabilitation program and matched healthy controls. We determined intestinal epithelial and vascular permeability (IP) (using urinary excretion of 51Cr-EDTA, fecal albumin content, and immunohistochemistry in distal duodenal biopsies), epithelial damage (histology, serum iFABP, and intestinal gene expression), and microbial translocation (Gram - and Gram + serum markers by ELISA). Duodenal mucosa-associated microbiota and fecal microbiota were analyzed by 16 S rRNA sequencing. ALD was staged by Fibroscan® (liver stiffness, controlled attenuation parameter) in combination with serum AST, ALT, and CK18-M65. RESULTS Only a subset of AUD patients had increased 51Cr-EDTA and fecal albumin together with disrupted tight junctions and vasculature expression of plasmalemma Vesicle-Associated Protein-1. The so-defined increased intestinal permeability was not related to changes of the duodenal microbiota or alterations of the intestinal epithelium but associated with compositional changes of the fecal microbiota. Leaky gut alone did not explain increased microbial translocation in AUD patients. By contrast, duodenal dysbiosis with a dominance shift toward specific potential pathogenic bacteria genera (Streptococcus, Shuttleworthia, Rothia), increased IP and elevated markers of microbial translocation characterized AUD patients with progressive ALD (steato-hepatitis, steato-fibrosis). CONCLUSION Progressive ALD already at early disease stages is associated with duodenal mucosa-associated dysbiosis and elevated microbial translocation. Surprisingly, such modifications were not linked with increased IP. Rather, increased IP appears related to fecal microbiota dysbiosis.
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Affiliation(s)
- Luca Maccioni
- Institute of Experimental and Clinical Research, Laboratory of Hepato-gastroenterology, UCLouvain, Université Catholique de Louvain, Brussels, Belgium
| | - Bei Gao
- Department of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Sophie Leclercq
- Institute of Neuroscience and Louvain Drug Research Institute, UCLouvain, Université Catholique de Louvain, Brussels, Belgium
| | - Boris Pirlot
- Institute of Experimental and Clinical Research, Laboratory of Hepato-gastroenterology, UCLouvain, Université Catholique de Louvain, Brussels, Belgium
| | - Yves Horsmans
- Department of Hepato-gastroenterology, Cliniques Universitaires Saint-Luc, Brussels, Belgium
| | - Philippe De Timary
- Department of Adult Psychiatry, Cliniques Universitaires Saint-Luc, Brussels, Belgium
| | - Isabelle Leclercq
- Institute of Experimental and Clinical Research, Laboratory of Hepato-gastroenterology, UCLouvain, Université Catholique de Louvain, Brussels, Belgium
| | | | - Bernd Schnabl
- Department of Medicine, University of California San Diego, La Jolla, CA, USA,Department of Medicine, VA San Diego Healthcare System, San Diego, CA, USA
| | - Peter Stärkel
- Institute of Experimental and Clinical Research, Laboratory of Hepato-gastroenterology, UCLouvain, Université Catholique de Louvain, Brussels, Belgium,Department of Hepato-gastroenterology, Cliniques Universitaires Saint-Luc, Brussels, Belgium,CONTACT Peter Stärkel Laboratory of Hepato-gastroenterology, Institute of Experimental and Clinical Research, UCLouvain, Université Catholique de Louvain, Brussels, Belgium
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Skinner C, Thompson AJ, Thursz MR, Marchesi JR, Vergis N. Intestinal permeability and bacterial translocation in patients with liver disease, focusing on alcoholic aetiology: methods of assessment and therapeutic intervention. Therap Adv Gastroenterol 2020; 13:1756284820942616. [PMID: 33149761 PMCID: PMC7580143 DOI: 10.1177/1756284820942616] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Accepted: 06/25/2020] [Indexed: 02/04/2023] Open
Abstract
Increased bacterial translocation (BT) across the gut barrier due to greater intestinal permeability (IP) is seen across a range of conditions, including alcohol-related liver disease (ArLD). The phenomenon of BT may contribute to both the pathogenesis and the development of complications in ArLD. There are a number of methods available to assess IP and in this review we look at their various advantages and limitations. The knowledge around BT and IP in ArLD is also reviewed, as well as the therapeutic strategies currently in use and in development.
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Affiliation(s)
- Charlotte Skinner
- Department of Metabolism, Digestion and Reproduction, St Mary’s Hospital Campus, Imperial College London, London, UK
| | - Alex J. Thompson
- Department of Surgery & Cancer, St. Mary’s Hospital Campus, Imperial College London, London, UK
| | - Mark R. Thursz
- Department of Metabolism, Digestion and Reproduction, St Mary’s Hospital Campus, Imperial College London, London, UK
| | - Julian R. Marchesi
- Department of Metabolism, Digestion and Reproduction, St Mary’s Hospital Campus, Imperial College London, London, UK
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Mehranfard N, Yazdi A, Sardooi AR, Shakerin Z, Ghasemi M. Honey protects against chronic unpredictable mild stress induced- intestinal barrier disintegration and hepatic inflammation. Mol Biol Rep 2020; 47:8475-8484. [PMID: 33047241 DOI: 10.1007/s11033-020-05888-4] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2020] [Accepted: 09/30/2020] [Indexed: 01/19/2023]
Abstract
Chronic stress is linked to liver injury by increasing intestinal permeability to lipopolysaccharide (LPS), which in turn can result in systemic and liver inflammation and damage. Beneficial effect of honey in the prevention of liver injury has been shown in previous studies, but mechanisms underlying are still less known. Here, we examined the therapeutic impacts of honey on intestinal nuclear factor-κB (NF-κB; an important regulator of stress-induced immune and inflammatory responses) and ileal tight junction (TJ) proteins of claudin-1 and ZO-1, serum LPS, liver inflammation and oxidative markers of malondialdehyde (MDA), nitric oxide (NO), (erythroid-derived 2)-like 2 (Nrf2), tumor necrosis factor (TNF)-α and total antioxidant capacity (TAC) following chronic unpredictable mild stress (CUMS) using Western blotting, ELISA kit and spectrophotometry. Male rats were subjected to CUMS for 28 consecutive days. Honey (0.2 and 2 g/kg/day, by gavage) was administered pretreatment (10 days) and during stress. Honey reduced stress-induced LPS elevation by preventing reduction in the intestinal TJ proteins of claudin-1 and ZO-1, while did not affect NF-kB levels. In liver, honey significantly suppressed stress-induced increase in MDA, NO, TNF-α and Nrf2 expression and normalized TAC. Noteworthy, honey high-dose provoked a greater decrease in TNF-α, Nrf2 and LPS levels than honey low-dose. Together, our study indicated that honey protects against stress-induced liver damage by modulating at least two pathways; intestinal barrier protection via increased TJ protein complex expression, and hepatic TAC protection that may be involved in the inhibition of MDA, NO, TNF-α and Nrf2 expression.
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Affiliation(s)
- Nasrin Mehranfard
- Neurophysiology Research Center, Cellular and Molecular Medicine Institute, Urmia University of Medical Sciences, Urmia, Iran
| | - Azadeh Yazdi
- Department of Physiology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Asiye Rafiee Sardooi
- Department of Physiology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Zeinab Shakerin
- PhD of Anatomical Science, Department of Anatomy, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Maedeh Ghasemi
- Department of Physiology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.
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Phosphoesterase complex modulates microflora and chronic inflammation in rats with alcoholic fatty liver disease. Life Sci 2020; 262:118509. [PMID: 33010280 DOI: 10.1016/j.lfs.2020.118509] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2020] [Revised: 09/07/2020] [Accepted: 09/24/2020] [Indexed: 02/08/2023]
Abstract
Phosphoesterase complex (Pho), a major active component of barley malt, has been demonstrated to be clinically effective in relieving alcoholic fatty liver disease (AFLD), and several lines of evidence have suggested that microbial dysbiosis, caused by chronic alcohol overconsumption, plays a key role in the progression of AFLD. The current study aimed to investigate the modulatory effect of Pho on gut microflora. The microbiota diversity, determined via detection of the V4 region of 16S rDNA genes, was analyzed in rats fed the Lieber-Decarli diet. Gut permeability was evaluated via mucus layer staining. Dysbiosis-associated chronic inflammation was investigated by observing the expression of the following inflammatory molecules in the liver: tumor necrosis factor α (TNF-α), monocyte chemotactic protein 1 (MCP-1), chemokine (C-X-C motif) ligand 1 (CXCL-1) and interleukin 1 beta (IL-1β). Pyrosequencing revealed that the gut microbiota in Pho-treated rats was different from that of AFLD rats at both the phylum and genus levels. In addition, Pho significantly alleviated dysbiosis-associated disruption of gut permeability and inflammation, increased mucus layer thickness and downregulated TNF-α, MCP-1, CXCL-1 and IL-1β expression. In summary, the current results revealed that the microflora, gut barrier and chronic inflammation in AFLD may be modulated by Pho.
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Mendes BG, Schnabl B. From intestinal dysbiosis to alcohol-associated liver disease. Clin Mol Hepatol 2020; 26:595-605. [PMID: 32911590 PMCID: PMC7641547 DOI: 10.3350/cmh.2020.0086] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Accepted: 07/27/2020] [Indexed: 12/11/2022] Open
Abstract
Alcohol-associated intestinal dysbiosis and bacterial overgrowth can lead to a dysregulation of tryptophan metabolism and lower production of indoles. Several of these indole derivatives are aryl hydrocarbon receptor ligands that, in turn, are involved in antimicrobial defense via induction of interleukin-22 (IL-22). IL-22 increases the expression of intestinal regenerating islet-derived 3 (Reg3) lectins, which maintain low bacterial colonization of the inner mucus layer and reduce bacterial translocation to the liver. Chronic alcohol consumption is associated with reduced intestinal expression of Reg3β and Reg3γ, increased numbers of mucosa-associated bacteria and bacterial translocation. Translocated microbial products and viable bacteria reach the liver and activate the innate immune system. Release of inflammatory molecules promotes inflammation, contributes to hepatocyte death and results in a fibrotic response. This review summarizes the mechanisms by which chronic alcohol intake changes the gut microbiota and contributes to alcohol-associated liver disease by changing microbial-derived metabolites.
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Affiliation(s)
- Beatriz Garcia Mendes
- Department of Clinical Analysis, Federal University of Santa Catarina, Florianopolis, SC, Brazil.,Department of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Bernd Schnabl
- Department of Medicine, University of California San Diego, La Jolla, CA, USA
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Chopyk DM, Grakoui A. Contribution of the Intestinal Microbiome and Gut Barrier to Hepatic Disorders. Gastroenterology 2020; 159:849-863. [PMID: 32569766 PMCID: PMC7502510 DOI: 10.1053/j.gastro.2020.04.077] [Citation(s) in RCA: 269] [Impact Index Per Article: 53.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2020] [Revised: 04/16/2020] [Accepted: 04/29/2020] [Indexed: 02/07/2023]
Abstract
Intestinal barrier dysfunction and dysbiosis contribute to development of diseases in liver and other organs. Physical, immunologic, and microbiologic (bacterial, fungal, archaeal, viral, and protozoal) features of the intestine separate its nearly 100 trillion microbes from the rest of the human body. Failure of any aspect of this barrier can result in translocation of microbes into the blood and sustained inflammatory response that promote liver injury, fibrosis, cirrhosis, and oncogenic transformation. Alterations in intestinal microbial populations or their functions can also affect health. We review the mechanisms that regulate intestinal permeability and how changes in the intestinal microbiome contribute to development of acute and chronic liver diseases. We discuss individual components of the intestinal barrier and how these are disrupted during development of different liver diseases. Learning more about these processes will increase our understanding of the interactions among the liver, intestine, and its flora.
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Affiliation(s)
- Daniel M. Chopyk
- Emory Vaccine Center, Division of Microbiology and Immunology, Yerkes National Primate Research Center, Emory University School of Medicine, Atlanta, GA
| | - Arash Grakoui
- Emory Vaccine Center, Division of Microbiology and Immunology, Yerkes National Primate Research Center, Emory University School of Medicine, Atlanta, Georgia; Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia.
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50
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A novel water pollution monitoring and treatment agent: Ag doped carbon nanoparticles for sensing dichromate, morphological analysis of Cr and sterilization. Microchem J 2020. [DOI: 10.1016/j.microc.2020.104855] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
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