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Liver–Gut Axis

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (30 April 2021) | Viewed by 45430

Special Issue Editor

Dr. Takemi Akahane

E-Mail Website
Guest Editor
Department of Gastroenterology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan
Interests: leaky gut; endotoxin; nonalcoholic fatty liver disease; alcoholic liver disease; liver fibrosis; Toll-like receptors; probiotics; antibiotics
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Gut-derived nutrients and other signals are delivered to the liver via the portal circulation. The liver as the largest immune organ hosts the entire spectrum of immune cell repertoire and has a remarkable capacity to recruit and activate immune cells in response to gut-derived metabolic or pathogen-derived signals. The crosstalk between the gut and liver is increasingly recognized, strengthened by the parallel rise in liver diseases and gastrointestinal and immune disorders. The gut–liver axis is widely implicated in the pathogenesis of liver disease, such as alcoholic liver disease, nonalcoholic fatty liver disease, primary biliary cholangitis, cirrhosis, hepatocellular carcinoma, and acute-on-chronic liver failure. The risk of damage to the liver increases when the intestinal barrier is damaged (“leaky gut”). Intestinal dysbiosis plays an important role in the development of chronic liver disease. The gut–liver axis has evolved from basic research to therapeutic strategies to improve the prognosis of chronic liver diseases. Further research on the gut–liver axis has led to new insights into the pathogenesis of liver disease and therapeutic strategies.

This Special Issue will be dedicated to “Liver–Gut Axis”; it welcomes submissions, including original papers and reviews, on these widely discussed topics.

Dr. Takemi Akahane
Guest Editor

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Keywords

  • Dysbiosis 
  • Leaky gut 
  • Gastrointestinal microbiome 
  • Endotoxin 
  • Antibiotics 
  • Probiotics 
  • Chronic liver disease 
  • Liver fibrosis 
  • Acute-on-chronic liver failure 
  • Hepatocellular carcinoma

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Published Papers (7 papers)

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Research

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16 pages, 3052 KiB  
Article
The Potential Protective Role of RUNX1 in Nonalcoholic Fatty Liver Disease
by Laia Bertran, Angela Pastor, Marta Portillo-Carrasquer, Jessica Binetti, Carmen Aguilar, Salomé Martínez, Margarita Vives, Fàtima Sabench, José Antonio Porras, David Riesco, Daniel Del Castillo, Cristóbal Richart and Teresa Auguet
Int. J. Mol. Sci. 2021, 22(10), 5239; https://doi.org/10.3390/ijms22105239 - 15 May 2021
Cited by 2 | Viewed by 3413
Abstract
The pathogenic mechanisms underlying nonalcoholic fatty liver disease (NAFLD) are beginning to be understood. RUNX1 is involved in angiogenesis, which is crucial in inflammation, but its role in nonalcoholic steatohepatitis (NASH) remains unclear. The aim of this study was to analyze RUNX1 mRNA [...] Read more.
The pathogenic mechanisms underlying nonalcoholic fatty liver disease (NAFLD) are beginning to be understood. RUNX1 is involved in angiogenesis, which is crucial in inflammation, but its role in nonalcoholic steatohepatitis (NASH) remains unclear. The aim of this study was to analyze RUNX1 mRNA hepatic and jejunal abundance in women with morbid obesity (MO) and NAFLD. RUNX1, lipid metabolism-related genes, and TLRs in women with MO and normal liver (NL, n = 28), NAFLD (n = 41) (simple steatosis (SS, n = 24), or NASH (n = 17)) were analyzed by RT-qPCR. The RUNX1 hepatic expression was higher in SS than in NL or NASH, as likewise confirmed by immunohistochemistry. An increased expression of hepatic FAS was found in NAFLD. Hepatic RUNX1 correlated positively with FAS. There were no significant differences in the jejunum RUNX1 expressions in the different groups. Jejunal FXR expression was lower in NASH than in NL, while the TLR9 expression increased as NAFLD progressed. Jejunal RUNX1 correlated positively with jejunal PPARγ, TLR4, and TLR5. In summary, the hepatic expression of RUNX1 seems to be involved in the first steps of the NAFLD process; however, in NASH, it seems to be downregulated. Our findings provide important insights into the role of RUNX1 in the context of NAFLD/NASH, suggesting a protective role. Full article
(This article belongs to the Special Issue Liver–Gut Axis)
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15 pages, 4460 KiB  
Article
Effective Combination Therapy of Angiotensin-II Receptor Blocker and Rifaximin for Hepatic Fibrosis in Rat Model of Nonalcoholic Steatohepatitis
by Yukihisa Fujinaga, Hideto Kawaratani, Daisuke Kaya, Yuki Tsuji, Takahiro Ozutsumi, Masanori Furukawa, Koh Kitagawa, Shinya Sato, Norihisa Nishimura, Yasuhiko Sawada, Hiroaki Takaya, Kosuke Kaji, Naotaka Shimozato, Kei Moriya, Tadashi Namisaki, Takemi Akahane, Akira Mitoro and Hitoshi Yoshiji
Int. J. Mol. Sci. 2020, 21(15), 5589; https://doi.org/10.3390/ijms21155589 - 4 Aug 2020
Cited by 27 | Viewed by 4010
Abstract
The progression of nonalcoholic steatohepatitis (NASH) is complicated. The multiple parallel-hits theory is advocated, which includes adipocytokines, insulin resistance, endotoxins, and oxidative stress. Pathways involving the gut–liver axis also mediate the progression of NASH. Angiotensin-II receptor blockers (ARB) suppress hepatic fibrosis via the [...] Read more.
The progression of nonalcoholic steatohepatitis (NASH) is complicated. The multiple parallel-hits theory is advocated, which includes adipocytokines, insulin resistance, endotoxins, and oxidative stress. Pathways involving the gut–liver axis also mediate the progression of NASH. Angiotensin-II receptor blockers (ARB) suppress hepatic fibrosis via the activation of hepatic stellate cells (HSCs). Rifaximin, a nonabsorbable antibacterial agent, is used for the treatment of hepatic encephalopathy and has been recently reported to improve intestinal permeability. We examined the inhibitory effects on and mechanism of hepatic fibrogenesis by combining ARB and rifaximin administration. Fischer 344 rats were fed a choline-deficient/l-amino acid-defined (CDAA) diet for 8 weeks to generate the NASH model. The therapeutic effect of combining an ARB and rifaximin was evaluated along with hepatic fibrogenesis, the lipopolysaccharide–Toll-like receptor 4 (TLR4) regulatory cascade, and intestinal barrier function. ARBs had a potent inhibitory effect on hepatic fibrogenesis by suppressing HSC activation and hepatic expression of transforming growth factor-β and TLR4. Rifaximin reduced intestinal permeability by rescuing zonula occludens-1 (ZO-1) disruption induced by the CDAA diet and reduced portal endotoxin. Rifaximin directly affect to ZO-1 expression on intestinal epithelial cells. The combination of an ARB and rifaximin showed a stronger inhibitory effect compared to that conferred by a single agent. ARBs improve hepatic fibrosis by inhibiting HSCs, whereas rifaximin improves hepatic fibrosis by improving intestinal permeability through improving intestinal tight junction proteins (ZO-1). Therefore, the combination of ARBs and rifaximin may be a promising therapy for NASH fibrosis. Full article
(This article belongs to the Special Issue Liver–Gut Axis)
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Review

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15 pages, 892 KiB  
Review
Intestinal Permeability Is a Mechanical Rheostat in the Pathogenesis of Liver Cirrhosis
by Norihisa Nishimura, Kosuke Kaji, Koh Kitagawa, Yasuhiko Sawada, Masanori Furukawa, Takahiro Ozutsumi, Yukihisa Fujinaga, Yuki Tsuji, Hiroaki Takaya, Hideto Kawaratani, Kei Moriya, Tadashi Namisaki, Takemi Akahane, Hiroshi Fukui and Hitoshi Yoshiji
Int. J. Mol. Sci. 2021, 22(13), 6921; https://doi.org/10.3390/ijms22136921 - 28 Jun 2021
Cited by 24 | Viewed by 3700
Abstract
Recent studies have suggested that an alteration in the gut microbiota and their products, particularly endotoxins derived from Gram-negative bacteria, may play a major role in the pathogenesis of liver diseases. Gut dysbiosis caused by a high-fat diet and alcohol consumption induces increased [...] Read more.
Recent studies have suggested that an alteration in the gut microbiota and their products, particularly endotoxins derived from Gram-negative bacteria, may play a major role in the pathogenesis of liver diseases. Gut dysbiosis caused by a high-fat diet and alcohol consumption induces increased intestinal permeability, which means higher translocation of bacteria and their products and components, including endotoxins, the so-called “leaky gut”. Clinical studies have found that plasma endotoxin levels are elevated in patients with chronic liver diseases, including alcoholic liver disease and nonalcoholic liver disease. A decrease in commensal nonpathogenic bacteria including Ruminococaceae and Lactobacillus and an overgrowth of pathogenic bacteria such as Bacteroidaceae and Enterobacteriaceae are observed in cirrhotic patients. The decreased diversity of the gut microbiota in cirrhotic patients before liver transplantation is also related to a higher incidence of post-transplant infections and cognitive impairment. The exposure to endotoxins activates macrophages via Toll-like receptor 4 (TLR4), leading to a greater production of proinflammatory cytokines and chemokines including tumor necrosis factor-alpha, interleukin (IL)-6, and IL-8, which play key roles in the progression of liver diseases. TLR4 is a major receptor activated by the binding of endotoxins in macrophages, and its downstream signal induces proinflammatory cytokines. The expression of TLR4 is also observed in nonimmune cells in the liver, such as hepatic stellate cells, which play a crucial role in the progression of liver fibrosis that develops into hepatocarcinogenesis, suggesting the importance of the interaction between endotoxemia and TLR4 signaling as a target for preventing liver disease progression. In this review, we summarize the findings for the role of gut-derived endotoxemia underlying the progression of liver pathogenesis. Full article
(This article belongs to the Special Issue Liver–Gut Axis)
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30 pages, 763 KiB  
Review
Nonalcoholic Fatty Liver Disease (NAFLD) as Model of Gut–Liver Axis Interaction: From Pathophysiology to Potential Target of Treatment for Personalized Therapy
by Francesca Fianchi, Antonio Liguori, Antonio Gasbarrini, Antonio Grieco and Luca Miele
Int. J. Mol. Sci. 2021, 22(12), 6485; https://doi.org/10.3390/ijms22126485 - 17 Jun 2021
Cited by 46 | Viewed by 6016
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the leading cause of liver disease worldwide, affecting both adults and children and will result, in the near future, as the leading cause of end-stage liver disease. Indeed, its prevalence is rapidly increasing, and NAFLD is becoming [...] Read more.
Nonalcoholic fatty liver disease (NAFLD) is the leading cause of liver disease worldwide, affecting both adults and children and will result, in the near future, as the leading cause of end-stage liver disease. Indeed, its prevalence is rapidly increasing, and NAFLD is becoming a major public health concern. For this reason, great efforts are needed to identify its pathogenetic factors and new therapeutic approaches. In the past decade, enormous advances understanding the gut–liver axis―the complex network of cross-talking between the gut, microbiome and liver through the portal circulation―have elucidated its role as one of the main actors in the pathogenesis of NAFLD. Indeed, evidence shows that gut microbiota is involved in the development and progression of liver steatosis, inflammation and fibrosis seen in the context of NAFLD, as well as in the process of hepatocarcinogenesis. As a result, gut microbiota is currently emerging as a non-invasive biomarker for the diagnosis of disease and for the assessment of its severity. Additionally, to its enormous diagnostic potential, gut microbiota is currently studied as a therapeutic target in NAFLD: several different approaches targeting the gut homeostasis such as antibiotics, prebiotics, probiotics, symbiotics, adsorbents, bariatric surgery and fecal microbiota transplantation are emerging as promising therapeutic options. Full article
(This article belongs to the Special Issue Liver–Gut Axis)
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16 pages, 1241 KiB  
Review
Bile Acids and Microbiota: Multifaceted and Versatile Regulators of the Liver–Gut Axis
by Niklas Grüner and Jochen Mattner
Int. J. Mol. Sci. 2021, 22(3), 1397; https://doi.org/10.3390/ijms22031397 - 30 Jan 2021
Cited by 73 | Viewed by 9506
Abstract
After their synthesis from cholesterol in hepatic tissues, bile acids (BAs) are secreted into the intestinal lumen. Most BAs are subsequently re-absorbed in the terminal ileum and are transported back for recycling to the liver. Some of them, however, reach the colon and [...] Read more.
After their synthesis from cholesterol in hepatic tissues, bile acids (BAs) are secreted into the intestinal lumen. Most BAs are subsequently re-absorbed in the terminal ileum and are transported back for recycling to the liver. Some of them, however, reach the colon and change their physicochemical properties upon modification by gut bacteria, and vice versa, BAs also shape the composition and function of the intestinal microbiota. This mutual interplay of both BAs and gut microbiota regulates many physiological processes, including the lipid, carbohydrate and energy metabolism of the host. Emerging evidence also implies an important role of this enterohepatic BA circuit in shaping mucosal colonization resistance as well as local and distant immune responses, tissue physiology and carcinogenesis. Subsequently, disrupted interactions of gut bacteria and BAs are associated with many disorders as diverse as Clostridioides difficile or Salmonella Typhimurium infection, inflammatory bowel disease, type 1 diabetes, asthma, metabolic syndrome, obesity, Parkinson’s disease, schizophrenia and epilepsy. As we cannot address all of these interesting underlying pathophysiologic mechanisms here, we summarize the current knowledge about the physiologic and pathogenic interplay of local site microbiota and the enterohepatic BA metabolism using a few selected examples of liver and gut diseases. Full article
(This article belongs to the Special Issue Liver–Gut Axis)
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16 pages, 771 KiB  
Review
The Role of the Gut Microbiome in Liver Cirrhosis Treatment
by Na Young Lee and Ki Tae Suk
Int. J. Mol. Sci. 2021, 22(1), 199; https://doi.org/10.3390/ijms22010199 - 28 Dec 2020
Cited by 66 | Viewed by 11153
Abstract
Liver cirrhosis is one of the most prevalent chronic liver diseases worldwide. In addition to viral hepatitis, diseases such as steatohepatitis, autoimmune hepatitis, sclerosing cholangitis and Wilson’s disease can also lead to cirrhosis. Moreover, alcohol can cause cirrhosis on its own and exacerbate [...] Read more.
Liver cirrhosis is one of the most prevalent chronic liver diseases worldwide. In addition to viral hepatitis, diseases such as steatohepatitis, autoimmune hepatitis, sclerosing cholangitis and Wilson’s disease can also lead to cirrhosis. Moreover, alcohol can cause cirrhosis on its own and exacerbate chronic liver disease of other causes. The treatment of cirrhosis can be divided into addressing the cause of cirrhosis and reversing liver fibrosis. To this date, there is still no clear consensus on the treatment of cirrhosis. Recently, there has been a lot of interest in potential treatments that modulate the gut microbiota and gut-liver axis for the treatment of cirrhosis. According to recent studies, modulation of the gut microbiome by probiotics ameliorates the progression of liver disease. The precise mechanism for relieving cirrhosis via gut microbial modulation has not been identified. This paper summarizes the role and effects of the gut microbiome in cirrhosis based on experimental and clinical studies on absorbable antibiotics, probiotics, prebiotics, and synbiotics. Moreover, it provides evidence of a relationship between the gut microbiome and liver fibrosis. Full article
(This article belongs to the Special Issue Liver–Gut Axis)
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24 pages, 937 KiB  
Review
Liver Cirrhosis and Sarcopenia from the Viewpoint of Dysbiosis
by Hiroki Nishikawa, Hirayuki Enomoto, Shuhei Nishiguchi and Hiroko Iijima
Int. J. Mol. Sci. 2020, 21(15), 5254; https://doi.org/10.3390/ijms21155254 - 24 Jul 2020
Cited by 34 | Viewed by 6362
Abstract
Sarcopenia in patients with liver cirrhosis (LC) has been attracting much attention these days because of the close linkage to adverse outcomes. LC can be related to secondary sarcopenia due to protein metabolic disorders and energy metabolic disorders. LC is associated with profound [...] Read more.
Sarcopenia in patients with liver cirrhosis (LC) has been attracting much attention these days because of the close linkage to adverse outcomes. LC can be related to secondary sarcopenia due to protein metabolic disorders and energy metabolic disorders. LC is associated with profound alterations in gut microbiota and injuries at the different levels of defensive mechanisms of the intestinal barrier. Dysbiosis refers to a state in which the diversity of gut microbiota is decreased by decreasing the bacterial species and the number of bacteria that compose the gut microbiota. The severe disturbance of intestinal barrier in LC can result in dysbiosis, several bacterial infections, LC-related complications, and sarcopenia. Here in this review, we will summarize the current knowledge of the relationship between sarcopenia and dysbiosis in patients with LC. Full article
(This article belongs to the Special Issue Liver–Gut Axis)
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