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      Role of the Gut–Liver Axis in Liver Inflammation, Fibrosis, and Cancer: A Special Focus on the Gut Microbiota Relationship

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      Author(s): 1 , , 2 ,
      Publication date (Electronic):
      Journal: Hepatology Communications
      Publisher: John Wiley and Sons Inc.

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          Abstract

          The gut and the liver are anatomically and physiologically connected, and this “gut–liver axis” exerts various influences on liver pathology. The gut microbiota consists of various microorganisms that normally coexist in the human gut and have a role of maintaining the homeostasis of the host. However, once homeostasis is disturbed, metabolites and components derived from the gut microbiota translocate to the liver and induce pathologic effects in the liver. In this review, we introduce and discuss the mechanisms of liver inflammation, fibrosis, and cancer that are influenced by gut microbial components and metabolites; we include recent advances in molecular‐based therapeutics and novel mechanistic findings associated with the gut–liver axis and gut microbiota.

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          Short-chain fatty acids and ketones directly regulate sympathetic nervous system via G protein-coupled receptor 41 (GPR41).

          Ikuo Kimura, Daisuke Inoue, Takeshi Maeda … (2011)
          The maintenance of energy homeostasis is essential for life, and its dysregulation leads to a variety of metabolic disorders. Under a fed condition, mammals use glucose as the main metabolic fuel, and short-chain fatty acids (SCFAs) produced by the colonic bacterial fermentation of dietary fiber also contribute a significant proportion of daily energy requirement. Under ketogenic conditions such as starvation and diabetes, ketone bodies produced in the liver from fatty acids are used as the main energy sources. To balance energy intake, dietary excess and starvation trigger an increase or a decrease in energy expenditure, respectively, by regulating the activity of the sympathetic nervous system (SNS). The regulation of metabolic homeostasis by glucose is well recognized; however, the roles of SCFAs and ketone bodies in maintaining energy balance remain unclear. Here, we show that SCFAs and ketone bodies directly regulate SNS activity via GPR41, a Gi/o protein-coupled receptor for SCFAs, at the level of the sympathetic ganglion. GPR41 was most abundantly expressed in sympathetic ganglia in mouse and humans. SCFA propionate promoted sympathetic outflow via GPR41. On the other hand, a ketone body, β-hydroxybutyrate, produced during starvation or diabetes, suppressed SNS activity by antagonizing GPR41. Pharmacological and siRNA experiments indicated that GPR41-mediated activation of sympathetic neurons involves Gβγ-PLCβ-MAPK signaling. Sympathetic regulation by SCFAs and ketone bodies correlated well with their respective effects on energy consumption. These findings establish that SCFAs and ketone bodies directly regulate GPR41-mediated SNS activity and thereby control body energy expenditure in maintaining metabolic homeostasis.
          Article 0 comments Cited 386 times – based on 0 reviews     Review now
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            Modulation of the fecal bile acid profile by gut microbiota in cirrhosis.

            Genta Kakiyama, William Pandak, Patrick Gillevet … (2013)
            The 7α-dehydroxylation of primary bile acids (BAs), chenodeoxycholic (CDCA) and cholic acid (CA) into the secondary BAs, lithocholic (LCA) and deoxycholic acid (DCA), is a key function of the gut microbiota. We aimed at studying the linkage between fecal BAs and gut microbiota in cirrhosis since this could help understand cirrhosis progression. Fecal microbiota were analyzed by culture-independent multitagged-pyrosequencing, fecal BAs using HPLC and serum BAs using LC-MS in controls, early (Child A) and advanced cirrhotics (Child B/C). A subgroup of early cirrhotics underwent BA and microbiota analysis before/after eight weeks of rifaximin. Cross-sectional: 47 cirrhotics (24 advanced) and 14 controls were included. In feces, advanced cirrhotics had the lowest total, secondary, secondary/primary BA ratios, and the highest primary BAs compared to early cirrhotics and controls. Secondary fecal BAs were detectable in all controls but in a significantly lower proportion of cirrhotics (p<0.002). Serum primary BAs were higher in advanced cirrhotics compared to the rest. Cirrhotics, compared to controls, had a higher Enterobacteriaceae (potentially pathogenic) but lower Lachonospiraceae, Ruminococcaceae and Blautia (7α-dehydroxylating bacteria) abundance. CDCA was positively correlated with Enterobacteriaceae (r=0.57, p<0.008) while Ruminococcaceae were positively correlated with DCA (r=0.4, p<0.05). A positive correlation between Ruminococcaceae and DCA/CA (r=0.82, p<0.012) and Blautia with LCA/CDCA (r=0.61, p<0.03) was also seen. Prospective study: post-rifaximin, six early cirrhotics had reduction in Veillonellaceae and in secondary/primary BA ratios. Cirrhosis, especially advanced disease, is associated with a decreased conversion of primary to secondary fecal BAs, which is linked to abundance of key gut microbiome taxa. Copyright © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
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              Selective depletion of macrophages reveals distinct, opposing roles during liver injury and repair.

              Jeremy Duffield, Stuart J Forbes, Christothea M. Constandinou … (2005)
              Macrophages perform both injury-inducing and repair-promoting tasks in different models of inflammation, leading to a model of macrophage function in which distinct patterns of activation have been proposed. We investigated macrophage function mechanistically in a reversible model of liver injury in which the injury and recovery phases are distinct. Carbon tetrachloride---induced liver fibrosis revealed scar-associated macrophages that persisted throughout recovery. A transgenic mouse (CD11b-DTR) was generated in which macrophages could be selectively depleted. Macrophage depletion when liver fibrosis was advanced resulted in reduced scarring and fewer myofibroblasts. Macrophage depletion during recovery, by contrast, led to a failure of matrix degradation. These data provide the first clear evidence that functionally distinct subpopulations of macrophages exist in the same tissue and that these macrophages play critical roles in both the injury and recovery phases of inflammatory scarring.
              Article 0 comments Cited 235 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Naoko Ohtani: ohtani.naoko@med.osaka-cu.ac.jp
                Norifumi Kawada: kawadanori@med.osaka-cu.ac.jp
                Journal
                Journal ID (nlm-ta): Hepatol Commun
                Journal ID (iso-abbrev): Hepatol Commun
                Journal ID (doi): 10.1002/(ISSN)2471-254X
                Journal ID (publisher-id): HEP4
                Title: Hepatology Communications
                Publisher: John Wiley and Sons Inc. (Hoboken )
                ISSN (Electronic): 2471-254X
                Publication date (Electronic): 01 March 2019
                Publication date Collection: April 2019
                Volume: 3
                Issue: 4 ( doiID: 10.1002/hep4.v3.4 )
                Pages: 456-470
                Affiliations
                [ 1 ] Department of Pathophysiology Osaka City University, Graduate School of Medicine Osaka Japan
                [ 2 ] Department of Hepatology Osaka City University, Graduate School of Medicine Osaka Japan
                Author notes
                [*] [* ] Address Correspondence and Reprint Requests to:

                Naoko Ohtani, M.D., Ph.D.

                Department of Pathophysiology

                Osaka City University, Graduate School of Medicine

                1‐4‐3, Asahi‐machi

                Abeno‐ku, Osaka, Japan 545‐8585

                E‐mail: ohtani.naoko@ 123456med.osaka-cu.ac.jp

                Tel.: +81‐6‐6645‐3710

                Or

                Norifumi Kawada, M.D., Ph.D.

                Department of Hepatology

                Osaka City University, Graduate School of Medicine

                1‐4‐3, Asahi‐machi

                Abeno‐ku, Osaka, Japan 545‐8585

                E‐mail: kawadanori@ 123456med.osaka-cu.ac.jp

                Tel.: +81‐6‐6645‐3897

                Article
                Publisher ID: HEP41331
                DOI: 10.1002/hep4.1331
                PMC ID: 6442695
                PubMed ID: 30976737
                SO-VID: e7265631-d3ae-4e12-8e08-d7d02c0936e1
                Copyright © © 2019 The Authors. Hepatology Communications published by Wiley Periodicals, Inc., on behalf of the American Association for the Study of Liver Diseases.
                License:

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

                History
                Date received : 17 October 2018
                Date accepted : 11 February 2019
                Page count
                Figures: 4, Tables: 0, Pages: 15, Words: 26898
                Funding
                Funded by: Japan Agency for Medical Research and Development (AMED)
                Award ID: 17929503
                Award ID: 18fk0210004h0003
                Funded by: JSPS KAKENHI
                Award ID: 16H04699
                Award ID: 16H05290
                Categories
                Subject: Review
                Subject: Review
                Custom metadata
                source-schema-version-number 2.0
                component-id hep41331
                cover-date April 2019
                details-of-publishers-convertor Converter:WILEY_ML3GV2_TO_NLMPMC version:5.6.2.1 mode:remove_FC converted:01.04.2019

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