Recent updates on the role of the gut-liver axis in the pathogenesis of NAFLD/NASH, HCC, and beyond

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Abstract

The gut and the liver are anatomically and physiologically connected, and this connection is called the “gut-liver axis,” which exerts various influences on liver physiology and pathology. The gut microbiota has been recognized to trigger innate immunity and modulate the liver immune microenvironment. Gut microbiota influences the physiological processes in the host, such as metabolism, by acting on various signaling receptors and transcription factors through their metabolites and related molecules. The gut microbiota has also been increasingly recognized to modulate the efficacy of immune checkpoint inhibitors. In this review, we discuss recent updates on gut microbiota-associated mechanisms in the pathogenesis of chronic liver diseases such as NAFLD and NASH, as well as liver cancer, in light of the gut-liver axis. We particularly focus on gut microbial metabolites and components that are associated with these liver diseases. We also discuss the role of gut microbiota in modulating the response to immunotherapy in liver diseases.

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Most cited references 103

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Bo Qu, Gladys Ferrere, Céline Clemenson … (2018)

Immune checkpoint inhibitors (ICI) targeting the PD-1/PD-L1 axis induce sustained clinical responses in a sizeable minority of cancer patients. Here, we show that primary resistance to ICI can be due to abnormal gut microbiome composition. Antibiotics (ATB) inhibited the clinical benefit of ICI in patients with advanced cancer. Fecal microbiota transplantation (FMT) from cancer patients who responded to ICI (but not from non-responding patients) into germ-free or ATB-treated mice ameliorated the antitumor effects of PD-1 blockade. Metagenomics of patient stools at diagnosis revealed correlations between clinical responses to ICI and the relative abundance of Akkermansia muciniphila. Oral supplementation with A. muciniphila post-FMT with non-responder feces restored the efficacy of PD-1 blockade in an IL-12-dependent manner, by increasing the recruitment of CCR9+CXCR3+CD4+ T lymphocytes into tumor beds.

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J. Wargo, M Davies, J E Gershenwald … (2018)

Pre-clinical mouse models suggest that the gut microbiome modulates tumor response to checkpoint blockade immunotherapy; however, this has not been well-characterized in human cancer patients. Here we examined the oral and gut microbiome of melanoma patients undergoing anti-PD-1 immunotherapy (n=112). Significant differences were observed in the diversity and composition of the patient gut microbiome of responders (R) versus non-responders (NR). Analysis of patient fecal microbiome samples (n=43, 30R, 13NR) showed significantly higher alpha diversity (p<0.01) and relative abundance of Ruminococcaceae bacteria (p<0.01) in responding patients. Metagenomic studies revealed functional differences in gut bacteria in R including enrichment of anabolic pathways. Immune profiling suggested enhanced systemic and anti-tumor immunity in responding patients with a favorable gut microbiome, as well as in germ-free mice receiving fecal transplants from responding patients. Together, these data have important implications for the treatment of melanoma patients with immune checkpoint inhibitors.

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Gut commensal microbes shape the mucosal immune system by regulating the differentiation and expansion of several types of T cell. Clostridia, a dominant class of commensal microbe, can induce colonic regulatory T (Treg) cells, which have a central role in the suppression of inflammatory and allergic responses. However, the molecular mechanisms by which commensal microbes induce colonic Treg cells have been unclear. Here we show that a large bowel microbial fermentation product, butyrate, induces the differentiation of colonic Treg cells in mice. A comparative NMR-based metabolome analysis suggests that the luminal concentrations of short-chain fatty acids positively correlates with the number of Treg cells in the colon. Among short-chain fatty acids, butyrate induced the differentiation of Treg cells in vitro and in vivo, and ameliorated the development of colitis induced by adoptive transfer of CD4(+) CD45RB(hi) T cells in Rag1(-/-) mice. Treatment of naive T cells under the Treg-cell-polarizing conditions with butyrate enhanced histone H3 acetylation in the promoter and conserved non-coding sequence regions of the Foxp3 locus, suggesting a possible mechanism for how microbial-derived butyrate regulates the differentiation of Treg cells. Our findings provide new insight into the mechanisms by which host-microbe interactions establish immunological homeostasis in the gut.

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Author and article information

Contributors

Naoko Ohtani:

ORCID: https://orcid.org/0000-0001-8934-0797

Tomonori Kamiya:

ORCID: https://orcid.org/0009-0002-6970-9512

Norifumi Kawada

Journal

Journal ID (nlm-ta): Hepatol Commun

Journal ID (iso-abbrev): Hepatol Commun

Journal ID (publisher-id): HC9

Title: Hepatology Communications

Publisher: Lippincott Williams & Wilkins (Hagerstown, MD )

ISSN (Electronic): 2471-254X

Publication date Collection: September 2023

Publication date (Electronic): 28 August 2023

Volume: 7

Issue: 9

Electronic Location Identifier: e0241

Affiliations

[1 ]Department of Pathophysiology, Osaka Metropolitan University, Graduate School of Medicine, Osaka, Japan

[2 ]Department of Hepatology, Osaka Metropolitan University, Graduate School of Medicine, Osaka, Japan

Author notes

Correspondence Naoko Ohtani, Department of Pathophysiology, Osaka Metropolitan University, Graduate School of Medicine, 1-4-3, Asahi-machi, Abeno-ku, Osaka, Japan 545-8585. Email: naoko.ohtani@ 123456omu.ac.jp

Author information

Naoko Ohtani https://orcid.org/0000-0001-8934-0797

Tomonori Kamiya https://orcid.org/0009-0002-6970-9512

Article

Publisher ID: HEP4-23-0300 Accession ID: 00009

DOI: 10.1097/HC9.0000000000000241

PMC ID: 10462074

PubMed ID: 37639702

SO-VID: 7da603d9-5249-4367-8bba-c195053c570b

License:

This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0/

History

Date received : 7 April 2023

Date accepted : 30 June 2023

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