Gut Microbiota-Liver-Axis (GLA)

Overview

The Gut Microbiota-Liver-Axis (GLA) actively connects the gastrointestinal system and the liver through portal circulation (1, 2, 15). The liver gets blood from the gut via the portal vein, and the gut gets bile from the liver through the bile duct (7). It explains how the gut microbiota and the liver communicate with each other. They actively communicate to maintain gut balance and repair tissues in both health and disease (3, 17).

Mechanisms

Dysfunction of the Gut Mucosal Barrier (“leaky Gut”) and Increased Bacterial Translocation / Intestinal permeability into the Liver via the Gut–liver Axis Probably Play Crucial Roles in Liver Disease Development and Progression (14).

Minimal levels of pathogen-associated molecular patterns (PAMPs), such as lipopolysaccharides (LPS), peptidoglycans, and flagellin, trigger NFKB through toll-like receptors (TLRs) and nod-like receptors (NLRs). This activation produces inflammatory cytokines and chemokines that enter the portal circulation (1).

Kim et al. show that the liver releases Pigment epithelium-derived factor (PEDF), which limits the growth of intestinal stem cells (ISCs). This indicates that the Gut Microbiota-Liver-Axis (GLA) regulates ISC health for intestinal stability (3).

Role of (microbial) metabolites

Intestinal bacteria actively metabolize nutrients into various Co-Metabolites. Host tissues can further process these metabolites, which possess metabolic, immune, and/or neuroactive properties (11, 12, 13).

The portal vein directly carries gut-derived products to the liver (8), including microbial products like endotoxins and metabolites. In return, the liver secretes bile acids and antibodies that influence gut microbial composition and strengthen intestinal barrier integrity (9, 10).

Under physiological conditions, the products and metabolites of gut microbiota (GM) play a crucial role in maintaining the balance of the gut-liver axis by exerting effects both locally and throughout the body (4). The gut microbiota and its metabolites actively modulate liver gene expression through the Gut Microbiota-Liver-Axis (GLA) (6).

Bile acids / Bile salts function as key regulators. They thereby maintain Bile acids / Bile salts and cholesterol homeostasis, hepatic glucose and lipid metabolism, energy balance, and inflammatory responses (5).

Impact on the pathogenesis of numerous diseases

The Gut Microbiota-Liver-Axis (GLA) has an impact on the pathogenesis of numerous chronic liver diseases such as Chronic Hepatitis B (CHB), Chronic Hepatitis C (CHC), alcoholic liver disease (ALD), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), development of liver cirrhosis, and hepatocellular carcinoma (HCC) (11). Exposure to gut-derived bacteria through portal circulation prompts the liver to activate the innate and adaptive immune systems, causing hepatic injury (14).

Hepatocyte damage triggers PAMPs (pathogen-associated molecular patterns) to activate stellate cells, which promote and progress fibrosis. Kupffer cells respond more strongly to Lipopolysaccharides (LPS) than hepatocytes. (16).

References

(1) Milosevic et al. 2019 Int. J. Mol. Sci. 20: 395
(2) Russo et al. 2022 World J Hepatol 14(2): 372-385
(3) Kim et al. 2024 Cell 187(4):
(4) Pabst et al. 2023 Nat Rev Gastroenterol Hepatol 20: 447-461
(5) Xia et al. 2026 Front Microbiol 17: 1832332
(6) Silveira et al. 2022 Trends in Cancer 8: 583
(7) Xu et al. 2021g Pathogens 10: 782
(8) Delzenne et al. 2019
(9) Ohtani & Kawada 2019 Hepatol Commun 3(4): 456-470
(10) Albillos et al. 2020 J Hepatol 72: 558-577
(11) Hubbard et al. 2015 Drug Metab Dispos 43: 1522-1535
(12) Husted et al. 2017 Cell Metab 25: 777-796
(13) Krishnan et al. 2018 Cell Rep 23: 1099-1111
(14) Konturek et al. 2018
(15) Brandl et al. 2017 Am. J. Physiol. Gastrointest. Liver Physiol. 312: G413–G419
(16) Yiu et al. 2017 J. Mol. Med. 95: 13-20
(17) Carotti et al. 2015 World J. Gastrointest. Pathophysiol. 6: 99–109

see also:
Cancer / Tumors & Gut Microbiota-Liver-Axis (GLA)
Bacterial metabolites / Microbial metabolites & Diseases / Disorders
Gut microbiota & Immunity
Gut Microbiota-Liver-Axis (GLA) & Hepatic Inflammation / Liver Inflammation
Gut Microbiota-Liver-Kidney Axis
Hepatic disease / Liver disease & Microbiota-Gut-Liver-Axis
Xenobiotics biodegradation / Drug metabolism