The Gut-Liver Axis in Health and Disease: The Role of Gut Microbiota-Derived Signals in Liver Injury and Regeneration

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.

Mitochondria as the Target of Hepatotoxicity and Drug-Induced Liver Injury: Molecular Mechanisms and Detection Methods

“…Taking into consideration the recently demonstrated role of dysbiosis in multiple liver diseases, including DILI, there is an urgent need for novel liver in vitro models that would incorporate gut microbiota as well, therefore increasing the relevance and translational power [ 342 , 343 , 344 ]. Advanced organ-on-a-chip and 3D models replicating the gut-liver axis with added microbiota components could represent the right direction for future interdisciplinary research in the DILI field [ 345 , 346 , 347 , 348 ].…”

Fine-tuning of regulatory T cells is indispensable for the metabolic steatosis-related hepatocellular carcinoma: A review

“…Likewise, excessive alcohol intake may damage microbiome balance, distort the intestinal barrier, and lead to a dysfunctional liver and other vital organs (Bishehsari et al, 2017). Alcohol-induced intestinal barrier disruption helps the endotoxins, including lipopolysaccharide (LPS), and cytokines, including IL-6 and TNFα, to translocate into the liver and interact with hepatocytes and immune cells (Bala et al, 2014;Bishehsari et al, 2017;Zheng and Wang, 2021), which play pivotal roles in ALD and hepatic inflammation. Evidence of the ethanoldependent modifications in the expression of CD4 + T Cell subsets in LPS-stimulated peripheral blood mononuclear cells suggests that ethanol impedes the Foxp3 kinetics and the production of IL-1 and TNF-α after the LPS challenge, thereby affecting the Treg/Th17 cells balance (von Haefen et al, 2011).…”

Integrating the Synergy of the Gut Microbiome into Regenerative Medicine: Relevance to Neurological Disorders

“…The gut-derived LPS by binding to Toll-like receptor 4 (TLR-4) activates Kupffer cells for the activation of NF-κB and stimulates the production of tumor necrosis factor-α (TNF-α), which causes the Kupffer cells to secrete interleukin-6 (IL-6). IL-6 trans-signaling induces hepatic stellate cells to produce a hepatocyte growth factor that, in coordination with other extrahepatic factors, such as T3, insulin, and epidermal growth factor, allows the remnant hepatocytes to overcome the cell-cycle checkpoint control and to proliferate towards liver regeneration after partial hepatectomy [ 27 ]. Administration of the Lactiplantibacillus plantarum AR113 probiotic has been shown to accelerate liver regeneration by increased hepatocyte proliferation and TNF-α, hepatocyte growth factor, and transforming growth factor-β expression [ 28 ].…”