https://orcid.org/0000-0002-1521-1746
Figures & data
Figure 1. The double line of defense in the gut-liver axis. a. The first line of defense is the gut barrier, which is composed of the mucus barrier, the intestinal epithelial barrier, and the GVB. The mucus layer consists of a microbiota-colonized outer layer and an almost sterile inner layer. The epithelial barrier below the mucus layer is formed by epithelial cells. The deepest protective layer is the GVB. Under physiological circumstances, the healthy intestine barrier allows the absorption of nutrients while prevents the penetration of most toxic and harmful substances. b. Once it is damaged, intestinal microorganisms and their metabolites will move into the liver through the portal vein. c. LSECs are highly fenestrated cells, which can remove recycled waste products by endocytosis and degradation to protect liver against microorganisms and toxicants. They can also induce hepatic immune tolerance and keep the quiescence of HSCs and Kupffer cells. d. Injured LSECs become capillarized and the main characteristics of capillarization are formation of basement membrane, reduction of fenestrae and increased expression of pro-inflammatory mediators. They recruit immune cells and activate HSCs and Kupffer cells to cause liver inflammation. GVB: gut vascular barrier; LSECs: liver sinusoid endothelial cells. HSCs: hepatic stellate cells
Figure 2. The mechanisms of ALD induced by the gut mycobiota. a. Ethanol abuse leads to disordered gut mycobiota. Epicoccum, Galactomyces, and Debaryomyces decrease, while Candida increases significantly in the intestine. 1,3-β-glucan, a main component of fungal cell walls, and Candidalysin, a fungal metabolite, translocate into the systemic circulation through the injured intestinal barrier and reach the liver first. b. 1,3-β-glucan binds to dectin-1 of Kupffer cells. Src kinases phosphorylate tyrosine residue of dectin-1 and recruit Syk, which can activate the CARD9/BCL10/MALT1 complex. Then NF-κB will be activated by the complex and produce pro-IL-1β. Syk also promotes the secretion of caspase-1 through the activated NLRP3/ASC/pro-caspase-1 complex. Caspase-1 then cleaves pro-IL-1β into mature IL-1β, mediating liver inflammation and damage. Syk, spleen tyrosine kinase; CARD9, caspase recruitment domain 9; BCL10, B-cell lymphoma 10; MALT1, mucosa-associated lymphoid tissue lymphoma-translocation gene 1; NF-κB, nuclear factor kappa B; NLRP3, NOD-like receptor family pyrin domain containing 3; ASC, apoptosis-associated speck-like protein containing a CARD
