Implications of microbiota and bile acid in liver injury and regeneration

Abstract

Studies examining the mechanisms by which the liver incurs injury and then regenerates usually focus on factors and pathways directly within the liver, neglecting the signaling derived from the gut-liver axis. The intestinal content is rich in microorganisms as well as metabolites generated from both the host and colonizing bacteria. Through the gut-liver axis, this complex "soup" exerts an immense impact on liver integrity and function. This review article summarizes data published in the past 30 years demonstrating the signaling derived from the gut-liver axis in relation to liver injury and regeneration. Due to the intricate networks of implicated pathways as well as scarcity of available mechanistic data, it seems that nutrigenomic, metabolomics, and microbiota profiling approaches are warranted to provide a better understanding regarding the interplay and impact between nutrition, bacteria, and host response in influencing liver function and healing. Therefore elucidating the possible molecular mechanisms that link microbiota alteration to host physiological response and vice versa.

Keywords: Bile acid receptor; FXR; Gut dysbiosis; Gut-liver axis; Nuclear receptor; Partial hepatectomy; Prebiotic; Probiotic.

Fig. 1. Bile acid homeostasis and its downstream effects on carbohydrate and lipid metabolism

Hepatic cholesterol through cholesterol-7α-hydroxylase (CYP7A1) and sterol 12α-hydroxylase (CYP8B1) is converted to bile acids (BAs). BA transporters are involved in the secretion of BAs from the liver into the duodenum, flowing back through the ileum and reabsorbed by the liver. Farnesoid x receptor (FXR) and its targets are involved in the enterohepatic recycling of BAs. FXR-induced small heterodimer partner (SHP) inhibits BA synthesis by down-regulating CYP7A1 and CYP8B1 expression. Additionally, intestinal FXR induces fibroblast growth factor 15 (FGF15) expression, which in turn represses CYP7A1 through fibroblast growth factor receptor 4 (FGFR4) and β-Klotho-mediated signaling. Regarding lipid and carbohydrate metabolism, hepatic FXR activation induces gluconeogenesis and represses lipogenesis through SHP [100, 101]. Intestinal BAs also activate G protein-coupled bile acid receptor (TGR5) to increase production and secretion of glucagon-like peptide-1 (GLP-1), an incretin hormone that promotes insulin sensitivity, and thereby improves glucose disposition [102, 103]. CYP7A1, cholesterol-7α-hydroxylase; CYP8B1, sterol 12α-hydroxylase; BAs, bile acids; FXR, farnesoid x receptor; SHP, small heterodimer partner; FGF15, fibroblast growth factor 15; FGFR4, fibroblast growth factor receptor 4; TGR5, G protein-coupled bile acid receptor; GLP-1, glucagon-like peptide-1.

Fig 2. Bile acid synthesis as mediated by hepatic and intestinal bacteria enzymes

There are two pathways responsible for bile acid (BA) synthesis in the liver. In the classic pathway, the rate-limiting step in BA formation is conversion of cholesterol to 7α-hydroxycholesterol by cholesterol 7α-hydroxylase (CYP7A1). Multiple sequential steps that modify the steroid nucleus and side chain produce two primary BAs, cholic acid (CA) and chenodeoxycholic acid (CDCA). The main enzymes in those modification steps are 3β-hydroxy-Δ⁵-C₂₇-steroid dehydrogenase (HSD3B7), sterol 12α-hydroxylase (CYP8B1), Δ⁴-3-oxosteroid-5β-reductase (AKR1D1), 3α-hydroxysteroid dehydrogenase (AKR1C4), and sterol 27-hydroxylase (CYP27A1). Through the alternative pathway, cholesterol is converted into CDCA and the key enzymes involved are CYP27A1 and 25-hydroxycholesterol 7-α-hydroxylase (CYP7B1). Free primary BAs are conjugated through two reactions. First, using BA-CoA synthase (BACS), BA-CoA is generated. Next, BA-CoA:amino acid N-acyltransferase (BAT) amidates BA-CoA with either a taurine or a glycine. In the intestines, 7α-dehydroxylation of CA and CDCA converts the primary BAs into secondary BAs including deoxycholic acid (DCA) and lithocholic acid (LCA), respectively. The known bacterial species possessing 7α-dehydroxylation activity are members of the Firmicutes phylum (Clostridium and Eubacterium) [104]. The taurine or glycine conjugated BAs are catalyzed by bile salt hydrolases (BSHs) to become free BAs. BSH can be detected in bacterial genera including Bacteroides, Bifidobacterium, Clostridium, Lactobacillus, and Listeria [105]. Free BAs can be oxidized by hydroxysteroid dehydrogenases (HSDHs). For example, CA can be converted into 3-dehyhydrocholic acid, 7-dehyhydrocholic acid, and 12-oxochenodehydrocholic acid by 3α-HSDH, 7α-HSDH, and 12α-HSDH, respectively, and further converted into isocholic acid, 7-epicholic acid, and 12-epicholic acid by 3β-HSDH, 7β-HSDH, and 12β-HSDH, respectively. HSDHs are expressed by Firmicutes phylum members, including Eubacterium, Peptostreptococcus, and Ruminococcus [106]. BAs, bile acids; CYP7A1, cholesterol 7α-hydroxylase; CA, cholic acid; CDCA, chenodeoxycholic acid; HSD3B7, 3β-hydroxy-Δ⁵-C₂₇-steroid dehydrogenase; CYP8B1, sterol 12α-hydroxylase; AKR1D1, Δ⁴-3-oxosteroid-5β-reductase; AKR1C4, 3α-hydroxysteroid dehydrogenase; CYP27A1, sterol 27-hydroxylase; CYP7B1, 25-hydroxycholesterol 7-α-hydroxylase; BACS, BA-CoA synthase; BAT, BA-CoA:amino acid N-acyltransferase; DCA, deoxycholic acid, LCA, lithocholic acid; HSDH, hydroxysteroid dehydrogenase.

Fig. 3. Overview of the interplay between bile acid dysregulation and gut dysbiosis in the context of liver and GI pathologies

The gut and the liver are intimately associated, and there is continuous bidirectional communication between these organs through bile acids, hormones, inflammatory mediators, and products of digestion and absorption. A variety of liver diseases affect the bile acid profile, which contributes to gut dysbiosis and intestinal pathogenesis. Similarly, intestinal diseases lead to dysbiosis and change the bile acid profile that in turn affect metabolism and inflammatory response in the liver.