Bile Acids and Microbiota: Multifaceted and Versatile Regulators of the Liver-Gut Axis

Abstract

After their synthesis from cholesterol in hepatic tissues, bile acids (BAs) are secreted into the intestinal lumen. Most BAs are subsequently re-absorbed in the terminal ileum and are transported back for recycling to the liver. Some of them, however, reach the colon and change their physicochemical properties upon modification by gut bacteria, and vice versa, BAs also shape the composition and function of the intestinal microbiota. This mutual interplay of both BAs and gut microbiota regulates many physiological processes, including the lipid, carbohydrate and energy metabolism of the host. Emerging evidence also implies an important role of this enterohepatic BA circuit in shaping mucosal colonization resistance as well as local and distant immune responses, tissue physiology and carcinogenesis. Subsequently, disrupted interactions of gut bacteria and BAs are associated with many disorders as diverse as Clostridioides difficile or Salmonella Typhimurium infection, inflammatory bowel disease, type 1 diabetes, asthma, metabolic syndrome, obesity, Parkinson's disease, schizophrenia and epilepsy. As we cannot address all of these interesting underlying pathophysiologic mechanisms here, we summarize the current knowledge about the physiologic and pathogenic interplay of local site microbiota and the enterohepatic BA metabolism using a few selected examples of liver and gut diseases.

Keywords: bile acids; enterohepatic recirculation; host–microbe interactions; intestinal microbiota; microbial metabolism.

Figure 1

Schematic overview of the enterohepatic circulation (EHC). Primary bile acids (BAs) are synthesized in the liver and secreted into the duodenum with the bile; 95% of the BAs are re-absorbed in the terminal ileum and transported back to the liver for recycling. The remaining 5% enter the colon, where they are transformed into secondary BAs by colonic microbiota.

Figure 2

Effects of bile acid (BA) receptor engagement on immune cell function. After binding to the farnesoid X receptor (FXR) or the G protein-coupled receptor (TGR5), primary and secondary BAs shift the cytokine profile of myeloid cells to an anti-inflammatory phenotype. Their agonistic functions thereby depend on the affinity of individual BAs for the respective receptor, as indicated in the figure [51]. (IL-10 = interleukin-10; TGF-β = transforming growth factor beta; IFNγ = interferon gamma; TNF-α = tumor necrosis factor alpha; IL-6 = interleukin-6; IL-1β = interleukin-1 beta).

Figure 3

Influence of bile acid (BA) composition on colonic cell responses to the toxin of Bacteroides fragilis. The disruption of intestinal microbiota reduces the accumulation of primary BAs in the gut. Subsequently, the protective effect of primary BAs on colonic cell responses is lost and renders these cells susceptible to damage upon exposure to the toxin of Bacteroides fragilis.

Figure 4

Inhibition of liver cell growth through natural killer T (NKT) cells. Chenodeoxycholic acid (CDCA) enhances the expression of CXCL16 on liver sinusoidal endothelial cells. Subsequently, CXCR6⁺-NKT-cells accumulate in the liver and protect against hepatocellular carcinoma (HCC).