The gut-liver axis and the intersection with the microbiome

Abstract

In the past decade, an exciting realization has been that diverse liver diseases - ranging from nonalcoholic steatohepatitis, alcoholic steatohepatitis and cirrhosis to hepatocellular carcinoma - fall along a spectrum. Work on the biology of the gut-liver axis has assisted in understanding the basic biology of both alcoholic fatty liver disease and nonalcoholic fatty liver disease (NAFLD). Of immense importance is the advancement in understanding the role of the microbiome, driven by high-throughput DNA sequencing and improved computational techniques that enable the complexity of the microbiome to be interrogated, together with improved experimental designs. Here, we review gut-liver communications in liver disease, exploring the molecular, genetic and microbiome relationships and discussing prospects for exploiting the microbiome to determine liver disease stage and to predict the effects of pharmaceutical, dietary and other interventions at a population and individual level. Although much work remains to be done in understanding the relationship between the microbiome and liver disease, rapid progress towards clinical applications is being made, especially in study designs that complement human intervention studies with mechanistic work in mice that have been humanized in multiple respects, including the genetic, immunological and microbiome characteristics of individual patients. These 'avatar mice' could be especially useful for guiding new microbiome-based or microbiome-informed therapies.

Figure 1:. Physiological manifestations of liver injury along a spectrum of progression.

Risk factors such as alcohol abuse, unbalanced diet, infection (HBV/HCV) or immune dysfunction (PBC/PSC) can independently lead to liver injury. Alcohol-abuse patients and obese individuals often develop steatosis (fatty liver), which is characterized by increased intestinal permeability and dysbiosis. Subsequently, bile acid and choline homeostasis is disturbed along with increased translocation of MAMPs across the gut-barrier, leading to steatohepatitis, the progressive form of liver damage. Both, steatosis-dependent and steatosis-independent liver damage can progress to cirrhosis (end-stage liver damage), which is marked by translocation of viable bacteria to the liver and severe inflammation. As liver function is progressively compromised, tumor-promoting metabolites and xenobiotics accumulate. These could activate oncogenic pathways causing hepatocellular carcinoma, the most predominant form of primary liver cancers. (MAMPs: Microbial-associated molecular patterns; ALD: Alcoholic liver disease; NAFLD: Nonalcoholic fatty liver disease; ASH: Alcoholic steatohepatitis; NASH: Nonalcoholic steatohepatitis; HBV: Hepatitis B virus; HCV: Hepatitis C virus; PSC: Primary sclerosing cholangitis; PBC: Primary biliary cholangitis)

Figure 2:. Bidirectional communication between gut and liver.

The liver transports bile salts and antimicrobial molecules (IgA, angiogenin 1) to the intestinal lumen through the biliary tract. This maintains gut eubiosis by controlling unrestricted bacterial overgrowth. Bile salts also act as important signaling molecules via nuclear receptors (such as FXR, TGR5) to modulate hepatic bile acid synthesis, glucose metabolism, lipid metabolism and energy utilization from diet. On the other hand, gut-products such as host and/or microbial metabolites and MAMPs translocate to the liver via the portal vein and influence liver functions. Additionally, systemic circulation extends the gut-liver axis by transporting liver metabolites from dietary, endogenous or xenobiotic substances (eg. FFAs, choline metabolites, ethanol metabolites) to the intestine through the capillary system. Owing to this medium of transport and ease of diffusion of systemic mediators across blood capillaries, these could affect the intestinal barrier both, positively (eg. butyrate) or negatively (eg. acetaldehyde) (TMA: Trimethylamine; TMAO: Trimethylamine N-oxide; MAMPs: Pathogen-associated molecular patterns; VLDL: Very low-density lipoprotein; FXR: Farnesoid X receptor; TGR5: Takeda G-protein coupled receptor 5; FFA: Free fatty acid)

Figure 3.. Interplay between the liver and gut microbiome in (A) Alcoholic liver disease (ALD) and (B) Nonalcoholic fatty liver disease (NAFLD).

Intestinal dysbiosis and bacterial overgrowth is observed in both, ALD and NAFLD. Bacterial overgrowth causes an increase in secondary BAs which disrupts FXR-mediated modulation of BA levels, leading to an overall increase in hepatic BA synthesis. A reduction in hepatic phosphatidylcholine is also seen in both ALD and NAFLD, which causes triglyceride accumulation in the liver (fatty liver). While ALD-associated dysbiosis is characterized by reduction in Lactobacillus and Candida overgrowth, NAFLD patients have higher abundance of Lactobacillus (effects on fungal population remain to be investigated). Both, in ALD and NAFLD, increased ethanol and its metabolite acetaldehyde in the intestinal lumen mediates weakening of intestinal tight junctions. Consequently, increased translocation of MAMPs (seen in ALD and NAFLD) and gut metabolites such as acetaldehyde, acetate (seen in ALD) and TMA (seen in NAFLD) elicits intestinal and hepatic inflammatory responses, leading to progressive liver damage. (AMP: Antimicrobial peptides; BA: Bile acids; EtOH: Ethanol; FXR: Farnesoid X receptor; HFD: High-fat diet; LCFA: Long-chain fatty acids; TMA: Trimethylamine; TMAO: Trimethylamine N-oxide)