Abstract
ABSTRACT There is increasing evidence for the role of gut microbial composition in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Nonalcoholic steatohepatitis (NASH) is the most serious form of NAFLD where inflammation causes liver damage that can progress to cirrhosis. We have characterized the gut microbiome composition in UK patients with biopsy-proven NASH (n = 65) and compared it to that in healthy controls (n = 76). We report a 7% lower Shannon alpha diversity in NASH patients without cirrhosis (n = 40) compared to controls (p = 2.7x 10−4) and a 14% drop in NASH patients with cirrhosis (n = 25, p = 5.0x 10−4). Beta diversity (Unweighted UniFrac distance) was also significantly reduced in both NASH (p = 5.6x 10−25) and NASH-cirrhosis (p = 8.1x 10−7) groups. The genus most strongly associated with NASH in this study was Collinsella (0.29% abundance in controls, 3.45% in NASH without cirrhosis (False Discovery Rate (FDR) p = .008), and 4.38% in NASH with cirrhosis (FDR p = .02)). This genus, which has been linked previously to obesity and atherosclerosis, was also positively correlated with fasting levels of triglycerides (p = .01) and total cholesterol (p = 1.2x 10−4) and negatively correlated with high-density lipoprotein cholesterol (p = 2.8x 10−6) suggesting that some of the pathways present in this microbial genus may influence lipid metabolism in the host. In patients, we also found decreased abundance of some of the Ruminococcaceae which are known to produce high levels of short-chain fatty acids which can lower inflammation. This may thus contribute to pathology associated with NASH.
Highlights
Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide[1,2,3] and includes a spectrum of pathologies ranging from simple steatosis through non-alcoholic steatohepatitis (NASH), characterised by the presence of inflammation, to cirrhosis[4] which is responsible for 2% of all deaths worldwide[5]
Clinical characteristics The descriptive characteristics of NASH patients and controls are presented in Diversity metrics A significant decrease in alpha diversity, indicated by Shannon index and operational taxonomic units (OTUs), was observed in both NASH and NASH-cirrhosis groups compared to controls
NASH after adjustment for covariates and false discovery rate (FDR), and 21 of these remained significant in the NASH-cirrhosis group
Summary
Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide[1,2,3] and includes a spectrum of pathologies ranging from simple steatosis through non-alcoholic steatohepatitis (NASH), characterised by the presence of inflammation, to cirrhosis[4] which is responsible for 2% of all deaths worldwide[5]. NAFLD has been associated with an increase in intestinal permeability[7], and the subsequent infiltration of Gram-negative bacteria could induce liver inflammation via TLR4 signalling, enabling the release of TNF-α and the activation of hepatic stellate cells[8]. As the liver is linked to the intestine through the portal circulation, gut-derived products including both nutrients from the diet and microbial components will arrive first at the liver[9]. Pathogenic interactions between the liver and microbiota range from straightforward effects, such as increased intestinal permeability leading to passage of Gram-negative bacteria into the portal circulation and subsequent inflammation[10], to more complex interactions with metabolites produced by the microbiota, under the influence of modifiable factors such as diet. Since the establishment of a gut microbiome characteristic of obesity[11], similar links between the intestinal microbiota and the development of NASH have been investigated
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