Susceptibility to gut leakiness: a possible mechanism for endotoxaemia in non-alcoholic steatohepatitis.

The term non-alcoholic fatty liver disease (NAFLD) has been coined to represent the spectrum of histological changes, from pure non-alcoholic fatty liver (steatosis) to non-alcoholic steatohepatitis (NASH), fibrosis and finally cirrhosis (1, 2) Recent epidemiological data suggest a prevalence of 3–6% for NAFLD in the general population, making NAFLD the most common liver disease in the USA (3, 4). The single most important predictor in the natural history of progression from benign simple steatosis to life-threatening cirrhosis is the presence of inflammation and fibrosis (5). Associated factors such as age and diabetes play a significant but secondary role in NAFLD. Steatosis, the most common form of NAFLD, appears to be a benign process resulting from abnormal lipid metabolism. In contrast, NASH is far less common than steatosis and does not appear to be benign in most patients; not infrequently, it progresses to cirrhosis and liver failure (5). Because only 15–25% of patients with steatosis progress to NASH (6), it is highly likely that a cofactor is required to cause inflammation and liver cell necrosis in a setting of abnormal hepatic lipid homoeostasis and steatosis. This so-called two-hit hypothesis postulates that simple steatosis is the liver’s manifestation of the metabolic syndrome, but it requires a second hit (insult) for progression to NASH (7). One proposed second-hit mechanism is gut-derived endotoxin (8). This is based on two sets of findings. (1) Gut-derived endotoxin is likely a prerequisite cofactor in the development of alcoholic steatohepatitis and cirrhosis in alcoholics (9, 10), fatty liver being extremely common in alcoholics, but steatohepatitis and cirrhosis occur in only 15–25% of alcoholics. This pattern is similar to the pattern for NAFLD. (2) More direct evidence for the role of gut-derived endotoxin in the pathogenesis of NASH comes from animal studies. Animal studies have shown that systemic endotoxaemia leads to steatohepatitis in genetically obese rats, via release of tumour necrosis factor-α (11). In addition, Brun et al. (12) showed that genetically obese mice display enhanced intestinal permeability leading to increased portal endotoxaemia, which makes hepatic stellate cells more sensitive to bacterial endotoxin. Possible mechanisms for endotoxaemia in patients with NASH include (a) bacterial overgrowth and (b) disrupted intestinal barrier integrity (leaky gut) that results in increased absorption of endotoxin (12–14). Indeed, we recently demonstrated increased intestinal permeability (leaky gut) in alcoholics with liver disease (15), a disorder with pathophysiological and histological features similar to NAFLD and NASH. It remains to be determined, however, whether leaky gut is also present in patients with NASH. Accordingly, we hypothesized that patients with NASH have either frank gut leakiness or easily triggered susceptibility to gut leakiness (intermittent gut leakiness), either of which results in increased passage of gut-derived bacterial products such as endotoxin into the portal circulation, where it initiates hepatic necroinflammatory cascades and results in liver cell injury. The aim of our study was to determine whether patients with NASH have leaky guts or susceptibility to gut leakiness.