NAFLD/NASH meets "Leaky Gut"

The effect of a disturbed intestinal barrier on the liver was investigated in a pilot study by a Japanese research group, which presented its results at the International Liver Congress (ILC) 2019.

A research group tries to influence the intestinal barrier in patients with NAFLD with drugs

The effect of a disturbed intestinal barrier on the liver was investigated in a pilot study by a Japanese research group, which presented its results at the International Liver Congress (ILC) 2019 (see source 1).

Patients with non-alcoholic fatty liver disease (NAFLD) have elevated endotoxin levels, according to study author Dr. Takaomi Kessoku of Yokohama State University. These are responsible for the elevated TNF-α level and neutrophil infiltration in the context of non-alcoholic steatohepatitis (NASH). Kessoku also cited studies showing that antibiotic therapy can be helpful in liver damage due to bacterial overgrowth of the small intestine (see source 2).

The cause of the increased toxin exposure of the liver is ultimately the leaky gut (see source 3). Behind the disturbance of the intestinal barrier, we can indicate high-fat foods, alcohol, fructose, changes in the intestinal flora, drugs, and dietary supplements - all factors that are also associated with fatty liver in another context.

The Japanese research group now tried to influence the intestinal barrier in patients with NAFLD with drugs. Lubiprostone, a chloride channel activator given in chronic idiopathic constipation that promotes the transport of chloride ions into the intestine via ClC-2 channels, was used and led to increased paracellular fluid secretion and promoted bowel emptying.

Lubiprostone is a laxative, but there is evidence from the animal model and also from a small human study that it also improves the intestinal barrier (see source 4). In the now presented Phase II study, two doses of Lubiprostone were compared with placebo in a population of patients with NAFLD over 12 weeks. The primary endpoint was alanine aminotransferase (ALT) improvement, the secondary endpoint was a reduction in intestinal permeability measured by the lactulose-mannitol ratio (LMR).

Significantly higher ALT reductions were found in the two verum groups. In each of the two Lubiprostone groups, about 50% of the patients achieved an ALT reduction of at least 50%, compared to about 25% under placebo. The difference was significant. In the Lubiprostone groups, a significant improvement of the intestinal barrier was also measured.

The reduction of intestinal permeability correlated with the reduction of ALT. In the discussion, some weak points of the study were also discussed. Patients were obstipated and it is not clear whether these results can be transferred to patients who are not obstipated. Also, no liver biopsies were performed to confirm the diagnosis and/or therapy success. However, the authors point out that these are the results of a small proof-of-concept study.

Sources:
1. Kessoku T et al.: Efficacy, safety, and tolerability of lubiprostone for the treatment of non-alcoholic fatty liver disease: the LUBIPRONE, double-blind, randomized, placebo-controlled, phase II study. ILC 2019, GS-01
2. Sajjad A et al.: Ciprofloxacin suppresses bacterial overgrowth, increases fasting insulin but does not correct low acylated ghrelin concentration in non-alcoholic steatohepatitis. Aliment Pharmacol Ther 2005; 22(4): 291-9
3. Dai X, Wang B: Role of gut barrier function in the pathogenesis of the nonalcoholic fatty liver disease. Gastroenterol Res Pract 2015; 2015: 287348
4. Kato T et al.: Lubiprostone improves intestinal permeability in humans, a novel therapy for the leaky gut: a prospective randomized pilot study in healthy volunteers. PLoS One 2017; 12(4): e0175626

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