A probiotic solution significantly reduced the risk of hospitalization for hepatic encephalopathy and markers of liver disease severity in patients with cirrhosis, researchers report in the December issue of Gastroenterology.
Hepatic encephalopathy develops in 50%–70% of patients with cirrhosis; fewer than 50% of these patients survive for 1 year. Rifaximin and lactulose are commonly used to try to prevent hepatic encephalopathy, but there are concerns about their cost and side effects. Many patients develop breakthrough episodes of hepatic encephalopathy despite prophylactic treatment with these agents.
Hepatic encephalopathy has been linked to alterations in the intestinal microbiota, increased production of gut-derived toxins such as ammonia and indoles, and endotoxemia, which lead to systemic and cerebral inflammation.
Probiotics can alter numbers, composition, and functions of bacteria in the intestinal microbiome and reduce levels of ammonia. Radha K. Dhiman et al therefore performed a randomized controlled trial to determine whether probiotics could prevent recurrence of hepatic encephalopathy and improve liver function in patients with cirrhosis.
At a hospital in India, 130 patients with cirrhosis who had recovered from an episode of hepatic encephalopathy in the previous month were randomly assigned to groups given a probiotic preparation (VSL#3, 9 × 1011 colony-forming units per sachet) or placebo (controls) each day for 6 months.
VSL#3 contains 4 Lactobacillus species (L paracasei, L plantarum, L acidophilus, and L delbrueckii subspecies bulgaricus), 3 Bifidobacterium species (B longum, B infantis, and B breve), and Streptococcus thermophiles.
After the 6 month period ended, only 34.8% of subjects in the probiotic group had developed hepatic encephalopathy, compared with 51.6% in the control group, although this difference was not significant.
However, significantly fewer patients in the probiotic group were hospitalized for hepatic encephalopathy (19.7% vs 42.2% of controls) or for complications of cirrhosis (24.2% vs 45.3% of controls). The mean time to hospitalization for any reason was 136 days in the probiotic group and 109 days in the placebo group.
There were no adverse events related to VSL#3. Thirty patients died during the study: 14 in the probiotic group and 16 in the placebo group.
Fasting blood ammonia levels decreased among patients in the probiotic group and increased among patients in the placebo group, although these were not statistically significant. Plasma indole levels decreased significantly only in the probiotic group.
Although plasma levels of the inflammatory cytokines tumor necrosis factor (TNF), IL1B, and IL6 decreased significantly in the probiotic group, there was no significant change in the placebo group. Plasma levels of renin and brain-type natriuretic peptide (BNP) also decreased significantly in the probiotic group but not the placebo group.
How could a probiotic reduce markers of liver disease, complications of cirrhosis, and even risk of hospitalization? Dhiman et al explain that bacterial overgrowth and impaired intestinal barrier integrity in patients with cirrhosis leads to endotoxemia. Endotoxemia initiates liver damage through its interaction with Toll-like receptors, which activate immune and inflammatory responses. Systemic inflammation and infection exacerbate the symptoms of hepatic encephalopathy in patients with all grades of cirrhosis. Production of inflammatory cytokines such as TNFa, IL1b, and IL6 can the increase the cerebral effects of ammonia.
Probiotics have been shown to improve the integrity of the gut epithelium, promote innate immunity in the gut, and reduce local and systemic inflammation.
Dhiman et al propose that in the patients receiving the probiotics, significant reductions in renin, aldosterone, and BNP probably resulted from improved cardiac function, systemic hemodynamics, and increased renal blood flow following reductions in inflammatory cytokines. However, further studies of hemodynamic parameters are needed to confirm model.
The authors conclude that probiotic use significantly reduces the risk of hospitalization, related primarily to the development of fewer complications and episodes of breakthrough hepatic encephalopathy in patients with cirrhosis. They say that this could translate into significant cost savings.
In an editorial that accompanies the article, David W. Victor, III and Eamonn M.M. Quigley state that additional studies, to demonstrate a clinically meaningful reduction in recurrence of hepatic encephalopathy, are required before this or any other probiotic can be recommended for treatment of patients.
They say it is also important to identify the bacterial populations whose presence, or absence, affect risk for hepatic encephalopathy. This would facilitate development of probiotic formulations best suited for therapy or prevention.