By Neal S. Parikh, MD, MS

Assistant Professor of Neurology, Weill Cornell Medical College

Dr. Parikh reports no financial relationships relevant to this field of study.

SYNOPSIS: Patients with cirrhosis and mild cognitive impairment and falls were randomized to a probiotic formulation vs. placebo. Probiotic treatment improved cognitive outcomes and reduced the risk of falls.

SOURCE: Román E, Nieto JC, Gely C, et al. Effect of a multistrain probiotic on cognitive function and risk of falls in patients with cirrhosis: A randomized trial. Hepatol Commun 2019;3:632-645.

Hepatic encephalopathy is a hallmark feature of decompensated liver cirrhosis. Cognitive impairment in the form of minimal or covert hepatic encephalopathy also is common in cirrhosis without decompensation. Individuals with cirrhosis and cognitive impairment experience poor outcomes, including traffic accidents and falls.

Cognitive impairment in cirrhosis is thought to be caused by hyperammonemia and neuroinflammation. Gut dysbiosis, or the disruption of a healthy gut microbiome, is an area of increasing research interest as it pertains to vascular and cognitive disorders. In cirrhosis, dysbiosis may contribute to systemic inflammation when there is a high burden of pathological bacterial translocation through a disrupted intestinal barrier. For these reasons, Román et al and other research groups have identified the gut microbiome as a potential target for the treatment of cognitive impairment in patients with cirrhosis. The authors of several prior studies found a favorable effect of probiotics on cognitive measures in this population.

Prior studies focused on the prevention and amelioration of hepatic encephalopathy, whereas Román et al shifted their focus to include fall prevention. They hypothesized that multistrain probiotic supplementation would decrease fall risk in part through improved cognition. Secondarily, they hypothesized that probiotic supplementation would decrease systemic inflammation and intestinal barrier disruption. They did not perform explicit tests of mediation to evaluate these hypotheses.

The authors included consecutive patients with cirrhosis and mild cognitive dysfunction and/or prior falls from a single center. Cognitive dysfunction was defined using the Psychometric Hepatic Encephalopathy Score (PHES), which is a gold standard, comprehensive, validated battery for the assessment of hepatic encephalopathy. Importantly, they excluded patients with overt hepatic encephalopathy, active alcohol users, and those on treatment for hepatic encephalopathy.

Patients were randomized to a probiotic or placebo for 12 weeks. They were evaluated at baseline, after 12 weeks of treatment, and eight weeks after the end of treatment. Key clinical outcomes were cognitive function using the PHES, risk of falls using validated gait metrics, and incidence of falls. Additionally, they measured C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-α), interleukins 6 and 10, neutrophil oxidative reserve, and markers of intestinal barrier integrity.

They screened 279 patients to randomize 36. The two groups were well-balanced. Overall, two patients died during the short study period. Cognitive function improved over 12 weeks with probiotic treatment (P = 0.006) but not with placebo. Similarly, patients randomized to probiotic treatment demonstrated significantly improved gait by two parameters, without changes in the placebo-treated patients. While the study lacked the power to detect statistically significant differences in incident falls, probiotic treatment resulted in nominally fewer falls (0 vs. 4; P = 0.10). They also lacked power for safety outcomes, but did not detect a difference in serious events.

These findings correlated with reductions in systemic inflammation as measured by CRP and TNF-α, in addition to improved neutrophil oxidative reserve, among only probiotic-treated patients. In parallel, probiotic treatment decreased markers of intestinal barrier disruption. The authors concluded that probiotic treatment may improve cognition and decrease falls in patients with cirrhosis, perhaps through amelioration of pathological bacterial translocation, intestinal barrier breakdown, and systemic inflammation.

COMMENTARY

As Román et al acknowledged, the small sample size was a key limitation. However, their study was elegant and rigorous. The found a consistent direction of effect across multiple complementary outcomes, which increases the validity of their results. The authors alleged that their exacting exclusion criteria — excluding those with overt hepatic encephalopathy — was a limitation. While this certainly limits generalizability, their selection criteria led to a fortuitous outcome: They demonstrated the effectiveness of probiotic treatment among patients with minimal or covert hepatic encephalopathy. This is important because minimal and covert encephalopathy are far more common and present earlier in cirrhosis. These patients have a longer period during which to derive cognitive and fall-related safety benefits. In this light, the findings of this study may, in fact, have more clinical translational potential. With increasing interest in understanding the role of chronic liver diseases in cognitive impairment, these findings may have therapeutic potential in a larger population than the authors anticipated. Further validation of their findings in patients with milder chronic liver diseases may yield novel opportunities for the treatment of cognitive impairment and the prevention of falls.