Effect of a specific Escherichia coli Nissle 1917 strain on minimal/mild hepatic encephalopathy treatment

Abstract

Background: Hepatic encephalopathy (HE) can be considered a result of dysregulated gut-liver-brain axis function, where cognitive impairment can be reversed or prevented by the beneficial effects induced by "gut-centric" therapies, such as the administration of nonabsorbable disaccharides, nonabsorbable antibiotics, probiotics and prebiotics.

Aim: To assess the short-term efficacy and safety of the probiotic Escherichia coli Nissle (EcN) 1917 strain compared to lactulose and rifaximin in patients with minimal/mild HE.

Methods: From January 2017 to March 2020, a total of 45 patients with HE were enrolled in this prospective, single-centre, open-label, randomized study. Participants were randomly assigned at a ratio of 1:1:1 to one of the treatment groups: The EcN group (n = 15), lactulose group (n = 15) or rifaximin group (n = 15) for a 1 mo intervention period. The main primary outcomes of the study were changes in serum ammonia and Stroop test score. The secondary outcomes were markers of a chronic systemic inflammatory response (ІL-6, ІL-8, and IFN-γ) and bacteriology of the stool flora evaluated by specialized nonculture techniques after a 1 mo intervention period.

Results: Patients who were given rifaximin or EcN showed a more significant reduction in serum ammonia and normalization of Bifidobacteria and Lactobacilli abundance compared to the lactulose group. However, the most pronounced restoration of the symbiotic microflora was associated with EcN administration and characterized by the absence of E. coli with altered properties and pathogenic enterobacteria in patient faeces. In the primary outcome analysis, improvements in the Stroop test parameters in all intervention groups were observed. Moreover, EcN-treated patients performed 15% faster on the Stroop test than the lactulose group patients (P = 0.017). Both EcN and rifaximin produced similar significant reductions in the proinflammatory cytokines INF-γ, IL-6 and IL-8. EcN was more efficient than lactulose in reducing proinflammatory cytokine levels.

Conclusion: The use of the probiotic EcN strain was safe and quite efficient for HE treatment. The probiotic reduced the ammonia content and the level of serum proinflammatory cytokines, normalized the gut microbiota composition and improved the cognitive function of patients with HE. The application of the EcN strain was more effective than lactulose treatment.

Keywords: Chronic liver disease; Cognitive functions; E. coli Nissle 1917; Gut microbiota; Hepatic encephalopathy; Lactulose; Rifaximin; Stroop test; cirrhosis.

Figure 1

Consolidated standards of reporting trials flow chart - trial protocol. AE: Adverse events.

Figure 2

Serum ammonia concentration in patients with hepatic encephalopathy receiving treatment with lactulose, rifaximin and probiotics E.coli Nissle 1917 (n = 14 in each group). ^a P < 0.05 as compared to pre-treatment levels; ^bP < 0.05 as compared to the lactulose treatment. E. coli: Escherichia coli.

Figure 3

The total time of evaluation of stimuli in Stroop test in patients with hepatic encephalopathy receiving treatment with lactulose, rifaximin and probiotics E.coli Nissle 1917 (n = 14 in each group). A: Stroop-off; B: Stroop-on. ^aP < 0.05 as compared to pre-treatment levels; ^bP < 0.05 as compared to the lactulose treatment. E. coli: Escherichia coli.

Figure 4

Serum cytokine levels in patients with HE receiving treatment with lactulose, rifaximin and probiotics E.coli Nissle 1917 (n = 14 in each group). A: INF-γ; B: IL-6; C: IL-8. ^aP < 0.05 as compared to pre-treatment levels; ^bP < 0.05 as compared to the lactulose treatment. E. coli: Escherichia coli.