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. 2017 Dec 21;23(47):8355-8366.
doi: 10.3748/wjg.v23.i47.8355.

Rifaximin ameliorates hepatic encephalopathy and endotoxemia without affecting the gut microbiome diversity

Kosuke Kaji  1 , Hiroaki Takaya  2 , Soichiro Saikawa  2 , Masanori Furukawa  2 , Shinya Sato  2 , Hideto Kawaratani  2 , Mitsuteru Kitade  2 , Kei Moriya  2 , Tadashi Namisaki  2 , Takemi Akahane  2 , Akira Mitoro  2 , Hitoshi Yoshiji  2
Affiliations

Rifaximin ameliorates hepatic encephalopathy and endotoxemia without affecting the gut microbiome diversity

Kosuke Kaji et al. World J Gastroenterol. .

Abstract

Aim: To determine the efficacy of rifaximin for hepatic encephalopathy (HE) with the linkage of gut microbiome in decompensated cirrhotic patients.

Methods: Twenty patients (12 men and 8 women; median age, 66.8 years; range, 46-81 years) with decompensated cirrhosis (Child-pugh score > 7) underwent cognitive neuropsychological testing, endotoxin analysis, and fecal microbiome assessment at baseline and after 4 wk of treatment with rifaximin 400 mg thrice a day. HE was determined by serum ammonia level and number connection test (NCT)-A. Changes in whole blood endotoxin activity (EA) was analyzed by endotoxin activity assay. Fecal microbiome was assessed by 16S ribosome RNA (rRNA) gene sequencing.

Results: Treatment with rifaximin for 4 wk improved hyperammonemia (from 90.6 ± 23.9 μg/dL to 73.1 ± 33.1 μg/dL; P < 0.05) and time required for NCT (from 68.2 ± 17.4 s to 54.9 ± 20.3 s; P < 0.05) in patients who had higher levels at baseline. Endotoxin activity was reduced (from 0.43 ± 0.03 to 0.32 ± 0.09; P < 0.05) in direct correlation with decrease in serum ammonia levels (r = 0.5886, P < 0.05). No statistically significant differences were observed in the diversity estimator (Shannon diversity index) and major components of the gut microbiome between the baseline and after treatment groups (3.948 ± 0.548 at baseline vs 3.980 ± 0.968 after treatment; P = 0.544), but the relative abundances of genus Veillonella and Streptococcus were lowered.

Conclusion: Rifaximin significantly improved cognition and reduced endotoxin activity without significantly affecting the composition of the gut microbiome in patients with decompensated cirrhosis.

Keywords: Endotoxin; Gut microbiome; Hepatic encephalopathy; Liver cirrhosis; Rifaximin.

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Conflict of interest statement

Conflict-of-interest statement: The authors declare that there is no conflict of interest regarding the publication of this paper.

Figures

Figure 1
Figure 1
The selection of the study population and experimental design. 20 patients except for 25 patients to meet the exclusion criteria and decline to participate were finally analyzed.
Figure 2
Figure 2
Effect of rifaximin on serum ammonia level. Comparison of the mean levels of serum ammonia between baseline and 4 wk post-rifaximin among (A) total patients (n = 20) and (B) the patients who showed high levels of serum ammonia (> 70 μg/dL) at baseline (n = 16). Data are means ± SD.
Figure 3
Figure 3
Effect of rifaximin on cognitive disturbance. Comparison of the mean time required for NCT between baseline and 4 wk post-rifaximin among (A) total patients (n =20) and (B) the patients who showed prolongation for NCT (> 50 s) at baseline (n = 10). Data are means ± SD.
Figure 4
Figure 4
Effect of rifaximin on endotoxin activity. Comparison of the endotoxin activities between baseline and 4 wk post-rifaximin among (A) total patients (n = 20) and (B) the patients who showed high levels of EA (> 0.4) at baseline (n = 11). C: Univariate correlation analysis between the decrease in EA level (Δ EA) and that in serum ammonia level (Δ NH3) by treatment with rifaximin (r = 0.5886, P < 0.05). Data are means ± SD.
Figure 5
Figure 5
Effect of rifaximin on the diversity and major compositions of gut microbiome. A: Shannon diversity between baseline and treatment groups (mean index ± SD 3.948 ± 0.548 at baseline vs 3.980 ± 0.968 at treatment, P = 0.544). B: Pco analysis (PcoA) of gut microbiota. Baseline samples (blue) were clustered together compared to 4 wk post-rifaximin (red). C-E: Effects of rifaximin on alterations in the composition of gut microbiome in phylum (C), class (D) and order (E).
Figure 6
Figure 6
Alterations in abundances of selected genera by treatment with rifaximin. Relative abundances of (A) Veillonella, (B) Streptococcus, (C) Lactobacillus, (D) Prevotella, (E) Haemophilus, (F) Megaspaera and (G) Fusobacterium. Data are means ± SD.
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