Randomised Double-Blind Placebo-Controlled Trial of Inulin with Metronidazole in Non-Alcoholic Fatty Liver Disease (NAFLD)

Clara Yieh Lin Chong, David Orr, Lindsay D Plank, Tommi Vatanen, Justin M O'Sullivan, Rinki Murphy, Clara Yieh Lin Chong, David Orr, Lindsay D Plank, Tommi Vatanen, Justin M O'Sullivan, Rinki Murphy

Abstract

Background: Non-alcoholic fatty liver disease (NAFLD) can be ameliorated by weight loss although difficult to maintain. Emerging evidence indicates that prebiotics and antibiotics improve NAFLD. Aim: To determine whether inulin supplementation after brief metronidazole therapy is effective in reducing alanine aminotransferase (ALT) and maintaining weight loss achieved through a very-low-calorie diet (VLCD) among people with NAFLD. Methods: Sixty-two people with NAFLD commenced 4-week VLCD using Optifast meal replacements (600 kcal/day). Sixty were then randomised into a 12-week double-blind, placebo-controlled, parallel three-arm trial: (1) 400 mg metronidazole twice daily in Week 1 then inulin 4 g twice daily OR (2) placebo twice daily in week one then inulin OR (3) placebo-placebo. Main outcomes were ALT and body weight at 12 weeks. Fecal microbiota changes were also evaluated. Results: Mean body mass index (BMI) and ALT reduced after VLCD by 2.4 kg/m2 and 11 U/L, respectively. ALT further decreased after metronidazole-inulin compared to after placebo-placebo (mean ALT change -19.6 vs. -0.2 U/L, respectively; p = 0.026); however, weight loss maintenance did not differ. VLCD treatment decreased the ratio of Firmicutes/Bacteroidetes (p = 0.002). Conclusion: Brief metronidazole followed by inulin supplementation can reduce ALT beyond that achieved after VLCD in patients with NAFLD.

Keywords: Optifast; alanine aminotransferase; antibiotic; gut microbiome; inulin; metronidazole; prebiotics.

Conflict of interest statement

The authors declare no conflicts of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Figures

Figure A1
Figure A1
Flow diagram showing different phases of the study and number of participants at each stage. EOT: end of treatment; MI: metronidazole-inulin; PI: placebo-inulin; PP: placebo-placebo.
Figure A2
Figure A2
Flow diagram showing total stool sample collection at different time points from different groups. MI: metronidazole-inulin; PI: placebo-inulin; PP: placebo-placebo.
Figure 1
Figure 1
Assessment and sample collection timeline.
Figure 2
Figure 2
Firmicutes and Bacteroidetes are the dominant phyla in the subjects before and after very-low-calorie diet (VLCD) treatment. The figure shows boxplots of five typical human microbiota phyla. The boxes indicate the interquartile range (IQR) while the notch region shows the 95% confidence interval for the median and the whiskers extending from the boxes represent the distribution within 1.5 × IQR, with points beyond this range shown as outliers.
Figure 3
Figure 3
The ratio of Firmicutes/Bacteroidetes phyla decreased (Wilcoxon signed-rank test, p = 0.002, n = 30) from baseline to Week 4 after the VLCD diet. Boxplots as in Figure 2.
Figure 4
Figure 4
The relative abundance of genera Roseburia (A), Streptococcus (B) and Dialister (C) were lower (linear mixed-effects model, q-value = 0.0005, 0.0005 and 0.03, respectively) after VLCD treatment compared to baseline. Baseline, n = 35; Week 4, n = 38. Boxplots as in Figure 2.

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