Fecal Microbial Transplant Capsules Are Safe in Hepatic Encephalopathy: A Phase 1, Randomized, Placebo-Controlled Trial

Jasmohan S Bajaj, Nita H Salzman, Chathur Acharya, Richard K Sterling, Melanie B White, Edith A Gavis, Andrew Fagan, Michael Hayward, Mary L Holtz, Scott Matherly, Hannah Lee, Majdi Osman, Mohammad S Siddiqui, Michael Fuchs, Puneet Puri, Masoumeh Sikaroodi, Patrick M Gillevet, Jasmohan S Bajaj, Nita H Salzman, Chathur Acharya, Richard K Sterling, Melanie B White, Edith A Gavis, Andrew Fagan, Michael Hayward, Mary L Holtz, Scott Matherly, Hannah Lee, Majdi Osman, Mohammad S Siddiqui, Michael Fuchs, Puneet Puri, Masoumeh Sikaroodi, Patrick M Gillevet

Abstract

Hepatic encephalopathy (HE) can cause major morbidity despite standard of care (SOC; rifaximin/lactulose). Fecal microbial transplant (FMT) enemas postantibiotics are safe, but the effect of FMT without antibiotics using the capsular route requires investigation. The aim of this work was to determine the safety, tolerability, and impact on mucosal/stool microbiota and brain function in HE after capsular FMT in a randomized, single-blind, placebo-controlled clinical trial in Virginia. Patients with cirrhosis with recurrent HE with MELD (Model for End-Stage Liver Disease) <17 on SOC were randomized 1:1 into receiving 15 FMT capsules versus placebo from a single donor enriched in Lachnospiraceae and Ruminococcaceae. Endoscopies with duodenal and sigmoid biopsies, stool analysis, cognition, serum lipopolysaccharide-binding protein (LBP), and duodenal antimicrobial peptide (AMP) expression at baseline were used. Clinical follow-up with SOC maintenance was performed until 5 months. FMT-assigned patients underwent repeat endoscopies 4 weeks postenrollment. Twenty subjects on lactulose/rifaximin were randomized 1:1. MELD score was similar at baseline (9.6 vs. 10.2) and study end (10.2 vs. 10.5). Six patients in the placebo group required hospitalizations compared to 1 in FMT, which was deemed unrelated to FMT. Infection/HE episodes were similar between groups. Baseline microbial diversity was similar in all tissues between groups. Post-FMT, duodenal mucosal diversity (P = 0.01) increased with higher Ruminococcaceae and Bifidobacteriaceae and lower Streptococcaceae and Veillonellaceae. Reduction in Veillonellaceae were noted post-FMT in sigmoid (P = 0.04) and stool (P = 0.05). Duodenal E-cadherin (P = 0.03) and defensin alpha 5 (P = 0.03) increased whereas interleukin-6 (P = 0.02) and serum LBP (P = 0.009) reduced post-FMT. EncephalApp performance improved post-FMT only (P = 0.02). Conclusion: In this phase 1 study, oral FMT capsules are safe and well tolerated in patients with cirrhosis and recurrent HE. FMT was associated with improved duodenal mucosal diversity, dysbiosis, and AMP expression, reduced LBP, and improved EncephalApp performance. Further studies are needed to prove efficacy.

Trial registration: ClinicalTrials.gov NCT03152188.

© 2019 by the American Association for the Study of Liver Diseases.

Figures

Figure 1A:
Figure 1A:
Schematic of Study Design
Figure 1B:
Figure 1B:
CONSORT Flow chart
Figure 2:
Figure 2:
2A: Median and 95% CI of Shannon microbial diversity in stool, sigmoid and duodenal microbiota at baseline between groups did not show any baseline significant differences. FMT group is in orange while placebo-assigned group is in the green. P values compared using Mann Whitney tests are displayed. 2B: Median and 95% CI of Shannon microbial diversity within the FMT group before and 4 weeks after FMT in the stool, sigmoid and duodenal microbiota. There was a significant increase only in the duodenal but not sigmoid or stool diversity on Wilcoxon signed rank pairs test. Orange bars are pre and green are post-FMT values. 2C: LEFSe results pre (red bars) and post (green bars) FMT in duodenal microbiota 2D: Median and 95% CI of selected taxa pre (orange) and post (green) FMT in duodenal microbiota. P values based on Wilcoxon signed rank pairs test, which showed a higher Ruminococcaceae and lower Veillonellaceae and Streptococcaceae in the post-FMT mucosa compared to pre-FMT. 2E: PCA shows pre-FMT duodenal microbiota (red) clustered apart from the post-FMT microbiota (green)
Figure 2:
Figure 2:
2A: Median and 95% CI of Shannon microbial diversity in stool, sigmoid and duodenal microbiota at baseline between groups did not show any baseline significant differences. FMT group is in orange while placebo-assigned group is in the green. P values compared using Mann Whitney tests are displayed. 2B: Median and 95% CI of Shannon microbial diversity within the FMT group before and 4 weeks after FMT in the stool, sigmoid and duodenal microbiota. There was a significant increase only in the duodenal but not sigmoid or stool diversity on Wilcoxon signed rank pairs test. Orange bars are pre and green are post-FMT values. 2C: LEFSe results pre (red bars) and post (green bars) FMT in duodenal microbiota 2D: Median and 95% CI of selected taxa pre (orange) and post (green) FMT in duodenal microbiota. P values based on Wilcoxon signed rank pairs test, which showed a higher Ruminococcaceae and lower Veillonellaceae and Streptococcaceae in the post-FMT mucosa compared to pre-FMT. 2E: PCA shows pre-FMT duodenal microbiota (red) clustered apart from the post-FMT microbiota (green)
Figure 3:
Figure 3:
3A: LEFSe in pre vs post FMT (red bars) in stool microbiota within the FMT group 3B: PCA shows relative clustering of pre-FMT (red) compared to the post-FMT stool microbiota (green) 3C: Median and 95% CI of selected taxa pre (orange) and post (green) FMT in stool microbiota. FPre: FMT group pre-FMT, F1: first post-FMT visit in FMT group, F2: end of study visit FMT group, PPre: Placebo group baseline, P1: first post-placebo visit, P2: end of study visit placebo group. P values based on Kruskal-Wallis tests showed reduction in Lachnospiraceae over time in placebo group and reduction of Veillonellaceae over time in the FMT group. 3D: LEFSe of end study visit in placebo vs FMT group at end of study visit showed a relatively higher abundance of Lachnospiraceae in the FMT compared to placebo group on the stool. 3E: PCA shows relative clustering of post-FMT away from post-placebo in stool microbiota 3F: LEFSe results pre (red bars) and post (green bars) FMT in sigmoid mucosal microbiota 3G: Median and 95% CI of selected taxa pre (orange) and post (green) FMT in sigmoid mucosal microbiota showed a lower Veillonellaceae post-FMT compared to baseline. P values based on Wilcoxon signed rank pairs test. 3H: PCA shows little separation between pre (red) and post-FMT (green) sigmoid microbiota
Figure 3:
Figure 3:
3A: LEFSe in pre vs post FMT (red bars) in stool microbiota within the FMT group 3B: PCA shows relative clustering of pre-FMT (red) compared to the post-FMT stool microbiota (green) 3C: Median and 95% CI of selected taxa pre (orange) and post (green) FMT in stool microbiota. FPre: FMT group pre-FMT, F1: first post-FMT visit in FMT group, F2: end of study visit FMT group, PPre: Placebo group baseline, P1: first post-placebo visit, P2: end of study visit placebo group. P values based on Kruskal-Wallis tests showed reduction in Lachnospiraceae over time in placebo group and reduction of Veillonellaceae over time in the FMT group. 3D: LEFSe of end study visit in placebo vs FMT group at end of study visit showed a relatively higher abundance of Lachnospiraceae in the FMT compared to placebo group on the stool. 3E: PCA shows relative clustering of post-FMT away from post-placebo in stool microbiota 3F: LEFSe results pre (red bars) and post (green bars) FMT in sigmoid mucosal microbiota 3G: Median and 95% CI of selected taxa pre (orange) and post (green) FMT in sigmoid mucosal microbiota showed a lower Veillonellaceae post-FMT compared to baseline. P values based on Wilcoxon signed rank pairs test. 3H: PCA shows little separation between pre (red) and post-FMT (green) sigmoid microbiota
Figure 4:
Figure 4:
Data presented as median and 95% CI. P values based on Wilcoxon signed rank pairs test. 4A: mRNA expression of duodenal IL-6 pre and post-FMT showed a significant reduction. 4B: mRNA expression of duodenal defensin A-5 and A-6 pre and post-FMT showed a significant increase in A-5 but not A-6 expression 4C: mRNA expression of duodenal e-cadherin protein (CDH) pre and post-FMT showed a significant increase in CDH. 4D: Serum LBP showed significant reduction post-FMT compared to baseline 4E: Serum LBP showed no significant change post-placebo compared to baseline
Figure 4:
Figure 4:
Data presented as median and 95% CI. P values based on Wilcoxon signed rank pairs test. 4A: mRNA expression of duodenal IL-6 pre and post-FMT showed a significant reduction. 4B: mRNA expression of duodenal defensin A-5 and A-6 pre and post-FMT showed a significant increase in A-5 but not A-6 expression 4C: mRNA expression of duodenal e-cadherin protein (CDH) pre and post-FMT showed a significant increase in CDH. 4D: Serum LBP showed significant reduction post-FMT compared to baseline 4E: Serum LBP showed no significant change post-placebo compared to baseline

Source: PubMed

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