Article Text
Abstract
Objective Targeting bacterial translocation in cirrhosis is limited to antibiotics with risk of antimicrobial resistance. This study explored the therapeutic potential of a non-absorbable, gut-restricted, engineered carbon bead adsorbent, Yaq-001 in models of cirrhosis and acute-on-chronic liver failure (ACLF) and, its safety and tolerability in a clinical trial in cirrhosis.
Design Performance of Yaq-001 was evaluated in vitro. Two-rat models of cirrhosis and ACLF, (4 weeks, bile duct ligation with or without lipopolysaccharide), receiving Yaq-001 for 2 weeks; and two-mouse models of cirrhosis (6-week and 12-week carbon tetrachloride (CCl4)) receiving Yaq-001 for 6 weeks were studied. Organ and immune function, gut permeability, transcriptomics, microbiome composition and metabolomics were analysed. The effect of faecal water on gut permeability from animal models was evaluated on intestinal organoids. A multicentre, double-blind, randomised, placebo-controlled clinical trial in 28 patients with cirrhosis, administered 4 gr/day Yaq-001 for 3 months was performed.
Results Yaq-001 exhibited rapid adsorption kinetics for endotoxin. In vivo, Yaq-001 reduced liver injury, progression of fibrosis, portal hypertension, renal dysfunction and mortality of ACLF animals significantly. Significant impact on severity of endotoxaemia, hyperammonaemia, liver cell death, systemic inflammation and organ transcriptomics with variable modulation of inflammation, cell death and senescence in the liver, kidneys, brain and colon was observed. Yaq-001 reduced gut permeability in the organoids and impacted positively on the microbiome composition and metabolism. Yaq-001 regulated as a device met its primary endpoint of safety and tolerability in the clinical trial.
Conclusions This study provides strong preclinical rationale and safety in patients with cirrhosis to allow clinical translation.
Trial registration number NCT03202498.
- BACTERIAL TRANSLOCATION
- ENDOTOXIN
- LIVER CIRRHOSIS
- LIVER FAILURE
Data availability statement
Data are available on reasonable request. All data relevant to the study are included in the article or uploaded as online supplemental information.
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Data availability statement
Data are available on reasonable request. All data relevant to the study are included in the article or uploaded as online supplemental information.
Footnotes
JL and JM are joint first authors.
X @Zac_MD, @DrLAEdwards, @Ijcox_nmr, @drgautammehta
JL and JM contributed equally.
Deceased Dr Soeda is deceased
Correction notice This article has been corrected since it published Online First. Figure 4A has been replaced.
Contributors JL: performed CCl4 animal experiments; data acquisition and analysis; intestinal organoid experiments; paper organisation, drafting and writing; JMacNaughtan and RJ: concept; study design; performed animal experiments; data acquisition and analysis; clinical trial lead; paper organisation, drafting and writing; AJCK, JMG, CJ, GZ, KH, MARG, PG, ES, HC-P, FD, PCordero, VV, GM and DG: Clinical trial; TP and YJ: Analysis of the microbiome data and correlation analyses; FC and SS: analysis of the microbiome data, correlation analyses and transcriptomics analyses; AH: performed all the bile duct ligation animal studies; sample analyses; HJ, QJ and HW: performed CCl4 animal experiments; data acquisition and analysis; AP: BDL animal experiments; data acquisition; FDC: BDL animal experiments; data acquisition and analysis; GI: BDL animal experiments; data acquisition and analysis; PCaraceni and JS: data acquisition and cell studies; LM, TA, MK and DG: Yaq-001 characterisation and manufacture; JO: concept; study design; data acquisition and cell studies; KC: regulatory and clinical trial design; JVL: analysis of metabolomics data; AJ: data acquisition and analysis; data organisation; SE: analysis of metabolic effects of Yaq-00; CM: clinical trial; study design; AG: data acquisition and analysis biobanking; LAE: data acquisition and analysis; IJC: analysis of metabolic effects of Yaq-001; RW and VA: clinical trial; study design; RE, JV and MP: statistics; ND: concept; study design; performed animal experiments; data acquisition and analysis; RM: concept; study design; paper organisation, drafting and writing; SSandeman: concept; study design; in vitro studies of Yaq-001; SShoaie: analysis of the microbiome data, correlation analyses and transcriptomics analyses; JMarchesi: microbiome sequencing and analysis of the microbiome data; AA: clinical trial and trial design; FA: concept; study design; data acquisition and analysis. RJ accepts full responsibility for the work presented in this paper. the conduct of the study, has access to all the data and controlled the decision to publish the study.
Funding This study was performed with support from a grant from the EU H2020, Grant Agreement number: 634579—CARBALIVE—H2020-PHC-2014-2015/H2020-PHC-2014 programme. JMarchesi and the Division of Digestive Diseases at Imperial College London receives financial support from the NIHR Imperial Biomedical Research Centre.
Competing interests JMacNaughtan: Shareholder in Yaqrit—no payments received; LM: Yaqrit Employee; KC: Yaqrit consultant; CM: Full-time employee of Yaqrit—salary, Share options in Yaqrit Discovery—no payment received; TA: Full-time employee of Yaqrit—Salary; MK: Full-time employee of Yaqrit—salary, Shares and Share options in Yaqrit Discovery—no payment received; DG: Share options—Yaqrit; AG: Shareholder—Yaqrit; RPM: Shareholder in Yaqrit —No payments received; SShoaie: Co-founder of Gigabiome, Bash Biotech and DAS Microbiome; JMarchesi: JMarchesi has received consultancy fees from EnteroBiotix and Cultech, and speaker fees from Falk Forum; RJ: RJ is the inventor of OPA, which has been patented by UCL and licensed to Mallinckrodt Pharma. He is also the founder of Yaqrit Discovery, Hepyx (spin out companies from University College London), and Cyberliver. He has research collaborations with Yaqrit Discovery. Yaq-001 was licensed by Yaqrit from UCL.
Patient and public involvement Patients and/or the public were involved in the design, or conduct, or reporting, or dissemination plans of this research. Refer to the Methods section for further details.
Provenance and peer review Not commissioned; externally peer reviewed.
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In the PDF this Figure is extremely squashed. It meeds to be on a full page or even 2 pages to allow full visibility
This Figure is very squashed in the PDF I saw. Should be expanded to a full page or even 2 pages please to allow readability
Once these have been corrected, please share the revised version with me to recheck please.