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Fecal microbiota transplantation in alcohol-associated acute-on-chronic liver failure: an open-label clinical trial

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Abstract

Background

Severe alcoholic hepatitis (SAH) presenting as acute-on-chronic liver failure (ACLF) carries a high short-term mortality. Alteration of gut microbiota is a crucial component implicated in its pathogenesis, whose modulation has been suggested as a potential therapeutic tool. We evaluated the safety of fecal microbiota transplantation (FMT) and its efficacy in improving short-term survival and clinical severity scores in patients with SAH–ACLF.

Methods

Thirty-three patients [13 in the FMT arm; 20 in the standard of care arm (SOC)] with SAH–ACLF were included in this open-label study. A single FMT session was administered as a freshly prepared stool suspension from pre-identified healthy family member stool donors through a nasojejunal tube. Patients were followed up on days 7, 28, and 90.

Results

Survival at 28 and 90 days was significantly better in the FMT arm (100% versus 60%, p = 0.01; 53.84% versus 25%, p = 0.02). Hepatic encephalopathy resolved in 100% versus 57.14% (FMT versus SOC, p = 0.11) patients, while ascites resolved in 100% versus 40% survivors (p = 0.04). Major adverse event rates, including spontaneous bacterial peritonitis and gastrointestinal bleeding, were similar in both groups (p = 0.77; p = 0.70). Median IL1beta decreased by 21.39% (IQR − 73.67 to 7.63) in the FMT group, whereas it increased in the SOC by 27.44% (IQR − 0.88 to 128.11) (p = 0.01). Percentage changes in bilirubin and ALT between baseline and day 7 emerged as predictors of 90-day mortality.

Conclusion

FMT is safe, improves short-term and medium-term survival, and leads to improvement in clinical severity scores in patients with SAH–ACLF.

Clinical trial number

NCT03827772 available from http://clinicaltrials.gov/ct2/show/NCT03827772

CTRI Reference number: CTRI/2019/02/017538 dated 7 February 2019.

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Data and code availability

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Abbreviations

ACLF:

Acute on chronic liver failure

APASL:

Asian Pacific Association for the study of the liver

ALT:

Alanine aminotransferase

Anti-HBc:

Antibodies to hepatitis B core antigen

AST:

Aspartate aminotransferase

CANONIC:

Chronic Liver Failure (CLIF) Consortium Acute-on-Chronic Liver Failure in Cirrhosis

CDI:

Clostridium difficile Infection

CDR:

Cirrhosis dysbiosis ratio

CLIF-C:

ACLF Chronic Liver Failure Consortium Acute-on-Chronic Liver Failure Score

CLIF-C:

OF Chronic Liver Failure Consortium-Organ Failure score

CLIF-SOFA:

Chronic Liver Failure-Sequential Organ Failure Assessment score

CTP:

Child–Turcotte–Pugh score

FMT:

Fecal microbiota transplantation

GM:

Gut microbiota

HAV:

Hepatitis A virus

HBsAg:

Surface antigen for hepatitis B

HCV:

Hepatitis C virus

HE:

Hepatic encephalopathy

HIV:

Human immunodeficiency virus

IL:

Interleukin

INR:

International normalized ratio

LFT:

Liver function tests

mDF:

Maddrey’s discriminant function

MELD:

Score model for end-stage liver disease

MELD-Na+ :

Score model for end-stage liver disease sodium score

PAMPs:

Pathogen-associated molecular patterns

PGIMER:

Postgraduate Institute of Medical Education and Research

PRR:

Pattern recognition receptor

SAH:

Severe alcoholic hepatitis

SOC:

Standard of care

VDRL:

Venereal Disease Research Laboratory test

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Funding

The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

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Authors and Affiliations

  1. Department of Hepatology, Postgraduate Institute of Medical Education and Research Chandigarh, Chandigarh, India

    Akash Roy, Madhumita Premkumar, Nipun Verma, Ajay Duseja, Sunil Taneja, Madhu Chopra & Radha K. Dhiman

  2. Department of Internal Medicine, Postgraduate Institute of Medical Education and Research Chandigarh, Chandigarh, India

    Anima Sharma

  3. Department of Psychiatry, Postgraduate Institute of Medical Education and Research Chandigarh, Chandigarh, India

    Sandeep Grover

  4. Department of Hepatology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, 226014, India

    Radha K. Dhiman

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  1. Anima Sharma
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Contributions

AS and AR: data compilation and manuscript writing; RKD: concept, manuscript writing, and editing; MPK: manuscript editing and revision; NV: statistical analysis; AD: manuscript editing and revision; SG: data compilation; MC: data extraction; ST: manuscript revision.

Corresponding author

Correspondence to Radha K. Dhiman.

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Conflict of interest

Anima Sharma, Akash Roy, Madhumita Premkumar, Nipun Verma, Ajay Duseja, Sunil Taneja, Sandeep Grover, Madhu Chopra and Radha K. Dhiman declare that they have no conflict of interest.

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The study has been approved by the institutional ethics committee and follows the ethical standards as laid down in the 1964 Declaration of Helsinki and revised in 2008.

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Sharma, A., Roy, A., Premkumar, M. et al. Fecal microbiota transplantation in alcohol-associated acute-on-chronic liver failure: an open-label clinical trial. Hepatol Int 16, 433–446 (2022). https://doi.org/10.1007/s12072-022-10312-z

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  • DOI: https://doi.org/10.1007/s12072-022-10312-z

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