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Impact of two-session fecal microbiota transplantation on minimal hepatic encephalopathy in cirrhosis
Ankit Agarwal, Samagra Agrawal, Daizee Talukdar, Manjeet Kaur, Sagnik Biswas, Shekhar Swaroop, Rithvik Golla, Bharti Kandiyal, Pradipta Jana, Subhash Tanwar, Arnav Aggarwal, Hem C Singh, Ayush Agarwal, Mridul Mahajan, Bipin Tiwari, Baibaswata Nayak, Amit Goel, Bhabatosh Das, Shalimar
Ankit Agarwal, Samagra Agrawal, Sagnik Biswas, Shekhar Swaroop, Rithvik Golla, Arnav Aggarwal, Hem C Singh, Ayush Agarwal, Mridul Mahajan, Bipin Tiwari, Baibaswata Nayak, Shalimar, Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi 110029, Delhi, India
Daizee Talukdar, Manjeet Kaur, Bharti Kandiyal, Pradipta Jana, Subhash Tanwar, Bhabatosh Das, Center for Microbial Research, BRIC-Translational Health Science and Technology Institute, Faridabad 121001, Haryāna, India
Amit Goel, Department of Hepatology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, Uttar Pradesh, India
Co-first authors: Ankit Agarwal and Samagra Agrawal.
Co-corresponding authors: Bhabatosh Das and Shalimar.
Author contributions: Agarwal A and Agarwal S contributed to study concept and design and they contributed equally to this manuscript and are co-first authors; Agarwal A, Biswas S, Swaroop S, Golla R, Aggarwal A, Singh HC, Agarwal A, Mahajan M, Tiwari B, Nayak B, Das B, and Shalimar contributed to analysis and interpretation of data; Agarwal A, Agarwal S, Talukdar D, Biswas S, Das B, and Shalimar contributed to drafting of the manuscript; Das B and Shalimar contributed to critical revision of the manuscript for important intellectual content, obtained funding, and they contributed equally to this manuscript and are co-corresponding authors; administrative, technical, or material support; Agarwal A, Agarwal S, Talukdar D, and Goel A contributed to statistical analysis; Shalimar contributed to study supervision.
Supported by the Department of Biotechnology, Government of India, No. BT/PR30159/MED/15/188/2018; Blockchain For Impact, No. 2025; and the Science and Engineering Research Board, India, No. SPR/2020/000315.
Institutional review board statement: This work was approved by the Institutional Ethics Committee, No. IEC-753/02.09.2022, RP-37/2022.
Clinical trial registration statement: This study was registrated in the Clinical Trials Registry of India, No. CTRI/2023/02/050008.
Informed consent statement: Informed consent has been obtained for this study.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
CONSORT 2010 statement: The authors have read the CONSORT 2010 Statement, and the manuscript was prepared and revised according to the CONSORT 2010 Statement.
Data sharing statement: The raw 16S rRNA gene sequencing data generated in the present study have been submitted to the Indian Nucleotide Data Archive. The 16S rRNA gene sequences will be available in the Indian Biological Data Center, study accession: No. INRP000315, and International Nucleotide Sequence Database Collaboration, study accession: No. ERP171343. The datasets used and analysed are available from the corresponding author on reasonable request.
Corresponding author: Shalimar, Professor, Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110029, Delhi, India.
drshalimar@gmail.com
Received: November 4, 2025
Revised: December 8, 2025
Accepted: February 6, 2026
Published online: April 27, 2026
Processing time: 168 Days and 19.2 Hours
BACKGROUND
The role of fecal microbiota transplantation (FMT) in the treatment of minimal hepatic encephalopathy (MHE) is unclear.
AIM
To compare the efficacy and safety of FMT with oral lactulose in the treatment of MHE in cirrhosis.
METHODS
In this randomized-controlled trial, 130 patients with cirrhosis and MHE were randomized to receive either 2 endoscopic infusions of donor stool one-month apart or daily oral lactulose for 3 months. The primary outcome was MHE resolution at 3 months (assessed by psychometric hepatic encephalopathy score > -5). We performed microbiome analysis using next-generation sequencing and evaluated 16 antimicrobial-resistance gene profiles using gene-specific oligonucleotides.
RESULTS
Among 122/130 (93.8%) patients eligible for analysis [FMT: 60; lactulose: 62; age: 44.3 ± 8.9 years; 96.7% male; child A/B/C: 32.1%/53.3%/14.6%; median model for end-stage liver disease: 13 (10-17)], rates of MHE resolution were similar in both groups [41/60 (68.3%) vs 41/62 (66.1%); absolute risk-difference: 2.2% (95% confidence interval: -14.4% to 18.9%); P = 0.80] at 3 months. Both groups exhibited similar improvements in psychometric hepatic encephalopathy score (intergroup difference: -0.12 ± 0.31; P = 0.71) and 36-item short form survey scores over this time with similar risk of progression to overt encephalopathy [2 (3.3%) vs 1 (1.6%); P = 1.0], serious adverse events, and mortality. At 3 months, microbial diversity remained unchanged in both groups; the FMT group showed only a modest, non-significant increase in Observed and Chao1 indices. FMT responders showed reduced proinflammatory taxa, ethanol-producing microbiota, and antimicrobial-resistance genes, indicating favourable gut microbiome modulation.
CONCLUSION
FMT and lactulose have comparable efficacy in improving MHE and health-related quality of life in patients with cirrhosis.
Core Tip: Minimal hepatic encephalopathy (MHE) is common in cirrhosis. Gut dysbiosis is a key pathogenic player of MHE. Lactulose has been demonstrated to reverse MHE and prevent progression to overt hepatic encephalopathy. This randomised trial compared two endoscopic fecal microbiota transplantations (1 month apart) with daily lactulose over 3 months for MHE reversal. We found fecal microbiota transplantation and lactulose to have similar efficacy in improving MHE, supporting microbiota-targeted therapy as a viable alternative to standard care for MHE. These findings justify larger trials to assess long-term outcomes and optimal microbiota-based strategies.
