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Munk Lauridsen M, Jonasson E, Bajaj JS. Microbial Approaches to Treat and Prevent Hepatic Encephalopathy. Gastroenterol Clin North Am 2025; 54:429-451. [PMID: 40348497 PMCID: PMC12066833 DOI: 10.1016/j.gtc.2024.12.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/14/2025]
Abstract
This review articulates the significance of the gut-liver-brain axis in understanding hepatic encephalopathy (HE), emphasizing the role of gut microbiota in influencing liver and brain health. Key treatments like lactulose, rifaximin, probiotics, and fecal microbiota transplantation are examined for their ability to modulate the gut microbiome, thereby mitigating HE symptoms through reduced neurotoxin production and enhanced gut barrier integrity. The synopsis highlights both established and emerging microbial therapies, presenting them as crucial to the management and future strategies of HE. This comprehensive overview explores current therapeutic approaches alongside promising future interventions, suggesting that personalized microbiome-focused treatments may revolutionize HE management.
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Affiliation(s)
- Mette Munk Lauridsen
- Department for Regional Health Research, University Hospital of Southern Denmark, Finsensgade 35 6700, Esbjerg, Denmark
| | - Elise Jonasson
- Department for Regional Health Research, University Hospital of Southern Denmark, Finsensgade 35 6700, Esbjerg, Denmark
| | - Jasmohan S Bajaj
- Department of Medicine, Virginia Commonwealth University, Richmond, VA, USA.
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2
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Kamath S, Bryant RV, Costello SP, Day AS, Forbes B, Haifer C, Hold G, Kelly CR, Li A, Pakuwal E, Stringer A, Tucker EC, Wardill HR, Joyce P. Translational strategies for oral delivery of faecal microbiota transplantation. Gut 2025:gutjnl-2025-335077. [PMID: 40301116 DOI: 10.1136/gutjnl-2025-335077] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2025] [Accepted: 04/09/2025] [Indexed: 05/01/2025]
Abstract
Faecal microbiota transplantation (FMT) has emerged as a transformative therapy for Clostridioides difficile infections and shows promise for various GI and systemic diseases. However, the poor patient acceptability and accessibility of 'conventional' FMT, typically administered via colonoscopies or enemas, hinders its widespread clinical adoption, particularly for chronic conditions. Oral administration of FMT (OralFMT) overcomes these limitations, yet faces distinct challenges, including a significant capsule burden, palatability concerns and poor microbial viability during gastric transit. This review provides a comprehensive analysis of emerging strategies that aim to advance OralFMT by: (1) refining processing technologies (eg, lyophilisation) that enable manufacturing of low-volume FMT formulations for reducing capsule burden and (2) developing delivery technologies that improve organoleptic acceptability and safeguard the microbiota for targeted colonic release. These advancements present opportunities for OralFMT to expand its therapeutic scope, beyond C. difficile infections, towards chronic GI conditions requiring frequent dosing regimens. While this review primarily focuses on optimising OralFMT delivery, it is important to contextualise these advancements within the broader shift towards defined microbial consortia. Live biotherapeutic products (LBPs) offer an alternative approach, yet the interplay between OralFMT and LBPs in clinical practice remains unresolved. We postulate that continued innovation in OralFMT and LBPs via a multidisciplinary approach can further increase therapeutic efficacy and scalability by enabling disease site targeting, co-delivery of therapeutic compounds and overcoming colonisation resistance. Realising these goals positions OralFMT as a cornerstone of personalised care across a range of diseases rooted in microbiome health.
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Affiliation(s)
- Srinivas Kamath
- UniSA Clinical & Health Sciences, University of South Australia, Adelaide, South Australia, Australia
| | - Robert V Bryant
- Department of Gastroenterology and Hepatology, The Queen Elizabeth Hospital, Woodville South, South Australia, Australia
- Faculty of Health Sciences, The University of Adelaide, Adelaide, South Australia, Australia
| | - Samuel P Costello
- Department of Gastroenterology and Hepatology, The Queen Elizabeth Hospital, Woodville South, South Australia, Australia
- The University of Adelaide, Adelaide, South Australia, Australia
| | - Alice S Day
- Faculty of Health Sciences, The University of Adelaide, Adelaide, South Australia, Australia
- Gastroenterology, The Queen Elizabeth Hospital, Woodville South, South Australia, Australia
| | | | - Craig Haifer
- Department of Gastroenterology, St Vincent's Hospital Sydney, Darlinghurst, New South Wales, Australia
- School of Clinical Medicine, University of New South Wales, Sydney, New South Wales, Australia
| | - Georgina Hold
- Microbiome Research Centre, University of New South Wales, Sydney, New South Wales, Australia
| | - Colleen R Kelly
- Harvard Medical School, Boston, Massachusetts, USA
- Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA
| | - Anna Li
- Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, South Australia, Australia
| | - Evance Pakuwal
- Health and Medical Sciences, The University of Adelaide, Adelaide, South Australia, Australia
| | - Andrea Stringer
- UniSA Clinical & Health Sciences, University of South Australia, Adelaide, South Australia, Australia
| | - Emily C Tucker
- Faculty of Health Sciences, The University of Adelaide, Adelaide, South Australia, Australia
- Infectious Diseases Unit, Central Adelaide Local Health Network, Adelaide, South Australia, Australia
| | - Hannah Rose Wardill
- Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, South Australia, Australia
- Precision Cancer Medicine Theme, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia
| | - Paul Joyce
- University of South Australia, Adelaide, South Australia, Australia
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3
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Xu XT, Jiang MJ, Fu YL, Xie F, Li JJ, Meng QH. Incidence and efficacy of strategies for preventing hepatic encephalopathy following transjugular intrahepatic portosystemic shunt: A meta-analysis. World J Hepatol 2025; 17:104890. [PMID: 40308821 PMCID: PMC12038425 DOI: 10.4254/wjh.v17.i4.104890] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2025] [Revised: 02/27/2025] [Accepted: 04/07/2025] [Indexed: 04/25/2025] Open
Abstract
BACKGROUND Hepatic encephalopathy (HE) is a primary complication following transjugular intrahepatic portosystemic shunt (TIPS), but the utility of pharmacological prophylaxis for HE is unclear. AIM To assess the HE incidence post-TIPS across various groups and the prophylactic efficacies of various medications. METHODS A thorough literature search was performed in PubMed, Web of Science, EMBASE, and the Cochrane Library databases from their inception to November 24, 2024, to collect data regarding HE incidence. The main outcome was HE incidence post-TIPS. A meta-analysis using a random effects model was performed to obtain odds ratios (ORs) and 95% confidence intervals. Statistical analyses were conducted using Stata and RevMan software. RESULTS This meta-analysis included nine studies with 1140 patients; 647 received pharmacological agents including lactulose, rifaximin, albumin, and l-ornithin-l-aspartate, and 493 did not (controls). (1) In the single-group meta-analysis, the control group had higher short- and long-term HE rates than the drug intervention group. Among patients with and without prior HE, the non-intervention group's HE rates were also higher; (2) Pharmacological prevention post-TIPS significantly reduced HE incidence [OR = 0.59 (0.45, 0.77), P = 0.0001]. Compared with the no prophylaxis, rifaximin reduced the risk of HE after TIPS [OR = 0.52 (0.29, 0.95), P = 0.03], but lactulose did not; (3) In patients without prior HE, pharmacological prevention significantly reduced post-TIPS HE incidence [OR = 0.62 (0.41,0.95), P = 0.03]; and (4) Network meta-analysis showed no significant differences among five prevention strategies. CONCLUSION The HE incidence after TIPS was relatively high, and the use of drugs after TIPS may reduce the HE incidence. However, research, especially large-scale randomized controlled trials, is still lacking.
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Affiliation(s)
- Xiao-Tong Xu
- Hepatic Disease and Oncology Minimally Invasive Interventional Center, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China
- Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China
| | - Min-Jie Jiang
- Department of Infectious Diseases, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, Shandong Province, China
| | - Yun-Lai Fu
- Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China
| | - Fang Xie
- Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China
| | - Jian-Jun Li
- Hepatic Disease and Oncology Minimally Invasive Interventional Center, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China
| | - Qing-Hua Meng
- Hepatic Disease and Oncology Minimally Invasive Interventional Center, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China.
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4
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Li Y, Wu YT, Wu H. Management of hepatic encephalopathy following transjugular intrahepatic portosystemic shunts: Current strategies and future directions. World J Gastroenterol 2025; 31:103512. [PMID: 40309228 PMCID: PMC12038546 DOI: 10.3748/wjg.v31.i15.103512] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2024] [Revised: 03/04/2025] [Accepted: 04/02/2025] [Indexed: 04/18/2025] Open
Abstract
Transjugular intrahepatic portosystemic shunts (TIPSs) are generally used for the management of complications of portal hypertension in patients with decompensated cirrhosis. However, hepatic encephalopathy (HE), which impairs neuropsychiatric function and motor control, remains the primary adverse effect of TIPS, limiting its utility. Prompt prevention and treatment of post-TIPS HE are critical, as they are strongly associated with readmission rates and poor quality of life. This review focuses on the main pathophysiological mechanisms underlying post-TIPS HE, explores advanced biomarkers and predictive tools, and discusses current management strategies and future directions to prevent or reverse HE following TIPS. These strategies include preoperative patient assessment, individualized shunt diameter optimization, spontaneous portosystemic shunt embolization during the TIPS procedure, postoperative preventive and therapeutic measures such as nutrition management, medical therapy, fecal microbiota transplantation, and stent reduction.
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Affiliation(s)
- Ying Li
- Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Yu-Tong Wu
- Chongqing Medical University-University of Leicester Joint Institute, Chongqing Medical University, Chongqing 400016, China
| | - Hao Wu
- Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
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Shawcross DL, Patel VC. FMT for hepatic encephalopathy? The THEMATIC trial aims to make it a 'no brainer'. J Hepatol 2025:S0168-8278(25)00165-5. [PMID: 40147790 DOI: 10.1016/j.jhep.2025.03.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2025] [Accepted: 03/07/2025] [Indexed: 03/29/2025]
Affiliation(s)
- Debbie L Shawcross
- Roger Williams Institute of Liver Studies, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, Foundation for Liver Research and King's College Hospital NHS Foundation Trust, London, UK.
| | - Vishal C Patel
- Roger Williams Institute of Liver Studies, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, Foundation for Liver Research and King's College Hospital NHS Foundation Trust, London, UK
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Xu X, Zhu T, Jing C, Jiang M, Fu Y, Xie F, Meng Q, Li J. Hepatic encephalopathy treatment after transjugular intrahepatic portosystemic shunt: a new perspective on the gut microbiota. Front Med (Lausanne) 2025; 12:1423780. [PMID: 40124683 PMCID: PMC11926149 DOI: 10.3389/fmed.2025.1423780] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2024] [Accepted: 02/24/2025] [Indexed: 03/25/2025] Open
Abstract
Transjugular intrahepatic portosystemic shunt (TIPS) placement alleviates portal hypertension symptoms. Hepatic encephalopathy (HE) is a common complication of TIPS, impacting patient quality of life and the healthcare burden. Post-TIPS HE is associated with portosystemic shunting, elevated blood ammonia levels, and inflammation. Increasing attention has been given to the liver and intestinal circulation in recent years. An imbalance in intestinal microecology plays a role in the occurrence of HE and may be a new target for treatment. This review discusses the causes, diagnosis, and treatment strategies for post-TIPS HE and focuses on exploring treatment strategies and their relationships with the gut microbiota, suggesting an innovative approach to address this complication.
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Affiliation(s)
- Xiaotong Xu
- Department of Oncology, Beijing Youan Hospital, Capital Medical University, Beijing, China
- Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Tong Zhu
- Interventional Therapy Center for Oncology, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Changyou Jing
- Interventional Therapy Center for Oncology, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Minjie Jiang
- Department of Oncology, Beijing Youan Hospital, Capital Medical University, Beijing, China
- Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Yunlai Fu
- Department of Oncology, Beijing Youan Hospital, Capital Medical University, Beijing, China
- Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Fang Xie
- Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Qinghua Meng
- Department of Oncology, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Jianjun Li
- Interventional Therapy Center for Oncology, Beijing Youan Hospital, Capital Medical University, Beijing, China
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7
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Turjeman S, Rozera T, Elinav E, Ianiro G, Koren O. From big data and experimental models to clinical trials: Iterative strategies in microbiome research. Cell 2025; 188:1178-1197. [PMID: 40054445 DOI: 10.1016/j.cell.2025.01.038] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2024] [Revised: 12/02/2024] [Accepted: 01/27/2025] [Indexed: 05/13/2025]
Abstract
Microbiome research has expanded significantly in the last two decades, yet translating findings into clinical applications remains challenging. This perspective discusses the persistent issue of correlational studies in microbiome research and proposes an iterative method leveraging in silico, in vitro, ex vivo, and in vivo studies toward successful preclinical and clinical trials. The evolution of research methodologies, including the shift from small cohort studies to large-scale, multi-cohort, and even "meta-cohort" analyses, has been facilitated by advancements in sequencing technologies, providing researchers with tools to examine multiple health phenotypes within a single study. The integration of multi-omics approaches-such as metagenomics, metatranscriptomics, metaproteomics, and metabolomics-provides a comprehensive understanding of host-microbe interactions and serves as a robust hypothesis generator for downstream in vitro and in vivo research. These hypotheses must then be rigorously tested, first with proof-of-concept experiments to clarify the causative effects of the microbiota, and then with the goal of deep mechanistic understanding. Only following these two phases can preclinical studies be conducted with the goal of translation into the clinic. We highlight the importance of combining traditional microbiological techniques with big-data approaches, underscoring the necessity of iterative experiments in diverse model systems to enhance the translational potential of microbiome research.
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Affiliation(s)
- Sondra Turjeman
- Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel.
| | - Tommaso Rozera
- Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, Rome, Italy; Department of Medical and Surgical Sciences, UOC Gastroenterologia, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy; Department of Medical and Surgical Sciences, UOC CEMAD Centro Malattie dell'Apparato Digerente, Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario Gemelli IRCCS, Rome, Italy
| | - Eran Elinav
- Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel; Microbiome & Cancer Division, DKFZ, Heidelberg, Germany
| | - Gianluca Ianiro
- Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, Rome, Italy; Department of Medical and Surgical Sciences, UOC Gastroenterologia, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy; Department of Medical and Surgical Sciences, UOC CEMAD Centro Malattie dell'Apparato Digerente, Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario Gemelli IRCCS, Rome, Italy
| | - Omry Koren
- Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel; Kyung Hee University, Seoul, Republic of Korea.
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Bloom PP, Bassis CM, Crossette E, Silber JL, Norman JM, Young VB, Lok AS. Safety and efficacy of a defined bacterial consortium, VE303, to treat HE. Hepatol Commun 2025; 9:e0650. [PMID: 39969428 PMCID: PMC11841841 DOI: 10.1097/hc9.0000000000000650] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2024] [Accepted: 12/24/2024] [Indexed: 02/20/2025] Open
Abstract
BACKGROUND Novel therapies are needed to treat HE, and microbiome modulation is a promising target. VE303 is a defined consortium of 8 purified, clonal bacterial strains, known to produce metabolites that may be beneficial in HE. We evaluated the safety and efficacy of VE303 to treat HE. METHODS We performed a single-center, randomized, placebo-controlled trial of VE303 in adult patients with a history of overt HE (NCT04899115). Eligible patients were taking lactulose and rifaximin, had no recent systemic antibiotics, and had MELD ≤20. All patients received 5 days of oral vancomycin followed by randomization to 14 days of VE303 or placebo (2:1). The primary endpoints were incidence of serious adverse events and change in psychometric HE score (PHES) from baseline to 4 weeks after treatment. Stool samples underwent metagenomic sequencing and metabolite quantification. RESULTS Eighteen patients completed the trial, 56% men, with a mean age of 59 years and a mean MELD of 11. Patients who received VE303 had a mean change in PHES of +1.5 versus -1.0 in those who received a placebo (p=0.20). Two of the 12 patients who received VE303 had at least 1 serious adverse event (all overt HE hospitalizations), compared with 0/6 patients who received a placebo. In the patients who received VE303, 2 of 8 strains engrafted in >50% of patients. Both VE303 strain engraftment and increased stool butyrate production had a trend toward improved PHES. CONCLUSIONS VE303 was well tolerated in patients with cirrhosis and a history of overt HE, leading to the engraftment of certain VE303 strains and a higher percentage of patients with improved PHES.
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Affiliation(s)
- Patricia P. Bloom
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, Michigan, USA
| | - Christine M. Bassis
- Department of Internal Medicine, Division of Infectious Diseases, University of Michigan, Ann Arbor, Michigan, USA
| | | | | | | | - Vincent B. Young
- Department of Internal Medicine, Division of Infectious Diseases, University of Michigan, Ann Arbor, Michigan, USA
- Department of Microbiology and Immunology, University of Michigan, Ann Arbor, Michigan, USA
| | - Anna S.F. Lok
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, Michigan, USA
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Lan Y, Song Y, Zhang W, Zhao S, Wang X, Wang L, Wang Y, Yang X, Wu H, Liu X. Quinoa Ethanol Extract Ameliorates Cognitive Impairments Induced by Hypoxia in Mice: Insights into Antioxidant Defense and Gut Microbiome Modulation. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2025; 73:3427-3443. [PMID: 39873455 DOI: 10.1021/acs.jafc.4c07530] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/30/2025]
Abstract
Quinoa, rich in pharmacologically active ingredients, possesses the potential benefit in preventing cognitive impairments induced by hypoxia. In this study, the efficacy of quinoa ethanol extracts (QEE) consumption (200 and 500 mg/kg/d, respectively) against hypobaric hypoxia (HH)-induced cognitive deficits in mice was investigated. QEE significantly ameliorated hypoxic stress induced by HH, as evidenced by improvements in baseline indices and reductions in hypoxia-inducible factor 1α levels. Furthermore, QEE enhanced antioxidant defense mechanisms, alleviated neuroinflammation in brain regions associated with memory, and improved HH-induced cognitive impairments by modulating the cyclic adenosine monophosphate response element-binding protein/brain-derived neurotrophic factor signaling pathway. Higher doses generally yielded more effective outcomes than lower doses. QEE also significantly reshaped the gut microbiome structure of HH mice, inhibited gut barrier damage, and reduced lipopolysaccharide migration, thereby increasing short-chain fatty acids (SCFAs) levels. Our findings suggest that QEE may be a promising strategy for preventing hypoxia-induced cognitive impairments by maintaining gut microbiome stability and increasing SCFAs levels.
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Affiliation(s)
- Yongli Lan
- College of Food Science and Engineering, Northwest A&F University, No. 22 Xinong Road, Yangling, Shaanxi 712100, China
| | - Yujie Song
- College of Food Science and Engineering, Northwest A&F University, No. 22 Xinong Road, Yangling, Shaanxi 712100, China
| | - Wengang Zhang
- College of Food Science and Engineering, Northwest A&F University, No. 22 Xinong Road, Yangling, Shaanxi 712100, China
- Laboratory for Research and Utilization of Qinghai Tibet Plateau Germplasm Resources, Qinghai University, Xining 810016, China
| | - Shiyang Zhao
- College of Food Science and Engineering, Northwest A&F University, No. 22 Xinong Road, Yangling, Shaanxi 712100, China
| | - Xinze Wang
- College of Food Science and Engineering, Northwest A&F University, No. 22 Xinong Road, Yangling, Shaanxi 712100, China
| | - Lei Wang
- College of Food Science and Engineering, Northwest A&F University, No. 22 Xinong Road, Yangling, Shaanxi 712100, China
| | - Yutang Wang
- College of Food Science and Engineering, Northwest A&F University, No. 22 Xinong Road, Yangling, Shaanxi 712100, China
| | - Xijuan Yang
- Laboratory for Research and Utilization of Qinghai Tibet Plateau Germplasm Resources, Qinghai University, Xining 810016, China
| | - Hao Wu
- Shandong Technology Innovation Center of Special Food, Qingdao 266109, China
- Qingdao Special Food Research Institute, Qingdao 266109, China
| | - Xuebo Liu
- College of Food Science and Engineering, Northwest A&F University, No. 22 Xinong Road, Yangling, Shaanxi 712100, China
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Rågård N, Baumwall SMD, Paaske SE, Hansen MM, Høyer KL, Mikkelsen S, Erikstrup C, Dahlerup JF, Hvas CL. Validation methods for encapsulated faecal microbiota transplantation: a scoping review. Therap Adv Gastroenterol 2025; 18:17562848251314820. [PMID: 39926318 PMCID: PMC11806493 DOI: 10.1177/17562848251314820] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2024] [Accepted: 01/03/2025] [Indexed: 02/11/2025] Open
Abstract
Faecal microbiota transplantation (FMT) is increasingly used for diseases associated with a disrupted intestinal microbiome, mainly Clostridioides difficile infection. Encapsulated FMT is a patient-friendly application method that improves accessibility and convenience. Capsule processing may be standardised, but validation protocols are warranted. This review aimed to describe published validation methods for encapsulated FMT. Original studies reporting using encapsulated faecal formulations were included, regardless of indication. Studies were excluded if they did not address processing and validation or used non-donor-derived content. We conducted a comprehensive scoping review, implementing a systematic search strategy in PubMed, Embase and Web of Science. Processing data and validation methods were registered during full-text analysis and combined to create an overview of approaches for assessing quality in encapsulated FMT processing. The searches identified 324 unique studies, of which 44 were included for data extraction and analysis. We identified eight validation covariables: donor selection, pre-processing, preservation, oxygen-sparing processing, microbial count, viability, engraftment and clinical effect outcomes, from which we constructed a model for quality assessment of encapsulated FMT that exhaustively categorised processing details and validation measures. Our model comprised three domains: (1) Processing (donor selection and processing protocol), (2) Content analysis (microbiota measures and dose measures) and (3) Clinical effect (engraftment and clinical outcomes). No studies presented a reproducible capsule protocol; their validation strategies were sparse and divergent. The validation of FMT capsules is heterogeneous, and processing requires relevant standardisation protocols, mainly focusing on capsule content. Future studies should report validation covariables to enable accurate comparative assessments of clinical effects.
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Affiliation(s)
- Nina Rågård
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
| | | | - Sara Ellegaard Paaske
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Mette Mejlby Hansen
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
| | - Katrine Lundby Høyer
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Susan Mikkelsen
- Department of Clinical Immunology, Aarhus University Hospital, Aarhus, Denmark
| | - Christian Erikstrup
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
- Department of Clinical Immunology, Aarhus University Hospital, Aarhus, Denmark
| | - Jens Frederik Dahlerup
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Christian Lodberg Hvas
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Palle Juul-Jensens Boulevard 35, DK-8200 Aarhus N, Denmark
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
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11
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Meroni M, Longo M, Paolini E, Dongiovanni P. A narrative review about cognitive impairment in Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD): Another matter to face through a holistic approach. J Adv Res 2025; 68:231-240. [PMID: 38369241 PMCID: PMC11785580 DOI: 10.1016/j.jare.2024.02.007] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2023] [Revised: 01/28/2024] [Accepted: 02/15/2024] [Indexed: 02/20/2024] Open
Abstract
BACKGROUND Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic hepatic disorder worldwide in both adults and children. It is well established that MASLD represents the hepatic manifestation of the metabolic syndrome whose definition includes the presence of obesity, type 2 diabetes (T2D), dyslipidemia, hypertension and hypercoagulability. All these conditions contribute to a chronic inflammatory status which may impact on blood brain barrier (BBB) integrity leading to an impaired function of central nervous system (CNS). AIM OF REVIEW Since the mechanisms underlying the brain-liver-gut axis derangement are still inconclusive, the present narrative review aims to make a roundup of the most recent studies regarding the cognitive decline in MASLD also highlighting possible therapeutic strategies to reach a holistic advantage for the patients. KEY SCIENTIFIC CONCEPTS OF REVIEW Due to its ever-growing prevalence, the MASLD-related mental dysfunction represents an enormous socio-economic burden since it largely impacts on the quality of life of patients as well as on their working productivity. Indeed, cognitive decline in MASLD translates in low concentration and processing speed, reduced memory, sleepiness but also anxiety and depression. Chronic systemic inflammation, hyperammonemia, genetic background and intestinal dysbiosis possibly contribute to the cognitive decline in MASLD patients. However, its diagnosis is still underestimated since the leading mechanisms are multi-faceted and unexplained and do not exist standardized diagnostic tools or cognitive test strategies. In this scenario, nutritional and lifestyle interventions as well as intestinal microbiota manipulation (probiotics, fecal transplantation) may represent new approaches to counteract mental impairment in these subjects. In sum, to face the "mental aspect" of this multifactorial disease which is almost unexplored, cognitive tools should be introduced in the management of MASLD patients.
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Affiliation(s)
- Marica Meroni
- Medicine and Metabolic Diseases, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Miriam Longo
- Medicine and Metabolic Diseases, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Erika Paolini
- Medicine and Metabolic Diseases, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Paola Dongiovanni
- Medicine and Metabolic Diseases, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy.
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12
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Bajaj JS, Fagan A, Gavis EA, Sterling RK, Gallagher ML, Lee H, Matherly SC, Siddiqui MS, Bartels A, Mousel T, Davis BC, Puri P, Fuchs M, Moutsoglou DM, Thacker LR, Sikaroodi M, Gillevet PM, Khoruts A. Microbiota transplant for hepatic encephalopathy in cirrhosis: The THEMATIC trial. J Hepatol 2025:S0168-8278(25)00005-4. [PMID: 39800192 DOI: 10.1016/j.jhep.2024.12.047] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2024] [Revised: 12/12/2024] [Accepted: 12/27/2024] [Indexed: 01/15/2025]
Abstract
BACKGROUND & AIMS Preventing hepatic encephalopathy (HE) recurrence in cirrhosis, which is associated with an altered gut-liver-brain axis, is an unmet need. Benefits of fecal microbiota transplantation (FMT) have been shown in phase I studies, but route and dose-related questions remain. METHODS We performed a phase II randomized, placebo-controlled, double-blind, clinical trial of capsule and enema FMT in patients with cirrhosis and HE on lactulose and rifaximin. Participants were randomized into four groups (3 active doses; 2 active and 1 placebo dose; 1 active and 2 placebo doses; 3 placebo doses). Each patient received two capsules and one enema (either placebo or FMT) and were followed for 6 months. The primary outcome was FMT-related (serious) adverse events ([s]AEs)/AEs using intention-to-treat analysis. Secondary outcomes were HE recurrence, all-cause hospitalizations, death, donor engraftment, and quality-of-life. FMT was from a vegan or omnivorous donor. RESULTS We enrolled 60 patients (15/group) with similar baseline characteristics. FMT was safe without any FMT-related SAEs/AEs. Overall SAEs (p = 0.96) or death (p = 1.0) were similar. There were significant differences in HE recurrence between groups (p = 0.035, Cramer's V = 0.39). On post hoc analysis, recurrence was highest in the all-placebo vs. any FMT group (40% vs. 9%; odds ratio 0.15, 95% CI 0.04-0.64). Within the FMT groups, HE recurrence rates were similar regardless of route, doses, or donor type. Quality of life improved in FMT-recipient groups. Engraftment was highest in those with high pre-FMT Lachnospiraceae and lower in those whose HE recurred. CONCLUSIONS In patients with cirrhosis and HE on maximal therapy, FMT regardless of dose, route, or donor was safe without any FMT-related AEs. On post hoc analysis, HE recurrence was highest in the placebo-only group and linked with lower baseline Lachnospiraceae and reduced donor engraftment. IMPACT AND IMPLICATIONS Patients with hepatic encephalopathy (HE) already on maximal therapy could have recurrences, which worsen prognosis and are not prioritized for liver transplant. In this phase II, double-blind, randomized, placebo-controlled trial in patients with cirrhosis and prior overt HE, we found that fecal microbiota transplant (FMT) was safe and well tolerated regardless of route of delivery (oral or enema), number of doses (1 through 3), or donor type (vegan or omnivorous). HE recurrence, which was a key secondary endpoint, was different between groups and, on post hoc analysis, lowest in groups that received any FMT. Donor engraftment was higher in those with higher relative abundance of Lachnospiraceae, which was associated with lower HE recurrence.
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Affiliation(s)
- Jasmohan S Bajaj
- Division of Gastroenterology, Hepatology, and Nutrition, Virginia Commonwealth University and Richmond VA Medical Center, Richmond, Virginia, USA.
| | - Andrew Fagan
- Division of Gastroenterology, Hepatology, and Nutrition, Virginia Commonwealth University and Richmond VA Medical Center, Richmond, Virginia, USA
| | - Edith A Gavis
- Division of Gastroenterology, Hepatology, and Nutrition, Virginia Commonwealth University and Richmond VA Medical Center, Richmond, Virginia, USA
| | - Richard K Sterling
- Division of Gastroenterology, Hepatology, and Nutrition, Virginia Commonwealth University and Richmond VA Medical Center, Richmond, Virginia, USA
| | - Mary Leslie Gallagher
- Division of Gastroenterology, Hepatology, and Nutrition, Virginia Commonwealth University and Richmond VA Medical Center, Richmond, Virginia, USA
| | - Hannah Lee
- Division of Gastroenterology, Hepatology, and Nutrition, Virginia Commonwealth University and Richmond VA Medical Center, Richmond, Virginia, USA
| | - Scott C Matherly
- Division of Gastroenterology, Hepatology, and Nutrition, Virginia Commonwealth University and Richmond VA Medical Center, Richmond, Virginia, USA
| | - Mohammed S Siddiqui
- Division of Gastroenterology, Hepatology, and Nutrition, Virginia Commonwealth University and Richmond VA Medical Center, Richmond, Virginia, USA
| | - Amy Bartels
- Division of Gastroenterology, Hepatology, and Nutrition, Virginia Commonwealth University and Richmond VA Medical Center, Richmond, Virginia, USA
| | - Travis Mousel
- Division of Gastroenterology, Hepatology, and Nutrition, Virginia Commonwealth University and Richmond VA Medical Center, Richmond, Virginia, USA
| | - Brian C Davis
- Division of Gastroenterology, Hepatology, and Nutrition, Virginia Commonwealth University and Richmond VA Medical Center, Richmond, Virginia, USA
| | - Puneet Puri
- Division of Gastroenterology, Hepatology, and Nutrition, Virginia Commonwealth University and Richmond VA Medical Center, Richmond, Virginia, USA
| | - Michael Fuchs
- Division of Gastroenterology, Hepatology, and Nutrition, Virginia Commonwealth University and Richmond VA Medical Center, Richmond, Virginia, USA
| | - Daphne M Moutsoglou
- Gastroenterology, Minneapolis VA Medical Center, Minneapolis, Minnesota, USA; Department of Medicine, University of Minnesota, Minneapolis, Minnesota, USA
| | - Leroy R Thacker
- Department of Biostatistics, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Masoumeh Sikaroodi
- Microbiome Analysis Center, George Mason University, Manassas, Virginia, USA
| | - Patrick M Gillevet
- Microbiome Analysis Center, George Mason University, Manassas, Virginia, USA
| | - Alexander Khoruts
- Division of Gastroenterology and Hepatology and Center for Immunology, University of Minnesota, Minneapolis, Minnesota, USA
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13
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Tang S, Wu S, Zhang W, Ma L, Zuo L, Wang H. Immunology and treatments of fatty liver disease. Arch Toxicol 2025; 99:127-152. [PMID: 39692857 DOI: 10.1007/s00204-024-03920-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2024] [Accepted: 11/26/2024] [Indexed: 12/19/2024]
Abstract
Alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD) are two major chronic liver diseases worldwide. The triggers for fatty liver can be derived from external sources such as adipose tissue, the gut, personal diet, and genetics, or internal sources, including immune cell responses, lipotoxicity, hepatocyte death, mitochondrial dysfunction, and extracellular vesicles. However, their pathogenesis varies to some extent. This review summarizes various immune mechanisms and therapeutic targets associated with these two types of fatty liver disease. It describes the gut-liver axis and adipose tissue-liver crosstalk, as well as the roles of different immune cells (both innate and adaptive immune cells) in fatty liver disease. Additionally, mitochondrial dysfunction, extracellular vesicles, microRNAs (miRNAs), and gastrointestinal hormones are also related to the pathogenesis of fatty liver. Understanding the pathogenesis of fatty liver and corresponding therapeutic strategies provides a new perspective for developing novel treatments for fatty liver disease.
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Affiliation(s)
- Sainan Tang
- Innovation and Entrepreneurship Laboratory for College Students, Anhui Medical University, Hefei, Anhui, China
- Laboratory of Molecular Biology, Department of Biochemistry, School of Basic Medical Science, Anhui Medical University, Hefei, 230022, Anhui, China
| | - Shanshan Wu
- Innovation and Entrepreneurship Laboratory for College Students, Anhui Medical University, Hefei, Anhui, China
- Department of Gastroenterology, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
- Inflammation and Immune-Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, Anhui, China
| | - Wenzhe Zhang
- Innovation and Entrepreneurship Laboratory for College Students, Anhui Medical University, Hefei, Anhui, China
- The First College of Clinical Medicine, Anhui Medical University, Hefei, Anhui, China
| | - Lili Ma
- Innovation and Entrepreneurship Laboratory for College Students, Anhui Medical University, Hefei, Anhui, China
- The First College of Clinical Medicine, Anhui Medical University, Hefei, Anhui, China
| | - Li Zuo
- Innovation and Entrepreneurship Laboratory for College Students, Anhui Medical University, Hefei, Anhui, China.
- Laboratory of Molecular Biology, Department of Biochemistry, School of Basic Medical Science, Anhui Medical University, Hefei, 230022, Anhui, China.
| | - Hua Wang
- Department of Oncology, the First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui, China.
- Inflammation and Immune-Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, Anhui, China.
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14
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Saha S, Schnabl B. Modulating the microbiome in chronic liver diseases - current evidence on the role of fecal microbiota transplantation. Expert Rev Gastroenterol Hepatol 2025; 19:53-64. [PMID: 39760535 PMCID: PMC11882407 DOI: 10.1080/17474124.2025.2450707] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2024] [Revised: 12/23/2024] [Accepted: 01/04/2025] [Indexed: 01/07/2025]
Abstract
INTRODUCTION The gut microbiota has a complex relationship with the human host and is key to maintaining health. Disruption of the healthy diverse gut microbial milieu plays an important role in the pathogenesis of several diseases including Clostridioides difficile infection (CDI), inflammatory bowel disease, irritable bowel syndrome, alcohol-related liver disease and metabolic-dysfunction associated steatotic liver disease (MASLD). Fecal microbiota transplantation (FMT) is highly effective in treating CDI, though its utility in other diseases is still being explored. AREAS COVERED In this narrative review, we explore the role of gut microbiota in liver diseases, focusing on key changes in the microbial composition and function. We summarize current evidence on the role of FMT, identifying gaps in current research and outlining future directions for investigation. We comprehensively searched PubMed through 15 October 2024 to identify relevant studies. EXPERT OPINION While data from available studies shows promise, more research is necessary before we can use FMT for liver diseases. Key areas that require further study are - determining the optimal FMT regimen for each disease, establishing efficacy and safety with larger clinical trials, ensuring safe and equitable access to the FMT product and mechanistic insights into the reasons for success or failure of FMT.
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Affiliation(s)
- Srishti Saha
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of California San Diego, San Diego, CA
| | - Bernd Schnabl
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of California San Diego, San Diego, CA
- Department of Medicine, VA San Diego Healthcare System, San Diego, CA, USA
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15
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Bloom PP, Chung RT. The future of clinical trials of gut microbiome therapeutics in cirrhosis. JHEP Rep 2025; 7:101234. [PMID: 39717506 PMCID: PMC11663965 DOI: 10.1016/j.jhepr.2024.101234] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2024] [Revised: 09/30/2024] [Accepted: 10/02/2024] [Indexed: 12/25/2024] Open
Abstract
The last two decades have witnessed an explosion of microbiome research, including in hepatology, with studies demonstrating altered microbial composition in liver disease. More recently, efforts have been made to understand the association of microbiome features with clinical outcomes and to develop therapeutics targeting the microbiome. While microbiome therapeutics hold much promise, their unique features pose certain challenges for the design and conduct of clinical trials. Herein, we will briefly review indications for microbiome therapeutics in cirrhosis, currently available microbiome therapeutics, and the biological pathways targeted by these therapies. We will then focus on the best practices and important considerations for clinical trials of gut microbiome therapeutics in cirrhosis.
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Affiliation(s)
- Patricia P. Bloom
- University of Michigan, Division of Gastroenterology, Ann Arbor, MI, USA
| | - Raymond T. Chung
- Massachusetts General Hospital, Division of Gastroenterology, Boston, MA, USA
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16
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Gil-Gómez A, Muñoz-Hernández R, Martínez F, Jiménez F, Romero-Gómez M. Hepatic encephalopathy: experimental drugs in development and therapeutic potential. Expert Opin Investig Drugs 2024; 33:1219-1230. [PMID: 39588934 DOI: 10.1080/13543784.2024.2434053] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2024] [Accepted: 11/21/2024] [Indexed: 11/27/2024]
Abstract
INTRODUCTION Hepatic encephalopathy (HE) presents a complex pathophysiology, creating multiple potential treatment avenues. This review covers current and emerging treatments for HE. AREAS COVERED Standard therapies, including non-absorbable disaccharides and rifaximin, are widely used but show inconsistent efficacy. Alternatives such as polyethylene glycol and L-ornithine L-aspartate have been effective in certain cases. Advancements in understanding HE reveal a growing need for personalized treatments. Novel approaches targeting immune modulation and neuroinflammation are under investigation, though clinical translation is slow. Nutritional interventions and fecal microbiota transplantation show potential but lack robust evidence. Innovative therapies like gene and cell therapies, as well as extracellular vesicles from mesenchymal stem cells, present promising avenues for liver disease treatment, potentially benefiting HE. EXPERT OPINION A key challenge in HE research is the design of randomized clinical trials, which often suffer from small sample sizes, heterogeneity in patient population, and inconsistent blinding. Additionally, the multifactorial nature of HE, together with a high spontaneous response rate, complicates efforts to isolate treatment effects. Despite current limitations, ongoing research and technological advances hold promise for more effective and individualized HE treatments in the future.
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Affiliation(s)
- Antonio Gil-Gómez
- SeLiver Group at Institute of Biomedicine of Seville (IBiS), Virgen del Rocio University Hospital/CSIC/University of Seville, Seville, Spain
- CIBERehd, Instituto de Salud Carlos III, Madrid, Spain
| | - Rocío Muñoz-Hernández
- SeLiver Group at Institute of Biomedicine of Seville (IBiS), Virgen del Rocio University Hospital/CSIC/University of Seville, Seville, Spain
- CIBERehd, Instituto de Salud Carlos III, Madrid, Spain
- Departamento de Fisiología, Facultad de Biología, Universidad de Sevilla, Seville, Spain
| | - Filomeno Martínez
- UCM Digestive Diseases, Virgen del Rocío University Hospital, Seville, Spain
| | - Fernando Jiménez
- UCM Digestive Diseases, Virgen del Rocío University Hospital, Seville, Spain
| | - Manuel Romero-Gómez
- SeLiver Group at Institute of Biomedicine of Seville (IBiS), Virgen del Rocio University Hospital/CSIC/University of Seville, Seville, Spain
- CIBERehd, Instituto de Salud Carlos III, Madrid, Spain
- UCM Digestive Diseases, Virgen del Rocío University Hospital, Seville, Spain
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17
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Ntuli Y, Shawcross DL. Infection, inflammation and hepatic encephalopathy from a clinical perspective. Metab Brain Dis 2024; 39:1689-1703. [PMID: 39212845 PMCID: PMC11535002 DOI: 10.1007/s11011-024-01402-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2024] [Accepted: 07/23/2024] [Indexed: 09/04/2024]
Abstract
Hepatic encephalopathy (HE) is a syndrome that is associated with both acute and chronic liver injury. It manifests as a wide spectrum of neuropsychological abnormalities, ranging from subtle impairments in executive higher functions observed in cirrhosis, through to coma in acute liver failure. In acute liver failure, the central role of ammonia in the development of brain oedema has remained undisputed for 130 years. It latterly became apparent that infection and inflammation were profound determinants for the development of severe hepatic encephalopathy, associated with the development of cerebral oedema and intracranial hypertension. The relationship of the development of hepatic encephalopathy with blood ammonia levels in cirrhosis is less clear cut and the synergistic interplay of inflammation and infection with ammonia has been identified as being fundamental in the development and progression of hepatic encephalopathy. A perturbed gut microbiome and the presence of an impaired gut epithelial barrier that facilitates translocation of bacteria and bacterial degradation products into the systemic circulation, inducing systemic inflammation and innate and adaptive immune dysfunction, has now become the focus of therapies that treat hepatic encephalopathy in cirrhosis, and may explain why the prebiotic lactulose and rifaximin are efficacious. This review summarises the current clinical perspective on the roles of inflammation and infection in hepatic encephalopathy and presents the evidence base for existing therapies and those in development in the setting of acute and chronic liver failure.
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Affiliation(s)
- Yevedzo Ntuli
- School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, King's College Hospital, 125 Coldharbour Lane, London, SE5 9NU, UK
- Institute of Liver Studies, King's College Hospital, Denmark Hill, London, SE5 9RS, UK
| | - Debbie L Shawcross
- School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, King's College Hospital, 125 Coldharbour Lane, London, SE5 9NU, UK.
- Institute of Liver Studies, King's College Hospital, Denmark Hill, London, SE5 9RS, UK.
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18
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Lee JY, Kim Y, Kim J, Kim JK. Fecal Microbiota Transplantation: Indications, Methods, and Challenges. J Microbiol 2024; 62:1057-1074. [PMID: 39557804 DOI: 10.1007/s12275-024-00184-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2024] [Revised: 09/25/2024] [Accepted: 10/16/2024] [Indexed: 11/20/2024]
Abstract
Over the past two decades, as the importance of gut microbiota to human health has become widely known, attempts have been made to treat diseases by correcting dysbiosis of gut microbiota through fecal microbiota transplantation (FMT). Apart from current knowledge of gut microbiota, FMT to treat disease has a long history, from the treatment of food poisoning in the fourth century to the treatment of Clostridioides difficile infections in the twentieth century. In 2013, FMT was recognized as a standard treatment for recurrent C. difficile because it consistently showed high efficacy. Though recurrent C. difficile is the only disease internationally recognized for FMT efficacy, FMT has been tested for other diseases and shown some promising preliminary results. Different FMT methods have been developed using various formulations and administration routes. Despite advances in FMT, some issues remain to be resolved, such as donor screening, manufacturing protocols, and unknown components in the fecal microbiota. In this review, we discuss the mechanisms, clinical indications, methods, and challenges of current FMT. We also discuss the development of alternative therapies to overcome the challenges of FMT.
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Affiliation(s)
- Jee Young Lee
- Department of Microbiology, Kosin University College of Medicine, Busan, 49267, Republic of Korea
| | - Yehwon Kim
- Department of Medicine, Kosin University College of Medicine, Busan, 49267, Republic of Korea
| | - Jiyoun Kim
- Department of Medicine, Kosin University College of Medicine, Busan, 49267, Republic of Korea
| | - Jiyeun Kate Kim
- Department of Microbiology, Kosin University College of Medicine, Busan, 49267, Republic of Korea.
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19
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Zou P, Bi Y, Tong Z, Wu T, Li Q, Wang K, Fan Y, Zhao D, Wang X, Shao H, Huang H, Ma S, Qian Y, Zhang G, Liu X, Jin Q, Ru Q, Qian Z, Sun W, Chen Q, You L, Wang F, Zhang X, Qiu Z, Lin Q, Lv J, Zhang Y, Geng J, Mao R, Liu J, Zheng Y, Ding F, Wang H, Gao H. Comparisons of efficacy and safety of 400 or 800 ml bacterial count fecal microbiota transplantation in the treatment of recurrent hepatic encephalopathy: a multicenter prospective randomized controlled trial in China. Trials 2024; 25:799. [PMID: 39605077 PMCID: PMC11600821 DOI: 10.1186/s13063-024-08578-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2024] [Accepted: 10/24/2024] [Indexed: 11/29/2024] Open
Abstract
BACKGROUND Hepatic encephalopathy (HE) represents a critical complications of end-stage liver disease, serving as an independent predictor of mortality among patients with cirrhosis. Despite effective treatment with rifaximin, some patients with HE still progress to recurrent episodes, posing a significant therapeutic challenge. Recurrent HE is defined as experiencing two or more episodes within a 6-month period. Previous research has suggested that FMT may emerge as a promising treatment for recurrent HE. However, there remains a critical need to explore the optimal dosage. This trial aims to abscess the efficacy and safety of two FMT dosages: 800 ml or 400 ml total bacterial count, including mortality and quality of life. METHODS This multicenter, prospective, randomized controlled trial will enroll 100 eligible patients from 31 hospitals in China. Participants will be randomly assigned in a 1:1 ratio to either the high-dose group (800 ml total bacterial count) or the low-dose group (400 ml total bacterial count). The primary objective is to assess the efficacy and safety of both dosages on outcomes at 24 and 48 weeks, including mortality and quality of life. DISCUSSION If either or both dosages of FMT demonstrate safe and effective treatment of recurrent HE, leading to improve quality of life and survival at 24 and 48 weeks, this trial would address a significant gap in the management of recurrent HE, carrying innovative and clinically significant implications. TRIAL REGISTRATION NCT05669651 on ClinicalTrials.gov. Registered on 29 December 2022. CHiCTR2200067135 on China Registered Clinical Trial Registration Center. Registered on 27 December 2022.
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Affiliation(s)
- Pengfei Zou
- Shulan (Hangzhou) Hospital Affiliated to Zhejiang, Shuren University Shulan International Medical College, Hangzhou, China
- Jinan Microecological Biomedicine Shandong Laboratory, Jinan, China
| | - Yunjiao Bi
- Zhejiang Chinese Medical University, Hangzhou, China
| | | | - Tao Wu
- Hainan General Hospital Branch - Ding'an Hospital, Ding'an, China
| | - Qiang Li
- Shandong Public Health Clinical Center, Jinan, China
| | - Kai Wang
- Department of Hepatology, Qilu Hospital of Shandong University, Jinan, China
| | - Yuchen Fan
- Department of Hepatology, Qilu Hospital of Shandong University, Jinan, China
| | - Dan Zhao
- Zhengzhou Third People's Hospital, Zhengzhou, China
| | - Xin Wang
- Shulan (Quzhou) Hospital, Quzhou, China
| | - Hui Shao
- Taizhou Hospital of Zhejiang, Taizhou, China
| | - Haijun Huang
- Zhejiang Provincial People's Hospital, Hangzhou, China
| | - Suping Ma
- The First Affiliated Hospital of Henan University of CM, Zhengzhou, China
| | | | | | - Xiao Liu
- Ningbo Zhenhai District People's Hospital, Ningbo, China
| | - Qiaofei Jin
- Hangzhou Xixi HospitalAffiliated to, Zhejiang University School of Medicine , Hangzhou, China
| | - Qingjing Ru
- The Second Affiliated Hospital of Zhejiang, Chinese Medical University, Hangzhou, China
| | - Zhiping Qian
- Shanghai Public Health Clinical Center, Shanghai, China
| | - Wei Sun
- The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Qiang Chen
- Zouping People's Hospital, Binzhou, China
| | - Liying You
- ALMETTE Hospital &, The First Hospital of Kunming, Kunming, China
| | - Fang Wang
- Zoucheng People's Hospital, Jining, China
| | - Xiaoting Zhang
- Shenzhen Bao'an District Songgang People's Hospital, Shenzhen, China
| | | | - Qing Lin
- The People's Hospital of Jiulongpo District, Chongqing, China
| | | | - Yongping Zhang
- People's Hospital of Xinjiang Uygur Autonomous Region, Ürümqi, China
| | - Jiawei Geng
- Department of Infectious Disease and Hepatic Disease, First People's Hospital of Yunnan Province, Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan, China
| | - Richeng Mao
- Department Of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Jinfeng Liu
- The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Yubao Zheng
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Feng Ding
- Affiliated Hospital of Shaoxing University, Shaoxing, China
| | - Hui Wang
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Hainv Gao
- Shulan (Hangzhou) Hospital Affiliated to Zhejiang, Shuren University Shulan International Medical College, Hangzhou, China.
- Jinan Microecological Biomedicine Shandong Laboratory, Jinan, China.
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20
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Pereira LTG, Vilela WR, Bellozi PMQ, Engel DF, de Paula GC, de Andrade RR, Mortari MR, de Melo Teixeira M, Coleine C, Figueiredo CP, de Bem AF, Amato AA. Fecal microbiota transplantation ameliorates high-fat diet-induced memory impairment in mice. J Neurochem 2024; 168:2893-2907. [PMID: 38934224 DOI: 10.1111/jnc.16156] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Revised: 05/28/2024] [Accepted: 06/05/2024] [Indexed: 06/28/2024]
Abstract
Gut dysbiosis is linked to metabolic and neurodegenerative diseases and comprises a plausible link between high-fat diet (HFD) and brain dysfunction. Here we show that gut microbiota modulation by either antibiotic treatment for 5 weeks or a brief 3-day fecal microbiota transplantation (FMT) regimen from low-fat (control) diet-fed mice decreased weight gain, adipose tissue hypertrophy, and glucose intolerance induced by HFD in C57BL/6 male mice. Notably, gut microbiota modulation by FMT completely reversed impaired recognition memory induced by HFD, whereas modulation by antibiotics had less pronounced effect. Improvement in recognition memory by FMT was accompanied by decreased HFD-induced astrogliosis in the hippocampal cornu ammonis region. Gut microbiome composition analysis indicated that HFD diminished microbiota diversity compared to control diet, whereas FMT partially restored the phyla diversity. Our findings reinforce the role of the gut microbiota on HFD-induced cognitive impairment and suggest that modulating the gut microbiota may be an effective strategy to prevent metabolic and cognitive dysfunction associated with unfavorable dietary patterns.
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Affiliation(s)
| | - Wembley Rodrigues Vilela
- Department of Physiological Sciences, Institute of Biology, University of Brasilia, Brasilia, Brazil
| | - Paula Maria Quaglio Bellozi
- Laboratory of Molecular Pharmacology, School of Health Sciences, University of Brasilia, Brasilia, Brazil
- Department of Physiological Sciences, Institute of Biology, University of Brasilia, Brasilia, Brazil
| | - Daiane Fátima Engel
- School of Pharmacy, Federal University of Ouro Preto, Ouro Preto, Minas Gerais, Brazil
| | | | | | - Márcia Renata Mortari
- Laboratory of Neuropharmacology, Department of Physiological Sciences, Biology Institute, University of Brasilia, Federal District, Brazil
| | | | - Claudia Coleine
- Department of Ecological and Biological Sciences, University of Tuscia, Viterbo, Italy
| | - Cláudia Pinto Figueiredo
- Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Andreza Fabro de Bem
- Department of Physiological Sciences, Institute of Biology, University of Brasilia, Brasilia, Brazil
- Brazilian National Institute of Science and Technology on Neuroimmunomodulation, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil
| | - Angélica Amorim Amato
- Laboratory of Molecular Pharmacology, School of Health Sciences, University of Brasilia, Brasilia, Brazil
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21
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Yang Z, Liu S, Wei F, Hu J. The effects of Qingchang Ligan formula on hepatic encephalopathy in mouse model: results from gut microbiome-metabolomics analysis. Front Cell Infect Microbiol 2024; 14:1381209. [PMID: 39220284 PMCID: PMC11362135 DOI: 10.3389/fcimb.2024.1381209] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2024] [Accepted: 07/29/2024] [Indexed: 09/04/2024] Open
Abstract
Background Hepatic encephalopathy (HE) is a neurological disorder resulting from advanced liver injury. HE has a high mortality rate and poor prognosis. The pathogenesis of HE is still unclear, which has led to the lack of a satisfactory specific treatment method. There is increasing evidence that the intestinal flora affects the communication between the gut and the brain in the pathogenesis of HE. Adjusting the intestinal flora has had a beneficial effect on HE in recent studies, and the Qingchang Ligan formula (QCLG) has been shown in previous studies to regulate intestinal flora and metabolites. In this study, we established a thioacetamide-induced HE mouse model to evaluate the protective effect of QCLG on HE and explore its potential mechanism, which also demonstrated that intestinal flora dysbiosis is involved in the pathogenesis of HE. Methods Mice were intraperitoneally injected with thioacetamide (TAA, 150 mg/kg) to induce HE. Additionally, they were orally administered Qingchang Ligan Formula (QCLG) at a dose of 6.725 g/kg·d for seven days, while control mice received an equal volume of saline via gavage. Subsequently, samples were subjected to 16S ribosomal ribonucleic acid (rRNA) gene sequencing, high-performance liquid chromatography-mass spectrometry (LC-MS), and RNA-sequencing (RNA-seq) analysis. Result QCLG improved weight loss, cognitive impairment, neurological function scores, blood ammonia, and brain gene expression of interleukin-6 (TNF-α), Interleukin-1β (IL-1β), and interleukin-6 (IL-6) induced by HE. Moreover, QCLG increased the levels of liver function indicators, including alanine aminotransferase (ALT), aspartate aminotransferase (AST), and serum TNF-α, IL-1β, and IL-6. 16S RNA sequencing revealed increased Oscillibacter, Colidextribacter, and Helicobacter in TAA-induced mouse fecal samples. Also, the abundance of Bifidobacterium decreases TAA-induced mouse fecal samples. In contrast, QCLG treatment significantly restored the gut microbial community. Metabolomics indicated significant differences in some metabolites among the normal control, treatment, and model groups, including 5-methoxytryptophan, Daidzein, Stercobilin, and Plumieride (PLU). Conclusion QCLG can alleviate neuroinflammation and prevent HE caused by liver injury by regulating intestinal flora in mouse models.
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Affiliation(s)
- Ziwei Yang
- Beijing Youan Hospital, Capital Medical University, Beijing, China
- Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Shuhui Liu
- Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Feili Wei
- Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Jianhua Hu
- Beijing Youan Hospital, Capital Medical University, Beijing, China
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22
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Smith ML, Wade JB, Wolstenholme J, Bajaj JS. Gut microbiome-brain-cirrhosis axis. Hepatology 2024; 80:465-485. [PMID: 36866864 PMCID: PMC10480351 DOI: 10.1097/hep.0000000000000344] [Citation(s) in RCA: 23] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Accepted: 02/10/2023] [Indexed: 03/04/2023]
Abstract
Cirrhosis is characterized by inflammation, degeneration, and fibrosis of liver tissue. Along with being the most common cause of liver failure and liver transplant, cirrhosis is a significant risk factor for several neuropsychiatric conditions. The most common of these is HE, which is characterized by cognitive and ataxic symptoms, resulting from the buildup of metabolic toxins with liver failure. However, cirrhosis patients also show a significantly increased risk for neurodegenerative diseases such as Alzheimer and Parkinson diseases, and for mood disorders such as anxiety and depression. In recent years, more attention has been played to communication between the ways the gut and liver communicate with each other and with the central nervous system, and the way these organs influence each other's function. This bidirectional communication has come to be known as the gut-liver-brain axis. The gut microbiome has emerged as a key mechanism affecting gut-liver, gut-brain, and brain-liver communication. Clinical studies and animal models have demonstrated the significant patterns of gut dysbiosis when cirrhosis is present, both with or without concomitant alcohol use disorder, and have provided compelling evidence that this dysbiosis also influences the cognitive and mood-related behaviors. In this review, we have summarized the pathophysiological and cognitive effects associated with cirrhosis, links to cirrhosis-associated disruption of the gut microbiome, and the current evidence from clinical and preclinical studies for the modulation of the gut microbiome as a treatment for cirrhosis and associated neuropsychiatric conditions.
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Affiliation(s)
- Maren L Smith
- Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia, USA
- Alcohol Research Center, Virginia Commonwealth University, Richmond, Virginia, USA
| | - James B Wade
- Department of Psychiatry, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Jennifer Wolstenholme
- Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia, USA
- Alcohol Research Center, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Jasmohan S Bajaj
- Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and Central Virginia Veterans Healthcare System, Richmond, Virginia, USA
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23
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Parthasarathy G, Malhi H, Bajaj JS. Therapeutic manipulation of the microbiome in liver disease. Hepatology 2024:01515467-990000000-00932. [PMID: 38922826 PMCID: PMC12167619 DOI: 10.1097/hep.0000000000000987] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2024] [Accepted: 06/13/2024] [Indexed: 06/28/2024]
Abstract
Myriad associations between the microbiome and various facets of liver physiology and pathology have been described in the literature. Building on descriptive and correlative sequencing studies, metagenomic studies are expanding our collective understanding of the functional and mechanistic role of the microbiome as mediators of the gut-liver axis. Based on these mechanisms, the functional activity of the microbiome represents an attractive, tractable, and precision medicine therapeutic target in several liver diseases. Indeed, several therapeutics have been used in liver disease even before their description as a microbiome-dependent approach. To bring successful microbiome-targeted and microbiome-inspired therapies to the clinic, a comprehensive appreciation of the different approaches to influence, collaborate with, or engineer the gut microbiome to coopt a disease-relevant function of interest in the right patient is key. Herein, we describe the various levels at which the microbiome can be targeted-from prebiotics, probiotics, synbiotics, and antibiotics to microbiome reconstitution and precision microbiome engineering. Assimilating data from preclinical animal models, human studies as well as clinical trials, we describe the potential for and rationale behind studying such therapies across several liver diseases, including metabolic dysfunction-associated steatotic liver disease, alcohol-associated liver disease, cirrhosis, HE as well as liver cancer. Lastly, we discuss lessons learned from previous attempts at developing such therapies, the regulatory framework that needs to be navigated, and the challenges that remain.
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Affiliation(s)
| | - Harmeet Malhi
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905
| | - Jasmohan S. Bajaj
- Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and Central Virginia Veterans Healthcare System, Richmond, Virginia, USA
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24
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Samanta A, Sen Sarma M. Fecal microbiota transplantation in the treatment of hepatic encephalopathy: A perspective. World J Hepatol 2024; 16:678-683. [PMID: 38818298 PMCID: PMC11135264 DOI: 10.4254/wjh.v16.i5.678] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Revised: 03/06/2024] [Accepted: 04/16/2024] [Indexed: 05/22/2024] Open
Abstract
Due to its complex pathogenesis, treatment of hepatic encephalopathy (HE) continues to be a therapeutic challenge. Of late, gut microbiome has garnered much attention for its role in the pathogenesis of various gastrointestinal and liver diseases and its potential therapeutic use. New evidence suggests that gut microbiota plays a significant role in cerebral homeostasis. Alteration in the gut microbiota has been documented in patients with HE in a number of clinical and experimental studies. Research on gut dysbiosis in patients with HE has opened newer therapeutic avenues in the form of probiotics, prebiotics and the latest fecal microbiota transplantation (FMT). Recent studies have shown that FMT is safe and could be effective in improving outcomes in advanced liver disease patients presenting with HE. However, questions over the appropriate dose, duration and route of administration for best treatment outcome remains unsettled.
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Affiliation(s)
- Arghya Samanta
- Department of Pediatric Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, India
| | - Moinak Sen Sarma
- Department of Pediatric Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, India.
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25
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Singh J, Ibrahim B, Han SH. Nontraditional Treatment of Hepatic Encephalopathy. Clin Liver Dis 2024; 28:297-315. [PMID: 38548441 DOI: 10.1016/j.cld.2024.01.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/02/2024]
Abstract
The pathophysiology of hepatic encephalopathy (HE) is complex, with hyperammonemia playing a central role in its development. Traditional therapies for HE have targeted ammonia and include medications such as lactulose and rifaximin. Although these agents are considered standard of care, nontraditional treatments seek to affect other factors in the pathogenesis of HE. Finally, procedural therapies include albumin dialysis, shunt closure, and the ultimate cure for HE, which is liver transplant. The treatments discussed provide alternative options for patients who have failed standard of care. However, more high-quality studies are needed to routinely recommend many of these agents.
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Affiliation(s)
- Jasleen Singh
- Department of Medicine, University of California at Los Angeles; Los Angeles, CA, USA.
| | - Brittney Ibrahim
- Department of Surgery, University of California at Los Angeles; Los Angeles, CA, USA
| | - Steven-Huy Han
- Department of Medicine, University of California at Los Angeles; Los Angeles, CA, USA; Department of Surgery, University of California at Los Angeles; Los Angeles, CA, USA
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26
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Buckholz AP, Brown RS. Future Therapies of Hepatic Encephalopathy. Clin Liver Dis 2024; 28:331-344. [PMID: 38548443 PMCID: PMC10987054 DOI: 10.1016/j.cld.2024.02.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/02/2024]
Abstract
Hepatic encephalopathy, either covert or overt, affects more than half of patients with cirrhosis and has lasting effects even after portal hypertension is corrected. Unfortunately, the current therapeutic options still result in high rates of relapse and progression, in part owing to cost barriers and side effects, leading to poor adherence. This review summarizes emerging treatment options, which could take advantage of alternative disease pathways to improve future care of those with hepatic encephalopathy.
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Affiliation(s)
- Adam P Buckholz
- Division of Gastroenterology and Hepatology, New York/Presbyterian-Weill Cornell Medical College, 1305 York Avenue, 4th Floor, New York, NY 10021, USA
| | - Robert S Brown
- Division of Gastroenterology and Hepatology, New York/Presbyterian-Weill Cornell Medical College, 1305 York Avenue, 4th Floor, New York, NY 10021, USA.
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27
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Herman C, Barker BM, Bartelli TF, Chandra V, Krajmalnik-Brown R, Jewell M, Li L, Liao C, McAllister F, Nirmalkar K, Xavier JB, Gregory Caporaso J. Assessing Engraftment Following Fecal Microbiota Transplant. ARXIV 2024:arXiv:2404.07325v1. [PMID: 38659636 PMCID: PMC11042410] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 04/26/2024]
Abstract
Fecal Microbiota Transplant (FMT) is an FDA approved treatment for recurrent Clostridium difficile infections, and is being explored for other clinical applications, from alleviating digestive and neurological disorders, to priming the microbiome for cancer treatment, and restoring microbiomes impacted by cancer treatment. Quantifying the extent of engraftment following an FMT is important in determining if a recipient didn't respond because the engrafted microbiome didn't produce the desired outcomes (a successful FMT, but negative treatment outcome), or the microbiome didn't engraft (an unsuccessful FMT and negative treatment outcome). The lack of a consistent methodology for quantifying FMT engraftment extent hinders the assessment of FMT success and its relation to clinical outcomes, and presents challenges for comparing FMT results and protocols across studies. Here we review 46 studies of FMT in humans and model organisms and group their approaches for assessing the extent to which an FMT engrafts into three criteria: 1) Chimeric Asymmetric Community Coalescence investigates microbiome shifts following FMT engraftment using methods such as alpha diversity comparisons, beta diversity comparisons, and microbiome source tracking. 2) Donated Microbiome Indicator Features tracks donated microbiome features (e.g., amplicon sequence variants or species of interest) as a signal of engraftment with methods such as differential abundance testing based on the current sample collection, or tracking changes in feature abundances that have been previously identified (e.g., from FMT or disease-relevant literature). 3) Temporal Stability examines how resistant post-FMT recipient's microbiomes are to reverting back to their baseline microbiome. Individually, these criteria each highlight a critical aspect of microbiome engraftment; investigated together, however, they provide a clearer assessment of microbiome engraftment. We discuss the pros and cons of each of these criteria, providing illustrative examples of their application. We also introduce key terminology and recommendations on how FMT studies can be analyzed for rigorous engraftment extent assessment.
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Affiliation(s)
- Chloe Herman
- Pathogen and Microbiome Institute, Northern Arizona University, Flagstaff, AZ, USA
- School of Informatics, Computing and Cyber Systems, Northern Arizona University, Flagstaff, AZ, USA
| | - Bridget M Barker
- Pathogen and Microbiome Institute, Northern Arizona University, Flagstaff, AZ, USA
| | - Thais F Bartelli
- Department of Clinical Cancer Prevention, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Vidhi Chandra
- Department of Clinical Cancer Prevention, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Rosa Krajmalnik-Brown
- Biodesign Center for Health Through Microbiomes, Arizona State University, Tempe, AZ, U.S.A
- School of Sustainable Engineering and the Built Environment, Arizona State University, Tempe, AZ, U.S.A
| | | | - Le Li
- Department of Clinical Cancer Prevention, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Chen Liao
- Program for Computational and Systems Biology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
| | - Florencia McAllister
- Department of Clinical Cancer Prevention, University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Khemlal Nirmalkar
- Biodesign Center for Health Through Microbiomes, Arizona State University, Tempe, AZ, U.S.A
| | - Joao B Xavier
- Program for Computational and Systems Biology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
| | - J Gregory Caporaso
- Pathogen and Microbiome Institute, Northern Arizona University, Flagstaff, AZ, USA
- School of Informatics, Computing and Cyber Systems, Northern Arizona University, Flagstaff, AZ, USA
- Department of Biological Sciences, Northern Arizona University, Flagstaff, AZ, USA
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28
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Bu L, Wang C, Bai J, Song J, Zhang Y, Chen H, Suo H. Gut microbiome-based therapies for alleviating cognitive impairment: state of the field, limitations, and future perspectives. Food Funct 2024; 15:1116-1134. [PMID: 38224464 DOI: 10.1039/d3fo02307a] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2024]
Abstract
Cognitive impairment (CI) is a multifaceted neurological condition that can trigger negative emotions and a range of concurrent symptoms, imposing significant public health and economic burdens on society. Therefore, it is imperative to discover a remedy for CI. Nevertheless, the mechanisms behind the onset of this disease are multifactorial, which makes the search for effective amelioration difficult and complex, hindering the search for effective measures. Intriguingly, preclinical research indicates that gut microbiota by influencing brain function, plays an important role in the progression of CI. Furthermore, numerous preclinical studies have highlighted the potential of probiotics, prebiotics, fecal microbiota transplantation (FMT), and diet in modulating the gut microbiota, thereby ameliorating CI symptoms. This review provides a comprehensive evaluation of CI pathogenesis, emphasizing the contribution of gut microbiota disorders to CI development. It also summarizes and discusses current strategies and mechanisms centered on the synergistic role of gut microbiota modulation in the microbiota-gut-brain axis in CI development. Finally, problems with existing approaches are contemplated and the development of microbial modulation strategies as therapeutic approaches to promote and restore brain cognition is discussed. Further research considerations and directions are highlighted to provide ideas for future CI prevention and treatment strategies.
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Affiliation(s)
- Linli Bu
- College of Food Science, Southwest University, Chongqing 400715, China.
- Modern "Chuan Cai Yu Wei" Food Industry Innovation Research Institute, Chongqing 400715, China
| | - Chen Wang
- College of Food Science, Southwest University, Chongqing 400715, China.
- Modern "Chuan Cai Yu Wei" Food Industry Innovation Research Institute, Chongqing 400715, China
| | - Junying Bai
- Citrus Research Institute, Southwest University, Chongqing 400715, China
| | - Jiajia Song
- College of Food Science, Southwest University, Chongqing 400715, China.
- Modern "Chuan Cai Yu Wei" Food Industry Innovation Research Institute, Chongqing 400715, China
| | - Yuhong Zhang
- Institute of Food Sciences and Technology, Tibet Academy of Agricultural and Animal Husbandry Sciences, Xizang 850000, China
| | - Hongyu Chen
- College of Food Science, Southwest University, Chongqing 400715, China.
- Modern "Chuan Cai Yu Wei" Food Industry Innovation Research Institute, Chongqing 400715, China
| | - Huayi Suo
- College of Food Science, Southwest University, Chongqing 400715, China.
- Modern "Chuan Cai Yu Wei" Food Industry Innovation Research Institute, Chongqing 400715, China
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Abstract
Alcohol-associated liver disease (ALD) is a major cause of chronic liver disease worldwide, and comprises a spectrum of several different disorders, including simple steatosis, steatohepatitis, cirrhosis, and superimposed hepatocellular carcinoma. Although tremendous progress has been made in the field of ALD over the last 20 years, the pathogenesis of ALD remains obscure, and there are currently no FDA-approved drugs for the treatment of ALD. In this Review, we discuss new insights into the pathogenesis and therapeutic targets of ALD, utilizing the study of multiomics and other cutting-edge approaches. The potential translation of these studies into clinical practice and therapy is deliberated. We also discuss preclinical models of ALD, interplay of ALD and metabolic dysfunction, alcohol-associated liver cancer, the heterogeneity of ALD, and some potential translational research prospects for ALD.
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30
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Shah YR, Ali H, Tiwari A, Guevara-Lazo D, Nombera-Aznaran N, Pinnam BSM, Gangwani MK, Gopakumar H, Sohail AH, Kanumilli S, Calderon-Martinez E, Krishnamoorthy G, Thakral N, Dahiya DS. Role of fecal microbiota transplant in management of hepatic encephalopathy: Current trends and future directions. World J Hepatol 2024; 16:17-32. [PMID: 38313244 PMCID: PMC10835490 DOI: 10.4254/wjh.v16.i1.17] [Citation(s) in RCA: 11] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2023] [Revised: 12/02/2023] [Accepted: 01/03/2024] [Indexed: 01/23/2024] Open
Abstract
Fecal microbiota transplantation (FMT) offers a potential treatment avenue for hepatic encephalopathy (HE) by leveraging beneficial bacterial displacement to restore a balanced gut microbiome. The prevalence of HE varies with liver disease severity and comorbidities. HE pathogenesis involves ammonia toxicity, gut-brain communication disruption, and inflammation. FMT aims to restore gut microbiota balance, addressing these factors. FMT's efficacy has been explored in various conditions, including HE. Studies suggest that FMT can modulate gut microbiota, reduce ammonia levels, and alleviate inflammation. FMT has shown promise in alcohol-associated, hepatitis B and C-associated, and non-alcoholic fatty liver disease. Benefits include improved liver function, cognitive function, and the slowing of disease progression. However, larger, controlled studies are needed to validate its effectiveness in these contexts. Studies have shown cognitive improvements through FMT, with potential benefits in cirrhotic patients. Notably, trials have demonstrated reduced serious adverse events and cognitive enhancements in FMT arms compared to the standard of care. Although evidence is promising, challenges remain: Limited patient numbers, varied dosages, administration routes, and donor profiles. Further large-scale, controlled trials are essential to establish standardized guidelines and ensure FMT's clinical applications and efficacy. While FMT holds potential for HE management, ongoing research is needed to address these challenges, optimize protocols, and expand its availability as a therapeutic option for diverse hepatic conditions.
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Affiliation(s)
- Yash R Shah
- Department of Internal Medicine, Trinity Health Oakland/Wayne State University, Pontiac, MI 48341, United States
| | - Hassam Ali
- Division of Gastroenterology and Hepatology, East Carolina University/Brody School of Medicine, Greenville, NC 27858, United States
| | - Angad Tiwari
- Department of Internal Medicine, Maharani Laxmi Bai Medical College, Jhansi 284001, India
| | - David Guevara-Lazo
- Faculty of Medicine, Universidad Peruana Cayetano Heredia, Lima 15102, Peru
| | | | - Bhanu Siva Mohan Pinnam
- Department of Internal Medicine, John H. Stroger Hospital of Cook County, Chicago, IL 60612, United States
| | - Manesh Kumar Gangwani
- Department of Internal Medicine, The University of Toledo, Toledo, OH 43606, United States
| | - Harishankar Gopakumar
- Department of Gastroenterology and Hepatology, University of Illinois College of Medicine at Peoria, Peoria, IL 61605, United States
| | - Amir H Sohail
- Department of Surgery, University of New Mexico, Albuquerque, NM 87106, United States
| | | | - Ernesto Calderon-Martinez
- Department of Internal Medicine, Universidad Nacional Autonoma de Mexico, Ciudad De Mexico 04510, Mexico
| | - Geetha Krishnamoorthy
- Department of Internal Medicine, Trinity Health Oakland/Wayne State University, Pontiac, MI 48341, United States
| | - Nimish Thakral
- Department of Digestive Diseases and Nutrition, University of Kentucky, Lexington, KY 40536, United States
| | - Dushyant Singh Dahiya
- Division of Gastroenterology, Hepatology & Motility, The University of Kansas School of Medicine, Kansas City, KS 66160, United States.
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31
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Kouroumalis E, Tsomidis I, Voumvouraki A. Viral Liver Disease and Intestinal Gut–Liver Axis. GASTROINTESTINAL DISORDERS 2024; 6:64-93. [DOI: 10.3390/gidisord6010005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2025] Open
Abstract
The intestinal microbiota is closely related to liver diseases via the intestinal barrier and bile secretion to the gut. Impairment of the barrier can translocate microbes or their components to the liver where they can contribute to liver damage and fibrosis. The components of the barrier are discussed in this review along with the other elements of the so-called gut–liver axis. This bidirectional relation has been widely studied in alcoholic and non-alcoholic liver disease. However, the involvement of microbiota in the pathogenesis and treatment of viral liver diseases have not been extensively studied, and controversial data have been published. Therefore, we reviewed data regarding the integrity and function of the intestinal barrier and the changes of the intestinal microbioma that contribute to progression of Hepatitis B (HBV) and Hepatitis C (HCV) infection. Their consequences, such as cirrhosis and hepatic encephalopathy, were also discussed in connection with therapeutic interventions such as the effects of antiviral eradication and the use of probiotics that may influence the outcome of liver disease. Profound alterations of the microbioma with significant reduction in microbial diversity and changes in the abundance of both beneficial and pathogenic bacteria were found.
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Affiliation(s)
- Elias Kouroumalis
- Department of Gastroenterology, Medical School, University of Crete, 71500 Heraklion, Greece
| | - Ioannis Tsomidis
- Department of Gastroenterology, Medical School, University of Crete, 71500 Heraklion, Greece
| | - Argyro Voumvouraki
- 1st Department of Internal Medicine, AHEPA University Hospital, 54621 Thessaloniki, Greece
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32
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Karna R, Babich M. Fecal microbiota transplant in liver diseases: Current evidence and future directions. Clin Liver Dis (Hoboken) 2024; 23:e0154. [PMID: 38841199 PMCID: PMC11152867 DOI: 10.1097/cld.0000000000000154] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2023] [Accepted: 02/02/2024] [Indexed: 06/07/2024] Open
Affiliation(s)
- Rahul Karna
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Minnesota, Minneapolis, Minnesota, USA
| | - Michael Babich
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Allegheny Health Network, Pittsburgh, Pennsylvania, USA
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33
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Bloom PP, Bajaj JS. The Current and Future State of Microbiome Therapeutics in Liver Disease. Am J Gastroenterol 2024; 119:S36-S41. [PMID: 38153225 DOI: 10.14309/ajg.0000000000002581] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Accepted: 10/31/2023] [Indexed: 12/29/2023]
Affiliation(s)
| | - Jasmohan S Bajaj
- Virginia Commonwealth University and Richmond VA Medical Center, Richmond, Virginia, USA
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34
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Sun X, Zhou X, He W, Sun W, Xu Z. Co-Housing and Fecal Microbiota Transplantation: Technical Support for TCM Herbal Treatment of Extra-Intestinal Diseases Based on Gut Microbial Ecosystem Remodeling. Drug Des Devel Ther 2023; 17:3803-3831. [PMID: 38155743 PMCID: PMC10753978 DOI: 10.2147/dddt.s443462] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2023] [Accepted: 12/13/2023] [Indexed: 12/30/2023] Open
Abstract
Dysregulation of the gut microbial ecosystem (GME) (eg, alterations in the gut microbiota, gut-derived metabolites, and gut barrier) may contribute to the onset and progression of extra-intestinal diseases. Previous studies have found that Traditional Chinese Medicine herbs (TCMs) play an important role in manipulating the GME, but a prominent obstacle in current TCM research is the causal relationship between GME and disease amelioration. Encouragingly, co-housing and fecal microbiota transplantation (FMT) provide evidence-based support for TCMs to treat extra-intestinal diseases by targeting GME. In this review, we documented the principles, operational procedures, applications and limitations of the key technologies (ie, co-housing and FMT); furthermore, we provided evidence that TCM works through the GME, especially the gut microbiota (eg, SCFA- and BSH-producing bacteria), the gut-derived metabolites (eg, IS, pCS, and SCFAs), and intestinal barrier to alleviate extra-intestinal diseases. This will be beneficial in constructing microecological pathways for TCM treatment of extra-intestinal diseases in the future.
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Affiliation(s)
- Xian Sun
- School of Chinese Medicine & School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, People’s Republic of China
| | - Xi Zhou
- School of Chinese Medicine & School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, People’s Republic of China
| | - Weiming He
- Department of Nephrology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, People’s Republic of China
| | - Wei Sun
- Department of Nephrology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, People’s Republic of China
| | - Zheng Xu
- School of Chinese Medicine & School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, People’s Republic of China
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Widjaja F, Rietjens IMCM. From-Toilet-to-Freezer: A Review on Requirements for an Automatic Protocol to Collect and Store Human Fecal Samples for Research Purposes. Biomedicines 2023; 11:2658. [PMID: 37893032 PMCID: PMC10603957 DOI: 10.3390/biomedicines11102658] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Revised: 09/22/2023] [Accepted: 09/24/2023] [Indexed: 10/29/2023] Open
Abstract
The composition, viability and metabolic functionality of intestinal microbiota play an important role in human health and disease. Studies on intestinal microbiota are often based on fecal samples, because these can be sampled in a non-invasive way, although procedures for sampling, processing and storage vary. This review presents factors to consider when developing an automated protocol for sampling, processing and storing fecal samples: donor inclusion criteria, urine-feces separation in smart toilets, homogenization, aliquoting, usage or type of buffer to dissolve and store fecal material, temperature and time for processing and storage and quality control. The lack of standardization and low-throughput of state-of-the-art fecal collection procedures promote a more automated protocol. Based on this review, an automated protocol is proposed. Fecal samples should be collected and immediately processed under anaerobic conditions at either room temperature (RT) for a maximum of 4 h or at 4 °C for no more than 24 h. Upon homogenization, preferably in the absence of added solvent to allow addition of a buffer of choice at a later stage, aliquots obtained should be stored at either -20 °C for up to a few months or -80 °C for a longer period-up to 2 years. Protocols for quality control should characterize microbial composition and viability as well as metabolic functionality.
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Affiliation(s)
- Frances Widjaja
- Division of Toxicology, Wageningen University & Research, 6708 WE Wageningen, The Netherlands;
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Dai M, Lui RN, Lau LH. The role of gut microbiome and fecal microbiota transplantation in liver cancer and related complications: mechanisms and therapeutic potentials. HEPATOMA RESEARCH 2023. [DOI: 10.20517/2394-5079.2023.33] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
Abstract
Liver cancer is the sixth commonest cancer and the third leading cause of cancer mortality worldwide. Accumulating evidence suggests a pivotal role of the gut microbiome in the progression of chronic liver disease and the subsequent development of liver cancer. Additionally, gut microbiome has been shown to contribute to the hosts’ antitumor responses following immunotherapy and chemotherapy for liver cancers, highlighting the therapeutic potential of gut microbiome modulation in enhancing treatment efficacy and reducing drug resistance. Fecal microbiota transplantation (FMT), a novel therapeutic modality to deliver a healthy donor's stool by endoscopy or capsule, has demonstrated potential in managing liver diseases and cancers by restoring and modulating the recipient’s gut microbiome composition. However, existing data on the clinical application of FMT in liver cancers are still limited. This review summarizes the underlying roles and mechanisms of gut microbiome in liver cancer and discusses the therapeutic potential of FMT in liver cancer treatment and the management of its related complications (e.g., hepatic encephalopathy).
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Kibble H, Shawcross DL. The microbiome in portal hypertension. Clin Liver Dis (Hoboken) 2023; 22:70-74. [PMID: 37663552 PMCID: PMC10473356 DOI: 10.1097/cld.0000000000000051] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2023] [Accepted: 04/10/2023] [Indexed: 09/05/2023] Open
Affiliation(s)
- Henry Kibble
- Institute of Liver Studies, School of Immunology and Microbial Sciences, King’s College London, London, UK
- Institute of Liver Studies, King’s College Hospital NHS Foundation Trust, Denmark Hill, London, UK
| | - Debbie L. Shawcross
- Institute of Liver Studies, School of Immunology and Microbial Sciences, King’s College London, London, UK
- Institute of Liver Studies, King’s College Hospital NHS Foundation Trust, Denmark Hill, London, UK
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Balzano T. Active Clinical Trials in Hepatic Encephalopathy: Something Old, Something New and Something Borrowed. Neurochem Res 2023; 48:2309-2319. [PMID: 36977964 PMCID: PMC10047473 DOI: 10.1007/s11064-023-03916-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Revised: 02/28/2023] [Accepted: 03/17/2023] [Indexed: 03/30/2023]
Abstract
Hepatic encephalopathy (HE) is a potentially reversible neurocognitive syndrome that occurs in patients with acute or chronic liver disease. Currently, most of the therapies for HE aim to reduce ammonia production or increase its elimination. To date, only two agents have been approved as treatments for HE: lactulose and rifaximin. Many other drugs have also been used, but data to support their use are limited, preliminary or lacking. The aim of this review is to provide an overview and discussion of the current development of treatments for HE. Data from ongoing clinical trials in HE were obtained from the ClinicalTrials.gov website, and a breakdown analysis of studies that were active on August 19th, 2022, was performed. Seventeen registered and ongoing clinical trials for therapeutics targeting HE were identified. More than 75% of these agents are in phase II (41.2%) or in phase III (34.7%). Among them, there are many old acquaintances in the field, such as lactulose and rifaximin, some new entries such as fecal microbiota transplantation and equine anti-thymocyte globulin, an immunosuppressive agent, but also some therapies borrowed from other conditions, such as rifamycin SV MMX and nitazoxanide, two antimicrobial agents FDA approved for the treatment of some types of diarrheas or VE303 and RBX7455, two microbiome restoration therapies, currently used as treatment of high-risk Clostridioides difficile infections. If working, some of these drugs could soon be used as valid alternatives to current therapies when ineffective or be approved as novel therapeutic approaches to improve the quality of life of HE patients.
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Affiliation(s)
- Tiziano Balzano
- HM CINAC (Centro Integral de Neurociencias Abarca Campal), Hospital Universitario HM Puerta del Sur, HM Hospitales, Madrid, Spain.
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Balzano T, Llansola M, Arenas YM, Izquierdo-Altarejos P, Felipo V. Hepatic encephalopathy: investigational drugs in preclinical and early phase development. Expert Opin Investig Drugs 2023; 32:1055-1069. [PMID: 37902074 DOI: 10.1080/13543784.2023.2277386] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Accepted: 10/26/2023] [Indexed: 10/31/2023]
Abstract
INTRODUCTION Hepatic encephalopathy (HE) is a neuropsychiatric syndrome, in patients with liver disease, which affects life quality and span. Current treatments are lactulose or rifaximin, acting on gut microbiota. Treatments aiming ammonia levels reduction have been tested with little success. AREAS COVERED Pre-clinical research shows that the process inducing HE involves sequentially: liver failure, altered microbiome, hyperammonemia, peripheral inflammation, changes in immunophenotype and extracellular vesicles and neuroinflammation, which alters neurotransmission impairing cognitive and motor function. HE may be reversed using drugs acting at any step: modulating microbiota with probiotics or fecal transplantation; reducing peripheral inflammation with anti-TNFα, autotaxin inhibitors or silymarin; reducing neuroinflammation with sulforaphane, p38 MAP kinase or phosphodiesteras 5 inhibitors, antagonists of sphingosine-1-phosphate receptor 2, enhancing meningeal lymphatic drainage or with extracellular vesicles from mesenchymal stem cells; reducing GABAergic neurotransmission with indomethacin or golexanolone. EXPERT OPINION A factor limiting the progress of HE treatment is the lack of translation of research advances into clinical trials. Only drugs acting on microbiota or ammonia reduction have been tested in patients. It is urgent to change the mentality on how to approach HE treatment to develop clinical trials to assess drugs acting on the immune system/peripheral inflammation, neuroinflammation or neurotransmission to improve HE.
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Affiliation(s)
- Tiziano Balzano
- Laboratory of Neurobiology, Centro de Investigación Príncipe Felipe, Valencia, Spain
- HM CINAC (Centro Integral de Neurociencias Abarca Campal), Hospital Universitario HM Puerta del Sur, HM Hospitales, Madrid, Spain
| | - Marta Llansola
- Laboratory of Neurobiology, Centro de Investigación Príncipe Felipe, Valencia, Spain
| | - Yaiza M Arenas
- Laboratory of Neurobiology, Centro de Investigación Príncipe Felipe, Valencia, Spain
- Departamento de Patología, Facultad de Medicina, Universidad Valencia, Valencia, Spain
| | | | - Vicente Felipo
- Laboratory of Neurobiology, Centro de Investigación Príncipe Felipe, Valencia, Spain
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Wang Q, Chen C, Zuo S, Cao K, Li H. Integrative analysis of the gut microbiota and faecal and serum short-chain fatty acids and tryptophan metabolites in patients with cirrhosis and hepatic encephalopathy. J Transl Med 2023; 21:395. [PMID: 37330571 PMCID: PMC10276405 DOI: 10.1186/s12967-023-04262-9] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Accepted: 06/09/2023] [Indexed: 06/19/2023] Open
Abstract
OBJECTIVE The purpose of this study was to describe the changes in the gut microbiome of patients with cirrhosis and hepatic encephalopathy (HE), as well as quantify the variations in short-chain fatty acid (SCFA) and tryptophan metabolite levels in serum and faeces. METHODS Fresh faeces and serum were collected from 20 healthy volunteers (NC group), 30 cirrhosis patients (Cir group), and 30 HE patients (HE group). Then, 16S rRNA sequencing and metabolite measurements were performed using the faeces. Gas chromatography‒mass spectrometry and ultrahigh-performance liquid chromatography-tandem mass spectrometry were used to measure SCFA and tryptophan levels, respectively. The results were analysed by SIMCA16.0.2 software. Differences in species were identified using MetaStat and t tests. The correlations among the levels of gut microbes and metabolites and clinical parameters were determined using Spearman correlation analysis. RESULTS Patients with cirrhosis and HE had lower microbial species richness and diversity in faeces than healthy volunteers; these patients also had altered β-diversity. Serum valeric acid levels were significantly higher in the HE group than in the Cir group. Serum SCFA levels did not differ between the Cir and NC groups. Serum melatonin and 5-HTOL levels were significantly higher in the HE group than in the Cir group. The Cir and NC groups had significant differences in the levels of eight serum tryptophan metabolites. Furthermore, the levels of faecal SCFAs did not differ between the HE and Cir groups. Faecal IAA-Ala levels were significantly lower in the HE group than in the Cir group. There were significant differences in the levels of 6 faecal SCFAs and 7 faecal tryptophan metabolites between the Cir and NC groups. Certain gut microbes were associated with serum and faecal metabolites, and some metabolites were associated with certain clinical parameters. CONCLUSION Reduced microbial species richness and diversity were observed in patients with HE and cirrhosis. In both serum and faeces, the levels of different SCFAs and tryptophan metabolites showed varying patterns of change. In HE patients, the levels of some serum tryptophan metabolites, and not SCFAs, were correlated with liver function and systemic inflammation. Systemic inflammation in patients with cirrhosis was correlated with faecal acetic acid levels. In summary, this study identified metabolites important for HE and cirrhosis.
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Affiliation(s)
- Qiang Wang
- Department of Hepatobiliary Surgery, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, People's Republic of China
- School of Clinical Medicine, Guizhou Medical University, Guiyang, Guizhou, People's Republic of China
| | - Chengxin Chen
- Department of Hepatobiliary Surgery, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, People's Republic of China
| | - Shi Zuo
- Department of Hepatobiliary Surgery, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, People's Republic of China
| | - Kun Cao
- Department of Hepatobiliary Surgery, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, People's Republic of China.
| | - Haiyang Li
- Department of Hepatobiliary Surgery, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, People's Republic of China.
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Fagan A, Gavis EA, Gallagher ML, Mousel T, Davis B, Puri P, Sterling RK, Luketic VA, Lee H, Matherly SC, Sanyal AJ, Stravitz RT, Patel V, Siddiqui MS, Asgharpour A, Fuchs M, Thacker L, Bajaj JS. A double-blind randomized placebo-controlled trial of albumin in outpatients with hepatic encephalopathy: HEAL study. J Hepatol 2023; 78:312-321. [PMID: 36152764 DOI: 10.1016/j.jhep.2022.09.009] [Citation(s) in RCA: 36] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 08/26/2022] [Accepted: 09/13/2022] [Indexed: 01/24/2023]
Abstract
BACKGROUND & AIMS Even after recovery from overt hepatic encephalopathy (HE), minimal HE (MHE), which impairs quality of life (QoL), can persist. A double-blind, placebo-controlled randomized clinical trial was performed to determine the impact of albumin vs. saline on MHE and QoL in individuals with prior HE already on standard of care. METHODS Outpatients with cirrhosis and prior HE, MHE and hypoalbuminemia already on treatment for HE were included. Patients on regular IV albumin infusions were excluded. Participants were randomized 1:1 to receive either weekly infusions of 25% IV albumin 1.5 g/kg or saline over 5 weeks. MHE was defined using either psychometric hepatic encephalopathy score (PHES), Stroop or critical clicker frequency. MHE, QoL (based on sickness impact profile [SIP] total, physical, psychosocial domain) and serum markers (inflammation, endothelial dysfunction, and ischemia-modified albumin) were compared between baseline, the final infusion visit (end-of-drug [EOD]) and 1-week post final infusion (end-of-study [EOS]). RESULTS Forty-eight (24/group) participants were randomized and balanced (including by HE medication use) at baseline. Adverse events were similar, with MELD and ammonia remaining stable between/within groups. Albumin levels increased and ischemia-modified albumin decreased only in the albumin group at EOD and EOS vs. baseline. PHES and Stroop MHE reversal and improvement were greater in the albumin group at EOD and persisted at EOS. SIP total and psychosocial, but not physical, domain improved only in the albumin group at EOD and EOS vs. baseline. A significant reduction in IL-1β and endothelial dysfunction markers was also observed in the albumin group. CONCLUSION In a double-blind, placebo-controlled trial of outpatients with cirrhosis, prior HE and current MHE, albumin infusions were associated with improved cognitive function and psychosocial QoL, likely due to amelioration of endothelial dysfunction. CLINICAL TRIALS REGISTRATION www. CLINICALTRIALS gov NCT03585257. IMPACT AND IMPLICATIONS Even after recovery from overt hepatic encephalopathy (HE), minimal HE (MHE), which impairs quality of life, can persist. We found that intravenous albumin infusions were associated with improved cognitive function and psychosocial quality of life, likely owing to amelioration of endothelial dysfunction, compared to placebo in outpatients with prior HE and current MHE. In patients who continue to demonstrate cognitive dysfunction and impaired quality of life despite standard of care therapy for HE, albumin infusions could be considered if these results are validated.
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Affiliation(s)
- Andrew Fagan
- Division of Gastroenterology, Hepatology and Nutrition, Richmond, Virginia, USA
| | - Edith A Gavis
- Division of Gastroenterology, Hepatology and Nutrition, Richmond, Virginia, USA
| | | | - Travis Mousel
- Division of Gastroenterology, Hepatology and Nutrition, Richmond, Virginia, USA
| | - Brian Davis
- Division of Gastroenterology, Hepatology and Nutrition, Richmond, Virginia, USA
| | - Puneet Puri
- Division of Gastroenterology, Hepatology and Nutrition, Richmond, Virginia, USA
| | - Richard K Sterling
- Division of Gastroenterology, Hepatology and Nutrition, Richmond, Virginia, USA
| | - Velimir A Luketic
- Division of Gastroenterology, Hepatology and Nutrition, Richmond, Virginia, USA
| | - Hannah Lee
- Division of Gastroenterology, Hepatology and Nutrition, Richmond, Virginia, USA
| | - Scott C Matherly
- Division of Gastroenterology, Hepatology and Nutrition, Richmond, Virginia, USA
| | - Arun J Sanyal
- Division of Gastroenterology, Hepatology and Nutrition, Richmond, Virginia, USA
| | - R Todd Stravitz
- Division of Gastroenterology, Hepatology and Nutrition, Richmond, Virginia, USA
| | - Vaishali Patel
- Division of Gastroenterology, Hepatology and Nutrition, Richmond, Virginia, USA
| | - Mohammad S Siddiqui
- Division of Gastroenterology, Hepatology and Nutrition, Richmond, Virginia, USA
| | - Amon Asgharpour
- Division of Gastroenterology, Hepatology and Nutrition, Richmond, Virginia, USA
| | - Michael Fuchs
- Division of Gastroenterology, Hepatology and Nutrition, Richmond, Virginia, USA
| | - Leroy Thacker
- Department of Biostatistics, Virginia Commonwealth University and Central Virginia Veterans Healthcare System, Richmond, Virginia, USA
| | - Jasmohan S Bajaj
- Division of Gastroenterology, Hepatology and Nutrition, Richmond, Virginia, USA.
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Won SM, Oh KK, Gupta H, Ganesan R, Sharma SP, Jeong JJ, Yoon SJ, Jeong MK, Min BH, Hyun JY, Park HJ, Eom JA, Lee SB, Cha MG, Kwon GH, Choi MR, Kim DJ, Suk KT. The Link between Gut Microbiota and Hepatic Encephalopathy. Int J Mol Sci 2022; 23:8999. [PMID: 36012266 PMCID: PMC9408988 DOI: 10.3390/ijms23168999] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Revised: 08/08/2022] [Accepted: 08/09/2022] [Indexed: 11/16/2022] Open
Abstract
Hepatic encephalopathy (HE) is a serious complication of cirrhosis that causes neuropsychiatric problems, such as cognitive dysfunction and movement disorders. The link between the microbiota and the host plays a key role in the pathogenesis of HE. The link between the gut microbiome and disease can be positively utilized not only in the diagnosis area of HE but also in the treatment area. Probiotics and prebiotics aim to resolve gut dysbiosis and increase beneficial microbial taxa, while fecal microbiota transplantation aims to address gut dysbiosis through transplantation (FMT) of the gut microbiome from healthy donors. Antibiotics, such as rifaximin, aim to improve cognitive function and hyperammonemia by targeting harmful taxa. Current treatment regimens for HE have achieved some success in treatment by targeting the gut microbiota, however, are still accompanied by limitations and problems. A focused approach should be placed on the establishment of personalized trial designs and therapies for the improvement of future care. This narrative review identifies factors negatively influencing the gut-hepatic-brain axis leading to HE in cirrhosis and explores their relationship with the gut microbiome. We also focused on the evaluation of reported clinical studies on the management and improvement of HE patients with a particular focus on microbiome-targeted therapy.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | - Ki Tae Suk
- Institute for Liver and Digestive Diseases, Hallym University College of Medicine, Chuncheon 24253, Korea
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Fecal Microbiota Transplantation in Decompensated Cirrhosis: A Systematic Review on Safety and Efficacy. Antibiotics (Basel) 2022; 11:antibiotics11070838. [PMID: 35884093 PMCID: PMC9311594 DOI: 10.3390/antibiotics11070838] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Revised: 06/17/2022] [Accepted: 06/20/2022] [Indexed: 11/17/2022] Open
Abstract
Background and Aims: Due to increasing knowledge of the “gut–liver axis”, there has been growing interest regarding the use of fecal microbiota transplant in the management of chronic liver disease. There are limited data available and current guidelines are mostly based on expert opinions. We aim to perform the first systematic review investigating safety and efficacy of fecal microbiota transplant particularly among high-risk decompensated cirrhosis patient populations. Methods: Literature search was performed using variations of the keywords “fecal microbiota transplant” and “cirrhosis” on PubMed/Medline from inception to 3 October 2021. The resulting 116 articles were independently screened by two authors. In total, 5 qualifying studies, including 2 randomized control trials and 3 retrospective case series, were found to meet established eligibility criteria and have adequate quality of evidence to be included in this review. Results: Of the total 58 qualifying patients, there were 2 deaths post fecal microbiota transplant, 1 of which could not rule out being related (1.7%). Among the remaining 56 participants, 8 serious adverse events were reported, of which 2 could not rule out being related (3.6%). The success rate of fecal microbiota transplantation in treating recurrent Clostridioides difficile infection among patients with decompensated cirrhosis was 77.8%. The success rate when used as investigational treatment for hepatic encephalopathy was 86.7%, with multiple studies reporting clinically significant improvement in encephalopathy testing scores. Conclusions: We found a marginally higher rate of deaths and serious adverse events from fecal microbiota transplant in our patient population compared with the average immunocompetent population, where it was previously found to have 0 deaths and SAE rate of 2.83%. The efficacy when used for recurrent C.difficile infection was 77.8% and 87% in the decompensated cirrhotic and general populations, respectively. Studies on efficacy in novel treatment of hepatic encephalopathy have been promising. This study concludes that fecal microbiota transplant use in decompensated cirrhosis patients should be used with caution and preferably be limited to research purposes until better data are available.
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