Copyright ©The Author(s) 2024.
World J Hepatol. Jan 27, 2024; 16(1): 17-32
Published online Jan 27, 2024. doi: 10.4254/wjh.v16.i1.17
Table 1 Overview of the prevalence of hepatic encephalopathy in different chronic hepatic conditions
Total, n = 166192
Did not develop HE, n = 117433
Developed HE, n = 48759
Alcoholic cirrhosis54194 (33)30011 (26)24183 (50)
Hepatitis C cirrhosis49599(30)31247(27)18352(38)
Nonalcoholic cirrhosis78111 (47)62433 (53)15678 (32)
Table 2 Classification of hepatic encephalopathy based on American Association for Study of Liver Diseases[11]
Suggested operational criteria3
CovertMinimalTests measuring psychomotor speed, executive function, or neurophysiological abilities may change psychometrically or neuropsychological without showing any signs of a mental shiftA non-phenomenological abnormality on recognized psychometric or neuropsychological tests
Grade 1Trivial lack of awareness; Euphoria or anxiety; Shortened addition or subtractionDespite being spatially and temporally oriented, this individual appears to have some cognitive/behavioral issues. decay concerning his clinical assessment that meets her standards, or to the carers
OvertGrade 2Lethargy or apathy; Gross disorientation; Obvious personality change; Inappropriate behaviorDisorientation with regard to time (at least three of the following are incorrect: day of the week, month, season, and year) plus/minus the other symptoms stated)
Grade 3Marked confusion; Somnolence to semi-stupor; Responsive to stimuli; Bizarre behaviorDisoriented also in terms of space (at least three of the incorrectly reported terms: nation, state or area, cities, location, plus/minus the other indicators)
Grade 4Comatose state; Unresponsive to pain; Decorticate or decerebrate posturingNever react, not even with painful stimuli
Table 3 Comparison of different modes of fecal microbiota transplant delivery
Mode of delivery
Upper gastrointestinal tract NasogastricFaster; Comparatively less expensive; Better tolerabilityRisk of aspiration; Discomfort; Increased risk of small intestinal bacterial overgrowth
NasojejunalFaster; Comparatively less expensive; Better tolerabilityRisk of aspiration; Risk of bowel perforation; Increased risk of small intestinal bacterial overgrowth
Oral capsuleLeast invasive; Cost-effective; Easy to storeRisk of aspiration; Vomiting; Sometimes failure to reach intestinal target
Lower gastrointestinal tractColonoscopyDirect visualization of GI tract; Standard risks of sedation and procedural interventionRisk of bowel perforation; Higher cost of performing procedure
Retention enemaUseful in patients with severe colitis or colon distention to avoid perforation; Less invasive as compared to colonoscopyDifficulty to retain transplanted stool; Need for repeated small volume infusion; Possible retention in patients with poor sphincter tone
Table 4 Comparison of different fecal microbiota transplant preparation methods
FMT preparation method
Efficacy range (%)
Preservation of microbial diversity
Fresh[40]85-100HighContains diverse microbial populationRequires immediate availability of the patient
Frozen[40]83-95ModerateAllows for long term storageLoss of some microbial diversity during freezing; Comprise on efficacy if not stored properly and use of incorrect thawing techniques
Frozen lyophilized[40]78-84ModerateLonger shelf life; Can be easily incorporated into a capsuleLoss of some microbial diversity during encapsulation
Table 5 Overview of important studies highlighting the efficacy and adverse effects of fecal microbiota transplant in the management of conditions associated with hepatic encephalopathy
Adverse effects
Cognitive impairment
Liver function
Not specified
Bajaj et al[77], 2017RCT20 cirrhotic patients experiencing recurrent HE while on lactulose/rifaximin treatmentFMT enema involving donor material enriched in Lachnospiraceae and RuminococcaceaeSOC (Lactulose and rifaximin)A significant improvement in both the PHES total score and EncephalApp Stroop was observed within the FMT group but not in the SOC groupFollowing antibiotic treatment, there was a decline in beneficial taxa and microbial diversity, coinciding with an expansion of Proteobacteria. However, FMT led to an increase in both diversity and beneficial taxa (Lactobacillaceae and Bifidobacteriaceae)No alterations were observed in AST, ALT, or albumin levels in either study armIn the SOC arm, MELD scores remained stable. However, in the FMT arm, antibiotics initially worsened the MELD scores, but subsequent FMT intervention successfully restored them to baseline levelsIn the SOC arm, the urine metabolic profile remained stable over time. Conversely, the FMT group exhibited altered metabolites due to antibiotics, which were subsequently restored post-FMTFMT arm: Tolerated treatment with no mental status hospitalizations; two unrelated hospitalizations occurred; SOC arm: Eleven SAEs, with higher incidences of HE and liver-related complications
Bajaj et al[65], 2021RCT, phase 110 patients with cirrhosis and alcohol use disorder, with an AUDIT-10 score of ≥ 8 during screening (FMT arm MELD score: 9.3 ± 2.6), and an equivalent of 10 patients in the placebo arm (9.5 ± 2.8)FMT enema involving donor material enriched in Lachnospiraceae and RuminococcaceaePlaceboCognitively, post-FMT patients exhibited improvements in both PHES and EncephalApp OffTime + OnTimePost-FMT, an increase in diversity was observed, alongside elevated levels of Odoribacter, Bilophila, Alistipes, and Roseburia; Conversely, no changes were noted in the pre-placebo microbiotaThere were no changes in AST, ALT, or albumin levels within the FMT groupThe MELD score within the FMT group was similar at the study's conclusion (score at the end of the study: 8.6 ± 2.8)In the FMT group, a noteworthy decrease in craving was evident among 90% of participants, whereas this reduction was observed in just 30% of the placebo groupA significant decrease in SAEs was observed in the FMT group compared to the placebo group (1 vs 7). The sole SAE in the FMT group was alcohol use disorder related, while 2 placebo-assigned patients required short-term antibiotics
Bloom et al[42], 2022RCT, phase 2A group of 10 cirrhotic patients, each having previously suffered at least one episode of overt HE and currently experiencing ongoing neurocognitive dysfunctionHealthy donors with normal BMI administered 15 oral FMT capsules on days 1, 2, 7, 14, and 21; Antibiotic pretreatment was not employedNonePHES demonstrated improvement after three doses of FMT (+ 2.1), after five doses of FMT (+ 2.9), and at the 4-wk mark following the fifth dose of FMT (+ 3.1)Baseline Bifidobacterium abundance was higher in FMT responders compared to nonrespondersNot reportedNot reportedTwo taxa, namely Bifidobacterium adolescentis and B. angulatum, displayed a positive correlation with PHES scores. On the contrary, Enterobacter asburiae and B. breve showed a negative correlation with PHES scoresFour minor adverse effects were noted: nausea, bloating, fatigue, and constipation; One SAE involved the transmission of extended-spectrum beta-lactamase-producing Escherichia coli bacteremia through FMT
Li et al[78], 2022Case series2 patients diagnosed with liver cirrhosis resulting from hepatitis B, who faced recurring Grade 2-3 HE following TIPS interventionFecal microbiota transplant conducted three times using 50 g of fresh fecal intestinal flora suspensionNoneSubsequent hospitalizations due to HE were not reported among the patientsNotable increases in Ruminococcus, Akkermansia, and Oscillospiraceae were observed, alongside decreased abundance of Veillonella and Megasphaera. These changes were accompanied by an overall increase in microbiota diversityLiver function demonstrated improvement in Case 1, while Case 2 exhibited a nonsignificant enhancementIn Case 1, Child Pugh Score decreased from 10 to 5; In Case 2, it decreased from 11 to 7There were no clinical manifestations, and the blood ammonia level decreased significantlyNo FMT-related adverse events or infection complications occurred in Case 1. Temporary constipation persisted for 7 d in Case 2 following FMT
Bajaj et al[22], 2019RCT, phase 120 cirrhotic patients experiencing recurrent HE and undergoing lactulose and rifaximin treatment. Out of these, ten were assigned to the FMT arm (MELD score of 9.5 ± 2.6) and ten were placed in the placebo arm (MELD score of 10.9 ± 4.2)Administration of 15 FMT capsules from a single donor enriched in Lachnospiraceae and RuminococcaceaePlaceboA noteworthy improvement in OffTime + OnTime was evident within the FMT group compared to baseline. Conversely, significant PHES improvement was not observed in the FMT group, and placebo exhibited no significant changesAfter FMT, duodenal mucosal diversity rose, featuring higher Ruminococcaceae and Bifidobacteriaceae, and reduced Streptococcaceae and Veillonellaceae. Similar reductions in Veillonellaceae were seen post-FMT in sigmoid and stool samplesNot reportedThe MELD score within the FMT group was similar at the study's conclusion (score at the end of the study: 8.7 ± 2.9)Following FMT, Duodenal E-cadherin and Defensin A5 increased, while IL-6 and serum LBP reducedIn the placebo group, 6 patients experienced SAEs: Five HE episodes, two infections, and one renal insufficiency case. In addition, 1 patient was transferred to hospice and deceased. In contrast, the FMT group had only one HE episode, with no reported deaths
Mehta et al[79], 2018Case series10 patients, previously treated with FMT for recurrent HE (defined as ≥ 2 episodes of West Haven grade II–IV HE in the last 6 mo)FMT was introduced via colonoscopy into the right colon 7–10 d after the episode of HENoneNot reportedNot reportedNot reportedA reduction in both CTP and MELD scores was observed from baseline to post-treatment week 20The arterial ammonia concentration showed a considerable decrease at post-treatment week 201 patient died due to bronchopneumonia complicated by sepsis 2 mo after FMT. Additionally, 2 patients were readmitted due to spontaneous bacterial peritonitis
Kao et al[9], 2016Case reportA 57-yr-old male with grade 1-2 HE, with liver cirrhosis (MELD score of 10), attributed to alcohol and hepatitis CWeekly FMT was administered, with the first application performed via colonoscopy and the subsequent sessions through retention enemaNoneMental status was assessed through the ICT and Stroop test. At 4 wk after the third FMT, the ICT score changed from 17 (baseline) to 5, and the Stroop test score changed from 250.9 to 183.5. However, by the 14-wk mark, these values reverted to baseline levelsFollowing FMT, there was a reduction in the relative abundance of LachnospiraceaeNot reportedNot reportedNot applicableNo adverse events or infectious complications linked to FMT occurred
Bajaj et al[80], 2019RCT, long term outcomes (> 12 mo) of a 2017 study20 patients with cirrhosis experiencing recurring episodes of HEFMT enema involving donor material enriched in Lachnospiraceae and RuminococcaceaeSOC (Lactulose and rifaximin)The FMT group experienced fewer HE episodes during long-term follow-up compared to SOC. Additionally, cognitive function, evaluated using the PHES total score and EncephalApp Stroop, significantly favored the FMT groupDuring long-term follow-up, FMT displayed increased Burkholderiaceae and decreased Acidaminococcaceae. However, Lachnospiraceae and Ruminococcaceae remained relatively stable. Microbiota composition remained similar post-FMT, regardless of short or long-term follow-up, when compared to the pre-FMT stateNot reportedChanges in MELD scores exhibited similarity between the two groupsThe FMT group experienced significantly fewer hospitalizations compared to the SOC group during the long-term follow-upThe intervention was well-tolerated in the FMT group, demonstrating a favorable long-term safety profile
Philips et al[63], 2017Pilot study8 patients diagnosed with steroid-ineligible severe alcohol-asSOCiated hepatitis (MELD score: 31 ± 5.6) and 18 control subjects (MELD score: 27 ± 5.2)Thirty grams of donor stool samples infused daily for 7 d through a nasoduodenal tubeSOC (specifics not provided)HE resolved in 6 out of 8 patients after FMT (71.4%).1 yr post-FMT, there was an increase in Firmicutes and a reduction in Proteobacteria and Actinobacteria. Noteworthy species changes included decreased Klebsiella pneumoniae and increased Enterococcus villorum, Bifidobacterium longum, and Megasphaera elsdeniiThe mean bilirubin levels significantly decreased from 20.5 ± 7.6 mg/dL to 2.86 ± 0.69 mg/dL after treatmentChild-Turcotte-Pugh, MELD, and MELD Sodium scores showed significant reductions post-treatment in comparison to baselineSurvival was notably better in the FMT group when compared to healthy controls. Additionally, post-FMT improvements were observed in bile, carotenoid, and pantothenate pathwaysExcessive flatulence was reported as a complaint by 50% of FMT patients
Philips et al[81], 2022Retrospective analysis47 patients diagnosed with severe alcohol-asSOCiated hepatitis (MELD score: 28.1 ± 4.7) and 25 control subjects (MELD score: 28.2 ± 6.3)The FMT group received 100 mL of freshly processed stool samples daily via a nasoduodenal tube for 7 dPentoxifylline (400 mg thrice daily for 28 d)During follow-up, the FMT group exhibited significantly lower HE incidences compared to the SOC groupIn the FMT group, there was a decrease in Proteobacteria and an increase in Actinobacteria and Bacteroides. Genus-level analysis revealed higher Bifidobacterium and lower Acinetobacter. Within the SOC group, higher levels of Erwinia and Porphyromonas were noted, along with lower beneficial Bifidobacterium at 1-2 yr. Beyond the 2-yr mark, FMT led to higher beneficial Bifidobacterium levelsNot reportedNot reportedDuring follow-up, the FMT group exhibited lower instances of ascites, infections, hospitalizations, and alcohol relapse in comparison to the SOC group. A longer time to relapse was noted, along with a trend towards improved survival at 3 yrAcute variceal bleeding was the most common cause of death in the FMT group, whereas infection predominated in the SOC group