Role of fecal microbiota transplant in management of hepatic encephalopathy: Current trends and future directions

Table 1 Overview of the prevalence of hepatic encephalopathy in different chronic hepatic conditions

Condition	Total, n = 166192	Did not develop HE, n = 117433	Developed HE, n = 48759
Alcoholic cirrhosis	54194 (33)	30011 (26)	24183 (50)
Hepatitis C cirrhosis	49599(30)	31247(27)	18352(38)
Nonalcoholic cirrhosis	78111 (47)	62433 (53)	15678 (32)

Data are shown in n (%). HE: Hepatic encephalopathy

Table 2 Classification of hepatic encephalopathy based on American Association for Study of Liver Diseases[11]

Grade1		Explanation2	Suggested operational criteria3
Covert	Minimal	Tests measuring psychomotor speed, executive function, or neurophysiological abilities may change psychometrically or neuropsychological without showing any signs of a mental shift	A non-phenomenological abnormality on recognized psychometric or neuropsychological tests
	Grade 1	Trivial lack of awareness; Euphoria or anxiety; Shortened addition or subtraction	Despite 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
Overt	Grade 2	Lethargy or apathy; Gross disorientation; Obvious personality change; Inappropriate behavior	Disorientation 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 3	Marked confusion; Somnolence to semi-stupor; Responsive to stimuli; Bizarre behavior	Disoriented 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 4	Comatose state; Unresponsive to pain; Decorticate or decerebrate posturing	Never react, not even with painful stimuli

¹Unimpaired.

²Absolutely no encephalopathy, no previous hepatic encephalopathy (HE) diagnosis.

³Examined and found to be normal.

Table 3 Comparison of different modes of fecal microbiota transplant delivery

Mode of delivery		Advantage	Disadvantage
Upper gastrointestinal tract	Nasogastric	Faster; Comparatively less expensive; Better tolerability	Risk of aspiration; Discomfort; Increased risk of small intestinal bacterial overgrowth
	Nasojejunal	Faster; Comparatively less expensive; Better tolerability	Risk of aspiration; Risk of bowel perforation; Increased risk of small intestinal bacterial overgrowth
	Oral capsule	Least invasive; Cost-effective; Easy to store	Risk of aspiration; Vomiting; Sometimes failure to reach intestinal target
Lower gastrointestinal tract	Colonoscopy	Direct visualization of GI tract; Standard risks of sedation and procedural intervention	Risk of bowel perforation; Higher cost of performing procedure
	Retention enema	Useful in patients with severe colitis or colon distention to avoid perforation; Less invasive as compared to colonoscopy	Difficulty 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	Advantages	Disadvantages
Fresh[40]	85-100	High	Contains diverse microbial population	Requires immediate availability of the patient
Frozen[40]	83-95	Moderate	Allows for long term storage	Loss of some microbial diversity during freezing; Comprise on efficacy if not stored properly and use of incorrect thawing techniques
Frozen lyophilized[40]	78-84	Moderate	Longer shelf life; Can be easily incorporated into a capsule	Loss of some microbial diversity during encapsulation

FMT: Fecal microbiota transplantation.

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

Ref.	Type	Population	Intervention	Comparison	Outcomes					Adverse effects
					Cognitive impairment	Microbiota	Liver function	Scores	Not specified
Bajaj et al[77], 2017	RCT	20 cirrhotic patients experiencing recurrent HE while on lactulose/rifaximin treatment	FMT enema involving donor material enriched in Lachnospiraceae and Ruminococcaceae	SOC (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 group	Following 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 arm	In 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 levels	In 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-FMT	FMT 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], 2021	RCT, phase 1	10 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 Ruminococcaceae	Placebo	Cognitively, post-FMT patients exhibited improvements in both PHES and EncephalApp OffTime + OnTime	Post-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 microbiota	There were no changes in AST, ALT, or albumin levels within the FMT group	The 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 group	A 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], 2022	RCT, phase 2	A group of 10 cirrhotic patients, each having previously suffered at least one episode of overt HE and currently experiencing ongoing neurocognitive dysfunction	Healthy donors with normal BMI administered 15 oral FMT capsules on days 1, 2, 7, 14, and 21; Antibiotic pretreatment was not employed	None	PHES 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 nonresponders	Not reported	Not reported	Two 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 scores	Four 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], 2022	Case series	2 patients diagnosed with liver cirrhosis resulting from hepatitis B, who faced recurring Grade 2-3 HE following TIPS intervention	Fecal microbiota transplant conducted three times using 50 g of fresh fecal intestinal flora suspension	None	Subsequent hospitalizations due to HE were not reported among the patients	Notable 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 diversity	Liver function demonstrated improvement in Case 1, while Case 2 exhibited a nonsignificant enhancement	In Case 1, Child Pugh Score decreased from 10 to 5; In Case 2, it decreased from 11 to 7	There were no clinical manifestations, and the blood ammonia level decreased significantly	No 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], 2019	RCT, phase 1	20 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 Ruminococcaceae	Placebo	A 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 changes	After 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 samples	Not reported	The 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 reduced	In 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], 2018	Case series	10 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 HE	None	Not reported	Not reported	Not reported	A reduction in both CTP and MELD scores was observed from baseline to post-treatment week 20	The arterial ammonia concentration showed a considerable decrease at post-treatment week 20	1 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], 2016	Case report	A 57-yr-old male with grade 1-2 HE, with liver cirrhosis (MELD score of 10), attributed to alcohol and hepatitis C	Weekly FMT was administered, with the first application performed via colonoscopy and the subsequent sessions through retention enema	None	Mental 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 levels	Following FMT, there was a reduction in the relative abundance of Lachnospiraceae	Not reported	Not reported	Not applicable	No adverse events or infectious complications linked to FMT occurred
Bajaj et al[80], 2019	RCT, long term outcomes (> 12 mo) of a 2017 study	20 patients with cirrhosis experiencing recurring episodes of HE	FMT enema involving donor material enriched in Lachnospiraceae and Ruminococcaceae	SOC (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 group	During 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 state	Not reported	Changes in MELD scores exhibited similarity between the two groups	The FMT group experienced significantly fewer hospitalizations compared to the SOC group during the long-term follow-up	The intervention was well-tolerated in the FMT group, demonstrating a favorable long-term safety profile
Philips et al[63], 2017	Pilot study	8 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 tube	SOC (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 elsdenii	The mean bilirubin levels significantly decreased from 20.5 ± 7.6 mg/dL to 2.86 ± 0.69 mg/dL after treatment	Child-Turcotte-Pugh, MELD, and MELD Sodium scores showed significant reductions post-treatment in comparison to baseline	Survival was notably better in the FMT group when compared to healthy controls. Additionally, post-FMT improvements were observed in bile, carotenoid, and pantothenate pathways	Excessive flatulence was reported as a complaint by 50% of FMT patients
Philips et al[81], 2022	Retrospective analysis	47 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 d	Pentoxifylline (400 mg thrice daily for 28 d)	During follow-up, the FMT group exhibited significantly lower HE incidences compared to the SOC group	In 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 levels	Not reported	Not reported	During 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 yr	Acute variceal bleeding was the most common cause of death in the FMT group, whereas infection predominated in the SOC group

ALT: Alanine transaminase; AST: Aspartate transaminase; BMI: Basal metabolic index; FMT: Fecal microbiota transplantation; HE: Hepatic encephalopathy; ICT: Inhibitory Control Test; MELD: Model for End-Stage Liver Disease; PHES: Psychometric Hepatic Encephalopathy Score; RCT: Randomized controlled trial; SAE: Serious adverse event; SOC: Standard of care.