Fecal microbiota transplantation for hepatic encephalopathy: Ready for prime time?

Potential conflict of interest: Dr. Kao received grants from Rebiotix. See Article On Page 1727 Hepatic encephalopathy (HE) is indisputably one of the most debilitating complications of cirrhosis, leading to significant reductions in quality of life of both patients and caregivers and increases in patient morbidity, mortality, and health care utilization.1 The two frontline therapies, lactulose and rifaximin, target the “gut‐liver‐brain axis,” their clear clinical benefits supporting a role for gut microbes in HE pathogenesis.2 Fecal microbiota transplantation (FMT) is the latest in the line of investigational therapies to target this axis. In FMT, fecal material from a healthy donor is given to a patient to ameliorate the gut's microbial imbalance (dysbiosis). FMT is highly effective for recurrent Clostridium difficile infection (rCDI) with a cure rate >80%.3 In this issue of Hepatology, Bajaj et al. add to the knowledge base in the area of cirrhosis4 by publishing the first open‐label randomized, controlled trial (RCT) of a single FMT versus standard of care (SOC) in 20 male patients with >2 episodes of overt HE.5 Patients randomized to the intervention received 5 days of antibiotic pretreatment followed by a single FMT enema from a “rationally selected stool donor.” The SOC arm did not receive antibiotic pretreatment. All patients were on stable doses of lactulose and rifaximin throughout the study. The primary study outcome was FMT‐related serious adverse events (SAEs) defined by a composite endpoint of death, hospitalizations, emergency room visits, or transmissible infections. At 150 days post‐FMT, SAEs were reported for 80% of SOC patients versus 20% of the intervention arm (P = 0.02); 60% of SOC patients and none of the intervention participants required hospitalization for recurrent HE. Secondary outcomes reported changes between baseline to 20 days post‐FMT and were also significant. Cognitive function (psychometric hepatic encephalopathy score and EncephalApp‐Stroop tests) improved in FMT (P < 0.05), with no changes observed in SOC. In the intervention arm, microbial diversity was predictably reduced following 5 days of antibiotics, but increased to pre‐FMT levels by day 20. The relative abundance of Lachnospiraceae and Ruminococcaceae, thought to be beneficial taxa in HE, also significantly reduced after antibiotics. These taxa recovered post‐FMT in all but 2 subjects in the intervention arm. No changes in microbial diversity were observed in the SOC arm. The study has several strengths, including the use of an RCT to systematically investigate the impact of FMT on recurrent overt HE, a condition with few treatment alternatives. The use of “rationale stool donor selection” was novel. A comprehensive range of outcomes was measured, including clinical events, cognitive testing, microbial composition analyses, and urine metabolites. The investigators' conclusions of safety, improved cognition, reductions in hospitalizations, and improved microbial diversity after a single FMT enema represent an important step forward, but these exciting findings must be tempered by the following study limitations, many of them acknowledged by the investigators. First, although the largest experience thus far in cirrhosis, the primary outcome of safety must be interpreted with caution given that the intervention was given to only 10 patients who had reasonably well‐preserved liver function (mean Model for End‐Stage Liver Disease of 12). Reassuringly, short‐term safety data from rCDI suggest that FMT is well tolerated, even in immunocompromised individuals.6 However, long‐term safety data are lacking and concerns exist about the transmission of unrecognized infectious agents and donor phenotypes, such as obesity.3 Second, 60% of SOC patients required hospitalization for recurrent HE within 150 days, which was surprisingly high and unexplained. In the landmark trial comparing rifaximin versus placebo, the HE‐related hospitalization rate was 13.6% within 182 days.7 Third, as the investigators noted, the use of antibiotics pre‐FMT limited our ability to discern whether the reported clinical improvement would have occurred regardless. Fourth, the microbiome and cognitive assessments were only performed up to day 20, which prevented linking of these objective results to HE recurrence or determining the durability of the therapeutic response to a single FMT enema. Nevertheless, given the burden of recurrent HE and the limited therapeutic options, this important work encourages and facilitates the design of future trials of FMT in HE. Among multiple unanswered questions, future studies will need to reflect on three key considerations brought to light by the investigators. Is There Evidence for Rational Donor Selection? The concept that donor stool characteristics may influence FMT efficacy has been recognized in inflammatory bowel disease.8 Bajaj et al. carried forward this novel concept by utilizing donor stool enriched with microbial taxa found to be beneficial in cross‐sectional HE studies.2 Although an excellent starting point for targeted donor selection, this “one‐size‐fits‐all” approach to donor selection will likely benefit from further refinement given that: (1) not all patients with the same disease have similar microbial profiles9 and (2) our current understanding of “beneficial” taxa from cross‐sectional HE studies is based on association rather than causation. Future prospective HE/FMT studies with careful donor profiling will enable better characterization of the microbial taxa and functionality associated with clinical response. A conceivable future will offer libraries of well‐characterized donor pools to facilitate microbial‐based therapy personalized to each recipient's needs. Sequencing and metabolomics technologies will concurrently have to become faster and cheaper to make this approach practical for clinical use. Is Antibiotic Pretreatment Required? The investigators note that there was little evidence to support antibiotic pretreatment to facilitate colonization of the donor microbiota.5 As evidenced by the three published randomized, placebo‐controlled trials of FMT to treat ulcerative colitis and the original case report of FMT for HE,4 engraftment (i.e., recipient stool takes on microbial taxa from the donor) is possible without pre‐FMT antibiotics.10 What is being evaluated in ongoing clinical studies is whether antibiotic pretreatment can enhance engraftment. Given the substantial risks associated with antibiotic therapy in cirrhosis and paucity of supporting data, we caution against antibiotic pretreatment for future HE studies until a clear evidence base is established. What Is the Optimal FMT Dosing Interval? Whereas a single FMT treatment is highly efficacious in rCDI, the majority of patients with chronic inflammatory conditions require multiple FMT treatments to sustain a response. This need for serial treatments supports the concept of distinct underlying mechanisms promoting and perpetuating gut dysbiosis. Although it is interesting and encouraging that a single FMT in the study by Bajaj et al. was associated with a sustained clinical response, given the need for repeated treatments in other conditions, this intriguing finding will benefit from replication. Moreover, to inform the durability of the microbiome changes and the need for either single or repeated FMTs, future HE/FMT studies should consider cognitive testing and microbial evaluation over the length of intervention and postintervention follow‐up period. Does FMT fit in the clinical care algorithm for HE? At present, it is too early to tell. The efficacy, durability, and long‐term safety data to support FMT are only beginning to emerge as, too, are questions regarding FMT trial design. Fortunately, microbiome‐based therapy is a rapidly progressing research area. The near future is likely to see the replacement of FMT with the oral administration of defined microbial communities selected based upon recipient microbial and metabolomic profiles. If proven to be effective, practical, and safe, it is exciting to consider that an individualized approach to microbial modulation by FMT could expand our frontline treatment options for HE.