FMT Modifies Gut Microbiome, Reduces Ammonia in Cirrhosis

VIENNA, Austria — Fecal microbiota transplants (FMT) can reset gut microbiota leading to strengthened gut barrier function and mucosal immunity, along with improved ammonia metabolism in patients with cirrhosis, show data from a pilot study now expanded into a large multisite UK trial.

Genome sequencing found that FMT increased the richness of species with significant donor engraftment. E. faecalis and other harmful species were reduced, as were biomarkers of inflammation; in contrast, markers of gut barrier repair rose. After 1 month, ammonia levels in the plasma were lower but higher in the feces, findings that were further enhanced at 3 months.

Modifying the microbial-associated ammonia production and utilization could reduce hepatic encephalopathy and deadly infections, said Lindsey A. Edwards, PhD, from the Institute of Liver Studies, King's College London, England, and co-lead investigator on the PROFIT trial, presenting here at the International Liver Congress of the European Association for the Study of the Liver (EASL) 2023.

Edwards' co-investigator, Debbie L. Shawcross, MD, also from King's College London, added: "This landmark trial provides evidence that a fecal transplant can improve gut health by modifying the gut microbiome and reducing ammonia levels in patients with cirrhosis. Initial findings from PROFIT are promising news for patients with chronic liver disease who are in desperate need of alternative treatment options."

The success of the PROFIT study has led to the start of the follow-on PROMISE study, also being conducted by Edwards and Shawcross, which aims to deliver FMT via capsules, removing the need for invasive endoscopy procedures as used in PROFIT.

Gut Microbiota in Chronic Liver Disease

Patients with cirrhosis have an underabundance of commensal microbes, an overabundance of pathogenic microbes, and reduced gut microbiome diversity, as well as gut barrier damage and bacterial translocation. Together, these disrupt healthy functioning of the immune system, which increases susceptibility to infection and mortality.

"These pathogenic bacteria can be deadly to liver disease patients, particularly if they pick up an antibiotic resistant infection," explained Edwards. "Through FMT, we want to reset the gut microbiome by returning the friendly, beneficial bacteria to patients."

Shawcross previously conducted a trial which showed that the gut microbiome could be reconfigured using the antibiotic rifaximin, but Edwards explained that administering repeat antibiotics was unwise because it can lead to the development of antibiotic resistance.

"FMT offers a different way of beneficially modifying the microbiome that is safe for patients with chronic liver disease," Shawcross emphasized.

The placebo-controlled, randomized, single-blinded feasibility trial involved 32 patients with advanced cirrhosis (MELD score, 10 - 16), who either received 50 g of license-produced, frozen FMT, administered via endoscopy into the jejunum, or placebo in a 3:1 (FMT:placebo) randomization. FMT stool was sourced from healthy, antibiotic-free, omnivorous individuals to ensure a good diversity of bacteria. In addition, the samples are thought to contain various metabolites that may play an active role in the beneficial effects seen, noted Edwards.

Modulation of patient microbiomes and inflammatory status were assessed by collecting blood and stool samples at baseline and at 7, 30, and 90 days after the study start. Samples were tested for cytokine production, markers of gut barrier integrity, metabolite profiles, and analysis of the fecal proteins (fecal proteomics).

Beneficial Proteins, Ammonia Metabolism, and Cytokines

After FMT, fecal proteomics detected 301 proteins composed of 154 of human origin — mostly related to gut barrier protection — and 147 of bacterial origin — mostly enzymes — at days 7, 30, and up to 90. "We found that the proteins produced after FMT enhance the antibacterial response of [gut] cells," Edwards pointed out.

Albumin, which is produced by the liver, is often reduced in chronic liver disease but "after FMT, blood albumin levels were found to increase dramatically because the liver is reset to produce this protein. Albumin is also very beneficial to gut barrier function," added the researcher.

FMT also led to a reduction in plasma ammonia (P = .0006; FMT vs placebo at days 30 [P = .011] and 90 [P = .025]). Edwards explained that FMT modifies the gut microbiome, which metabolically reprograms by replenishing enzymes sourced from commensal bacteria that were previously depleted, causing a rise in ammonia metabolism such that it produces energy for the immune system and gut barrier.

Bacterial enzymes involved in denitrification and ammonification were increased in the stool following FMT, particularly aspartate ammonia-lyase, with 17 high-confident peptides also enhanced (FMT vs placebo, P = .031), and likewise secretion of urinary Hippurate at day 30 in FMT vs placebo (P = .0299).

In liver disease, ammonia is both poorly metabolized due to insufficient bacterial enzymes and poorly excreted, hence there is an accumulation in the blood. "One the biggest problems for liver disease patients is the buildup of ammonia in the blood, which can cause hepatic encephalopathy and death. By reducing ammonia levels through the reprogramming effect of FMT, we could stop liver disease-related death for two reasons: encephalopathy and infection," said Edwards.

The researchers also found that beneficial cytokine production rose after FMT, in particular those in the Th17 family that are involved in mucosal immunity, inflammation, and fighting infection.

Liver Disease and Antimicrobial Resistance

Chronic liver disease patients are particularly at risk of antimicrobial-resistant infections because they take daily prophylactic antibiotics — 25% are on long-term antibiotics — and the loss of gut barrier and increased inflammation further exacerbates the risk. "These patients are at such high risk of infections," said Edwards. "Of note, the antibiotics they take are often quinolones, which are frequently associated with driving antimicrobial resistance."

Liver disease and antimicrobial resistance are intricately linked — they are both leading causes of mortality worldwide — so tackling both problems in concert reaps benefits for two public health crises. "Most people don't realize how closely linked antibiotic resistance and liver disease are. They have the same etiology of disruption to the gut microbiome, and gut barrier. Liver disease is sharply rising, and these same people are also at very high risk of antibiotic resistance. Here we are trying to tackle both problems," the researcher explained.

She also pointed out that in many cases the only definitive treatment option for cirrhosis patients is a liver transplant, but antibiotic resistant infections often exclude these patients.

Further study of FMT over the longer-term might find additional benefits to the liver. The process of cirrhosis (fibrosis) is a reaction to damage caused by infection and inflammation and poor resolution of the immune response so, "if FMT improves the gut barrier and enriches the microbiome, and reduces inflammation and infection, it may reduce cirrhosis," said Edwards. "It is possible that the earlier we intervene the better."

Jonel Trebicka, MD, PhD, from University Clinic Münster, Münster, Germany, and lead of a large European Liver Microbiome Consortium called MICROB-PREDICT, welcomed the research, noting it was a "wonderful piece of work which clearly outlines that gut-liver-axis depends on the microbiome-host interaction in health and disease."

"One high level message is that it means that we need to take care of the gut environment to restore and maintain liver health. The interaction of the microbiome with the gut epithelium is crucial for metabolism of toxins that damage the liver, and also drive inflammation in the gut and blood and aggravate liver disease," he said.

Co-moderator Aleksander Krag, MD, professor and head of hepatology at the University of Southern Denmark and Odense University Hospital, Denmark, and vice-secretary of EASL remarked that, "This is [such an] exciting study and beautiful presentation."

The PROMISE Trial

The PROMISE trial started very recently and is an expansion of PROFIT that aims to enroll 300 patients across the UK. Shawcross said that patients in PROFIT had suggested that tablets would be preferred to endoscopy for FMT delivery. Unlike the pilot study, that only dosed once and followed participants for 90 days, PROMISE will randomize participants to receive either FMT capsules or placebo every 3 months for 2 years.

Edwards and Shawcross have disclosed no relevant financial relationships. Trebicka declared speaker fees from GORE, and is lead of the MICROB-PREDICT, which is funded via the European Union's Horizon 2020 research and innovation program. Krag has served as speaker for Norgine, Siemens, and Nordic Bioscience, and participated in advisory boards for Norgine and Siemens, all outside the submitted work. He receives royalties from Gyldendal and Echosense. He is also part of the MICROB-PREDICT project.

International Liver Congress (ILC) 2023: Abstract GS-007. Presented June 23, 2023.

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