FMT bodes well for AMR

The PROFIT trial turns waste into gains by showing how faecal microbiota transplantation (FMT) can combat antimicrobial resistance (AMR) in patients with liver cirrhosis.

“The third biggest killer behind AMR is liver disease, and most liver disease patients die of a drug-resistant infection. [As such,] we are trying to meet the challenge of tackling AMR and liver disease at the same time by modifying the microbiome,” said Dr Lindsey Ann Edwards from the Centre for Host-Microbiome Interactions, King’s College London, UK, at ESCMID Global 2025. “We can try to reduce inflammation and repair the gut barrier by FMT or phage therapy.”

The team evaluated 21 patients (mean age 57.1 years) with alcohol-related liver disease (52 percent alcohol-related cirrhosis) who were not on antibiotics at the time of transplantation and were alcohol-free for a minimum of 6 weeks. Liquid stool preparations obtained from healthy donors were transplanted in 15 participants; the rest received placebo. Most patients followed a Western diet high in sugar and animal protein. [ESCMID Global 2025, abstract L0021]

There was an increase in gut microbial richness 7 days following FMT, with eradication of the pathobiont Enterococcus faecalis, which is particularly driven by a Western diet. This was not seen in the placebo arm.

There was also a reduction in vancomycin-resistant gene carriage with FMT. “We tried to replace it with obligate anaerobes such as Faecalibacterium (F.) prausnitzii, which can modify the immune system,” Edwards said. F. prausnitzii metabolizes immunosuppressive butyrate and is a marker of intestinal health.

Deeper dive

However, it is difficult to determine what FMT does to the gut barrier via noninvasive means, underscored Edwards. Hence, the team developed an assay that can isolate proteins and evaluate mucosal immune response and barrier function via electrochemiluminescence. “Essentially, liver [disease] patients have excessive Th-17 cytokine levels and barrier damage at baseline. FMT reversed this.”

Faecal proteomics analysis quantified 301 proteins (154 of human origin, 147 bacterial) that were modified post-FMT. According to Edwards, antimicrobial mucosal barrier defence molecules were enhanced, and markers of barrier damage were reduced.

“What was interesting [is that FMT modified various] enzymes involved in ammonia metabolism, which is surprising because it is particularly deadly to liver [disease] patients,” she pointed out.

Edwards further explained that because the liver is diseased, patients have microbiome dysbiosis and are unable to metabolize ammonia. This leads to ammonia retention in the blood and robs patients of energy to repair intestinal barrier function and fight off infection. With such limited response to infection, hepatic encephalopathy or death may ensue.

Post-FMT, there were enhanced responses to infection and increased ammonia excretion. “By boosting the host immunity, we might reduce deadly infections and the need for antibiotic prescriptions,” Edwards said.

Microbiome modulation

In liver disease, intestinal inflammation and AMR gene carriage increase. These lead to pathogenic bacterial adherence to the epithelia, resulting in intestinal epithelial barrier disruption and microbial translocation.

However, liver disease patients have immune paralysis, which impairs their ability to combat infection when translocation occurs. This is where prophylactic antibiotics come into play, but Edwards highlighted that this further exacerbates AMR.

FMT aims to restore the gut barrier and antimicrobial immunity and eliminate drivers of AMR transmission, Edwards said. “[Our results show that] modulation of the microbiome by FMT/phages promotes restoration of ammonia metabolism, intestinal barrier function, and mucosal immunity. FMT shows great promise for tackling AMR, particularly gram-positives, but it is not as effective for gram-negatives.”

For gram-negative pathogens, augmenting FMT with other therapies (eg, phage therapy, vaccines) may be necessary. Caution should also be exercised when prescribing broad-spectrum gram-positive-targeting antibiotics post-FMT, she added.

Edwards called for larger trials with longer-term follow-up to ascertain the findings. “We need to continue to uncover the mechanisms of action of FMT, phages, and AMR gene transmission. We [need to] know what role phages play in restoring metabolic capability.”