Effective therapies for liver disease may need to include interventions aimed at the microbiome, especially in the gut. While much of the relationship between the gut microbiome and the liver is still a black box, a growing body of research is starting to make the connection clearer.

At the American Society for Parenteral and Enteral Nutrition’s Nutritional Science & Practice Conference 2023, Gail Cresci, PhD, RD, a microbiome researcher with Cleveland Clinic’s Department of Pediatric Gastroenterology, Hepatology and Nutrition, in Ohio, discussed the key role the gut microbiome appears to play in liver disease.

Understanding the Gut–Liver Connection

According to Dr. Cresci, the gut and the liver constantly engage in cross-talk. Existing research has already shown that dysbiosis in the gut microbiome, which can produce markers in the blood or stool, could help physicians determine how advanced a patient’s liver disease is (Front Cell Infect Microbiol 2022;12:997018).

Studies have shown that different types and stages of liver failure have different microbiome signatures, Dr. Cresci said. Some have suggested that gut microbiota can drive the advancement of metabolic dysfunction– associated steatotic liver disease (MASLD) (formerly nonalcoholic fatty liver disease) and accelerate its progression to cirrhosis (JHEP Rep 2021;3[2]:100220; Microorganisms 2021;9[1]:199).

According to Phillipp Hartmann, MD, an assistant professor of pediatric gastroenterology at the University of California, San Diego, who studies the microbiome in liver diseases, a number of pathogenic microbes, notably Enterococcus and Veillonella, are typically increased, while beneficial Faecalibacterium prausnitzii often are seen at lower-than-normal levels (JHEP Rep 2021;3[2]:100220).

Several studies have shown that some specific gut microbiota and metabolites, including short-chain fatty acids, bile acids, lipopolysaccharide, choline and trimethylamine, change with disease severity in people with MASLD, making them potential diagnostic markers for the disease (Nat Commun 2020;11:4982; Hepatology 2017;65[2]:451-464).

Although most research has focused on bacteria, Dr. Hartmann said important changes in gut fungi also appear to play a role in liver disease, especially in nonobese patients, and deserve a closer look.

In another study, investigators documented an increased abundance of Candida and a reduction in both bacterial and fungal diversity in people with alcohol-associated liver disease (JHEP Rep 2021;3[2]:100220).

New Interventions for Cirrhosis

One way to possibly help regulate gut microbiota in patients with liver disease could be fecal microbiota transplant (FMT), according to new research presented at the European Association for the Study of the Liver’s International Liver Congress 2023. In a placebo-controlled, randomized, single-blinded feasibility study, investigators found that patients with advanced cirrhosis (Model for End-stage Liver Disease score, 10-16) benefited from FMT by increasing their metabolism of ammonia and reducing inflammation in the gut barrier (abstract GS-007). Thirty days after receiving the FMT via endoscopy, patients in the intervention group had a reduction in plasma ammonia (P=0.0006) and an increase in fecal ammonia (P=0.011). The investigators reported that FMT also increased biomarkers associated with gut repair and reduced inflammation markers.

The researchers are continuing their research with the PROMISE trial, a multicenter randomized controlled trial of FMT capsules for patients with cirrhosis. The 300 patients involved in the study will receive the capsules and follow-up for two years. According to principal investigator Lindsey Ann Edwards, PhD, the research director of the Fecal Microbiota Transplant Program at King’s College London, the investigators aim to elucidate FMT’s effects on immune health in patients with liver disease. “Patients with chronic liver disease are often prescribed antibiotics. However, they are at high risk of multidrug-resistant infections, and this is contributing to the global health crisis of antimicrobial resistance,” Dr. Edwards noted in a press statement.”

Reducing Infections Related to Transplants

An altered immune response is something that may play an under-recognized role in the health of patients with liver disease, especially during and after a liver transplant, Dr. Cresci said. It’s possible that altering the gut microbiome either before or after a liver transplant could improve a patient’s immune function and help fight infection.

“That cross-talk in healthy situations is very important for reducing inflammation and producing optimal immune responses. When there is overgrowth of these potential pathogenic bacteria, that could contribute to even more dysregulated immune responses, and potentially more infections,” Dr. Cresci said. “The question is: Can you intervene and get a better immune response?”

According to Dr. Hartmann, simple interventions with prebiotics, probiotics and synbiotics could have an outsized influence when it comes to correcting liver disease. One meta-analysis that included four controlled studies with 246 patients showed that giving prebiotics and probiotics on the day of surgery can decrease a patient’s risk for infection post-transplant (Clin Gastroenterol Hepatol 2015;13[9]:1567-1574.e3).

In a space where few therapies exist—and the ones that do cause damage to the balanced gut microbiome—using established diet, FMT or supplement-based therapies may play an increasing role in liver disease care. Such gut microbiome–focused therapies may create opportunities for precision medicine and lessen the need for immunosuppression.

Working Toward Individualized Care

This possibility adds to the host of questions that still need to be answered.

“By modulating the microbiome post-transplant, can you limit how much immunosuppressant medication you can give to a patient because now they are harnessing their own immune system instead?” Dr. Cresci asked.

It’s also possible that modulating the gut microbiome before or after transplantation is a necessary process, since the liver, but not the gut, is replaced, Dr. Cresci said. “You’re taking out the liver and putting a new liver in, but the microbiome is still intact in that scenario,” she said. “Do we need to correct the microbiome at the same time as a liver transplant, or do some preconditioning of the microbiome pre-transplant because of that cross-talk? If not, are you seeding that new liver with bad stuff coming from the gut, compromising the graft integrity?”

As of now, the microbiome is not a part of standard protocol for transplants, but Dr. Cresci said research is already beginning to show that microbiome intervention may be linked with reduced post-transplant infection. With more pointed information, tailored microbiome treatments may improve patient care in the future.

—Kaitlin Sullivan and Meaghan Lee Callaghan

The sources reported no relevant financial disclosures.