The gut-liver axis plays an important role in many liver diseases, especially ALD. Apart from direct damage to hepatocytes via alcohol metabolism by cytochrome P450 enzymes and the release of free radicals, dysbiosis and increased gastrointestinal permeability induced by alcohol play an important role, resulting in bacterial translocation and endotoxemia. Taken together, these effects of alcohol result in inflammatory signaling, mitochondrial dysfunction with oxidative stress, fibrosis, and cirrhosis. 

The alteration of gut microbiota with fecal matter transplant (FMT) has been successfully used in several conditions. Five years ago, Phillips et al from India demonstrated the feasibility and benefits of FMT by using purified stool samples from healthy donors in patients with severe alcohol-associated hepatitis. At this year’s The Liver Meeting, 3-year follow-up data were presented (abstract 11) in 61 patients with severe alcohol-associated hepatitis (35 received FMT and 26 were treated with prednisolone for 28 days). The authors concluded that, compared with standard of care, FMT improved patient outcomes (ie, hepatic encephalopathy, critical infections, hospitalizations, and alcohol relapse) and tended to improve patient survival. 

The group at Virginia Commonwealth University led by Dr Bajaj is opening another chapter on the benefits of FMT on the gut-brain axis. Previously, their phase 1 trial showed that FMT could be safely given to patients with alcohol-associated cirrhosis. In this trial, the microbiota came from a healthy donor and was enriched in beneficial bacteria Lachnospiraceae and Ruminococcaceae. At 15 days, FMT was associated with reductions in alcohol craving and alcohol consumption as well as favorable microbial changes as compared with placebo. At The Liver Meeting 2021, the investigators presented their extended work (abstract 3), with mice gavaged with fecal microbiota material from the patients who were enrolled in the pilot study described above. Researchers reported that mice that were exposed to the post-FMT microbiota had significantly reduced initial ethanol acceptance and 24-hour ethanol intake and preference compared with mice that were gavaged with pre-FMT material. These findings strongly support that FMT may be a promising treatment for reducing alcohol intake. 

Gut leakiness with bacterial translocation is considered to be a driver of ALD, and Llorente et al elucidated aspects of the underlying pathophysiology (abstract 112). Researchers found that chronic alcohol use increases goblet cells and mucin production, blocks goblet cell–associated antigen passages (GAPs), and hinders the delivery of luminal antigens and bacteria to antigen-presenting cells in the lamina propria. In a mouse model, researchers showed that GAPs are controlled by the intestinal interleukin-6 signal transducer glycoprotein 130 via muscarinic acetylcholine receptor 4, and their opening induces REG3 lectin–mediated antibacterial defense, reducing bacterial translocation to the liver and preventing alcoholic steatohepatitis. The authors suggested muscarinic acetylcholine receptor 4 as a potential therapeutic target and its pharmacologic manipulation as a strategy for drug development for ALD. 

Another interesting study presented at The Liver Meeting this year examined the role of acute alcohol consumption in the translocation of the gut microbiota into the circulation (abstract 183). It is well known that gut leakiness is increased in those who are susceptible to or have established ALD, and not in every person with a harmful use of alcohol. Israelsen et al recruited 39 patients (14 with biopsy-proven ALD, 15 with biopsy-proven nonalcoholic fatty liver disease, and 10 healthy controls), and everyone received 2.5 mL of 40% ethanol per kg body weight, infused over 30 minutes via a nasogastric tube. None of the patients had decompensated cirrhosis. Investigators sampled hepatic and systemic venous blood simultaneously at 9 time points within 4 hours, and they measured bacterial DNA levels. The results indicated bacterial translocation in patients with early ALD, suggesting gut-liver axis as a potential therapeutic target in those with early ALD.