Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD), is the most common chronic liver disease worldwide, affecting more than 30% of population. This type of steatosis is caused by factors other than excessive alcohol use and occurs alongside other metabolic disorders such as obesity. While early-stage MASLD does not usually cause any harm, it can lead to an increased risk of liver transplantation and hepatocellular carcinoma.
While the exact cause of MASLD isn’t completely understood, recently an altered gut microbiome has been identified as a potential contributor of the disease at different stages. For instance, previous findings revealed that endotoxin-producing strains of the opportunistic pathogens Enterobacter cloacae, Escherichia coli, and Klebsiella pneumoniae may exacerbate hepatic steatosis and contribute to predict or control metabolic liver disease progression.
A new study, which I led with a team of researchers from Université Paris-Saclay and Université d’Angers, in collaboration with NovoBiome and Enterome, reveals that gut commensal Adlercreutzia equolifaciens has anti-inflammatory properties and decreases as the severity of metabolic liver disease increases.
Through analyzing the fecal microbiome through shotgun metagenomics, we observed that the gut commensal A. equolifaciens-a bacterium belonging to Actinomycetota from the Eggerthellaceae family-is reduced in patients with MASLD at different stages of the disease compared to healthy controls. These findings suggest that A. equolifaciens is a marker of a healthy gut microbiome, while it is reduced in patients with metabolic liver diseases.
It is important to acknowledge that the depletion of A. equolifaciens was also associated with the severity of the liver disease. Indeed, its relative abundance was very low in patients that developed cirrhosis, with almost disappearance in patients with acute decompensation of cirrhosis with advanced fibrosis.
We also showed that A. equolifaciens has anti-inflammatory properties, both in vitro and in vivo, in a humanized mouse model of MASLD. A. equolifaciens displayed anti-inflammatory effects through increasing the caecal levels of butyrate, decreasing the caecal levels of branched-chain fatty acids iso-butyrate and iso-valerate, and reducing the expression of interleukin-6 in the caecum and the liver.
In line with these results, we previously found that gut microbiome transfer from a patient affected by metabolic liver disease in early stages can induce the disease in mice. These data suggest that the gut microbiome can influence the early onset of MASLD and could have a role in its prevention or management.
Currently there are no approved pharmacological treatments to limit the progression of metabolic liver diseases, although a promising candidate has been tested in a phase 3 trial. While our findings suggest that correcting the altered gut microbiome seen in patients with MASLD could improve the severity of the disease, it is important to state that the first treatment for metabolic liver diseases is healthy diet and sufficient exercise.
References:
Rinella ME, Lazarus JV, Ratziu V, et al. A multisociety Delphi consensus statement on new fatty liver disease nomenclature. Hepatology. 2023; 78(6):1966-1986. doi: 10.1097/HEP.0000000000000520.
Fei N, Bruneau A, Zhang X, et al. Endotoxin producers overgrowing in human gut microbiota as the causative agents for nonalcoholic fatty liver disease. mBio. 2020; 11(1):e03263-19. doi: 10.1128/mBio.03263-19.
Plaza Oñate F, Chamignon C, Burz SD, et al. Adlercreutzia equolifaciens is an anti-inflammatory commensal bacterium with decreased abundance in gut microbiota of patients with metabolic liver disease. Int J Mol Sci. 2023; 24(15):12232. doi: 10.3390/ijms241512232.
Burz SD, Monnoye M, Philippe C, et al. Fecal microbiota transplant from human to mice gives insights into the role of the gut microbiota in non-alcoholic fatty liver disease (NAFLD). Microorganisms. 2021; 9(1):199. doi: 10.3390/microorganisms9010199.
Harrison SA, Bedossa P, Guy CD, et al. A phase 3, randomized, controlled trial of resmetirom in NASH with liver fibrosis. N Engl J Med. 2024; 390(6):497-509. doi: 10.1056/NEJMoa2309000.
