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Liver Disease in Obese Women Linked to Gut Microbes, Metabolites

NEW YORK (GenomeWeb) – The gut microbiome appears to contribute to a liver condition called hepatic steatosis in obese individuals, according to a new study, suggesting new potential treatments with fecal microbiota transplants.

Hepatic steatosis can lead to non-alcoholic fatty liver disease (NAFLD), liver failure, cancer, cardiovascular disease, and type 2 diabetes.In an effort to understand microbe-host interactions contributing to the condition, researchers from the UK, Spain, Italy, and elsewhere brought together fecal metagenomic sequencing, array-based host expression profiling, and metabolomics of urine and plasma to explore interactions between gut microbiome community features, liver gene expression, and molecular phenomics in more than 100 non-diabetic obese women gearing up for gastric bypass surgery.

From the molecular networks ascertained using the data, along with experiments in mouse models treated with fecal microbiota transplantation, the team detected gut microbial shifts, hepatic inflammation, and altered metabolic features contributing to hepatic steatosis. The results were reported online yesterday in Nature Medicine.

"Our investigations … support the view that the molecular crosstalk between the microbiome and its human host is of utmost importance for patient health and highlights the need for integrative analyses of metagenomes and broad-sense phenomes," senior author Marc-Emmanuel Dumas, an integrative systems medicine and digestive diseases researcher at Imperial College London, and his colleagues wrote.

The researchers focused on 44 women treated at a hospital in Spain and another 61 women treated in Italy. All of the women donated samples — including stool, urine, blood plasma, and liver biopsy samples — in the week leading up to elective bypass surgery to treat their obesity. All of the participants had been classified as morbidly obese and were free from viral hepatitis, type 2 diabetes, and related treatments known to alter the gut microbiome.

Along with shotgun metagenomic sequencing on fecal samples from 56 of the participants, the team generated NMR-based blood and urine metabolite profiles and array-based liver transcriptome data, which was analyzed in combination with hepatic fat measurements, liver histology profiles, and other clinical data for each participant.

The results pointed to increased microbial gene richness in the gut microbiomes of the individuals with less severe liver steatosis, the researchers reported, while higher-grade liver steatosis cases were marked by lower microbial gene richness in the gut. They noted that the liver condition also seemed to coincide with the presence of certain gene functions in the gut microbiome, including pathways involved in producing fatty acids, sugars, and certain branched-chain or aromatic amino acids.

On the metabolome side, the researchers flagged 124 urine metabolites and 80 plasma metabolites that appeared to correspond with the diminished gene richness in the gut microbial community, hepatic steatosis, and related clinical phenotypes. That analysis again highlighted branched-chain amino acids, which were present at more pronounced levels in blood and urine samples from participants with liver steatosis.

Another microbe-related compound — an amino acid breakdown product called phenylacetic acid (PAA) — was found at higher-than-usual levels in the blood of hepatic steatosis-affected individuals, prompting speculation that PAA may eventually serve as a blood-based biomarker for fatty liver development.

From these and other metabolite patterns they detected, the authors proposed the "existence of a metabolic phenotype associated with hepatic steatosis and low [microbial gene richness], pinpointing elevated [branched-chain amino acids], [aromatic amino acids], and microbial metabolite levels coupled to a potential imbalance in hepatic oxidation and conjugation of those microbial substrates."

In a series of follow-up experiments, the team brought in liver gene expression profiles to look at the convergence of gene networks, gut microbial gene richness, and metabolite shifts involved in liver steatosis, before verifying the apparent ties between gut microbes and liver disease in mouse models receiving donor gut microbes from affected and unaffected animals.

"We now need to explore this link further and to see if compounds like PAA can indeed be used to identify patients at risk and even predict the course of disease," Dumas said in a statement. "The good news is that by manipulating gut bacteria, we may be able to prevent fatty liver disease and its long-term cardio-metabolic complications."