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Gut Microbiome Signature to Be Developed as Nonalcoholic Fatty Liver Disease Diagnostic

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NEW YORK (GenomeWeb) – Researchers plan to develop a gut microbiome signature of nonalcoholic fatty liver disease-linked cirrhosis into a diagnostic test for the condition.

Between 20 percent and 30 percent of US adults have nonalcoholic fatty liver disease (NAFLD), a condition in which excess fat is stored in the liver, according to the National Institute of Diabetes and Digestive and Kidney Diseases. It's more common among people with obesity and type 2 diabetes and can lead to cirrhosis, which is itself a risk factor for liver cancer.

As there are ties between risk factors for NAFLD like obesity and the gut microbiome, as well as other links between the liver and gut, Rohit Loomba, a gastroenterologist at the University of California, San Diego, and his colleagues investigated the association between the gut microbiome and NAFLD. They reported in a paperlast month that a panel of mostly bacterial features could detect which people in a cohort had NAFLD with cirrhosis. Once verified, Loomba said the panel could be developed into a microbiome-based diagnostic and complement other diagnostic approaches like MRI.

"It just increases the scale of where the screening could be done," Loomba said of microbiome-based diagnostic he is working on.

Loomba and his colleagues identified these 30 features in their analysis of the microbiomes of individuals with NAFLD with cirrhosis, NAFLD without advanced fibrosis, and controls without NAFLD and their first-degree relatives, a total of 203 individuals, including twin pairs. As they described in Nature Communications, the researchers examined the 16S gut microbiome composition of these individuals, who had also undergone MRI protein density fat fraction and MR-elastography analysis to assess the extent of their hepatic steatosis and liver fibrosis.

While they reported that first-degree relatives tended to have similar gut microbiomes — particularly if they lived in the same household — the researchers also uncovered microbial differences by disease state. They found, for instance, that bacteria belonging to the family Enterobacteriaceae and the genera Streptococcus and Gallibacterium were enriched among the NAFLD with cirrhosis group.

They combined 27 of these bacterial features plus age, sex, and body mass index into a Random Forest Model to predict NAFLD with cirrhosis, a model they reported had a diagnostic accuracy of 92 percent in their initial cohort.

As Loomba and his colleagues had previously found that first-degree relatives of individuals with NAFLD have a high risk of advanced fibrosis, they also used this classifier to identify family members with fibrosis, again with high diagnostic accuracy. In an unrelated validation cohort, they likewise reported the classifier to be robust with an accuracy of 86 percent.

Such a diagnostic, Loomba said, could be used to screen individuals who are at high risk of NAFLD or nonalcoholic steatohepatitis (NASH). "So if somebody who has a first-degree relative, and at a certain age, and maybe age 50, they come and say, 'My dad had cirrhosis due to NASH, do you think I need to be tested?' And you screen them using a stool test," he said in an interview.

In particular, he noted a microbiome-based test could be useful in regions where MRI-based and other tests are scarce, as a stool sample could be sent to a central laboratory for analysis. He added that the stool test could then identify people who then need follow-up testing.

As there are also stool-based tests for colorectal cancer, Loomba envisions testing being combined so that high-risk individuals could be assessed for multiple conditions using one sample.

But first, Loomba said more validation is needed, including in another independent validation cohort. He has teamed with other centers to expand their validation testing cohort.

In particular, he said they'd be looking to confirm that the bacteria they are relying upon are consistent and to take samples from patients to confirm using PCR the presence of those bacteria. Once that's done, he said the next step would be to develop this panel into a 16S rRNA sequencing-or PCR-based test that identifies bacterial genomes linked to advanced fibrosis.

He added they still have to figure which technology platform — 16S rRNA sequencing or PCR — to use as they scale the test up.

Currently, stool-based microbiome diagnostic test might cost about $1,500, Loomba said in a statement, but during the next five years, the price may drop to less than $400 as genomic sequencing and analysis technologies improve.

Eventually, Loomba said that a stool microbiome test could be expanded to uncover hepatocellular carcinoma. Its incidence, he noted, is increasing not only in the US, but around the world, and cirrhosis is the biggest risk factor for its development.

"So I think once we validate these data, these would have great implications and improving screening and surveillance or cirrhosis," Loomba said. "And then eventually, we might even develop signatures for hepatocellular carcinoma."