A new analysis published in PLOS One identified six liver genes that may help explain how substances produced by gut bacteria are connected to high-risk primary biliary cholangitis (PBC). High-risk PBC describes disease that is more likely to progress and lead to poorer outcomes.
Previous studies have linked changes in gut bacteria and the substances they produce to greater fibrosis severity in PBC and poorer response to treatment. These substances can reach the liver and affect inflammation and immune activity. The researchers therefore looked for liver genes that showed different activity in high-risk PBC and had previously been associated with these substances.
Of the six genes found, CCL2 ranked highest. It was much more active in liver tissue from people with high-risk PBC and had the greatest number of previously reported associations with substances produced by gut bacteria.
A reference atlas of human liver cells showed CCL2 expression mainly in immune-related cells, supporting a possible role in liver inflammation.
Read more about the relationship between gut bacteria and PBC
To identify these genes, researchers compared gene activity in liver samples from nine people with high-risk PBC and seven with low-risk PBC. They identified 163 genes that differed between the groups.
They then narrowed the list using two public databases: one containing previously reported relationships between genes and substances produced by gut bacteria, and another containing genes already linked to PBC. Six genes met all three criteria: CCL2, CDKN1A, BCL2, CD44, FOS and MAPK3.
Researchers also tested the six genes in an independent dataset containing blood samples from 90 people with PBC and 47 healthy controls. CD44, FOS and CDKN1A were significantly more active in people with PBC. In contrast to the liver analysis, however, CCL2 was not.
The findings suggest CCL2 could be more closely associated with the immune environment inside the liver than with changes detectable in the blood. As the researchers explained, blood-based analyses “may not capture local hepatic immune-inflammatory signals.”
The study did not directly measure gut bacteria-related substances in people with PBC. Therefore, the findings cannot prove that these substances caused the gene changes or high-risk disease. Larger studies using liver tissue, direct measurements and laboratory experiments are needed to confirm the findings.
Sign up here to get the latest news, perspectives, and information about PBC sent directly to your inbox. Registration is free and only takes a minute.
