NEWS | June 6, 2017

How gender, diet, microbiota and molecules contribute to metabolic disease and liver cancer

(SACRAMENTO, Calif.)

Researchers at UC Davis Health and other institutions have shown that gender differences in mice microbiota can modulate the risk of developing metabolic disease and liver cancer. In addition, the team found that a bile acid receptor protein, called FXR, has a profound impact on mouse microbiota and bile acid profiles and is differentially expressed based on gender. The study was published in the journal Scientific Reports.

Yvonne Wan's mouse study found gender differences in gut microbiota. Yvonne Wan's mouse study found gender differences in gut microbiota.

“Liver cancer is a male-predominant disease,” said Yu-Jui Yvonne Wan, vice chair for research in the Department of Pathology and Laboratory Medicine and senior author on the paper. “The gender difference is in part due to differences in gut microbiota. Men and women have different bacterial compositions, which plays a role in metabolism and disease development.”

The research team’s quest to understand liver disease revolved around steatosis, or fatty liver, which sometimes leads to cancer. Gut microbes play a significant role, as some strains convert primary bile acid into secondary, toxic bile acid. This relationship between microbiota and bile acid may modulate whether a person develops a fatty liver or a fatty liver that becomes cancerous.

In addition, the researchers wanted to understand the role FXR plays in metabolic disease. Previous studies have shown that patients suffering from cirrhosis or cancer have low levels of this protein.

To investigate these complex pathways, the lab fed high-fat, high-carbohydrate Western diets or healthier control diets to normal and FXR knockout mice. They found that both the Western diet and the loss of FXR generated compromised microbiota and bile acid profiles.

Male FXR knockouts feasting on a Western diet fared worst, exhibiting severe steatosis, high liver and blood lipids and insulin resistance. Females did substantially better.

“Gender differences in gut microbiota and bile acid profiles can explain the difference in steatosis development,” Wan said.

Gi tract illustration istockFXR-deficient mice had higher levels of potentially dangerous gut bacteria, such as Helicobacteraceae, Desulfovibrionaceae and Deferribacteraceae, as well as secondary bile acids. They also developed a form of steatosis that could lead to liver cancer. Helicobacteraceae levelsincreased by 40 percent in these mice. Through its ability to modulate microbiota and bile acid profiles, FXR may inadvertently act as a cancer suppressor.

“The key differences between simple steatosis and cancer-promoting steatosis are microbiota and bile acid,” Wan said.

These findings indicate that potential probiotic therapies should be customized to a patient’s gender. In addition, researchers can now explore biomarkers that clarify a patient’s risk of developing steatosis and liver cancer based upon their microbiota and bile acid profiles.

“We might be able to use bacteria to predict metabolic disease or cancer development,” said Wan. “We could probably use bile acid as well to accomplish the same thing.”

UC Davis researchers Lili Sheng and Prasant Jena were co-first authors, and David Mills helped lead the study. Other authors included: Hui-Xin Liu, Karen M. Kalanetra and Viswanathan V. Krishnan at UC Davis; Frank J. Gonzalez at the National Cancer Institute and Samuel W. French at UCLA.

This research, “Gender Differences in Bile Acids and Microbiota in Relationship with Gender Dissimilarity in Steatosis Induced by Diet and FXR Inactivation,” was funded by a grant from the National Institutes of Health (U01CA179582).