Microbiome plays key role in serious liver disease

New clues to non-alcoholic fatty liver disease (NAFLD), which affects nearly all obese adults and a rising percentage of obese children, have been reported in a paper published earlier this month in the journal Gut.

The incidence of NAFLD, found in 90 percent of obese adults and rarely found in individuals who are not obese, is rapidly rising, as is the incidence among children. The annual cost of the disease is estimated at $103 billion.

“Because NAFLD patients often progress to liver inflammation, fibrosis, cirrhosis and eventually liver transplantation, it is imperative that new treatment modes be explored and developed,” says Susan Baker, senior author and professor and co-chief of the Division of Gastroenterology in the Department of Pediatrics, Jacobs School of Medicine and Biomedical Sciences. She sees patients at UBMD Pediatrics.

Baker says the rising incidence of the disease, especially among children, is worrisome. “NAFLD often goes unrecognized in children because pediatricians do not routinely assess liver function,” she explains.

In 2006, she adds, when the prevalence of obesity among children was less than it is currently, the prevalence of fatty liver was 9.6 percent in children aged 2 to 19 years in California. Since the prevalence is likely similar for the entire U.S., approximately 6.5 million children and adolescents have fatty liver disease, and thus are at risk for the disease’s most serious consequences.

Baker and her UB colleagues are studying NAFLD in children as participants in the National Institutes of Health Nonalcoholic Steatohepatitis Clinical Research Network.

The current work draws on Baker’s pioneering 2013 research that revealed that NAFLD patients have altered gut microbiomes characterized by increased abundance of alcohol-producing bacteria within the gut — a somewhat ironic finding given that the condition is called “non-alcoholic” fatty liver disease. That paper was the most highly cited original research article submitted by a UB researcher within the past five years, according to Web of Science.

“The new research reveals that the gut microbiome may affect the physiology and pathology of NAFLD patients in many other ways, too,” Baker notes.

According to the new research, the microbiome in NAFLD modifies bile acids, which help digest and absorb fats, and also help regulate fat and sugar metabolism. In addition to elevating levels of primary and secondary bile acids, the researchers found NAFLD also impairs bile acid-mediated signaling in the liver.

The UB researchers studied 16 NAFLD patients and 11 healthy controls, as well as laboratory animals on high-fat diets designed to result in a condition mimicking NAFLD, and a group of controls. Total serum bile levels were elevated for the NAFLD individuals, with levels approximately three times as high as the healthy controls; they also had a higher percentage of secondary bile acids.

“These results suggest that components in the bile acid signaling pathway, including bile acid metabolizing bacteria in the gut, are new targets for the treatment of NAFLD,” says Lixin Zhu, co-author and assistant professor in the Department of Pediatrics.

The UB researchers are beginning to explore possible interventions. “We are looking into finding out which bacterial species in the gut are missing in patients who are obese and have NAFLD,” Zhu says.

“Our novel idea is that probiotics should be personalized, based on the microbial composition of each individual,” he continues. “For NAFLD patients, the most effective probiotic species should be those that will help to reconstitute a healthy microbiota, leading to more balanced bile acid signaling.”

The research was funded by an award from UB’s Genome, Environment and Microbiome (GEM) Community of Excellence and by the Peter and Tommy Fund, a Buffalo-based charitable organization.

In addition to Baker and Zhu, other co-authors on the paper are Na Jiao and Ruixin Zhu of Tongji University, Shanghai; Adrian Chapa-Rodriguez, Wensheng Liu, Colleen Nugent and Robert D. Baker, professor and co-chief of the Digestive Diseases and Nutrition Center in the UB Department of Pediatrics and a physician with UBMD Pediatrics; Maria Tsompana and Michael J. Buck of the Department of Biochemistry and UB’s New York State Center of Excellence in Bioinformatics and Life Sciences; Lucy Mastreandrea, associate professor and associate chief of the Division of Endocrinology/Diabetes in the Department of Pediatrics, Digestive Diseases and Nutrition Center; and Robert J. Genco, SUNY Distinguished Professor of Oral Biology in the School of Dental Medicine and director of the UB Microbiome Center.