Finding Potential Interventions for Common, Serious Liver Disease

“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,” explains Baker, professor and co-chief of the Division of Gastroenterology in the Department of Pediatrics.

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

Baker said 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,” says Baker, who sees patients at UBMD Pediatrics.

In 2006, she added, when the prevalence of obesity among children was less than it is currently, the prevalence of fatty liver was 9.6 percent in children ages 2 to 19 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 are at risk for the disease’s most serious consequences.

Baker’s current work draws on her pioneering 2013 research that revealed that NAFLD patients have altered gut microbiomes characterized by increased abundance of alcohol-producing bacteria within the gut  — a seemingly paradoxical finding given that the condition is called “non-alcoholic” fatty liver disease. That paper, published in Hepatology, 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 explains.

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. The investigators observed elevated levels of primary and secondary bile acids in NAFLD, which is likely the cause of impaired bile acid-mediated signaling in the liver.

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

The 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.

Total serum bile levels were elevated for the individuals with NAFLD, 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 co-author Lixin Zhu, PhD, assistant professor of pediatrics.

The 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,” says Zhu.

“Our novel idea is that probiotics should be personalized, based on the microbial composition of each individual,” he adds.

“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.”

“Suppressed Hepatic Bile Acid Signaling Despite Elevated Production of Primary and Secondary Bile Acids in NAFLD” was published in the journal Gut in August. 

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

In addition to Baker and Zhu, co-authors from the Department of Pediatrics are:

• Robert D. Baker, MD, PhD, professor and co-chief of the Division of Gastroenterology
• Wensheng Liu, PhD, research assistant professor
• Lucy D. Mastrandrea, MD, PhD, associate professor of pediatrics and associate chief of the Division of Endocrinology and Diabetes
• Colleen A. Nugent, MD, clinical assistant professor

Michael Buck, PhD, associate professor of biochemistry, and Robert J. Genco, DDS, PhD, SUNY Distinguished Professor in the School of Dental Medicine and director of the UB Microbiome Center are also co-authors.

Other co-authors include:

• Adrian Chapa-Rodriguez, MD, a former trainee in UB’s gastroenterology, hepatology and nutrition fellowship
• Na Jiao, PhD, and Ruixin Zhu, PhD, of Tongji University in Shanghai
• Maria Tsompana, PhD