Bacterial Enzyme's New Role in Gut Metabolism Uncovered

Penn State

UNIVERSITY PARK, Pa. — Bile acids long have been known to play a role in human metabolism. Synthesized from cholesterol in the liver, bile acids are involved in digestive processes, particularly in absorbing fat. They also are modified extensively by bacteria, which greatly expand the types of bile acids found in the host.

For most of a century, scientists believed that was the end of the bile-acid story. Recent technological advances, however, have led to a greater understanding of the origins of bile acids as well as their chemical relationships to the organisms in the gut microbiome and their host. Deploying some of these technologies, a team led by Penn State researchers has uncovered the mechanism by which bacteria generate a wide variety of new bile acid species, the functions of which are not yet clear.

The researchers, who published their results recently in Nature, identified a new role for an old bacterial enzyme, known as bile salt hydrolase, or BSH. The enzyme modifies human- and mouse-generated bile acids and changes their configurations by, for example, adding amino acids, leading to new molecules known as bacteria bile acid amidates, or BBAAs.

The team also showed, for the first time, that these BBAAs are made in humans at birth, coinciding with the establishment of the gut microbiome in newborns.

"The influence of bile acids on health and disease is well established," said corresponding author Andrew Patterson, professor of molecular toxicology and the John T. and Paige S. Smith Professor in Penn State's College of Agricultural Sciences. "But now we're finding that they can serve as signaling molecules between us and our microbial counterparts. It's like a communication network between us and microbes, with bile acids being the messenger."

Patterson, who also holds an appointment as professor of biochemistry and molecular biology in the Eberly College of Science, explained that the hundreds — and perhaps thousands — of new bile acid species created by BSH-producing bacteria may have far-reaching signaling properties.

"Researchers have reported finding bile acids in the brain, skin and other tissues," he said. "This suggests that they probably have a broader role beyond just helping us consume fat. Discovering what this role could be is a question we're still trying to answer, and that's what's really exciting about this research."

Although the researchers are unsure about the long-term implications of their study, they pointed out that BSH and bile acids have been linked with many health conditions, such as inflammatory bowel disease, some cancers and obesity. Understanding their role eventually could lead to therapies, they said.

"There are many diseases associated with abnormal lipid or bile acid metabolism — if you can't absorb fat properly, you're going to have problems," Patterson said. "Teasing out the functions of these new bile acid species opens a lot of new doors to explore."

To test their hypothesis that bile salt hydrolase is involved in the creation of bile acids, the researchers took a multipronged approach. In some experiments, they used an inhibitor to block the bacterial activity of BSH, and in others, they modified bacteria to remove the gene that encodes for BSH. In the absence of BSH, there was no production of BBAAs, the team found.

Working with the Children's Hospital of Philadelphia and the University of Pennsylvania, the researchers also tested stool samples of infants from birth to 12 months old. They found that a rise in bile acids, including BBAAs, coincided with the colonization of BSH-producing bacteria in the infants' guts. It is the first time scientists have connected BBAA production with BSH-expressing bacteria during human infant development, according to the researchers.

The results of this study reinforce, and are reinforced by, a parallel study that was conducted at Michigan State University and published in the same issue of Nature. Although the research teams did not work together directly — and approached the topic from different angles — they shared information and collaborated to publish their studies simultaneously, Patterson explained.

"Publishing these papers at the same time was a great example of land-grant collaboration," he said. "Having two independent labs come up with the same answer really bolsters the significance of the findings, which in some ways upend 100 years of thinking in the field."

Robert Quinn, whose lab published the MSU study, noted that his team showed that the BSH enzyme produced bile acids, while the Patterson lab did the reverse, identifying the enzyme and inhibiting it, which revealed that these molecules went away.

"It was perfectly complementary," said Quinn, assistant professor in MSU's Department of Biochemistry and Molecular Biology.

Bipin Rimal, co-first author of the Penn State paper, echoed the sentiment.

"These highly interdisciplinary collaborations at Penn State, Michigan State and places across the country helped transform a simple idea into something that reshapes our understanding of the role of BSH," said Rimal, who received his doctorate in 2023 while working in Patterson's lab.

Patterson credited talented graduate students, a diverse interdisciplinary team cooperating across campus and coast-to-coast, and the availability of technologies such as mass spectrometry and nuclear magnetic resonance platforms for making his lab's discoveries possible.

Penn State study co-first author Stephanie Collins, a doctoral alumna of the Patterson Lab, agreed. "Without the technological capabilities and having the right mix of people here at the right time, we could not have accomplished what we did," she said.

Also part of the research team from Penn State were Megan Granda, Fuhua Hao and John Vanden Heuvel, Department of Veterinary and Biomedical Sciences; Nushrat Hoque, Department of Chemistry; Imhoi Koo, Huck Institutes of the Life Sciences; Erin Reilly, Min Soo Kim, Jordan E. Bisanz and Emily Weinert, Department of Biochemistry and Molecular Biology; Devendra Paudel and Vishal Singh, Department of Nutritional Sciences; and Dhimant Desai and Shantu Amin, Department of Pharmacology.

Other researchers on the paper represented Children's Hospital of Philadelphia, East Carolina University, the University of Michigan, the University of California San Diego, the National Cancer Institute and the University of Pennsylvania.

The National Institutes of Health, the Rosalind E. Franklin Science Achievement Graduate Fellowship program in Penn State's Eberly College of Science, the Huck Institutes of the Life Sciences at Penn State, the American Beverage Foundation for a Healthy America, the Crohn's and Colitis Foundation, the American Heart Association postdoctoral fellowship program, the Pennsylvania Department of Health, the U.S. Department of Agriculture's National Institute of Food and Agriculture, and Penn State supported this work.

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