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Exploring bile acids produced by gut microbes

A scanning electron micrograph of bacteria cultured from a sample of human faeces. Microbially-conjugated bile acids (MCBAs) have been detected in faecal samples from infants.© STEVE GSCHMEISSNER/SCIENCE PHOTO LIBRARY/Science Photo Library/Getty

How did you discover MCBAs?

Bile acids were first described chemically in 1849, and Heinrich Wieland was awarded a Nobel Prize in 1927 for comprehensively describing their chemistry. This description included the final step of their synthesis — the conjugation of the amino acids taurine or glycine by our liver. Almost a century later, our discovery has revealed that the amino-acid conjugation of bile acids is a much more complex process than previously thought, and that much of it is done by our microbiome. We identified these molecules while studying the global effects of the microbiome on the biochemistry of an entire animal. We did this by comparing the metabolites in germ-free and normal mice using advanced metabolomics technologies developed in the Dorrestein lab. We dissected 29 different organs from germ-free and normal mice and compared the two groups, seeking to identify molecules unique to the microbiome. After a year of searching this massive dataset, we identified three unknown bile acids unique to the mice with a microbiome. Analysis of mass-spectrometry data elegantly revealed that these molecules had unique amino acids conjugated to the bile acid core. We quickly realized that, unlike most conjugated bile acids, these MCBAs originated from gut microbes rather than the liver.

What will your project explore?

Biology doesn’t just happen; there is likely some selective pressure on the gut microbiome for the ability to make these molecules, but the question is why? In this next project, we hope to determine how MCBAs are made and how they affect the human gut. The project has three dimensions. Firstly, we know that the gut bacterium Enterocloster bolteae can conjugate multiple bile acids, so we will mine its genome to find the enzyme responsible. Secondly, we want to find out why MCBAs are prevalent in stools from humans and other mammals, particularly early in life, and to examine the role they may play in health. We have detected MCBAs via metabolomic analysis of 1,400 faecal samples collected from developing infants by our collaborator Julie Lumeng at the University of Michigan. We hope to link their presence in faeces with developmental and health outcomes of this infant population. This work will be led by my graduate student, Douglas Guzior. Finally, we plan to use a new knockout mouse model we have established here at Michigan State University to further explore the effects of MCBAs on the developing mouse gut.

What is special about this knockout mouse model?

The previously mentioned taurine- and glycine-conjugated bile acids are made by a liver enzyme called bile acid–coenzyme A:amino acid N-acyltransferase (BAAT). Our guts and those of mice are full of taurine- or glycine-conjugated bile acids made by BAAT — this confounds our study of the microbial ones, which are around 10 to 50 times less abundant. We have, therefore, developed a BAAT knockout mouse in our lab that lacks these taurine- and glycine-conjugated bile acids. By introducing MCBAs to the guts of these BAAT knockout mice, we will be able to study their biology more independently. Clearing out the highly abundant, liver-conjugated bile acids will allow us to study aspects of gastrointestinal health and disease that may be unique to MCBAs. This BAAT knockout model will have several applications beyond this project. For example, because the pathogens of many gut infections, including cholera and Clostridioides difficile, germinate only in the presence of particular conjugated bile acids, this mouse could be a useful model to study these diseases.

Are MCBAs a positive or negative influence on the gut?

They may be both, and it may depend on the amino acid. A diverse complement of amino acids are conjugated to bile acids by bacteria, and the resulting MCBAs have very different chemical properties. For example, we have evidence that if bacteria use a large hydrophobic amino acid like phenylalanine, the molecule becomes a potent antimicrobial. That antimicrobial activity will be lost if the bacteria conjugate with, say, serine, which is a smaller, hydrophilic amino acid. We know that MCBAs are abundant in Crohn’s disease patients, but we don’t yet know if that is a cause or consequence. They are also more abundant in mice fed a high-fat diet, but again we don’t know why. MCBAs may be good for us or they may be bad; the chemistry of the conjugation could matter a lot.

Doug Guzior, a PhD candidate researcher in Robert Quinn’s lab investigating microbially-conjugated bile acids and their effect on gut health.© Robert Quinn

How might MCBAs be useful?

We think they, or the bacteria that make them, may make good drug candidates — the ‘bugs as drugs’ idea. You could engineer bacterial activity to produce a particular MCBA with useful properties. For example, we know that certain bile acids are bad for us and it would be advantageous to excrete them in our stool. We have evidence that MCBAs are readily excreted in faeces, so if we could engineer a bacterium to conjugate harmful bile acids and facilitate their excretion, it could serve as a treatment for many diseases.

What are your plans for future research?

In the short term, we hope to improve our understanding of bile-acid signalling and metabolism and show how MCBAs interact with and affect the host. The broader, long-term goal is to use this knowledge to develop new probiotics. If we can use the bacteria that make MCBAs to generate molecules with specific beneficial properties, these could provide novel treatment options.

On a final note, I never envisioned I would study the gut microbiome! I had been mostly working on lung diseases until this point. As a message to other young scientists: if you discover something unique in your research, pursue it, even if it seems to be outside your field — these are by far the most exciting moments in science.

A new window into the microbiome: Robert Quinn’s lab at Michigan State University is exploring bile acids that are conjugated by gut microbes and how they influence health.© Robert Quinn

Biography

© Robert Quinn

Robert Quinn’s career has spanned several microbiome fields, from fish and corals to lungs and guts. He received his undergraduate degree in microbiology from the University of Guelph in Ontario, Canada, and his PhD from the University of Louisiana at Lafayette, where he studied bacterial shell disease of the American lobster. Quinn was then inspired to focus more on human microbiomes and began a postdoc with Forest Rohwer at San Diego State University with a fellowship from a non-profit cystic fibrosis institute. His postdoctoral research focused on lung disease in cystic fibrosis, but working in the microbiome research hub of San Diego enabled him to expand his knowledge into other systems. He transitioned to the University of California San Diego under the mentorship of Pieter Dorrestein to learn advanced metabolomics methods. In his current faculty position at Michigan State University, Quinn and his team use microbial ecology theory and metabolomics to understand the dynamics of microbiomes in the cystic fibrosis lung, human gut and coral reefs.

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