The microbes in our gut produce different bile acids to communicate with each other and regulate different processes in our body. But the number of these signaling molecules is much larger and the “language” of the microbes is much more complex than previously thought: As researchers have discovered, our intestinal inhabitants produce not just hundreds, but thousands of different bile acids. This discovery sheds new light on human metabolism and diseases that can be caused or treated by bile acids.
Bile acids are an essential part of our digestion. They are produced by the liver, stored in the gallbladder and from there released into the small intestine in order to better utilize nutrients such as vitamins and fatty acids. This process is supported by microorganisms living in the intestine, our intestinal flora, which convert the bile acids. This creates numerous new molecules called secondary bile acids, which are usually better absorbed by the intestines than the original molecules from the liver.
But the microbes do not convert the bile acids entirely selflessly: they also use the various molecules as an energy source and as signals to communicate with one another, as previous studies have shown. In a kind of side effect, the bacteria also influence various functions in our immune system, our metabolism and the interaction of various organs via these signal molecules. What has so far been a mystery is how this “language” of microbes works in detail and how far its influence on our health extends.
Data collection reveals diversity of bile acids
A team led by Ipsita Mohanty from the University of California in San Diego has now examined these secondary bile acids in more detail. To do this, they used a previously elaborately generated digital library that collects information about microorganisms and the molecules they produce. This included around 1.2 billion publicly available mass spectrometer measurement data from animal and human samples as well as reference samples. “So far, there has been no infrastructure for microbial metabolomics researchers to exchange data,” explains senior author Pieter Dorrestein from the University of California at San Diego. Using this library from the Collaborative Microbial Metabolite Center (CMMC), Mohanty's team developed an algorithm that can assign the microbes to the metabolites they produce. The researchers then use this filter tool to specifically examine the secondary bile acids of human intestinal microbes.
It turned out that the secondary bile acids are significantly more diverse and fulfill many more functions than previously assumed. “When I started working in the lab, there were about a few hundred known bile acids,” says Mohanty. “Now we have discovered thousands more and are increasingly realizing that these bile acids do much more than just support digestion.” The results provide previously unknown insights into the biochemical language that microbes use not only to enter the intestines, but also further affect distant organ systems. “Bile acids are an important part of the language of the gut microbiome, and the discovery of these many new types of molecules radically expands our vocabulary for understanding what our gut microbes do and how they do it,” says Dorrestein. This changes the overall understanding of human metabolism.
Bile acids as a trigger and remedy against diseases
The discovery also sheds new light on diseases that can be caused or treated by bile acids. “Due to their interaction with our microbiome, the influence of bile acids extends far beyond the digestive system. This also applies to the diseases we treat with it,” explains co-author Helena Mannochio-Russo, also from the University of California. “The list of diseases associated with bile acids is miles long and there are several FDA approvals for these types of acids as therapeutic agents.” These include gallstones and ALS. Many potential bile acid treatments are also currently being researched in clinical trials, for example for diabetes and hepatitis.
In follow-up studies, the team now wants to find out which functions the newly discovered bile acids can fulfill. They also want to use their database at the CMMC and its filter function to investigate the functions of other molecules produced by microbes, such as lipids or other acids. “We expect the CMMC to bring many more breakthroughs,” said Dorrestein.
Source: Ipsita Mohanty (University of California) et al., Cell Reports, doi: 10.1016/j.cell.2024.02.019