Bile acids originate in the liver, are stored in the gallbladder, and finally released into the intestines, where they are used to aid digestion after consuming a meal. Microbes in our gut metabolize bile acids produced by the liver, turning them into a wide range of different molecules called secondary bile acids, which tend to be easier for the body to absorb. Although many studies have shed light on the intricate and indispensable role that the gut microbiota plays in the physiological and pathological states of its hosts, much remains unexplored. With emerging omics technologies integrated into studies related to the gut microbiota, new insights have been generated that reveal critical associations between certain bile acids derived from microbial metabolism and human health. There is evidence that some of these compounds can also influence the appearance of intestinal cancers.
Lithocholic acid (LCA) and deoxycholic acid (DCA) derivatives act as important signaling molecules that regulate the differentiation of Th17 and Treg cells, which further modulate intestinal inflammation. Distinct derivatives of LCA and DCA including iso-, 3-oxo-LCA/DCA, allo-, 3-oxoallo-, and iso-alloLCA are produced by the cooperation of 5α/β-reductase and 3α/β-HSDH in human tissues. 3-OxoLCA binds directly to the T cell transcription factor RORγt and inhibits Th17 cell differentiation, while isoalloLCA enhances anti-inflammatory Treg cell differentiation through the production of mitochondrial reactive oxygen species (ROS) that increase the expression of FOXP3. This transcription factor in Treg cells is involved in maintaining the homeostasis of the intestinal immune system to maintain the intestinal barrier system.
Until now, the rich diversity and range of functions of secondary bile acids have been underestimated by scientists. Researchers at the University of California San Diego’s Skaggs School of Pharmacy and Pharmaceutical Sciences have discovered thousands of previously unknown bile acids used by our gut microbiome to communicate with the rest of the body. The findings, as described by study co-author and bile acid expert Lee Hagey, PhD, are similar to a molecular “Rosetta table,” providing previously unknown information about the biochemical language used by microbes to influence distant organ systems. In addition to aiding digestion, bile acids are also important signaling molecules that help regulate the immune system and perform important metabolic functions, such as controlling lipid and glucose metabolism from the intestine to the liver.
These molecules also help explain how microbes in the gut are able to influence distant organ systems. Because of their interaction with our microbiome, the influence of bile acids spreads far beyond the digestive system, and so might the diseases we treat with them: the list of bile acid-related diseases is long and there are several FDA approvals for these types of acids as treatments. Earlier this year, the team launched a new tool that can instantly match microbes to the metabolites they produce. The present study is the first of potentially many studies to use the tool for specific types of biomolecules. The researchers then hope to explore the specific functions of the newly discovered bile acids and use their approach on other types of biomolecules, such as lipids or other types of acids.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Scientific references
Mohanty I, Mannochio-Russo H et al. Cell 2024; in press.
Nat Rev Microbiol. 2023; 21(4):236.
Cai J et al. Cell Host Microbe 2022; 30(3): 289-300.