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Human gut bacteria produce ΤΗ17-modulating bile acid metabolites
Donggi Paik1, Lina Yao2, Yancong Zhang3,4
1Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
Nature
|March 17, 2022
Summary
Gut bacteria produce bile acids that inhibit T helper 17 (TH17) cell differentiation. Reduced levels of these immunomodulatory bile acids are linked to inflammatory bowel disease, suggesting a role in gut inflammation.
Area of Science:
- Microbiology
- Immunology
- Gastroenterology
Background:
- The gut microbiota plays a crucial role in maintaining immune homeostasis.
- Bacteria influence the development and function of host immune cells, notably T helper 17 (TH17) cells.
- Bile acid metabolites, such as 3-oxolithocholic acid (3-oxoLCA), are known to modulate TH17 cell differentiation.
Purpose of the Study:
- To identify specific gut bacteria responsible for producing 3-oxoLCA and related immunomodulatory bile acids.
- To investigate the mechanism by which these bile acids affect TH17 cell differentiation.
- To determine the association of these bile acids and their biosynthetic pathways with inflammatory bowel disease (IBD).
Main Methods:
- Utilized bacterial culturing and enzymatic assays to identify bacteria producing 3-oxoLCA and isolithocholic acid (isoLCA) from lithocholic acid.
- Assessed the impact of 3-oxoLCA and isoLCA on TH17 cell differentiation in vitro.
- Quantified bile acid and gene expression levels in patient samples from individuals with and without IBD.
Main Results:
- Identified specific human gut bacteria and their 3α-hydroxysteroid dehydrogenase enzymes capable of synthesizing 3-oxoLCA and isoLCA.
- Demonstrated that both 3-oxoLCA and isoLCA suppress TH17 cell differentiation by inhibiting the transcription factor RORγt.
- Found significantly reduced levels of 3-oxoLCA, isoLCA, and their biosynthetic genes in patients with IBD.
- Observed an inverse correlation between these bile acid levels and TH17-cell-associated gene expression in IBD patients.
Conclusions:
- Bacterially produced bile acids, including 3-oxoLCA and isoLCA, are potent inhibitors of TH17 cell function.
- The reduction of these immunomodulatory bile acids and their biosynthetic pathways in IBD suggests a protective role.
- These findings highlight a novel link between gut bacteria, bile acid metabolism, and the pathogenesis of inflammatory disorders like IBD.
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