Summary: Two Harvard studies in mice reveal how bile acids influence immune balance and intestinal inflammation.
Source: Harvard
Do bile acids—the fat-emulsifying fluids produced by the liver and stored in the gallbladder—also shape immunity and inflammation?
Evidence from two independent studies by Harvard Medical School teams, both published in Nature, points to a clear yes. The studies show that bile acids, after being transformed by gut microbes, act as signaling molecules that directly affect T cell differentiation and activity. These effects alter the balance between proinflammatory and anti-inflammatory responses in the intestine and may help explain mechanisms that underlie inflammatory bowel disease (IBD) and related autoimmune conditions.
The first study, led by immunologist Jun Huh and published Nov. 27, demonstrates that gut bacteria convert primary bile acids into distinct metabolites that interact with adaptive immune cells. Once bile acids complete their digestive role, microbes in the intestine chemically modify them into immune-active derivatives. Those derivatives influence two important classes of T cells: regulatory T cells (Tregs), which limit inflammation, and Th17 effector cells, which can promote inflammation to fight infection but may cause tissue damage when uncontrolled.
Normally, Th17 and Treg cells are balanced to protect the host from pathogens while avoiding excessive inflammation. Huh’s team screened a library of bile acid metabolites using naïve mouse T cells and found two derivatives of lithocholic acid with opposing effects: one metabolite encouraged Treg differentiation, while another inhibited Th17 development. When given to mice, each metabolite produced the expected shift in Th17 and Treg frequencies in the intestinal lamina propria. Importantly, both metabolites were also detected in human stool samples—including samples from people with IBD—suggesting that the same mechanisms likely operate in humans.
Huh summarized the findings as identifying “an important regulatory mechanism in gut immunity,” where intestinal microbes modify bile acids and thereby generate molecules that regulate inflammation. If validated in further studies, these bile-acid–derived pathways could become targets for small-molecule therapies aimed at restoring immune balance in gut autoimmune diseases.
The second study, led by Dennis Kasper and published Dec. 25, focused on a specialized subset of colonic regulatory T cells (colon Tregs) that arise in response to signals from the gut microbiome rather than originating in the thymus. Low levels of these colonic RORγ+ FOXP3+ Tregs are associated with higher risk of inflammatory disorders such as IBD and Crohn’s disease.
Kasper’s team showed that both diet and microbial bile-acid metabolism shape the pool of colonic Tregs in mice. By genetically disabling bile-acid–converting pathways in specific gut bacteria and colonizing germ-free mice with these modified or unmodified microbes, the researchers demonstrated that the presence of bile-acid–transforming bacteria is necessary to maintain normal Treg levels. Animals colonized with microbes lacking bile acid–converting genes had significantly fewer colonic Tregs.
Dietary intake also mattered. Mice with normal microbiota that were fed a nutrient-poor diet showed reduced bile acid levels and fewer colonic Tregs compared with mice on nutrient-rich diets. Germ-free mice remained low in Treg counts regardless of diet, indicating that both dietary stimulation of bile acid production and microbial conversion are required to generate the immune-regulatory metabolites.
To test causality, the researchers supplemented drinking water of animals on minimal diets with specific bile acid molecules. Within weeks, these animals showed an increase in colonic Tregs. In a colitis model induced by a pro-inflammatory agent, only mice on a minimal diet without bile-acid supplementation developed significant colitis; mice receiving either a nutrient-rich diet or bile-acid–supplemented water were protected. These results support a three-way interaction in which diet, gut microbes, and bile acids collectively regulate Treg homeostasis and influence colitis risk.
Overall, the two studies describe complementary mechanisms: specific microbial conversions of bile acids generate metabolites that (1) directly inhibit Th17 differentiation by targeting the RORγt transcription factor, and (2) promote Treg differentiation through mitochondrial signaling and FOXP3 induction. Together, these pathways demonstrate how the gut microbiome and host diet influence adaptive immunity via the bile-acid metabolome.
These findings have practical implications for therapies that aim to rebalance intestinal immunity. Approaches could include designing small molecules that mimic beneficial bile acid metabolites, restoring or engineering microbial species that produce those metabolites, or dietary strategies that favor generation of immune-regulatory bile acids. While the current work was performed in mice, the detection of similar metabolites in human stool supports further translational research toward treating IBD and related inflammatory disorders.
Source:
Harvard
Media Contacts:
EKATERINA PESHEVA – Harvard
Image Source:
The image is adapted from the Harvard news release.
Original research (closed access):
“Bile acid metabolites control TH17 and Treg cell differentiation”. Hang, S., Paik, D., Yao, L. et al. Nature. DOI: 10.1038/s41586-019-1785-z.
“Microbial bile acid metabolites modulate gut RORγ+ regulatory T cell homeostasis”. Song, X., Sun, X., Oh, S.F. et al. Nature. DOI: 10.1038/s41586-019-1865-0.
Abstract summaries
Bile acid metabolites control TH17 and Treg cell differentiation
A targeted screen identified two lithocholic acid derivatives, 3-oxoLCA and isoalloLCA, that differentially regulate T cell fate in mice. 3-oxoLCA inhibits TH17 differentiation by binding the transcription factor RORγt, while isoalloLCA promotes Treg differentiation through mitochondrial reactive oxygen species and increased FOXP3 expression. These metabolites alter the TH17/Treg balance in the intestinal lamina propria when administered in vivo, offering a mechanism by which bile acid metabolites shape adaptive immune responses.
Microbial bile acid metabolites modulate gut RORγ+ regulatory T cell homeostasis
Diet and microbiome-driven modifications of the bile acid pool regulate a population of colonic FOXP3+ RORγ+ Tregs. Genetic disruption of bile-acid metabolic pathways in gut symbionts reduces this Treg population, while restoration of bile acids increases RORγ+ Tregs and reduces susceptibility to inflammatory colitis via bile-acid receptors. These results highlight a host–microbe biliary network that controls immunological homeostasis through metabolite-mediated signaling.