Nature | Vol 577 | 16 January 2020 | 415mice. As in minimal-diet mice, deficiency of VDR in mice worsened
the DSS-induced colitis phenotype (Extended Data Fig. 10a–c). The
protective role of VDR signalling was also consistently observed in
another mouse colitis model: naive CD4+ T cell adaptive transfer into
RAG1-deficient mice (Extended Data Fig. 10d–g). Importantly, severe
DSS-induced colitis developed in Vdr flox/floxFoxp3YFP-cre mice (Fig. 4e, f),
implying that the BA–VDR axis has an intrinsic role in Treg cell control
of colonic inflammation.
As important molecular mediators, intestinal BAs are critical in
maintaining a healthy colonic RORγ+ Treg cell pool through BARs. Gut
bacteria differ in the types and quantities of BA derivatives they can
generate. For instance, across different phyla, many gut bacterial spe-
cies harbour genes encoding BSH that are involved in the primary BA
deconjugation process. As their regulation and substrate specificity
may vary, both primary and secondary BA metabolic profiles of these
bacteria are likely to be affected^2 ,^15. In addition, the microbial diversity
of secondary BA metabolism adds another layer of complexity to BA
derivative production in individual species that may ultimately affect
their capacity for RORγ+ Treg cell induction.
In view of the complexity of BA derivatives, our study suggests
that dominant intestinal primary BA species—for example, cholic/
chenodeoxycholic/ursodeoxycholic acids—along with certain potent
secondary BA species—for example, lithocholic/3-oxo-lithocholic
acids—modulate RORγ+ Treg cells through the BAR VDR. Dysregulation
of intestinal BAs has been proposed as a mediator of the pathogenesis
of human inflammatory bowel diseases and colorectal cancers^1 ,^24. The
essential role of VDR in modulating peripheral RORγ+ Treg cells and
colitis susceptibility raises the interesting possibility that human VDR
genetic variants associated with inflammatory bowel diseases^25 might
affect disease susceptibility through improper control of the intes-
tinal Treg cell pool. Mechanistically, it is intriguing to speculate that
the nuclear receptor VDR—a colonic Treg cell-preferring transcription
factor^21 —may modulate colonic Treg cell homeostasis by coordinating
BA signals with transcription factor activity. An understanding of the
molecular mechanisms underlying the regulation of colonic Treg cells
by this biliary network between hosts and their associated microorgan-
isms will be valuable in improving therapy for human gastrointestinal
inflammatory disorders.
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acknowledgements, peer review information; details of author con-
tributions and competing interests; and statements of data and code
availability are available at https://doi.org/10.1038/s41586-019-1865-0.
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