A275 COMMENSAL BACTERIA IN THE SMALL INTESTINE INFLUENCE IMMUNE CELLS TO DICTATE HOST DRUG METABOLISM

The ability of the intestinal microbiota to influence drug responses has been recognized, however the mechanisms through which this occurs remain unexplored. Work in germ free mice has demonstrated that colonization with different microbiota influences the expression of cytochrome P450 (CYP) enzymes in the liver. Like the liver, the small intestine (SI) expresses CYP enzymes including CYP3A11 which can metabolize over 60% of commercially available drugs. The activity of CYP enzymes in the SI has been shown to influence circulating levels of orally administered drugs, but how the microbiota affects this process is unknown. To investigate if distinct microbiota differentially modulate host drug-metabolism in the SI to influence drug activity and efficacy. SFB-free (SFB-) mice were obtained from Jackson (Jax) and SFB+ mice were obtained from Taconic (Tac). Feces from SFB+ Tac mice were mixed in PBS and orally gavaged to mice. 14 days later sections of ileum were used for PCR array or digested in collagenase to isolate lamina propria cells for flow cytometry. A monoclonal antibody for Thy1.2 was used to deplete innate lymphoid cells (ILCs) in RAG1-/- mice (lacking T- and B-cells). CYP3A11 activity was determined through the colourmetric breakdown of the substrate 7-benzyloxyresorufin. PCR array analysis of ileal sections revealed CYP3A11 as one of the most downregulated genes in both SFB+ Tac mice and Jax mice colonized with a SFB+ microbiota when compared to SFB- Jax mice. Further analysis showed that colonization of Jax mice with a SFB+ microbiota induced IL-22 production by type 3 innate lymphoid cells (ILC3). Increase IL-22 production positively correlated with fecal levels of SFB and reduced ileal CYP3A11 expression. Colonization of IL-22 KO mice with a SFB+ microbiota had no effect on the ileal expression of CYP3A11. Furthermore, depletion of ILCs in RAG1-/- mice colonized with a SFB+ microbiota prevented a decrease in the expression of CYP3A11. In mouse SI enteroid cultures, recombinant IL-22 dose-dependently reduced the expression of CYP3A11, an effect that was blocked by the STAT3 inhibitor Stattic. IL-22 treatment also significantly decreased the ability of SI enteroids to metabolize CYP3A11 specific substrates. Our data suggest that colonization with a specific microbiota can influence the expression and activity of the drug metabolising enzyme CYP3A11. This occurs through the production of IL-22 by SI ILC3, which down regulated CYP3A11 in a STAT3-specific manor and altered the ability of the small intestine to metabolise CYP3A11 specific substrates. These findings provide an understanding of how the intestinal microbiota modulates host drug metabolism, and how the microbiota can be manipulated to render various drug therapies, such as those for IBD, more effective. CAG, CCC, CIHRAlberta Innovates

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