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Interactions among the Steroid and Xenobiotic Receptor (SXR/PXR), environmental toxicants and the gut microbiome and their effects on inflammation, oxidative stress, and cancer


The Steroid and Xenobiotic Receptor (SXR/PXR) is a nuclear receptor that regulates inducible xenobiotic metabolism. SXR is also implicated in other processes and perturbing its function can lead to adverse health consequences. The work described here investigates connections between SXR and adverse health consequences induced by the gut microbiome and xenobiotic chemicals.

The B-1a B cell lymphoma phenotype previously reported in SXRKO mice was lost following a change in the diet; it was not recovered after returning to the previous diet (Chapter 1), suggesting the microbiome may be involved. The studies in Chapter 2 characterized the results of a fecal microbiome transplant from a mouse with a phenotype resembling the B-1a B cell lymphoma into wild-type and SXRKO mice. This transplant did not lead to B-1a B cell lymphoma in SXRKO mice. However, gene expression analysis revealed that SXRKO mice resisted some changes in gene expression induced by the gut microbiome, likely attributable to elevated intestinal inflammation. Chapter 3 investigated differences between the microbiomes in current and archival samples with and without tumors and revealed Akkermansia sp. and Prevotella sp. as candidate microbes linked to lymphoma in SXRKO mice. Expansion of these microbes in the gut increased the number of B-1a B cells in the peritoneal cavity of SXRKO mice and revealed differences in microbiome-induced gene expression changes between wild-type and SXRKO mice. These studies established SXR as a potential bridge between the gut microbiome and adverse impacts on the host.

Chapter 4 explored the role of SXR during exposure to the environmental toxicant PCB-153, revealing that SXRKO mice developed hemolytic anemia, increased oxidative stress and accumulation of hydroxylated metabolites. Chapter 5 revealed that wild-type and SXRKO mice did not respond differently to oxidative stress or anemia induced by phenylhydrazine. These findings demonstrated that SXR is protective against xenobiotic-induced oxidative stress and the associated health consequences, due to its role in the metabolism and/or clearance of toxic metabolites.

The gut microbiome and oxidative stress both have large impacts on health. Taken together, these results demonstrate a protective role of SXR in these processes and the corresponding adverse health consequences.

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