The xenobiotic sensing pregnane X receptor regulates tissue damage and inflammation triggered byC difficiletoxins

Abstract

Clostridioides difficile (formerly Clostridium difficile; C difficile), the leading cause of nosocomial antibiotic-associated colitis and diarrhea in the industrialized world, triggers colonic disease through the release two toxins, toxin A (TcdA) and toxin B (TcdB), glucosyltransferases that modulate monomeric G-protein function and alter cytoskeletal function. The initial degree of the host immune response to C difficile and its pathogenic toxins is a common indicator of disease severity and infection recurrence. Thus, targeting the intestinal inflammatory response during infection could significantly decrease disease morbidity and mortality. In the current study, we sought to interrogate the influence of the pregnane X receptor (PXR), a modulator of xenobiotic and detoxification responses, which can sense and respond to microbial metabolites and modulates inflammatory activity, during exposure to TcdA and TcdB. Following intrarectal exposure to TcdA/B, PXR-deficient mice (Nr1i2 −/− ) exhibited reduced survival, an effect that was associated with increased levels of innate immune cell influx. This exacerbated response was associated with a twofold increase in the expression of Tlr4. Furthermore, while broad-spectrum antibiotic treatment (to deplete the intestinal microbiota) did not alter the responses in Nr1i2 −/− mice, blocking TLR4 signaling significantly reduced TcdA/B-induced disease severity and immune responses in these mice. Lastly, to assess the therapeutic potential of targeting the PXR, we activated the PXR with pregnenolone 16α-carbonitrile (PCN) in wild-type mice, which greatly reduced the severity of TcdA/B-induced damage and intestinal inflammation. Taken together, these data suggest that the PXR plays a role in the host's response to TcdA/B and may provide a novel target to dampen the inflammatory tissue damage in C difficile infections. K E Y W O R D SClostridioides difficile, eosinophils, neutrophils, Nr1i2, pregnane X receptor, toxinThis is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Dietary Derived Propionate Regulates Pathogenic Fibroblast Function and Ameliorates Experimental Arthritis and Inflammatory Tissue Priming

“…Under germ-free conditions, reduced fibroblast migration and activation was observed. Additional evidence is now beginning to emerge that microbial metabolites are also directly sensed by fibroblasts and modulate inflammation and fibrosis in mice [ 37 ]. Direct effects of SCFAs on structural cells are mostly known from fibroblasts of the periodontal pocket that are in direct contact with the microbiota [ 38 , 39 ] and skin fibroblasts [ 40 ].…”

St. John’s Wort alleviates dextran sodium sulfate‐induced colitis through pregnane X receptor‐dependent NFκB antagonism

“…Since the mutual repression between PXR and NFκB signaling was demonstrated in 2006, 4 pharmacologically activating PXR to antagonize NFκB activity was suggested for treating various diseases, 48 particularly the IBD. 5,8,49 In contrast to the adverse effects of the clinical PXR activator RIF, the herbal PXR activator SJW as a readily available anti-depressant and an FDA-classified dietary supplement, has a long history of long-term use and is generally believed to be safe.…”

The Interface between Cell Signaling Pathways and Pregnane X Receptor

“…The interplay between PXR and NF-кB has been well described in the literature [74,91,98,[106][107][108][109][110][111][112][113]. The balance between these two proteins allows for negative crosstalk between drug metabolism and inflammation.…”