UCSF

Dyes are a ubiquitous part of the human diet and also added to pills as excipients. While traditionally considered inert, emerging literature suggests that these compounds can have far-reaching impacts on host health and disease. Moreover, many dyes contain azo-bonds (R-N=N-R’), which are subject to gut bacterial metabolism. However, the mechanisms through which gut bacteria impact azo dyes, their sensitivity to environmental factors, and their downstream consequences for host health and disease remain poorly understood. In this thesis, I demonstrate that azo dyes inhibit drug absorption by blocking intestinal OATP2B1 uptake transporters; gut bacterial metabolism of these azo dyes rescues this effect. Using the model gut bacterium Escherichia coli, discovered that the canonical azoreductase gene is unnecessary for azoreduction due to an alternative pathway in which hydrogen sulfide produced from L-Cysteine depletes these dyes. Further, I dissect the signaling pathways that control this process, revealing that oxygen sensing via the fumarate nitrate reductase regulator (fnr) alters L-Cysteine import via the small regulatory RNA, fnrS. Consistent with these findings, the gut microbiota impacts hydrogen sulfide levels and the pharmacokinetics of the azo bonded anti-inflammatory drug sulfasalazine. Taken together, these results demonstrate the critical role of diet and environmental factors like oxygen in shaping the metabolic activity of human gut bacteria and add to the growing literature demonstrating that the gut microbiome controls both drug metabolism and absorption. Our results provide a strong foundation to dissect how the microbiome impacts azo dyes and other compounds in the context of the complex microbial, host, and dietary pressures found in the gastrointestinal tract.