Iron deficiency modulates metabolic landscape of Bacteroidetes promoting its resilience during inflammation

Abstract

Bacteria have to persist in low iron conditions in order to adapt to host's nutritional immunity. Since the knowledge of iron stimulon of Bacteroidetes is sparse, we examined oral (Porphyromonas gingivalis and Prevotella intermedia) and gut (Bacteroides thataiotaomicron) representatives for their ability to adapt to iron deplete and iron replete conditions. Our transcriptomics and comparative genomics analysis shows that many iron-regulated mechanisms are conserved within the phylum. Those include genes upregulated in low iron: fldA (flavodoxin), hmu (hemin uptake operon) and loci encoding ABC transporters. Downregulated were: frd (ferredoxin), rbr (rubrerythrin), sdh (succinate dehydrogenase/fumarate reductase), vor (oxoglutarate oxidoreductase/dehydrogenase), and pfor (pyruvate:ferredoxin/flavodoxin oxidoreductase). Some genus-specific mechanisms, such as the B. thetaiotaomicron's sus coding for carbohydrate metabolism and the xusABC coding for xenosiderophore utilization, were also identified. While all bacteria tested in our study had the nrfAH operon coding for nitrite reduction and were able to reduce nitrite levels present in culture media, the expression of the operon was iron dependent only in B. thetaiotaomicron. It is noteworthy that we identified a significant overlap between regulated genes found in our study and the B. thetaiotaomicron colitis study (Zhu et al; Cell Host Microbe 27: 376-388). Many of those commonly regulated genes were also iron regulated in the oral bacterial genera. Overall, this work points to iron being the master regulator enabling bacterial persistence in the host and paves the way for more generalized investigation of the molecular mechanisms of iron homeostasis in Bacteroidetes.