Channeling macrophage polarization by rocaglates increases macrophage resistance to Mycobacterium tuberculosis

Macrophages contribute to host immunity and tissue homeostasis via alternative activation programs. M1-like macrophages control intracellular bacterial pathogens and tumor progression. In contrast, M2-like macrophages shape reparative microenvironments that can be conducive for pathogen survival or tumor growth. An imbalance of these macrophages phenotypes may perpetuate sites of chronic unresolved inflammation, such as infectious granulomas and solid tumors. We have found that plant-derived and synthetic rocaglates sensitize macrophages to low concentrations of the M1-inducing cytokine IFN-gamma and inhibit their responsiveness to IL-4, a prototypical activator of the M2-like phenotype. Treatment of primary macrophages with rocaglates enhanced phagosome-lysosome fusion and control of intracellular mycobacteria. Thus, rocaglates represent a novel class of immunomodulators that can direct macrophage polarization toward the M1-like phenotype in complex microenvironments associated with hypofunction of type 1 and/or hyperactivation of type 2 immunity, e.g., chronic bacterial infections, allergies, and, possibly, certain tumors.R35 GM118173 - NIGMS NIH HHS; R01 HL126066 - NHLBI NIH HHS; R01 GM120272 - NIGMS NIH HHS; R01 CA218500 - NCI NIH HHS; R01 HL133190 - NHLBI NIH HHS; R33 AI105944 - NIAID NIH HHSPublished versio

Genetic basis for the cooperative bioactivation of plant lignans by Eggerthella lenta and other human gut bacteria.

Plant-derived lignans, consumed daily by most individuals, are thought to protect against cancer and other diseases1; however, their bioactivity requires gut bacterial conversion to enterolignans2. Here, we dissect a four-species bacterial consortium sufficient for all five reactions in this pathway. A single enzyme (benzyl ether reductase, encoded by the gene ber) was sufficient for the first two biotransformations, variable between strains of Eggerthella lenta, critical for enterolignan production in gnotobiotic mice and unique to Coriobacteriia. Transcriptional profiling (RNA sequencing) independently identified ber and genomic loci upregulated by each of the remaining substrates. Despite their low abundance in gut microbiomes and restricted phylogenetic range, all of the identified genes were detectable in the distal gut microbiomes of most individuals living in northern California. Together, these results emphasize the importance of considering strain-level variations and bacterial co-occurrence to gain a mechanistic understanding of the bioactivation of plant secondary metabolites by the human gut microbiome

Dietary- and host-derived metabolites are used by diverse gut bacteria for anaerobic respiration

Respiratory reductases enable microorganisms to use molecules present in anaerobic ecosystems as energy-generating respiratory electron acceptors. Here we identify three taxonomically distinct families of human gut bacteria (Burkholderiaceae, Eggerthellaceae and Erysipelotrichaceae) that encode large arsenals of tens to hundreds of respiratory-like reductases per genome. Screening species from each family (Sutterella wadsworthensis, Eggerthella lenta and Holdemania filiformis), we discover 22 metabolites used as respiratory electron acceptors in a species-specific manner. Identified reactions transform multiple classes of dietary- and host-derived metabolites, including bioactive molecules resveratrol and itaconate. Products of identified respiratory metabolisms highlight poorly characterized compounds, such as the itaconate-derived 2-methylsuccinate. Reductase substrate profiling defines enzyme–substrate pairs and reveals a complex picture of reductase evolution, providing evidence that reductases with specificities for related cinnamate substrates independently emerged at least four times. These studies thus establish an exceptionally versatile form of anaerobic respiration that directly links microbial energy metabolism to the gut metabolome