Abstract
Paraoxonases (PON) are a family of proteins (PON1, 2 and 3) with multiple enzymatic activities. PON1 interferes with homoserine lactone-mediated quorum sensing in bacteria and with reactive oxygen species (ROS) in humans and mice. PON1 gene mutations have been linked to multiple traits, including aging, and diseases of the cardiovascular, nervous and gastrointestinal system. The overlapping enzymatic activities in the PON family members and high linkage disequilibrium rates within their polymorphisms confound animal and human studies of PON1 function. In contrast, arthropods such as Drosophila melanogaster have no PON homologs, resulting in an ideal model to study interactions between PON genotype and host phenotypes. We hypothesized that expression of PON1 in D. melanogaster would alter ROS. We found that PON1 alters expression of multiple oxidative stress genes and decreases superoxide anion levels in normal and germ-free D. melanogaster. We also found differences in the composition of the gut microbiota, with a remarkable increase in levels of Lactobacillus plantarum and associated changes in expression of antimicrobial and cuticle-related genes. PON1 expression directly decreased superoxide anion levels and altered bacterial colonization of the gut and its gene expression profile, highlighting the complex nature of the interaction between host genotype and gut microbiota. We speculate that the interaction between some genotypes and human diseases may be mediated by the presence of certain gut bacteria that can induce specific immune responses in the gut and other host tissues.
Highlights
The human paraoxonases (PON1, PON2 and PON3) are proteins with promiscuous enzymatic activities and with distinct tissue expression profiles [1,2,3,4,5,6]
As an initial screen to determine whether PON1 decreases oxidative stress in D. melanogaster, we analyzed data from gene expression microarrays of +/Tub and PON1/Tub flies (Gene Expression Omnibus accession #GSE29534 in http:// www.ncbi.nlm.nih.gov/geo/) (Figure S1)
These data suggest that PON1 alters oxidative stress in D. melanogaster
Summary
The human paraoxonases (PON1, PON2 and PON3) are proteins with promiscuous enzymatic activities and with distinct tissue expression profiles [1,2,3,4,5,6] Members of this gene family exhibit phosphotriesterase, esterase and lactonase activity to varying degrees [1,7,8,9]; of these, PON1 has been the most extensively studied. PON1 can hydrolyze acyl-homoserine lactones used by quorum-sensing bacteria to regulate multiple virulence factors during colonization of new environments [19,20,21,22] This could at least indirectly explain the association of mutations in PON1 with Crohn’s disease and ulcerative colitis, or perhaps other phenotypes associated with the gut microbiota such as obesity and cardiovascular disease [23,24,25,26,27,28,29]
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