How Good Gut Microbes Resist Inflammation
Gut commensal bacteria survive inflammation by making a simple switch to their protective coats, researchers show.
When harmful microbes like salmonella infect the gut, the innate immune system produces antimicrobial peptides to kill them. But these pathogenic microbes are often similar to the commensal microbes that live in the gut—it was not clear how commensal microbes could survive in the presence of these peptides.
T.W. Cullen et al. exposed 17 commensal species and 4 gut pathogens to various antimicrobial peptides. They report in the 9 January issue of Science that commensal species from all 3 major phyla that colonize the gut could survive greater concentrations of the antimicrobial peptides than the pathogens could.
To determine how the commensals were defending themselves, the authors randomly mutated the genes of 5 commensal Bacteroidetes at various loci and screened the bacteria for resistance to high levels of antimicrobial peptides. Although each bacterial species had multiple genes that aided in resisting antimicrobial peptides, only 1 resistance gene was shared across all 5 species.
The Scientist reported that the researchers named this gene lpxF because it closely resembled a phosphatase-encoding gene of the same name found in a few pathogens that are also resistant to antimicrobial peptides. The phosphatase LpxF removes a negatively charged phosphate from the lipopolysaccharide (LPS), a component of bacterial membranes. The shift in charge makes it more difficult for the positively charged antimicrobial peptides to bind to the bacterial membrane and disrupt it.
Cullen et al. introduced mutant strains of Bacteroides thetaiotaomicron that could not remove this single phosphate group from their LPS into germ-free mice, and found that these mutants were displaced when inflammation was induced by a pathogen (Citrobacter rodentium). Displacement occurred at the onset of inflammation and concurrent with increased antimicrobial peptide secretion.
However, the lpxF deletion mutant strain was able to persist in mice that had not been infected with a competing pathogen and in mice infected with a noninflammatory mutant strain of C rodentium. Furthermore the lpxF deletion mutant species was also lost from gnotobiotic mice upon induction of inflammation with dextran sulfate sodium.
Cullen et al. showed that commensal microbes from human fecal samples also survived exposure to antimicrobial peptides. However, some members of the Proteobacteria phylum, which includes many pathogens, did not.
The authors reported identifying LpxF orthologs in all sequenced human-associated Bacteroidetes. Furthermore, all characterized LPS structures in this phylum have an underphosphorylated lipid A structure, so it seems that human intestinal Bacteroidetes also use this mechanism to resist the inflammatory response.
According to The Scientist, Goodman was surprised to find a single enzyme that so thoroughly conferred bacterial resistance to antimicrobial peptides. “We had assumed that microbial host interaction was going to be so complicated that no single factor alone would do anything, and that’s not what we saw at all,” he said.
“Most folks didn’t anticipate that commensal microbes would be resistant to antimicrobial peptides,” Charles Bevins (University of California, Davis), who was not involved with the project, told The Scientist. Rather, scientists assumed that antimicrobial peptides only killed commensals in local regions of the gut, allowing their population to bounce back, or that commensals were far away from the antimicrobial peptide-releasing cells on the margins the gut, and were therefore not affected.
Further studies are necessary to determine other mechanisms by which a broad range of commensals, beyond Bacteroidetes, resist the inflammatory response. They authors wrote that even Bacteroidetes likely have many methods of fighting off host defenses.