Breathless in the Gut: Implications of Luminal O 2 for Microbial Pathogenicity
2016; Cell Press; Volume: 19; Issue: 4 Linguagem: Inglês
10.1016/j.chom.2016.03.014
ISSN1934-6069
Autores Tópico(s)Indoor Air Quality and Microbial Exposure
ResumoSalmonella employs a variety of strategies to survive and colonize the colon. In this issue of Cell Host & Microbe, Rivera-Chávez et al., 2016Rivera-Chávez F. Zhang L.F. Faber F. Lopez C.A. Byndloss M.X. Olsan E.E. Xu G. Velazquez E.M. Lebrilla C.B. Winter S.E. et al.Cell Host Microbe. 2016; 19 (this issue): 443-454Abstract Full Text Full Text PDF PubMed Scopus (441) Google Scholar identify a new mechanism whereby antibiotic-mediated depletion of anaerobes (e.g., Clostridia) and associated decreases in butyrate result in increased tissue oxygen and increased aerobic expansion of Salmonella. Salmonella employs a variety of strategies to survive and colonize the colon. In this issue of Cell Host & Microbe, Rivera-Chávez et al., 2016Rivera-Chávez F. Zhang L.F. Faber F. Lopez C.A. Byndloss M.X. Olsan E.E. Xu G. Velazquez E.M. Lebrilla C.B. Winter S.E. et al.Cell Host Microbe. 2016; 19 (this issue): 443-454Abstract Full Text Full Text PDF PubMed Scopus (441) Google Scholar identify a new mechanism whereby antibiotic-mediated depletion of anaerobes (e.g., Clostridia) and associated decreases in butyrate result in increased tissue oxygen and increased aerobic expansion of Salmonella. The healthy mammalian gastrointestinal tract harbors trillions of bacteria. A finely tuned mutualism exists within the intestinal mucosa, where microbes that are essential for host health can also contribute to the development and maintenance of multiple mucosal diseases (Lozupone et al., 2012Lozupone C.A. Stombaugh J.I. Gordon J.I. Jansson J.K. Knight R. Nature. 2012; 489: 220-230Crossref PubMed Scopus (3072) Google Scholar). Nutrient provision by microbes is one benefit enjoyed by the host. Microbial metabolism in the gut liberates energy in the form of short-chain fatty acids (SCFAs) such as butyrate, which is the primary energy source for colonic epithelial cells. The low-O2 conditions that enable SCFA production also establish a unique niche for the adjacent colonic epithelium. A steep O2 gradient exists between the lamina propria and the gut lumen (Albenberg et al., 2014Albenberg L. Esipova T.V. Judge C.P. Bittinger K. Chen J. Laughlin A. Grunberg S. Baldassano R.N. Lewis J.D. Li H. et al.Gastroenterology. 2014; 147: 1055-1063.e8Abstract Full Text Full Text PDF PubMed Scopus (496) Google Scholar, Kelly et al., 2015Kelly C.J. Zheng L. Campbell E.L. Saeedi B. Scholz C.C. Bayless A.J. Wilson K.E. Glover L.E. Kominsky D.J. Magnuson A. et al.Cell Host Microbe. 2015; 17: 662-671Abstract Full Text Full Text PDF PubMed Scopus (829) Google Scholar), which is dominated by anaerobic organisms. Situated at this interface, the colonic epithelium functions at a partial pressure of oxygen (pO2) well below that of other tissues. Recent studies have demonstrated that active inflammation results in a further decrease in tissue pO2, to localized levels that approach anoxia (Campbell et al., 2014Campbell E.L. Bruyninckx W.J. Kelly C.J. Glover L.E. McNamee E.N. Bowers B.E. Bayless A.J. Scully M. Saeedi B.J. Golden-Mason L. et al.Immunity. 2014; 40: 66-77Abstract Full Text Full Text PDF PubMed Scopus (308) Google Scholar). Such decreases in local O2 during inflammation are driven largely by the activation of enzymes that generate reactive oxygen species (ROS), such as leukocyte NADPH oxidase (Campbell et al., 2014Campbell E.L. Bruyninckx W.J. Kelly C.J. Glover L.E. McNamee E.N. Bowers B.E. Bayless A.J. Scully M. Saeedi B.J. Golden-Mason L. et al.Immunity. 2014; 40: 66-77Abstract Full Text Full Text PDF PubMed Scopus (308) Google Scholar). In addition to ROS, other byproducts of inflammation (e.g., reactive nitrogen species) can be used as respiratory electron acceptors by some pathogens under anaerobic conditions (Lopez et al., 2015Lopez C.A. Rivera-Chávez F. Byndloss M.X. Bäumler A.J. Infect. Immun. 2015; 83: 3470-3478Crossref PubMed Scopus (78) Google Scholar). From this perspective, surprisingly little is known about the influence of the tissue microenvironment on the expansion or retraction of specific microflora under inflammatory conditions. A study by Rivera-Chavez et al. in this issue of Cell Host & Microbe (Rivera-Chávez et al., 2016Rivera-Chávez F. Zhang L.F. Faber F. Lopez C.A. Byndloss M.X. Olsan E.E. Xu G. Velazquez E.M. Lebrilla C.B. Winter S.E. et al.Cell Host Microbe. 2016; 19 (this issue): 443-454Abstract Full Text Full Text PDF PubMed Scopus (441) Google Scholar) addresses this question head on. They proposed that aerobic respiration enzymes encoded within the bacterial genome might prove beneficial for the expansion of Salmonella in conditions where anaerobes become depleted (e.g., following antibiotic use). For these purposes, they utilized Salmonella enterica subsp. Typhimurium (S. Typhimurium) mutants lacking functional cytochrome bd subunits and examined competitive fitness advantages in vitro and in vivo. Results from these studies revealed that mice depleted of major anaerobic microorganisms (especially Clostridia) generate a more aerobic environment, which then allows for the luminal expansion of aerobic S. Typhimurium (Figure 1). These experiments revealed that the lack of cytochrome bd oxidase resulted in a growth disadvantage for S. Typhimurium that manifested only in antibiotic-treated animals. Further analysis revealed that cytochrome bd oxidase synergizes with nitrate reductases to drive postantibiotic S. Typhimurium expansion. Indeed, recovery of targeted S. Typhimurium nitrate respiration mutants (narG, napA narZ mutant) was nearly 8-fold less than wild-type S. Typhimurium following antibiotic-mediated depletion of anaerobes. To document increases in tissue oxygenation associated with antibiotic treatment, these investigators employed the use of pimonidazole dyes, which adduct with various macromolecules at pO2 < 10 mmHg (Lord et al., 1993Lord E.M. Harwell L. Koch C.J. Cancer Res. 1993; 53: 5721-5726PubMed Google Scholar). This observation of antibiotic-dependent increases in tissue oxygenation confirmed previous work (Kelly et al., 2015Kelly C.J. Zheng L. Campbell E.L. Saeedi B. Scholz C.C. Bayless A.J. Wilson K.E. Glover L.E. Kominsky D.J. Magnuson A. et al.Cell Host Microbe. 2015; 17: 662-671Abstract Full Text Full Text PDF PubMed Scopus (829) Google Scholar) and revealed a loss of “physiologic hypoxia” with antibiotic treatment. This observation also confirmed a role for butyrate in local oxygen depletion (Kelly et al., 2015Kelly C.J. Zheng L. Campbell E.L. Saeedi B. Scholz C.C. Bayless A.J. Wilson K.E. Glover L.E. Kominsky D.J. Magnuson A. et al.Cell Host Microbe. 2015; 17: 662-671Abstract Full Text Full Text PDF PubMed Scopus (829) Google Scholar). To examine whether S. Typhimurium might deplete Clostridia in the context of a natural course of infection, they extended their studies to examine infection of a genetically resistant mouse line (CBA mice) in the absence of antibiotics. Somewhat surprisingly, the authors found that a number of S. Typhimurium virulence factors were required for inducing intestinal inflammation and subserve this role by reducing the overall abundance of Clostridia. This phenotype was, at least in part, reversed by inoculation of mice with either a cocktail of 17 human Clostridial isolates or the stabilized butyrate analog trubutyrin. These results have profound implications for our current view of the microbial ecology at the gut surface. For instance, these studies implicate a pathogen-induced metabolic depletion that could significantly impair the host response. Indeed, the finding that S. Typhimurium depletes the butyrate-producing microbiota could significantly impact colonic health and host response to infection. Butyrate typically constitutes 15%–20% of SCFA in the human colon with absolute concentrations above 10 mM in human feces (Hamer et al., 2008). Butyrate is efficiently absorbed by the epithelium, and its metabolism provides the majority of ATP for healthy colonic epithelia (Donohoe et al., 2011Donohoe D.R. Garge N. Zhang X. Sun W. O’Connell T.M. Bunger M.K. Bultman S.J. Cell Metab. 2011; 13: 517-526Abstract Full Text Full Text PDF PubMed Scopus (1081) Google Scholar). One important side effect of butyrate metabolism is stabilization of the transcription factor hypoxia-inducible factor (HIF) within colonic epithelial cells (Kelly et al., 2015Kelly C.J. Zheng L. Campbell E.L. Saeedi B. Scholz C.C. Bayless A.J. Wilson K.E. Glover L.E. Kominsky D.J. Magnuson A. et al.Cell Host Microbe. 2015; 17: 662-671Abstract Full Text Full Text PDF PubMed Scopus (829) Google Scholar), where HIF has been shown on many levels to support barrier properties of intestinal epithelial cells (Colgan et al., 2016Colgan S.P. Campbell E.L. Kominsky D.J. Annu. Rev. Pathol. 2016; 11: 77-100Crossref Scopus (72) Google Scholar). The work by Rivera-Chávez et al., 2016Rivera-Chávez F. Zhang L.F. Faber F. Lopez C.A. Byndloss M.X. Olsan E.E. Xu G. Velazquez E.M. Lebrilla C.B. Winter S.E. et al.Cell Host Microbe. 2016; 19 (this issue): 443-454Abstract Full Text Full Text PDF PubMed Scopus (441) Google Scholar provides further rationale for antibiotic stewardship and informs new strategies to improve patient care. For example, it is recently appreciated that the dysbiosis in inflammatory bowel disease is often characterized by reduced abundance of butyrate-producing organisms (e.g., certain Roseburia and Faecalibacterium genera), and lower concentrations of luminal butyrate are associated with disease (Miquel et al., 2013Miquel S. Martín R. Rossi O. Bermúdez-Humarán L.G. Chatel J.M. Sokol H. Thomas M. Wells J.M. Langella P. Curr. Opin. Microbiol. 2013; 16: 255-261Crossref PubMed Scopus (626) Google Scholar). Likewise, it is known that treatment with antibiotics increases susceptibility of human patients to salmonellosis and significantly exacerbates disease in chronic S. Typhimurium carriers (Keeney et al., 2014Keeney K.M. Yurist-Doutsch S. Arrieta M.C. Finlay B.B. Annu. Rev. Microbiol. 2014; 68: 217-235Crossref PubMed Scopus (187) Google Scholar). It is interesting to speculate that the promotion of butyrate-producing strains or the selective elimination of butyrate-depleting strains might serve the overall intestinal health of such patients. It is yet to be determined if these findings are limited to butyrate and growth of Salmonella or if similar mechanisms underlie additional host-microbe interactions that determine human health. Depletion of Butyrate-Producing Clostridia from the Gut Microbiota Drives an Aerobic Luminal Expansion of SalmonellaRivera-Chávez et al.Cell Host & MicrobeApril 13, 2016In BriefParadoxically, antibiotic treatment can promote relapse of Salmonella gastroenteritis. Rivera-Chávez et al. show that antibiotic treatment lowers colonization resistance by depleting butyrate-producing Clostridia. Decreased butyrate availability increases epithelial oxygenation, thereby fueling aerobic pathogen expansion in the gut lumen. Aerobic respiration synergizes with nitrate respiration to drive fecal-oral transmission of Salmonella. Full-Text PDF Open Archive
Referência(s)