Post antibiotic treatment expansion of pathogenic gut microbes induced by availability of oxidised sugars

Antibiotic resistance is frequently publicized in the popular media such as television advertisement and newspapers and has helped inform the general public about the perils of not completing a course of antibiotic treatment. Briefly, antibiotic resistance arises when a subpopulation of microorganisms developed resistance to antibiotic treatment either through reducing their metabolic rate (e.g., persistence or stringent response) or acquiring mutations that helped modulate the impact of antibiotic on cellular health (e.g., the generation of more efflux pumps that push the antibiotic out of the cell).

 

In general, antibiotics can be broadly classified into broad spectrum antibiotics and narrow spectrum antibiotics, where the former uses a drug that targets a generic mechanism or machinery necessary for cell growth (e.g., ribosome), while the latter binds to specific proteins or biomolecules associated with a particular species of microorganisms.

 

Thus, do broad spectrum antibiotics or their narrow spectrum brethren more readily induce antibiotic resistance? The answer is their effects are dissimilar and cannot be compared. For example, a broad spectrum antibiotic may be able to kill most members of a gut microbiome community, where a microbiome is a collection of distinct microorganisms with different metabolism and genetic repertoire. However, cases exist where a particular species of microbe developed or has, within the cellular milieu, capability of mediating the toxic effect of antibiotic; thereby, allowing it to expand its population where the numbers of other microbes are decimated by the antibiotic. Chances of dysbiosis (a disequilibrium in the health and composition of the gut microbiota) is larger with the use of broad spectrum antibiotics due to the removal of commensal species capable of keeping pathogenic species in check.

 

Similar in post antibiotic treatment induced expansion of microbial species, but different in cellular logic, is the effect of narrow spectrum antibiotics on the gut microbiome. Specifically, a narrow spectrum antibiotic targets a small group of related microbial species while leaving other species unaffected; thus, the general structure of the microbiota remains intact, which allows the community of microbes to help prevent the emergence of a pathogenic strain capable of wiping out the entire gut microbial community.

 

Related to the above concept but slightly different in how antibiotic treatment helped the population expansion of specific species or groups of microorganisms is the observation of possible release of nutrients from microbes killed off by antibiotic treatment, which, in turn, helped propel the growth of more microorganisms of pathogenic strains. While the effect has been documented, the specific mechanisms by which it occurs as well as possible simultaneous occurrence of other metabolic effect is less well understood.

 

Writing in Nature in “Host-mediated sugar oxidation promotes post-antibiotic pathogen expansion”,1 Baumler and coworkers answered the question through experimentation, of how antibiotic treatment mediates colony expansion of specific pathogenic microbial species (in this case: Salmonella Typhimurium). Using a combination of instrumented analysis methods such as gas chromatography mass spectrometry (GC-MS) together with recombinant S. Typhimurium harbouring a gene cassette for galactarate import and catabolism, the study progressively lifts the veil on the mechanisms underpinning the provision of nutrients for aiding the colonal expansion of S. Typhimurium. Positing that sugars released by dead microbes after antibiotic treatment are oxidized into alcohols and aldehydes, gene cassette capable of importing and metabolizing galactarate was constructed and transfected into S. Typhimurium recombinant strains.

 

In a series of experiments examining more detailed questions, some at a granular (fine) level, the authors worked through and verified the steps where sugars such as glucose and galactose were oxidised by reactive nitrogen species produced by host cells’ inducible nitric oxide synthase (iNOS) gene to form glucarate and galactarate. The oxidised sugars were subsequently imported into the recombinant S. Typhimurium strain carrying a mutant importer capable of importing glucarate and galactarate.

 

Demonstrated in mice, the experiment findings lend credence to the hypothesized mechanism where host inducible systemic signalling machinery could be co-opted in a smart way to help produce oxidised sugars fermentable only by members of a clonal population harbouring specific importers for the metabolites. Being able to import the sugars and utilize them via fermentation, the mutant pathogenic strains are endowed with a survival and growth advantage over the residual microbiota, thereby, helping them to outcompete other species in the microbial war in the gut.

 

Overall, utilizing the analytical power of gas chromatography mass spectrometry for detecting specific metabolites in difficult analytical conditions, the well conceived set of experiments delineated the molecular logic where antibiotic treatment induced a host signalling system that, in turn, oxidised released sugars from dead microbes as xenobiotic metabolites only fermentable by pathogenic species with specific mutant forms of transporters mediating their import.

 

Future work may clarify the presence of other species of oxidised alcohols and aldehydes present through reactive nitrogen species mediated oxidation of released sugars. Additionally, possible presence of carboxylic acids could also be verified by GC-MS. More importantly, the question of why antibiotic treatment would trigger the inducible nitric oxide synthase system that mediates the oxidation of sugars, and thus, changes the metabolic profile of the gut, as well as its implications in health and disease, is a fascinating question for follow on research. Specifically, what is the evolutionary underpinnings for the coupling of a systemic signalling system with the metabolism of the gut microbiota? Finally, the broad question of the evolutionary significance of oxidised sugars in microbial metabolism and their roles in pathogenicity may also be of interest to microbiologists and biochemists.

 

Interested readers can download a pdf copy of this commentary at figshare: https://figshare.com/articles/Post_antibiotic_treatment_expansion_of_pathogenic_gut_microbes_induced_by_availability_of_oxidised_sugars/4284356

 

Categories: microbiology, health, instrument,

Tags: antibiotic resistance, glucarate, galactarate, Salmonella Typhimurium, inducible nitric oxide synthase, gas chromatography mass spectrometry,

 

References

  1. Faber, F. et al. Host-mediated sugar oxidation promotes post-antibiotic pathogen expansion. Nature 534, 697–699 (2016).
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